Please Scroll Down to See Forums Below How can Femara not lower IGF-1 while Arimidex can? They both work through the same pathways. If lower estrogen it related to lower IGF-1 levels Femara should actually lower IGF-1 more than Arimidex since it lowers estrogen to a greater degree. Any antiestrogen pimps have any thoughts about this? Thanks.
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Femara lowers IGF-1 as much as Arimidex?
- Thread starter pumped21
- Start date
Have you considered the possibility that letrozole does decrease IGF-1 ? One study looked at administration of letrozole and testosterone to boys going through puberty. One group got test alone, the other test plus letrozole. Test is a potent stimulator of IGF-1 production, as you probably know.
The group of boys who got test showed an increse in IGF-1, as expected. The test plus letrozole group showed no change in IGF-1. (1)
The logical interpretation is that the letrozole blocked the test induced increase in IGF-1.
What is also interesting is that the research group that showed letrozole increased IGF-1 just published a paper that showed arimidex also increases IGF-1, contradicting every other study done on arimidex. (2)
(1) Eur J Endocrinol 2002 Mar;146(3):339-46
The role of sex steroids in the regulation of insulin sensitivity and serum lipid concentrations during male puberty: a prospective study with a P450-aromatase inhibitor.
Wickman S, Saukkonen T, Dunkel L.
(2) J Steroid Biochem Mol Biol 2002 Apr;80(4-5):411-8
Short-term effects of anastrozole treatment on insulin-like growth factor system in postmenopausal advanced breast cancer patients.
Ferrari L, Martinetti A, Zilembo N, Pozzi P, Buzzoni R, La Torre I, Gattinoni L, Catena L, Vitali M, Celio L, Seregni E, Bombardieri E, Bajetta E.
The group of boys who got test showed an increse in IGF-1, as expected. The test plus letrozole group showed no change in IGF-1. (1)
The logical interpretation is that the letrozole blocked the test induced increase in IGF-1.
What is also interesting is that the research group that showed letrozole increased IGF-1 just published a paper that showed arimidex also increases IGF-1, contradicting every other study done on arimidex. (2)
(1) Eur J Endocrinol 2002 Mar;146(3):339-46
The role of sex steroids in the regulation of insulin sensitivity and serum lipid concentrations during male puberty: a prospective study with a P450-aromatase inhibitor.
Wickman S, Saukkonen T, Dunkel L.
(2) J Steroid Biochem Mol Biol 2002 Apr;80(4-5):411-8
Short-term effects of anastrozole treatment on insulin-like growth factor system in postmenopausal advanced breast cancer patients.
Ferrari L, Martinetti A, Zilembo N, Pozzi P, Buzzoni R, La Torre I, Gattinoni L, Catena L, Vitali M, Celio L, Seregni E, Bombardieri E, Bajetta E.
If this is the case it seems like everyone is jumping on the Femara wagon a little too soon. Seems like the best route for maximum muscle gain on a cycle (beside taking no antiestro's) would be to take Arimidex unless gyno syptoms are still starting to appear or massive amounts of test are being used (gram or more per week).
I am sure letrozole is an excellent aromatase inhibitor. I am just not convinced that
(1) It does not lower IGF-1
(2) It lowers estrogen in men any more than arimidex does.
The studies where letrozole lowers estrogen so dramatically involved postmenopausal women. In these women the ovaries are not producing estrogen. All the estrogen comes from the aromatization of adrenal androgens, principally androstenedione.
The adrenal glands are not under feedback control from the hypothalamus, so when estrogen levels go down, there is no message sent from the brain for the adrenals to churn out more androstenedione to make more estrogen.
If you tried to use these drugs in premenopausal breast cancer patients, the brain would simply tell the ovaries to make more estrogen and the aromatase inhibitors would be ineffective. This is why they are not used in premenopausal breast cancer patients. Nolvadex is used instead.
Men are like premenopausal women. When the brain senses that the aromatase inhihibitors are lowering estrogen, it sends a signal to the testes to make more testosterone to be aromatized, ultimately swamping the ability of the aromatase inhibitors to keep up.
When test levels get high enough, the testosterone can displace the aromatase inhibitor from the aromatase enzyme, allowing aromatization to occur.
The only possible exception to this is the aromatase inhibitor exemestane. Once it binds to aromatase, it cannot be displaced by testosterone. To use pharmacological jargon, exemestane is a so called suicide inhibitor. Letrozole and anastrozole are competitive inhibitors.
(1) It does not lower IGF-1
(2) It lowers estrogen in men any more than arimidex does.
The studies where letrozole lowers estrogen so dramatically involved postmenopausal women. In these women the ovaries are not producing estrogen. All the estrogen comes from the aromatization of adrenal androgens, principally androstenedione.
The adrenal glands are not under feedback control from the hypothalamus, so when estrogen levels go down, there is no message sent from the brain for the adrenals to churn out more androstenedione to make more estrogen.
If you tried to use these drugs in premenopausal breast cancer patients, the brain would simply tell the ovaries to make more estrogen and the aromatase inhibitors would be ineffective. This is why they are not used in premenopausal breast cancer patients. Nolvadex is used instead.
Men are like premenopausal women. When the brain senses that the aromatase inhihibitors are lowering estrogen, it sends a signal to the testes to make more testosterone to be aromatized, ultimately swamping the ability of the aromatase inhibitors to keep up.
When test levels get high enough, the testosterone can displace the aromatase inhibitor from the aromatase enzyme, allowing aromatization to occur.
The only possible exception to this is the aromatase inhibitor exemestane. Once it binds to aromatase, it cannot be displaced by testosterone. To use pharmacological jargon, exemestane is a so called suicide inhibitor. Letrozole and anastrozole are competitive inhibitors.
Well shit, nandi12.........you are a novice? Only on this board. This is useful information, both of you.
I have said the same.....I'm not scientific, but I have tried everything out there for 3 decades, and anti-e's always degraded my progress. We had none in the past, and the incidence of gyno seemed no worse than today. Either you are pre-disposed to the side effects or you are not.
I take no anti-e's, but I have them on hand at all times, just in case, and my doses are in the 2 gram a week range.
Bodybuilders who rely on GH, like I do, should take special note of this issue and research it thoroughly..........cause that expensive somatropin REQUIRES the presence of insulin growth factors to be effective.
I have said the same.....I'm not scientific, but I have tried everything out there for 3 decades, and anti-e's always degraded my progress. We had none in the past, and the incidence of gyno seemed no worse than today. Either you are pre-disposed to the side effects or you are not.
I take no anti-e's, but I have them on hand at all times, just in case, and my doses are in the 2 gram a week range.
Bodybuilders who rely on GH, like I do, should take special note of this issue and research it thoroughly..........cause that expensive somatropin REQUIRES the presence of insulin growth factors to be effective.
While the IGF-1 effects of ana and let seem to be under a lot of contention, the fact that let is a more powerfull anti-e is not. If your cycle is mild enough for you to use ana then by all means do so. However, if you on an ubercycle then let is the way to go.
I have lots of abstracts on both but its large, let me see if I can get them added to this thread.
I have lots of abstracts on both but its large, let me see if I can get them added to this thread.
anastrozole
1: Cancer 2001 Oct 15;92(8):2095-101
Use of the aromatase inhibitor anastrozole in the treatment of patients with
advanced prostate carcinoma.
Santen RJ, Petroni GR, Fisch MJ, Myers CE, Theodorescu D, Cohen RB.
Department of Medicine, University of Virginia Health System, Charlottesville,
Virginia.
BACKGROUND: Men with prostate carcinoma initially respond to therapies designed
to inhibit androgen secretion or block its action. Later, the tumors in these
patients become refractory to androgen-related therapies. Therefore, additional
hormonal maneuvers that would benefit these men currently are needed. Reports of
androgen receptor mutations and historic clinical observations raised the
hypothesis that estrogens might be involved in the proliferation of
androgen-refractory prostate carcinoma. METHODS: To explore this hypothesis, 14
men with advanced prostate carcinoma that was refractory to medical or surgical
orchiectomy and antiandrogens were entered into a clinical Phase II trial
involving suppression of estrogens. After complete evaluation, each patient
received 1 mg daily of the third-generation aromatase inhibitor anastrozole
until disease progression. Follow-up included serial determinations of prostate
specific antigen (PSA), measurements of evaluable lesions, and assessment of
intensity of pain. RESULTS: No patient experienced an objective response or
disease stabilization as measured by PSA level or the greatest dimension of the
lesion. Minimal improvement of bone pain was reported in two patients receiving
intensive analgesic medication. CONCLUSIONS: It was concluded that the
dependence of androgen-insensitive prostate carcinoma on estrogens for
proliferation is uncommon and that aromatase inhibitors may not have a place in
the treatment of prostate carcinoma at this stage of the disease. Copyright 2001
American Cancer Society.
PMID: 11596025 [PubMed - in process]
2: Clin Cancer Res 2001 Sep;7(9):2620-35
Advances in aromatase inhibition: clinical efficacy and tolerability in the
treatment of breast cancer.
Buzdar A, Howell A.
Department of Breast Medical Oncology, M. D., Anderson Cancer Center, University
of Texas, Houston, 77030, USA.
Publication Types:
Review
Review, Tutorial
PMID: 11555572 [PubMed - indexed for MEDLINE]
3: Am J Ther 2001 Sep-Oct;8(5):333-44
Aromatase, aromatase inhibitors, and breast cancer.
Brueggemeier RW.
Medicinal Chemistry and Pharmacognosy, College of Pharmacy, and Hormones and
Cancer Program, Comprehensive Cancer Center, The Ohio State University,
Columbus, OH 43210, USA. [email protected]
Estrogens are involved in numerous physiologic processes and have crucial roles
in particular disease states, such as mammary carcinomas. Estradiol, the most
potent endogenous estrogen, is biosynthesized from androgens by the cytochrome
P-450 enzyme complex called aromatase. Aromatase is found in breast tissue, and
the importance of intratumoral aromatase and local estrogen production is being
unraveled. Inhibition of aromatase is an important approach for reducing growth
stimulatory effects of estrogens in hormone-dependent breast cancer. Effective
aromatase inhibitors have been developed as therapeutic agents for controlling
estrogen-dependent breast cancer. Investigations into the development of
aromatase inhibitors began in the 1970s and have expanded greatly in the past
three decades. Competitive aromatase inhibitors are molecules that compete with
the substrate androstenedione for noncovalent binding to the active site of the
enzyme to decrease the amount of product formed. Steroidal inhibitors that have
been developed to date build on the basic androstenedione nucleus and
incorporate chemical substituents at varying positions on the steroid. The
structure-activity relationships for steroidal inhibitors have become more
refined in the past decade, and only some modifications can be made to the
steroid and still keep its affinity for aromatase. Nonsteroidal aromatase
inhibitors can be divided into three classes: aminoglutethimide-like molecules,
imidazole/triazole derivatives, and flavonoid analogs. Mechanism-based aromatase
inhibitors are inhibitors that mimic the substrate, are converted by the enzyme
to a reactive intermediate, and result in the inactivation of aromatase.
Aromatase inhibitors, both steroidal and nonsteroidal, have shown clinical
efficacy for the treatment of breast cancer. The initial nonselective nature of
nonsteroidal inhibitors such as aminoglutethimide has been greatly reduced in
the later generations of inhibitors, anastrozole and letrozole. Mechanism-based
steroidal inhibitors such as 4-hydroxyandrostenedione and exemestane produce
prolonged aromatase inhibition in patients. The potent and selective
third-generation aromatase inhibitors anastrozole, letrozole, and exemestane are
approved for clinical use as second-line endocrine therapy in postmenopausal
patients failing antiestrogen therapy alone or multiple hormonal therapies.
Publication Types:
Review
Review, Tutorial
PMID: 11550075 [PubMed - indexed for MEDLINE]
4: Oncology (Huntingt) 2001 Aug;15(8):965-72; discussion 972, 977-9
Nonsteroidal and steroidal aromatase inhibitors in breast cancer.
Hamilton A, Volm M.
Kaplan Comprehensive Cancer Center, New York University, School of Medicine, New
York 10016, USA. [email protected]
Anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are
members of the third generation of aromatase inhibitors that has now replaced
aminoglutethimide (Cytadren), the progestins, and tamoxifen (Nolvadex) as the
hormonal therapy of choice in estrogen-receptor-positive, postmenopausal,
metastatic breast cancer. This article will review the role of aromatase in the
pathogenesis of breast cancer and the results of recent studies that have
established the role of its inhibitors in estrogen-receptor-positive breast
cancer. We will also briefly outline the rationale and design of ongoing
studies.
PMID: 11548977 [PubMed - in process]
5: Tumori 2001 May-Jun;87(3):A6-14
[Evolvement of hormone therapy for breast cancer. Florence, March 14, 2001].
[Article in Italian]
Longo F, Mansueto G.
Oncologia Medica, Policlinico Umberto I, Roma.
Publication Types:
Congresses
PMID: 11505951 [PubMed - indexed for MEDLINE]
6: Br J Cancer 2001 Aug 3;85(3):317-24
Pharmacokinetics of anastrozole and tamoxifen alone, and in combination, during
adjuvant endocrine therapy for early breast cancer in postmenopausal women: a
sub-protocol of the 'Arimidex and tamoxifen alone or in combination' (ATAC)
trial.
ATAC Trialists' Group.
CRC and UCL Cancer Trials Centre, University College London, Stephenson House,
158-160 N Gower Street, London, NW1 2ND, UK.
The ATAC trial evaluates in a randomized, double-blind design, Arimidextrade
mark (anastrozole) alone or in combination with tamoxifen, relative to tamoxifen
alone as 5-year adjuvant treatment in postmenopausal women with early breast
cancer. Patients included in the pharmacokinetic (PK) sub-protocol had been in
ATAC for > or =3 months, taking their medication in the morning and were 100%
compliant for the preceding 14 days. Blood samples were collected 24 +/- 4 h
after last dose. Trough (C(min)) plasma concentrations of anastrozole, tamoxifen
and desmethyltamoxifen (DMT) were measured by validated methods. The PK results
were based on a total of 347 patients (131 anastrozole (1 mg o.d.), 111
tamoxifen (20 mg o.d.), 105 anastrozole and tamoxifen (1 and 20 mg o.d.
respectively)). The geometric mean steady-state trough plasma concentrations of
tamoxifen and DMT were statistically equivalent in patients receiving tamoxifen
alone or in combination with anastrozole: geometric mean tamoxifen = 94.8 ng
ml(-1)and 95.3 ng ml(-1)in tamoxifen alone and combination groups, respectively;
geometric mean DMT = 265.1 and 277.6 ng ml(-1)in the tamoxifen and anastrozole
and tamoxifen groups, respectively. The geometric mean anastrozole levels were
27% lower (90% Cl 20-33%;P< 0.001) in the presence of tamoxifen than with
anastrozole alone. Baseline plasma oestradiol levels were not obtained in the PK
sub-protocol, however, such information was available from a similar ATAC
sub-protocol, which evaluated bone mineral density. Mean oestradiol levels were
21.3, 19.3, and 21.6 pmol l(-1)prior to treatment and 3.7, 20.9 and 3.6 pmol
l(-1)after 3 months in the anastrozole, tamoxifen, and combination groups,
respectively (n = 167). On-treatment values were below the detection limit (3
pmol l(-1)) in 43.6 and 38.5% of the anastrozole alone and anastrozole in
combination with tamoxifen groups, respectively. As a result of (a) the lack of
effect of anastrozole on tamoxifen and DMT levels and (b) the observed fall in
blood anastrozole levels having no significant effect on oestradiol suppression
by anastrozole, we conclude that the observed reduction in anastrozole levels by
tamoxifen is unlikely to be of clinical significance when anastrozole and
tamoxifen are administered together. Copyright 2001 Cancer Research Campaign.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 11487258 [PubMed - indexed for MEDLINE]
7: Gan To Kagaku Ryoho 2001 Jul;28(7):909-16
[Endocrine therapy for advanced or recurrent breast cancer].
[Article in Japanese]
Sonoo H, Kurebayashi J.
Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577
Matsushima, Kurashiki 701-0192, Japan.
Endocrine therapy of advanced or recurrent breast cancer was described. The
presence of ER or PgR in primary breast tumors is the best-established marker
for response to endocrine therapy. However, ER-positive breast tumors
overexpressing EGF-R and/or HER-2 (Erb B2) are resistant to endocrine therapy.
Recently it was suggested that an elevated level of the circulating
extracellular domain of HER-2 could be a predictor for poor response to
endocrine therapy. LH-RH agonist is used as a first-line therapy for
premenopausal patients. And LH-RH agonist plus tamoxifen (TAM) has shown a
higher response rate and more prolonged survival than LH-RH agonist or TAM
alone. As two new aromatase inhibitors, anastrozole (ANA) and letrozole, have
shown an equal or higher response rate and a prolonged time to progression than
TAM as a first-line therapy, these could be used as a first-line therapy instead
of TAM. In a cross-over trial of ANA and TAM, the response rate of ANA after TAM
failure was equal to that of TAM after ANA failure. As these drugs showed an
equal or higher response rate and longer survival than progestin in TAM
resistant cases, these drugs could also used as a second-line therapy. In
addition, the trend of recent studies regarding the mechanisms of hormone
resistance is also described.
Publication Types:
Review
Review, Tutorial
PMID: 11478139 [PubMed - indexed for MEDLINE]
8: Gan To Kagaku Ryoho 2001 Jul;28(7):892-901
[Developments of hormonal agents for breast cancer].
[Article in Japanese]
Tominaga T.
Breast Cancer Center Toyosu Hospital, Showa University School of Medicine,
4-1-18 Toyosu, Koto-ku, Tokyo 135-8577, Japan.
Endocrine therapy for breast cancer, which began with ovariectomy, has a history
of more than 100 years. Tamoxifen has been an epoch-making drug during the late
20th century. Recently LHRH analogues which work as downregulators of estrogen
production and many aromatase inhibitors (AI), both non-steroidal and steroidal
have been developed in Japan. Fadrozole was the only AI until anastrozole was
approved a few months ago. Letrozole was shown to be a better AI than fadrozole
by prospective randomized double blind examination; however, it is not licenced
yet. The reason is that the appropriate dosage is not identical to that of
Western countries. We have reached a time when order-made medicine should take
into consideration such differences as race and individuality.
Publication Types:
Review
Review, Tutorial
PMID: 11478137 [PubMed - indexed for MEDLINE]
9: Br J Clin Pharmacol 2001 May;51(5):429-35
The effect of anastrozole on the single-dose pharmacokinetics and anticoagulant
activity of warfarin in healthy volunteers.
Yates RA, Wong J, Seiberling M, Merz M, Marz W, Nauck M.
AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK.
AIMS: The aims of this study were to determine the effects of the nonsteroidal,
selective aromatase inhibitor, anastrozole, at steady-state concentrations, on
the pharmacokinetics and pharmacodynamics of warfarin, and to assess whether or
not anastrozole alone has any anticoagulant activity. METHODS: This was a
randomized, double-blind, placebo-controlled, two-way crossover trial conducted
at a single centre. The study comprised two treatment periods of 11 days,
separated by a 3 week washout. Healthy male volunteers (n = 16, median age 28.5
years) were randomized to receive either anastrozole (7 mg loading dose on day
1, followed by 1 mg daily on days 2-11) in the first treatment period and
placebo in the second treatment period, or vice versa. In addition to their
randomized treatment, all volunteers received a single dose of 25 mg warfarin on
day 3 of each treatment period. Blood samples for pharmacokinetic and
pharmacodynamic assessment were taken at frequent intervals during each
treatment period. The safety of volunteers was monitored throughout the study.
RESULTS: Administration of anastrozole resulted in no clinically significant
changes in the pharmacokinetics of either R- or S-warfarin compared with placebo
for AUC (ng ml-1 h) (glsmean, R-warfarin; anastrozole 93619.9, placebo 91127.91,
95%CI 0.988-1.068; S-warfarin; anastrozole 57129.21, placebo 55676.34, 95%CI
0.979-1.076), CL/F (ml min-1) (glsmean, R-warfarin; anastrozole 2.23, placebo
2.29, 95%CI 0.937-1.012; S-warfarin; anastrozole 3.65, placebo 3.74, 95%CI
0.929-1.021) and t1/2 (h) (lsmean, R-warfarin; anastrozole 55.40, placebo 55.15,
95%CI-2.083-2.592; S-warfarin; anastrozole 39.38, placebo 40.98,
95%CI-6.189-2.996). In addition, anastrozole had no clinically significant
effect on the pharmacodynamic effects of warfarin, as assessed 240 h after
warfarin dosing by measurement of prothrombin time (s) (glsmean, anastrozole
11.56, placebo 11.31, 95%CI 0.987-1.059), thrombin time (s) (glsmean,
anastrozole 19.06, placebo 18.75, 95%CI 0.980-1.054) activated partial
thromboplastin time (s) (glsmean, anastrozole 29.94, placebo 29.74, 95%CI
0.968-1.047) and factor VII (%) (glsmean, anastrozole 97.81, placebo 107.26,
95%CI 0.821-1.012). Anastrozole alone had no effect on these indicators of the
clotting process. CONCLUSIONS: Overall, there was no evidence to suggest that
anastrozole has any clinically relevant effects on the pharmacokinetics of
warfarin. Anastrozole had no effect on clotting mechanisms or on the
pharmacodynamic activity of warfarin, as assessed by prothrombin time, thrombin
time, activated partial thromboplastin time, and factor VII.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 11422000 [PubMed - indexed for MEDLINE]
10: Semin Oncol 2001 Jun;28(3):291-304
Endocrine therapy in the treatment of metastatic breast cancer.
Buzdar AU.
Department of Breast Medical Oncology, M.D. Anderson Cancer Center, 1515
Holcombe Blvd., Houston, TX 77037, USA.
The goals of treating patients with metastatic breast cancer are to prolong
survival, slow or halt disease progression, and enhance the patient's quality of
life. In patients with estrogen receptor (ER)-positive cancers that are not
progressing rapidly, endocrine therapy is generally the first treatment option.
If a patient initially responds to an endocrine agent and then progresses,
another endocrine agent may still provide benefit. Tamoxifen has been used as
first-line therapy for metastatic breast cancer for many years. Until recently,
no other endocrine agent has shown superiority to tamoxifen in this setting. The
nonsteroidal aromatase inhibitors, anastrozole and letrozole, have been widely
accepted as second-line therapy after failure of tamoxifen; they have replaced
megestrol acetate in this setting. Recently, anastrozole was shown to have at
least equivalent efficacy and a superior side effect profile compared with
tamoxifen for treating postmenopausal women in the first-line setting. Thus,
this aromatase inhibitor has become a viable option for first-line therapy in
postmenopausal women. Trials of letrozole in this setting are nearing
completion. Exemestane has been shown to be an effective second-line agent and
to have at least some efficacy as a third-line agent even after failure of a
nonsteroidal aromatase inhibitor. Results are anxiously awaited from trials of
new endocrine agents including the first member of a new class of endocrine
agent, the estrogen-receptor downregulator class. Semin Oncol 28:291-304.
Copyright 2001 by W.B. Saunders Company.
Publication Types:
Review
Review, Tutorial
PMID: 11402439 [PubMed - indexed for MEDLINE]
11: Drugs 2001;61(6):807-13; discussion 814
Fulvestrant.
Curran M, Wiseman L.
Adis International Limited, Mairangi Bay, Auckland, New Zealand.
[email protected]
Fulvestrant is a 7alpha-alkylsulphinyl analogue of estradiol that competes with
endogenous estrogen for binding to the estrogen receptor. Once bound to the
receptor, fulvestrant attenuates receptor dimerisation, effecting a rapid
degradation of the estrogen receptor protein and inhibition of transcription.
Fulvestrant is a potent inhibitor of the growth of human breast cancer cells in
vitro and in vivo. It has demonstrated pure anti-estrogenic activity in animal
systems. Intramuscular fulvestrant 250 mg once a month was as effective as the
oral aromatase inhibitor anastrozole 1 mg/day in 2 phase III trials in
postmenopausal women with advanced breast cancer who had received prior
endocrine therapy. Median time to disease progression (the primary end-point)
with fulvestrant and anastrozole was 5.4 and 3.4 months (North American trial)
and 5.5 and 5.1 months (European trial). The median duration of response was
19.3 and 10.5 months (North American trial) and 14.3 and 14.0 months (European
trial). The most common adverse events with fulvestrant are gastrointestinal
disturbances and hot flushes. Fulvestrant showed similar tolerability to
anastrozole in 2 phase III trials.
Publication Types:
Review
Review, Tutorial
PMID: 11398912 [PubMed - indexed for MEDLINE]
12: Strahlenther Onkol 2001 May;177(5):273-4
[Aromatase inhibitors: anastrozole versus tamoxifen as first-ine therapy for
advanced postmenopausal breast cancer].
[Article in German]
Bergmann L.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 11398617 [PubMed - indexed for MEDLINE]
13: J Clin Endocrinol Metab 2001 Jun;86(6):2869-74
The effect of aromatase inhibition on sex steroids, gonadotropins, and markers
of bone turnover in older men.
Taxel P, Kennedy DG, Fall PM, Willard AK, Clive JM, Raisz LG.
Division of Endocrinology and Metabolism, Center on Aging, University of
Connecticut Health Center, Farmington, Connecticut 06030-1317, USA.
[email protected]
There is evidence that estrogen decreases bone turnover in men as well as women.
We therefore hypothesized that older men would show increased bone resorption in
response to inhibition of the aromatase enzyme, which converts androgens to
estrogen. Fifteen eugonadal men over 65 yr were treated for 9 weeks with 2.0
mg/day of anastrozole, an aromatase inhibitor. After 9 weeks of treatment, there
were significant decreases in estradiol, estrone, and sex hormone-binding
globulin levels by 29%, 73%, and 16%, respectively, and total testosterone
increased significantly by 56%. Despite the limited decrease of estrogen and the
increase in testosterone, C-telopeptide of type 1 collagen showed a progressive
significant increase of 11%, 24%, and 33% (P for trend = 0.033) above baseline
at 3, 6, and 9 weeks, respectively. N-telopeptide of type 1 collagen values were
highly correlated with C-telopeptide of type 1 collagen, but the change in
N-telopeptide of type 1 collagen was not statistically significant.
Bone-specific alkaline phosphatase and N-terminal type I procollagen peptides
showed significant decreases of 8% and 11% of baseline at 9 weeks. Osteocalcin
decreased significantly by 30% at 18 weeks. We conclude that aromatase
inhibition can reduce estrogen levels in older men, but this effect is limited,
perhaps because of feedback stimulation of testosterone production, and that
endogenous estrogen derived from aromatization of testosterone plays a role in
bone metabolism of older men by limiting the rate of bone resorption.
PMID: 11397902 [PubMed - indexed for MEDLINE]
14: J Clin Endocrinol Metab 2001 Jun;86(6):2600-6
Aromatization mediates testosterone's short-term feedback restraint of 24-hour
endogenously driven and acute exogenous gonadotropin-releasing
hormone-stimulated luteinizing hormone and follicle-stimulating hormone
secretion in young men.
Schnorr JA, Bray MJ, Veldhuis JD.
Division of Endocrinology, Department of Internal Medicine, General Clinical
Research Center, Center for Biomathematical Technology, University of Virginia
School of Medicine, Charlottesville, Virginia 22908, USA.
The present clinical study examines the neuroregulatory hypothesis that feedback
restraint of LH and FSH secretion by testosterone requires in vivo
aromatization. To test this postulate, we prospectively and randomly assigned 47
healthy young men to 1 of 5 parallel short-term (5-day) double-blind
interventions with: 1) placebo; 2) high-dose ketoconazole (KTCZ, 400 mg orally 4
times daily) to block both Leydig-cell and adrenal steroidogenesis; 3) KTCZ and
transdermal testosterone delivery (7.5 mg daily); 4) KTCZ and transdermal
estradiol (0.05 mg daily); or 5) KTCZ, testosterone, and the selective and
potent aromatase inhibitor, anastrazole (5 mg orally twice daily). Blood was
sampled every 10 min for 27 h on the last day of intervention to quantitate 24-h
mean spontaneous and 3-h post-GnRH-stimulated (100 ng/kg iv bolus) LH and FSH
release. KTCZ administration lowered the serum total testosterone concentration
markedly from (mean +/- SEM) 423 +/- 57 ng/dL (15 +/- 2.0 nmo/L) during placebo
ingestion to 58 +/- 8.6 ng/dL (2.0 +/- 0.3 nmol/L) (P < 10(-3)). Transdermal
androgen addback along with KTCZ blockade increased testosterone levels to 607
+/- 57 ng/dL (21 +/- 2.0 nmol/L). KTCZ exposure alone drove a 3-fold increase in
serum LH concentrations (P < 10(-3)) and a 2.5-fold rise in FSH secretion (P =
0.015), as assessed by high-specificity immunoradiometric assays. Concomitant
transdermal testosterone (or estradiol) delivery repressed the elevated
secretion of both LH and FSH to mid-normal baseline values. A 3-fold
administration of anastrazole, KTCZ, and testosterone completely opposed
exogenous testosterone's suppression of 24-h LH and FSH secretion. Anastrazole
coadministration likewise abolished testosterone-dependent inhibition of 3-h
GnRH-stimulated LH and FSH release. In summary, assuming the specificity of
anastrazole's inhibition of aromatase activity, we conclude that circulating
testosterone in healthy men curtails endogenously driven as well as exogenous
GnRH-stimulated LH and FSH secretion conditional on its in vivo aromatization.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 11397860 [PubMed - indexed for MEDLINE]
15: Oncology (Huntingt) 2001 May;15(5 Suppl 7):28-34
Aromatase inhibition and antiestrogen therapy in early breast cancer treatment
and chemoprevention.
Ingle JN.
Mayo Clinic, Rochester, Minnesota, USA. [email protected]
The aromatase inhibitors represent an important class of hormonal agents for the
management of breast cancer. The third-generation aromatase inhibitors have
replaced megestrol acetate as second-line hormonal therapy in advanced breast
cancer, and large clinical trials are maturing to establish their efficacy
relative to tamoxifen (Nolvadex) in the first-line metastatic setting. The
increased potency, increased specificity, and established efficacy of aromatase
inhibitors in advanced breast cancer have provided the rationale for a large
number of randomized trials in the adjuvant setting evaluating anastrozole
(Arimidex), exemestane (Aromasin), and letrozole (Femara). These trials are
addressing the value of these agents in sequence with, instead of, and in
combination with tamoxifen. The relationship between estrogen exposure and
breast cancer risk has long been accepted and traditionally related to
estrogen-receptor-mediated events. The emergence of the estrogen genotoxicity
hypothesis as a mechanism for breast cancer carcinogenesis provides additional
rationale for considering aromatase inhibitors in the chemoprevention setting.
PMID: 11396362 [PubMed - in process]
16: J Steroid Biochem Mol Biol 2001 Jan-Mar;76(1-5):199-202
Intracellular aromatase and its relevance to the pharmacological efficacy of
aromatase inhibitors.
Bhatnagar AS, Brodie AM, Long BJ, Evans DB, Miller WR.
Novartis Pharma AG, CH-4002, Basel, Switzerland.
An important feature of the pharmacological profile of aromatase inhibitors is
the ability of the various inhibitors to inhibit intracellular aromatase. It is
now well documented that a large proportion of breast tumors express their own
aromatase. This intratumoral aromatase produces estrogen in situ and therefore
may contribute significantly to the amount of estrogen to which the cell is
exposed. Thus it is not only important that aromatase inhibitors potently
inhibit the peripheral production of estrogen and eliminate the external supply
of estrogen to the tumor cell, but that they in addition potently inhibit
intratumoral aromatase and prevent the tumor cell from making its own estrogen
within the cell. To study the inhibition of intracellular aromatase we have
compared the aromatase-inhibiting potency of the non-steroidal aromatase
inhibitors, letrozole, anastrozole and fadrozole in a variety of model cellular
endocrine and tumor systems which contain aromatase. We have used hamsters
ovarian tissue fragments, adipose tissue fibroblasts from normal human breast,
the MCF-7Ca human breast cancer cell line transfected with the human aromatase
gene and the JEG-3 human choriocarcinoma cell line. Although letrozole and
anastrozole are approximately equipotent in a cell-free aromatase system (human
placental microsomes), letrozole is consistently 10-30 times more potent than
anastrozole in inhibiting intracellular aromatase in intact rodent cells, normal
human adipose fibroblasts and human cancer cell lines. Whether these differences
between letrozole and anastrozole are seen in the clinical setting will have to
await the results of clinical trials which are currently in progress.
PMID: 11384878 [PubMed - indexed for MEDLINE]
17: Vopr Onkol 2001;47(2):195-9
[Modern approaches to hormone therapy of breast cancer as a reflection of
pathogenesis of the disease].
[Article in Russian]
Semiglazov VP.
N.N. Petrov Research Institute of Oncology, Ministry of Health of the RF, St.
Petersburg.
Experimental and epidemiological studies have pointed to a major role of
estrogens in the pathogenesis of human breast cancer. The Oxford meta-analysis
(1998) once again confirmed the efficacy of antiestrogens (tamoxifen) as
adjuvant therapy. We need to know whether the new non-steroid antiestrogens
(idoxifen, droloxifen and TAT-59) and selective estrogen receptor modulator
(raloxifen), whith preclinical characteristics better than those of tamoxifen
will be more efficient clinically. Large-scale trials to compare the new drugs
with tamoxifen are under way. Faslodex, a pure antiestrogen, looks highly
promising, too. Zoladex, a luteinising hormone-releasing hormone agonist, is
looking as a better choice than ovariectomy or irradiation of the pelvis for
ovarian ablation in premenopausal breast cancer. New aromatase inhibitors are
more efficient than progestins and much safer than aminoglutethimide. It has
been shown recently that these inhibitors keep metastatic breast cancer at bay
longer, and with longer survival. The non-steroid inhibitors (anastrozole and
letrozole) and the steroid oral drug exemestane are undergoing clinical trials
as means of adjuvant treatment of breast cancer. The trial of arimidex and
tamoxifen administered alone or in combination (ATAC) is unique since it is
using a combination of tamoxifen and an aromatase inhibitor (anastrozole). New
methods of endocrine therapy have resulted in less toxic and more convenient
procedures. Also, longer therapeutic effects and survival are becoming more
apparent.
PMID: 11383456 [PubMed - indexed for MEDLINE]
18: J Clin Oncol 2001 May 15;19(10):2767
Aromatase inhibitors and arthralgia.
Donnellan PP, Douglas SL, Cameron DA, Leonard RC.
Publication Types:
Letter
PMID: 11352973 [PubMed - indexed for MEDLINE]
19: Clin Cancer Res 2001 May;7(5):1230-6
Influence of neoadjuvant anastrozole (Arimidex) on intratumoral estrogen levels
and proliferation markers in patients with locally advanced breast cancer.
Geisler J, Detre S, Berntsen H, Ottestad L, Lindtjorn B, Dowsett M, Einstein
Lonning P.
Department of Oncology, Haukeland University Hospital, N-5021 Bergen, Norway.
Anastrozole (Arimidex) is a novel, selective, and potent aromatase inhibitor
used for the treatment of postmenopausal breast cancer. The drug has been shown
to inhibit in vivo aromatization by 96--97% and to suppress plasma estrogen
levels by 84--94%. However, the effects of anastrozole on intratumoral estrogen
levels have not been studied. Here we report the effects of neoadjuvant
treatment with anastrozole on intratumoral levels of estrone (E(1)), estradiol
(E(2)), and estrone sulfate (E(1)S), measured by a highly sensitive RIA
following a multistep purification procedure involving high-pressure liquid
chromatography. Tumor tissue was obtained prior to treatment and after 15 weeks
on therapy with anastrozole (1 mg once daily) from 12 postmenopausal women with
locally advanced breast cancer (T(3)--T(4) and/or N(2)). Pretreatment tissue
levels of E(2), E(1), and E(1)S were 217.9 (69.8--679.9), 173.6 (83.9--358.9),
and 80.7 (31.4--207.3) fmol/g tissue (geometric mean values with 95% confidence
interval, respectively). Treatment with anastrozole suppressed tissue E(2),
E(1), and E(1)S levels by 89.0% (73.2--95.5%), 83.4% (63.2--92.5%), and 72.9%
(47.3--86.1%), respectively, compared with baseline levels, with no significant
difference between responders and nonresponders. Plasma levels of E(2), E(1),
and E(1)S were suppressed by 86.1, 83.9, and 94.2%, respectively. Anastrozole
caused a decrease in the immunoexpression of the proliferation markers Ki67 and
pS2 in all of the patients, with a trend for a more profound suppression in
those achieving an objective response. The mean percentage of apoptotic cells
was found to be decreased in responders and increased in nonresponders after 15
weeks of anastrozole therapy. Our results reveal anastrozole to cause a
significant suppression of tissue estrogen levels and to influence the biology
of primary estrogen receptor-positive breast cancers in postmenopausal women.
Publication Types:
Clinical Trial
PMID: 11350888 [PubMed - indexed for MEDLINE]
20: Breast J 1999 May;5(3):176-181
Efficacy of Anastrozole in a Consecutive Series of Advanced Breast Cancer
Patients Treated with Multiple Prior Chemotherapies and Endocrine Agents: M. D.
Anderson Cancer Center Experience.
Knoche AJ, Michaud LB, Buzdar AU.
University of Texas M. D. Anderson Cancer Center, Houston, Texas.
Anastrozole is a highly selective, nonsteroidal aromatase inhibitor approved by
the U.S. Food and Drug Administration (FDA) in January 1996 for the treatment of
advanced breast cancer in postmenopausal women with disease progression
following tamoxifen therapy. To date, information on anastrozole's use has been
limited to breast cancer patients with minimal prior therapy. The purpose of
this review was to determine, in clinical practice, the benefits of anastrozole
in advanced breast cancer patients treated with multiple prior cytotoxic and
endocrine therapies. This was a retrospective review of a consecutive series of
117 patients who received anastrozole after marketing in January 1996. As this
was not a prospective study, rigorous response criteria could not be applied.
Responses were categorized as improvement in disease (ID), stable disease (SD),
or progressive disease (PD). One hundred eight patients were evaluable for
response with a median age of 61 years and the number of prior therapies ranging
from one to nine. Response, defined as improvement of disease or stable disease
>/=8 weeks, was seen in 59% of patients. Patients with three or more prior
endocrine therapies demonstrated a 61% response (ID + SD) and patients with
ER-negative tumors demonstrated 50% response. Patients with prior
aminoglutethamide therapy exhibited similar response rates to the overall group.
One male patient received anastrozole without benefit. This data determines the
activity of anastrozole even in heavily pretreated patients and suggests that
patients who have tumors that are ER-negative may also benefit from anastrozole
therapy.
PMID: 11348281 [PubMed - as supplied by publisher]
21: J Clin Oncol 2001 May 1;19(9):2580; discussion 2580-2
Is anastrozole superior to tamoxifen as first-line therapy for advanced breast
cancer?
Costa SD, Kaufmann M.
Publication Types:
Letter
PMID: 11331346 [PubMed - indexed for MEDLINE]
22: J Clin Oncol 2001 May 1;19(9):2579-80; discussion 2580-2
Is anastrozole superior to tamoxifen as first-line therapy for advanced breast
cancer?
Tonkin K.
Publication Types:
Letter
PMID: 11331344 [PubMed - indexed for MEDLINE]
23: J Clin Oncol 2001 May 1;19(9):2578; discussion 2580-2
Is anastrozole superior to tamoxifen as first-line therapy for advanced breast
cancer?
Copur MS, Ledakis P, Bolton M, Norvell M, Muhvic J.
Publication Types:
Letter
PMID: 11331343 [PubMed - indexed for MEDLINE]
24: J Clin Oncol 2001 May 1;19(9):2578-9; discussion 2580-2
Is anastrozole superior to tamoxifen as first-line therapy for advanced breast
cancer?
Bagley CM Jr, Rowbotham RK.
Publication Types:
Letter
PMID: 11331342 [PubMed - indexed for MEDLINE]
25: J Clin Oncol 2001 May 1;19(9):2578; discussion 2580-2
Is anastrozole superior to tamoxifen as first-line therapy for advanced breast
cancer?
Panasci LC.
Publication Types:
Letter
PMID: 11331341 [PubMed - indexed for MEDLINE]
26: Gan To Kagaku Ryoho 2001 Apr;28(4):549-60
[Development of a novel aromatase inhibitor, anastrozole (Arimidex)--its basic
and clinical studies].
[Article in Japanese]
Tsukagoshi S.
Cancer Institute, Japanese Foundation for Cancer Research.
Anastrozole (JAN), developed by Zeneca UK (presently AstraZeneca UK), is a new
aromatase inhibitor which belongs to triazole. Anastrozole shows selective
aromatase inhibition and negligible effects on other steroid hormone
biosyntheses. The daily dose of 3 mg/kg anastrozole inhibited the growth of DMBA
mammary tumours significantly. Anastrozole inhibited the tumor growth at 5
micrograms/mouse/day (s.c.) in androstenedione-treated ovariectomized nude mice
inoculated with MCF-7CA cells transfected with aromatase gene. In the Japanese
Phase IIa study, the response rate was 27.8% (10/36) in the 0.5 mg group, and
38.2% (13/34) in the 1 mg group. The most common adverse drug reactions were
leucopenia in the 0.5 mg group, and LDH increased and leucopenia in the 1 mg
group. There were no early deaths, other serious adverse events, or adverse drug
reactions of grade 3 or above in this trial; anastrozole was well tolerated. In
the Japanese Phase IIb study, the response rates were 33.3% (117/351 patients)
and 32.8% (114/348 patients) for anastrozole and tamoxifen, respectively,
showing non-inferiority of anastrozole. The median time to disease progression
(TTP) was 251 days and 252 days for anastrozole and tamoxifen, respectively.
Group comparison using a Cox regression model revealed non-inferiority of
anastrozole. Therefore, anastrozole was found to be at least as effective as
tamoxifen (in the response rate and TTP). In US study compared anastrozole with
tamoxifen, TTP with anastrozole is a significantly longer than that of tamoxifen
(p = 0.005, two-sides). Anastrozole has shown to be at least as effective as
tamoxifen, standard endocrine therapy for breast cancer, with good safety
profiles. Thus, anastrozole is a promising first-line endocrine therapy in the
treatment of postmenopausal breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 11329794 [PubMed - indexed for MEDLINE]
27: Tumori 2000 Nov-Dec;86(6):A13-8
[National Conference of Medical Oncology. Controversies in the treatment of
breast cancer. Genova, October 28, 2000].
[Article in Italian]
Longo F.
Publication Types:
Congresses
PMID: 11271674 [PubMed - indexed for MEDLINE]
28: Curr Med Res Opin 2001;16(4):276-84
The Twenty-third Annual San Antonio Breast Cancer Symposium.
Mokbel K.
St George's Hospital, Blackshaw Road, London SW17 0QT, UK.
[email protected]
This paper reviews the recent Twenty-third Annual San Antonio Breast Cancer
Symposium. A total of 580 studies were presented either orally or as posters.
Two phase III multi-centre clinical trials found that fulvestrant (Falsodex),
given as a once-monthly intramuscular injection (250 mg), was well-tolerated and
at least as good as anastrozole (1 mg) in postmenopausal women with advanced
breast cancer that had progressed or recurred on prior endocrine therapy.
Another phase III randomised trial found that letrozole (2.5 mg daily) was
superior to tamoxifen as a neoadjuvant therapy in postmenopausal women with ER-
and/or PgR-positive breast cancer unsuitable for breast-conserving surgery. In a
phase III study, capecitabine (Xeloda) was found to be well-tolerated and able
to improve survival by three months when added to Taxotere. Cutting edge data on
microarray gene profiling in breast cancer were presented. The potential role of
this new technology in predicting outcome and selecting therapy was discussed.
Furthermore, its limitations and the need for validation were highlighted. The
role of new diagnostic tools, such as fibre-optic ductoscopy (FDS) and
microcatheters to obtain ductal cells, was discussed. Finally, the worldwide
overview was presented.
Publication Types:
Congresses
PMID: 11268712 [PubMed - indexed for MEDLINE]
29: Bull Cancer 2000 Dec;87 Spec No:31-39
[Aromatase inhibitors: a review of clinical trials].
[Article in French]
Kerbrat P, Lefeuvre C.
Departement d'oncologie medicale, Centre Eugene-Marquis, rue de la
Bataille-Flandres-Dunkerque, CS 44229, 35042 Rennes Cedex, France.
To increase the therapeutic index of second line hormonal treatment of breast
cancer, new aromatase inhibitors have been synthetized; they belong to two
groups: type I (formestane and exemestane) are steroidal irreversible and
specific inhibitors, type II (anastrozole, letrozole and vorozole) are non
steroidal reversible inhibitors, interfering with the aromatase heme. Several
phase II and III trials demonstrated that these drugs are, at least, as active
as aminoglutethimid or progestins in second line treatment, and are less toxic.
Recently, an identical activity have been observed for anastrozole and tamoxifen
in first line. In metastatic and adjuvant settings, large trials are ongoing to
clarify the exact value of these drugs.
Publication Types:
Review
Review Literature
PMID: 11250606 [PubMed - indexed for MEDLINE]
30: Bull Cancer 2000 Dec;87 Spec No:23-29
[Aromatase inhibitors: pharmacological aspects].
[Article in French]
de Cremoux P.
Laboratoire de physiopathologie et de pharmacologie, Institut Curie, 26, rue
d'Ulm, 75248 Paris Cedex 05, France.
Selective new aromatase inhibitors are a new class of agents that are of
considerable interest in the treatment of hormone-dependent breast cancer in
postmenopausal women. Aromatase is an enzymic complex that catalyses the
conversion of the adrenal androgens androstenedione and testosterone to estrone.
In postmenopausal women, the process of peripheral aromatisation accounts for
the majority of circulating estrogens. The selective inhibition of estrogen
production by aromatase inhibitors is an efficient strategy for breast cancer
treatment. These compounds are classified as irreversible inhibitors of
aromatase (type I), and comprise steroidal compounds. Reversible inhibitors of
aromatase, which comprises non-steroidal compounds are type II aromatase
inhibitors. Second and third generation aromatase inhibitors are considerably
more potent and more specific in their ability to inhibit aromatase, as compared
with first generation compounds (aminoglutethimide).
Publication Types:
Review
Review Literature
PMID: 11250605 [PubMed - indexed for MEDLINE]
31: Bull Cancer 2000 Dec;87 Spec No:7-22
[Preclinical evaluation of aromatase inhibitors antitumor activity].
[Article in French]
Auvray P, Bichat F, Genne P.
Oncodesign Biotechnology, Parc technologique de la Toison-d'Or, 28, rue de
Broglie, 21000 Dijon, France.
Aromatase is an enzymatic complex responsible for the conversion of androgens
into estrogens; these hormones are important in development, reproduction, but
also in the growth of estrogen-dependent cancer. This enzyme is present in
60-70% of the breast cancer. The aromatase inhibitors are important drugs in the
breast cancer treatment of postmenopausal women. In order to study their in vivo
activity, animal models have been developed, e.g. rat with tumour induced by
7,12-dimethylbenz[a]anthracene, PMSG-primed immature rat or athymic nude mice
with aromatase transfected MCF-7 xenograft. In this review, we were interested
in preclinical results obtained with both classes: steroidal and nonsteroidal
inhibitors. The former group, as substrate analogs formestane or exemestane, are
irreversible, selective and long-lasting inhibitors of aromatase. The
nonsteroidal molecules, such as letrozole or anastrozole, are reversible
inhibitors with high affinity. Finally, knowledge of the enzyme active site,
with molecular modeling and site-directed mutagenesis, could be useful to
develop new inhibitor families, more specific and potent in vivo.
Publication Types:
Review
Review Literature
PMID: 11250604 [PubMed - indexed for MEDLINE]
32: Mol Reprod Dev 2001 Apr;58(4):417-23
Estrogenic upregulation of DNA polymerase beta in oocytes of preovulatory ovine
follicles.
Murdoch WJ, Van Kirk EA.
Department of Animal Science, University of Wyoming, Laramie, Wyoming.
The basic premise of this investigation was that local hormonal control of
stockpiling of the base excision repair polymerase (poly) beta within oocytes of
preovulatory follicles occurs as a function of cytoplasmic maturation. There was
an increase in immunoreactive poly beta in sectioned oocytes of preovulatory
ovine follicles during a 12-36-hour interval following the onset of
prostaglandin (PG) F2alpha-induced (Day 14 of the estrous cycle) luteal
regression; this response was not observed in subordinate (nonovulatory)
follicles. Accumulation of poly beta in oocytes at 36 hr after PGF2alpha was
negated by treatment of ewes at 12 hr with the aromatase inhibitor Arimidex or
an ovulatory dose of GnRH (which, via surge gonadotropin stimulation, acutely
downregulates the proestrous rise in follicular estrogen biosynthesis).
Estradiol-17beta stimulated poly beta expression (transcriptional control) in
oocytes of explanted (12 hr after PGF2alpha) follicles (24-hour incubation). We
suggest that a critical period of estrogen amplification in the preovulatory
follicle underscores the capacity of its oocyte to efficiently repair DNA and
therefore reconcile spontaneous infidelities in genomic integrity that
inevitably occur during preimplantation embryogenesis.
PMID: 11241778 [PubMed - indexed for MEDLINE]
33: Nippon Rinsho 2001 Jan;59 Suppl 1:157-60
[Endometriosis and aromatase inhibitor].
[Article in Japanese]
Takayama K, Bulun SE.
Yamagata Prefectural Central Hospital.
Publication Types:
Review
Review, Tutorial
PMID: 11235156 [PubMed - indexed for MEDLINE]
34: J Clin Endocrinol Metab 2001 Jan;86(1):53-8
Differential regulation of gonadotropin secretion by testosterone in the human
male: absence of a negative feedback effect of testosterone on
follicle-stimulating hormone secretion.
Hayes FJ, DeCruz S, Seminara SB, Boepple PA, Crowley WF Jr.
Reproductive Endocrine Unit of the Department of Medicine and National Center
for Infertility Research, Massachusetts General Hospital, Boston, Massachusetts
02114, USA. [email protected]
Studies of sex steroid regulation of gonadotropin secretion in the human male
have focused primarily on the respective site(s) of negative feedback of
testosterone (T) and estradiol (E(2)). The use of pharmacological doses of sex
steroids in these studies has precluded conclusions about the relative roles of
T and E(2) in gonadotropin feedback. Thus, the aims of the present study were to
1) determine the relative contributions of T vs. E(2) to the sex steroid
component of gonadotropin regulation, and 2) distinguish the feedback effects of
T that that are direct (i.e. mediated by the androgen receptor) vs. indirect
(mediated by aromatization to E(2)). Two experimental interventions were used:
1) inhibition of aromatization by a selective aromatase inhibitor to examine the
impact of selective E(2) withdrawal; and 2) acute medical castration to examine
the effect of ablating both T and E(2). Sixteen normal (NL) men (mean age, 30.5
+/- 2.2 yr) were studied. Nine NL subjects were treated with the aromatase
inhibitor, anastrozole (10 mg, orally, daily, for 5 days). Twelve NL men
underwent medical castration with ketoconazole (1-g loading dose followed by 400
mg, orally, four times a day for 5 days). Ketoconazole-treated subjects received
concomitant treatment with dexamethasone (0.5 mg twice daily) to prevent the
development of adrenal insufficiency. Single blood samples were drawn daily
between 0800-1000 h. To ensure that dexamethasone was not altering the
gonadotropin response to sex steroid ablation by a direct pituitary effect, five
GnRH-deficient men (mean age, 37.6 +/- 3.9 yr) underwent GnRH dose-response
studies at baseline and after treatment with dexamethasone (0.5 mg twice daily).
Aromatase blockade caused significant lowering of E(2) (33 +/- 3 to 14 +/- 1
pg/mL; P: < 0.0005) with a corresponding increase in T levels (563 +/- 42 to 817
+/- 81 ng/dL; P: < 0.05). Treatment with ketoconazole resulted in equivalent
suppression of E(2) (41 +/- 4 to 14 +/- 1 pg/mL; P: < 0.0005), but also induced
castrate levels of T (491 +/- 28 to 40 +/- 3 ng/dL; P: < 0.0005). Both treatment
regimens were associated with a significant increase in gonadotropin levels. For
LH, the percent increase in serum levels after castration was almost 3-fold
greater than that seen after selective E(2) withdrawal (275 +/- 23% with
ketoconazole vs. 95.6 +/- 21% with anastrozole; P: < 0.005). Despite the
divergent changes in T levels with these two maneuvers (a marked decrease after
ketoconazole and a significant increase with anastrozole), the percent rise in
FSH levels was similar in the two protocols (91 +/- 6% vs. 71 +/- 7%,
respectively; P: = NS). Inhibin B levels were unchanged after selective E(2)
withdrawal (156 +/- 23 vs. 176 +/- 19 pg/mL), but decreased slightly with
ketoconazole (156 +/- 15 to 131 +/- 11 pg/mL; P: < 0.05). In contrast to the
effects of glucocorticoid administration on gonadotropin secretion in women, no
significant changes were observed in the GnRH-deficient men treated with
dexamethasone in terms of mean LH levels (19.8 +/- 3.2 vs. 23.3 +/- 5.4 IU/L),
mean LH pulse amplitude after GnRH (16.0 +/- 2.5 vs. 19.0 +/- 5.1 IU/L), or mean
FSH levels (8.0 +/- 1.9 vs. 9.2 +/- 2.4 IU/L, pre vs. post). These studies
provide evidence of differential regulation of gonadotropin secretion by T in
the human male. T exerts both direct and indirect feedback on LH secretion,
whereas its effects on FSH appear to be mediated largely by aromatization to
E(2). From these data we conclude that in terms of sex steroid feedback, E(2) is
the predominant regulator of FSH secretion in the human male.
PMID: 11231978 [PubMed - indexed for MEDLINE]
35: J Endocrinol Invest 2000 Dec;23(11):721-3
Delayed closure of epiphyseal cartilages induced by the aromatase inhibitor
anastrozole. Would it help short children grow up?
Faglia G, Arosio M, Porretti S.
Institute of Endocrine Sciences, Ospedale Maggiore IRCCS, University of Milan,
Italy. [email protected]
Estrogens locally generated from androgen precursors due to the action of
aromatase play a main role in epiphyseal cartilage fusion. Treatment with an
aromatase inhibitor (anastrozole, 1 mg/day for 3 yr) in a boy previously
operated on for a hamartoma causing precocious puberty and presenting with
advanced bone maturation and nearly fused epiphyseal cartilages, slowed
cartilage fusion consenting a higher final stature than expected (164.4 cm vs
158.4 cm). It is suggested that treatment with aromatase inhibitors, alone or in
combination with rh-GH, may also be useful in children with constitutional short
stature in order to delay epiphyseal closure and improve the final height.
PMID: 11194703 [PubMed - indexed for MEDLINE]
36: Oncologist 2001;6(1):4-11
Drug approval summaries: arsenic trioxide, tamoxifen citrate, anastrazole,
paclitaxel, bexarotene.
Cohen MH, Hirschfeld S, Flamm Honig S, Ibrahim A, Johnson JR, O'Leary JJ, White
RM, Williams GA, Pazdur R.
Division of Oncology Drug Products, Center for Drug Evaluation and Research,
U.S. Food and Drug Administration, Rockville, Maryland 20852, USA.
[email protected]
This report summarizes information on drugs recently approved by the Food and
Drug Administration, Office of Drug Evaluation I, Division of Oncology Drug
Products. Five applications supporting new claims will be discussed: Trisenox
(arsenic trioxide) for induction of remission and consolidation in patients with
acute promyelocytic leukemia who are refractory to, or have relapsed from,
retinoid and anthracycline chemotherapy, and whose disease is characterized by
the presence of the t(15;17) translocation or PML/RAR-alpha gene expression;
Nolvadex (tamoxifen citrate) in women with ductal carcinoma in situ, following
breast surgery and radiation, to reduce the risk of invasive breast cancer;
Arimidex (anastrazole) for first-line treatment of postmenopausal women with
hormone receptor positive or hormone receptor unknown locally advanced or
metastatic breast cancer; Taxol (paclitaxel), 175 mg/m(2) by 3 h infusion in
combination with cisplatin for first-line treatment of advanced ovarian cancer;
and Targretin gel (bexarotene) for the topical treatment of cutaneous lesions in
patients with stage IA and IB cutaneous T-cell lymphoma who have not tolerated
other therapies or who have refractory or persistent disease. Information
provided includes rationale for drug development, study design, efficacy and
safety results, and pertinent literature references.
PMID: 11161223 [PubMed - indexed for MEDLINE]
37: J Clin Oncol 2001 Feb 1;19(3):881-94
Aromatase inhibitors in the treatment and prevention of breast cancer.
Goss PE, Strasser K.
Division of Hematology/Oncology, Princess Margaret Hospital, Toronto, Ontario,
Canada. [email protected]
PURPOSE: The purpose of this article is to provide an overview of the current
clinical status and possible future applications of aromatase inhibitors in
breast cancer. METHODS: A review of the literature on the third-generation
aromatase inhibitors was conducted. Some data that have been presented but not
published are included. In addition, the designs of ongoing trials with
aromatase inhibitors are outlined and the implications of possible results
discussed. RESULTS: All of the third-generation oral aromatase
inhibitors--letrozole, anastrozole, and vorozole (nonsteroidal, type II) and
exemestane (steroidal, type I)--have now been tested in phase III trials as
second-line treatment of postmenopausal hormone-dependent breast cancer. They
have shown clear superiority compared with the conventional therapies and are
therefore considered established second-line hormonal agents. Currently, they
are being tested as first-line therapy in the metastatic, adjuvant, and
neoadjuvant settings. Preliminary results suggest that the inhibitors might
displace tamoxifen as first-line treatment, but further studies are needed to
determine this. CONCLUSION: The role of aromatase inhibitors in premenopausal
breast cancer and in combination with chemotherapy and other anticancer
treatments are areas of future exploration. The ongoing adjuvant trials will
provide important data on the long-term safety of aromatase inhibitors, which
will help to determine their suitability for use as chemopreventives in healthy
women at risk of developing breast cancer.
Publication Types:
Review
Review Literature
PMID: 11157042 [PubMed - indexed for MEDLINE]
38: Ann Oncol 2000 Nov;11(11):1371-3
Clinical trials in cancer: what makes for a successful study?
Tobias JS, Baum M, Thornton H.
Publication Types:
Editorial
PMID: 11142473 [PubMed - indexed for MEDLINE]
39: Toxicol Lett 2001 Jan 3;118(3):165-9
The uterotrophic activity of nonylphenol in the rat is not mediated by aromatase
enzyme induction.
Odum J, Tinwell H, Van Miller J, Joiner R, Ashby J.
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, SK10 4TJ,
Cheshire, UK.
p-Nonylphenol (NP) is weakly estrogenic to rodents and to some species of fish.
All evidence to date has indicated that the estrogenic effects of NP are due to
the interaction of NP with the estrogen receptor. Recent findings of increased
plasma estradiol in fish exposed to NP have, however, led to the proposal of an
alternative mechanism for NP-induced estrogenicity in this species, possibly via
induction of aromatase enzymes. In the present studies, this hypothesis was
investigated in rats using the aromatase inhibitor anastrozole. The results
indicated that the uterotrophic action of NP, as with estradiol used as a
positive control, is mediated directly by its interaction with uterine ER,
rather than an indirect effect via aromatase enzyme induction. Circulating
levels of estradiol were unchanged after NP treatment and the aromatase
inhibitor anastrozole failed to inhibit NP-induced uterine growth. These results
are consistent with previous published data on NP in rodents.
PMID: 11137323 [PubMed - indexed for MEDLINE]
40: Anticancer Drugs 2000 Oct;11(9):701-6
Survival in patients with metastatic breast cancer: analysis of randomized
studies comparing oral aromatase inhibitors versus megestrol.
Messori A, Cattel F, Trippoli S, Vaiani M.
Laboratorio SIFO di Farmacoeconomia, Centro Informazione Farmaci, Azienda
Ospedaliera Careggi, Florence, Italy. [email protected]
In patients with metastatic breast cancer, second-line therapy with aromatase
inhibitors can improve survival in comparison with megestrol. We conducted a
meta-analysis to assess the effectiveness of aromatase inhibitors versus
megestrol. After a Medline search, three trials (evaluating letrozole,
anastrozole or exemestane versus megestrol) were included in the survival
meta-analysis. Our methodology retrieved patient-level information on survival.
In comparison with megestrol, aromatase inhibitors prolonged survival at levels
of statistical significance (relative death risk for oral aromatase
inhibitors=0.79, 95% confidence interval 0.69-0.91; p=0.0011). A lifetime
analysis of the pooled survival curves of aromatase inhibitors versus megestrol
found a mean survival gain of 4.1 months per patient. Aromatase inhibitors
confer a significant survival benefit to patients with metastatic breast cancer
as compared with megestrol. A preliminary calculation of the cost per life year
gained shows that the pharmacoeconomic profile of these drugs is favorable.
Publication Types:
Meta-Analysis
PMID: 11129731 [PubMed - indexed for MEDLINE]
41: J Clin Oncol 2000 Dec 15;18(24):4109
Clarification of anastrozole/megestrol acetate trial program design.
Howell A.
Publication Types:
Letter
PMID: 11118472 [PubMed - indexed for MEDLINE]
42: Breast Cancer 2000;7(4):345-9
Endocrine options for breast cancer treatment: looking beyond tamoxifen.
Watanabe T, Sonoo H.
Department of Internal Medicine, National Cancer Center Hospital, 5-1-1 Tsukiji,
Chuo-ku, Tokyo 104-0045, Japan.
PMID: 11114863 [PubMed - indexed for MEDLINE]
43: Oncology 2000;59 Suppl 1:19-23
Gonadotropins stimulate growth of MCF-7 human breast cancer cells by promoting
intracellular conversion of adrenal androgens to estrogens.
Tanaka Y, Kuwabara K, Okazaki T, Fujita T, Oizumi I, Kaiho S, Ogata E.
Third Department of Internal Medicine, National Defense Medical College,
Tokorozawa, Saitama, Japan. [email protected]
Estrogen receptor (ER)-positive breast cancers initially respond well to
estrogen ablation treatment but finally acquire refractoriness, the phenomenon
that is a major clinical problem. Because some breast cancers synthesize
estradiol (E(2)) and E(2) synthesis is regulated by gonadotropins in normal
ovaries, and because circulating gonadotropins are elevated in postmenopausal
women and during estrogen ablation treatment, we hypothesized that gonadotropins
might modulate estrogen synthesis/metabolism in breast cancer tissue as well. To
test this possibility, MCF-7 cells were treated with dehydroepiandrosterone
(DHEA) or human chorionic gonadotropin (hCG; approximately LH), each alone or in
combination. Cell growth (3-day treatment) was assayed by the MTT method and
estrogen synthesis (24-hour treatment) was measured using the ERE-luciferase
reporter system. First, MCF-7 cell growth was stimulated by DHEA in a
concentration-dependent manner with a maximal effect at 10(-4) M. Although hCG
alone did not have a significant proliferative effect, hCG significantly and
dose dependently stimulated MCF-7 cell growth in the presence of a submaximal
concentration of DHEA (10(-7 )M). This stimulatory effect of DHEA and hCG was
blocked by a pure antiestrogen ICI182,780 and an aromatase inhibitor, arimidex.
Using MCF-7 cells transfected with the ERE-luciferase reporter system, hCG
treatment was shown to increase ERE-mediated transcription. These results
indicate that MCF-7 cells intrinsically converted DHEA into E(2) upon hCG
stimulation, then grew their own cells DHEA- and hCG-dependently. We conclude
that gonadotropins can act on breast cancer cells and accelerate conversion of
DHEA into estrogens, thereby stimulating growth of estrogen-dependent tumor
cells. This phenomenon, at least in part, could explain: (1) an increased tissue
concentration of E(2) in postmenopausal breast cancer; (2) acquisition of
hormone refractoriness during estrogen ablation treatment, and (3) the
effectiveness of GnRH antagonist/superagonist in some postmenopausal breast
cancer patients. Copyright 2000 S. Karger AG, Basel
PMID: 11096352 [PubMed - indexed for MEDLINE]
44: J Clin Oncol 2000 Nov 15;18(22):3758-67
Anastrozole is superior to tamoxifen as first-line therapy for advanced breast
cancer in postmenopausal women: results of a North American multicenter
randomized trial. Arimidex Study Group.
Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, Steinberg M,
Webster A, von Euler M.
Cancer-Cross Institute, Edmonton, Alberta, Canada. jean-marc.nabholtz@bcom
PURPOSE: The efficacy and tolerability of anastrozole (Arimidex; AstraZeneca,
Wilmington, DE, and Macclesfield, United Kingdom) and tamoxifen were compared as
first-line therapy for advanced breast cancer in 353 postmenopausal women.
PATIENTS AND METHODS: The randomized, double-blind, multicenter study was
designed to evaluate anastrozole 1 mg once daily relative to tamoxifen 20 mg
once daily in patients with hormone receptor-positive tumors or tumors of
unknown receptor status who were eligible for endocrine therapy. Primary end
points were objective response (OR), defined as complete (CR) or partial (PR)
response, time to progression (TTP), and tolerability. RESULTS: Anastrozole was
as effective as tamoxifen in terms of OR (21% v 17% of patients, respectively),
with clinical benefit (CR + PR + stabilization > or = 24 weeks) observed in 59%
of patients on anastrozole and 46% on tamoxifen (two-sided P =.0098,
retrospective analysis). Anastrozole had a significant advantage over tamoxifen
in terms of TTP (median TTP of 11.1 and 5.6 months for anastrozole and
tamoxifen, respectively; two-sided P =.005). The tamoxifen:anastrozole hazards
ratio was 1.44 (lower one-sided 95% confidence limit, 1.16). Both treatments
were well tolerated. However, thromboembolic events and vaginal bleeding were
reported in fewer patients who received anastrozole compared with those who
received tamoxifen (4.1% v 8.2% [thromboembolic events] and 1.2% v 3.8% [vaginal
bleeding], respectively). CONCLUSION: Anastrozole satisfied the predefined
criteria for equivalence to tamoxifen. Furthermore, we observed both a
significant increase in TTP and a lower incidence of thromboembolic events and
vaginal bleeding with anastrozole. These findings indicate that anastrozole
should be considered as first-line therapy for postmenopausal women with
advanced breast cancer.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 11078488 [PubMed - indexed for MEDLINE]
45: J Clin Oncol 2000 Nov 15;18(22):3748-57
Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in
668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group
Efficacy and Tolerability study.
Bonneterre J, Thurlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P,
Vergote I, Webster A, Steinberg M, von Euler M.
Centre Oscar Lambret, Lille, France. [email protected]
PURPOSE: To compare the efficacy and tolerability of anastrozole (Arimidex;
AstraZeneca, Wilmington, DE, and Macclesfield, United Kingdom) with that of
tamoxifen as first-line therapy for advanced breast cancer (ABC) in
postmenopausal women. PATIENTS AND METHODS: This randomized, double-blind,
multicenter study evaluated the efficacy of anastrozole 1 mg once daily relative
to tamoxifen 20 mg once daily in patients with tumors that were hormone
receptor-positive or of unknown receptor status who were eligible for endocrine
therapy. The primary end points were time to progression (TTP), objective
response (OR), and tolerability. RESULTS: A total of 668 patients (340 in the
anastrozole arm and 328 in the tamoxifen arm) were randomized to treatment and
followed-up for a median of 19 months. Median TTP was similar for both
treatments (8.2 months in patients who received anastrozole and 8.3 months in
patients who received tamoxifen). The tamoxifen:anastrozole hazards ratio was
0.99 (lower one-sided 95% confidence limit, 0.86), demonstrating that
anastrozole was at least equivalent to tamoxifen. Anastrozole was also as
effective as tamoxifen in terms of OR (32.9% of anastrozole and 32.6% of
tamoxifen patients achieved a complete response [CR] or partial response [PR]).
Clinical benefit (CR + PR + stabilization of > or = 24 weeks) rates were 56.2%
and 55.5% for patients receiving anastrozole and tamoxifen, respectively. Both
treatments were well tolerated. However, incidences of thromboembolic events and
vaginal bleeding were reported in fewer patients treated with anastrozole than
with tamoxifen (4.8% v 7.3% [thromboembolic events] and 1.2% v 2.4% [vaginal
bleeding], respectively). CONCLUSION: Anastrozole satisfied the predefined
criteria for equivalence to tamoxifen. Together with the lower observed
incidence of thromboembolic events and vaginal bleeding, these findings indicate
that anastrozole should be considered as first-line therapy for postmenopausal
women with ABC.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 11078487 [PubMed - indexed for MEDLINE]
46: Eur J Cancer 2000 Sep;36 Suppl 4:S84-5
Randomised study of anastrozole versus tamoxifen as first-line therapy for
advanced breast cancer in postmenopausal women.
Vergote I, Bonneterre J, Thurlimann B, Robertson J, Krzakowski M, Mauriac L,
Koralewski L, Webster A, Steinberg M, von Euler M.
Department Gynaecological Oncology, University Hospitals Leuven, Herestraat 49,
B3000, Leuven, Belgium. [email protected]
A total of 668 patients (340 anastrozole and 328 tamoxifen) were randomised in a
double-blind, double-dummy multicentre study. Anastrozole was given in a dose of
1 mg once daily and compared with tamoxifen 20 mg daily in postmenopausal
patients with tumours that were hormone-receptor positive or of unknown receptor
status. The efficacy and tolerability of anastrozole was compared with that of
tamoxifen as first-line therapy for advanced breast cancer. The median time to
progression was similar for both treatments (8.2 months in anastrozole patients
and 8.3 months in tamoxifen patients). Anastrozole was also as effective as
tamoxifen in terms of objective response-rate with 33% in the anastrozole group
and 32.6% in the tamoxifen group achieving a complete or partial response. Both
treatments were well tolerated. However, incidences of thromboembolic events and
vaginal bleeding were reported in fewer patients treated with anastrozole than
with tamoxifen. In conclusion, these findings indicate that anastrozole can be
considered as first-line therapy for postmenopausal women with advanced breast
cancer.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 11056332 [PubMed - indexed for MEDLINE]
47: Eur J Cancer 2000 Sep;36 Suppl 4:S82-4
An overview of the use of non-steroidal aromatase inhibitors in the treatment of
breast cancer.
Buzdar A.
Department of Medical Oncology, The University of Texas - MD University Cancer
Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
[email protected]
A number of potent and selective non-steroidal aromatase inhibitors are now
available for the treatment of advanced breast cancer in postmenopausal women.
In particular, anastrozole represents a significant advantage over earlier
agents, such as aminoglutethimide and formestane, in terms of both efficacy and
tolerability. These agents are now established as the second-line therapy of
choice in postmenopausal women with advanced disease progressing on tamoxifen
and, furthermore, data are now available on the efficacy and tolerability of
anastrozole as first-line treatment of advanced breast cancer compared with
tamoxifen. The full potential of the new-generation aromatase inhibitors in the
treatment of breast cancer is currently being investigated in a large programme
of clinical trials, including evaluation as neoadjuvant treatment in
postmenopausal women with newly-diagnosed locally-advanced or large operable
breast cancers, as first-line treatment of advanced breast cancer in
postmenopausal women. Aromatase inhibitors have been available for over 20
years; the ability of these compounds to reduce circulating oestradiol levels
has been shown to produce clinical benefit in postmenopausal women with advanced
breast cancer. Early aromatase inhibitors, however, such as aminoglutethimide
and formestane, were not specific for the aromatase enzyme and resulted in
significant side-effects.
PMID: 11056331 [PubMed - indexed for MEDLINE]
48: Eur J Cancer 2000 Sep;36 Suppl 4:S81-2
Clinico-pharmacological aspects of different hormone treatments.
Lonning PE.
Department of Oncology, Haukeland University Hospital, N-5021, Bergen, Norway.
[email protected]
During the last decade, several new drugs and classes of drugs have become
available for breast cancer treatment. Thus, in addition to tamoxifen we have
got several new selective oestrogen receptor modulators (SERMs) with a partially
different pharmacological profile. The first generation aromatase inhibitor,
aminoglutethimide, has been replaced by more potent and less toxic inhibitors
belonging to the triazole class (anastrozole and letrozole) and, more recently,
the steroidal aromatase inactivator exemestane [1-3]. These drugs have all
revealed a better toxicity profile and, in general, an improved antitumour
activity, compared with conventional therapy. Faslodex, the first representative
of the so-called 'pure' oestrogen antagonists, has shown beneficial effects in
patients resistant to tamoxifen [4].
PMID: 11056330 [PubMed - indexed for MEDLINE]
49: Eur J Cancer 2000 Sep;36 Suppl 4:112-3
Apoptosis and anti-apoptosis in oestrogen-receptor negative endometrial cancer
cells in response to anastrozole, 4-hydroxytamoxifen and medroxyprogesterone
acetate
Morsi HM, Leers MP, Nap M, Bjorklund V V, El Kabarity H, Jaeger W.
Department of Obstetrics and Gynaecology, Ain Shams University, Cairo, Egypt.
PMID: 11056358 [PubMed - as supplied by publisher]
50: Anticancer Drugs 2000 Aug;11(7):591-601
Cost-utility analysis of second-line hormonal therapy in advanced breast cancer:
a comparison of two aromatase inhibitors to megestrol acetate.
Dranitsaris G, Leung P, Mather J, Oza A.
Department of Pharmacy, Ontario Cancer Institute/Princess Margaret Hospital,
Toronto, Canada. [email protected]
Randomized trials comparing the aromatase inhibitors, anastrozole and letrozole,
to megestrol acetate (MA) in postmenopausal women with advanced breast cancer
demonstrated that both agents are better tolerated than MA with comparable
efficacy. In addition, one trial revealed that tumor response and time to
treatment failure were significantly better with letrozole. Since oncologists
are faced with a choice between three agents with at least comparable efficacy
but different toxicity profiles and cost, a cost-utility analysis was conducted
to quantify these differences and to determine if the new agents are more
cost-effective than MA. In the absence of a randomized three-arm trial, a
decision model was developed to simulate the most common therapeutic outcomes.
The clinical data were obtained from an overview analysis of randomized trials.
Total hospital resource consumption was collected from 87 patients with advanced
disease that had failed second-line hormonal therapy. Utility estimates were
obtained from interviewing a random sample of 25 women from the general public
and 25 female health care professionals using the Time Trade-Off technique. The
model suggested a similar duration of quality-adjusted progression-free survival
between drugs (letrozole 150 days, anastrozole 153 days and MA 146 days).
Letrozole had an overall cost of Can$2949 per patient which was comparable to MA
at Can$2966 per patient. In contrast, anastrozole was slightly more costly than
MA at $Can3149 per patient, respectively. The analysis revealed that letrozole
has comparable overall costs relative to MA while providing at least equivalent
quality-adjusted progression-free survival. These outcomes were largely related
to its higher tumor response rate, which translated to a lower proportion of
patients requiring chemotherapy. Anastrozole was slightly more costly than MA
and did not demonstrate superiority in quality-adjusted progression-free
survival in this palliative setting.
PMID: 11036964 [PubMed - indexed for MEDLINE]
51: Int J Oncol 2000 Nov;17(5):1037-41
New aromatase inhibitors in the treatment of advanced breast cancer.
Crucitta E, Lorusso V, Attolico M, Sambiasi D, Mazzei A, De Lena M.
Operative Unit of Medical Oncology, Oncology Institute of Bari, Bari, Italy.
New aromatase inhibitors are an exciting treatment option for postmenopausal
women with hormone sensitive breast cancer. They have been shown to reduce
tumors in a significant number of patients, and exhibit definite antitumor
activity at a relatively low daily dose, and are highly potent, highly
selective, and well-tolerated. Results from recent clinical phase III studies
have confirmed their efficacy and the key role they have in the therapy for
advanced breast cancer in postmenopausal women. The agents available for
clinical use are: letrozole, anastrozole, and exemestane. These drugs have
demonstrated high activity in women failing tamoxifen in locally advanced or
metastatic disease. This communication reviews the clinical use of aromatase
inhibitors, particularly in second and first line hormonal treatment of advanced
breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 11029510 [PubMed - indexed for MEDLINE]
52: Nippon Rinsho 2000 Apr;58 Suppl:322-7
[Aromatase inhibitors for treatment of advanced breast cancers].
[Article in Japanese]
Sonoo H.
Department of Breast & Thyroid Surgery, Kawasaki Medical School.
Publication Types:
Review
Review, Tutorial
PMID: 11026013 [PubMed - indexed for MEDLINE]
53: Rev Med Suisse Romande 2000 Jun;120(6):495-500
[Aromatase inhibitors in the treatment of breast cancer].
[Article in French]
Perey L.
Centre pluridisciplinaire d'oncologie, Lausanne.
PMID: 11014093 [PubMed - indexed for MEDLINE]
54: J Clin Endocrinol Metab 2000 Sep;85(9):3027-35
Comment in:
J Clin Endocrinol Metab. 2000 Sep;85(9):3024-6
Aromatase inhibition in the human male reveals a hypothalamic site of estrogen
feedback.
Hayes FJ, Seminara SB, Decruz S, Boepple PA, Crowley WF Jr.
Department of Medicine and National Center for Infertility Research,
Massachusetts General Hospital, Boston 02114, USA. [email protected]
The preponderance of evidence states that, in adult men, estradiol (E2) inhibits
LH secretion by decreasing pulse amplitude and responsiveness to GnRH consistent
with a pituitary site of action. However, this conclusion is based on studies
that employed pharmacologic doses of sex steroids, used nonselective aromatase
inhibitors, and/or were performed in normal (NL) men, a model in which
endogenous counterregulatory adaptations to physiologic perturbations confound
interpretation of the results. In addition, studies in which estrogen
antagonists were administered to NL men demonstrated an increase in LH pulse
frequency, suggesting a potential additional hypothalamic site of E2 feedback.
To reconcile these conflicting data, we used a selective aromatase inhibitor,
anastrozole, to examine the impact of E2 suppression on the
hypothalamic-pituitary axis in the male. Parallel studies of NL men and men with
idiopathic hypogonadotropic hypogonadism (IHH), whose pituitary-gonadal axis had
been normalized with long-term GnRH therapy, were performed to permit precise
localization of the site of E2 feedback. In this so-called tandem model, a
hypothalamic site of action of sex steroids can thus be inferred whenever there
is a difference in the gonadotropin responses of NL and IHH men to alterations
in their sex steroid milieu. A selective GnRH antagonist was also used to
provide a semiquantitative estimate of endogenous GnRH secretion before and
after E2 suppression. Fourteen NL men and seven IHH men were studied. In Exp 1,
nine NL and seven IHH men received anastrozole (10 mg/day po x 7 days). Blood
samples were drawn daily between 0800 and 1000 h in the NL men and immediately
before a GnRH bolus dose in the IHH men. In Exp 2, blood was drawn (every 10 min
x 12 h) from nine NL men at baseline and on day 7 of anastrozole. In a subset of
five NL men, 5 microg/kg of the Nal-Glu GnRH antagonist was administered on
completion of frequent blood sampling, then sampling continued every 20 min for
a further 8 h. Anastrozole suppressed E2 equivalently in the NL (136 +/- 10 to
52 +/-2 pmol/L, P < 0.005) and IHH men (118 +/- 23 to 60 +/- 5 pmol/L, P <
0.005). Testosterone levels rose significantly (P < 0.005), with a mean increase
of 53 +/- 6% in NL vs. 56 +/- 7% in IHH men. Despite these similar changes in
sex steroids, the increase in gonadotropins was greater in NL than in IHH men
(100 +/- 9 vs. 58 +/- 6% for LH, P = 0.07; and 85 +/- 6 vs. 41 +/- 4% for FSH, P
< 0.002). Frequent sampling studies in the NL men demonstrated that this rise in
mean LH levels, after aromatase blockade, reflected an increase in both LH pulse
frequency (10.2 +/- 0.9 to 14.0 +/- 1.0 pulses/24 h, P < 0.05) and pulse
amplitude (5.7 +/- 0.7 to 8.4 +/- 0.7 IU/L, P < 0.001). Percent LH inhibition
after acute GnRH receptor blockade was similar at baseline and after E2
suppression (69.2 +/- 2.4 vs. 70 +/- 1.9%), suggesting that there was no change
in the quantity of endogenous GnRH secreted. From these data, we conclude that
in the human male, estrogen has dual sites of negative feedback, acting at the
hypothalamus to decrease GnRH pulse frequency and at the pituitary to decrease
responsiveness to GnRH.
Publication Types:
Clinical Trial
PMID: 10999781 [PubMed - indexed for MEDLINE]
55: Cancer 2000 Aug 15;89(4):817-25
Erratum in:
Cancer 2001 Jan 15;91(2):455
ICI 182,780 (Faslodex): development of a novel, "pure" antiestrogen.
Howell A, Osborne CK, Morris C, Wakeling AE.
Department of Medical Oncology, Christie Hospital National Health Service Trust,
Manchester, United Kingdom.
BACKGROUND: The nonsteroidal antiestrogen tamoxifen is well established as an
effective treatment for patients with breast carcinoma, both for the treatment
of metastatic disease and as an adjuvant to surgery for patients with primary
breast carcinoma. In addition to exerting antagonistic effects on the estrogen
receptor, tamoxifen and its derivatives act as partial agonists on certain
tissues. These agonistic effects, for example, endometrial stimulation and
stimulation of tumor growth after previous response to tamoxifen, may limit
their clinical efficacy. ICI 182,780 (Faslodex) from AstraZeneca (Cheshire,
United Kingdom) is a novel, steroidal estrogen antagonist that was designed to
be devoid of estrogen agonist activity in preclinical models. METHODS: ICI
182,780 was tested in a large number of in vitro and in vivo preclinical models,
and its value was assessed clinically when administered before surgery for
breast carcinoma and hysterectomy for benign conditions and after failure of
tamoxifen in patients with advanced breast carcinoma. RESULTS: All data
indicated that ICI 182,780 is devoid of agonist activity in preclinical models
and in clinical trials. It inhibits growth of the breast and endometrium. In
animal models, it does not cross the blood-brain barrier and appears to be
neutral with respect to lipids and bone. ICI 182,780 down-regulates the estrogen
receptor and is active in tamoxifen-resistant breast carcinoma. In a small,
Phase II study, durable responses were seen: Phase III clinical trials are in
progress comparing ICI 182,780 with anastrozole and tamoxifen in the treatment
of patients with advanced breast carcinoma. CONCLUSIONS: ICI 182,780
specifically down-regulates the estrogen receptor and, thus, represents the
first of a new class of therapeutic agents. In this report, the authors present
the current evidence that distinguishes ICI 182,780 from tamoxifen and related
nonsteroidal compounds and establishes ICI 182,780 as the first in a new class
of therapeutic agents. Copyright 2000 American Cancer Society.
PMID: 10951345 [PubMed - indexed for MEDLINE]
56: Gan To Kagaku Ryoho 2000 Jul;27(8):1225-32
[Chemo/endocrine therapy for breast cancer patients].
[Article in Japanese]
Ikeda T, Masamura S, Matsui A, Hohjoh T, Kawaguchi M, Takayama S, Tokura H,
Mitsui Y, Fujiwara K, Kitajima M.
Dept. of Surgery, Keio University School of Medicine.
Standard adjuvant chemo/endocrine therapy for breast cancer patient is based
upon St. Gallen's consensus 1998. Recent development in the field of adjuvant
chemo/endocrine therapy is an usage of LH-RH analogue with tamoxifen for
premenopausal hormone receptor positive women, and also an emerging role of
taxans. Orally given 5-FU derivatives may work in adjuvant settings. The third
generation aromatase inhibitors have established their role in second line
hormone therapy for the advanced or recurrent breast cancer patients. High dose
chemotherapy should not be used in outside clinical trials.
Publication Types:
Review
Review, Tutorial
PMID: 10945021 [PubMed - indexed for MEDLINE]
57: Tumori 2000 May-Jun;86(3):A3
[In Europe Anastrozole approved for first-line treatment of advanced breast
cancer in postmenopausal patients].
[Article in Italian]
Publication Types:
News
PMID: 10939612 [PubMed - indexed for MEDLINE]
58: Gynecol Oncol 2000 Aug;78(2):212-6
A phase II trial of anastrozole in advanced recurrent or persistent endometrial
carcinoma: a Gynecologic Oncology Group study.
Rose PG, Brunetto VL, VanLe L, Bell J, Walker JL, Lee RB.
Department of Obstetrics and Gynecology, University Hospital of Cleveland, Ohio,
44106, USA.
BACKGROUND: Some endometrial cancers are hormonally dependent. A principal
source of circulating estrogen is conversion of adrenal androstenedione by
aromatase. Anastrozole (Arimidex) is an oral nonsteroidal aromatase inhibitor
which is active in recurrent breast cancer. This Phase II study was undertaken
to evaluate anastrozole in recurrent endometrial carcinoma. METHODS: Patients
with advanced or recurrent endometrial cancer not curable with either surgery or
radiation therapy and with measurable disease, a GOG (Zubrod) performance status
of < or = 2, no more than one prior hormonal therapy regimen, and no prior
chemotherapy were eligible. Anastrozole was administered at a dose of 1 mg/day
orally for at least 28 days. RESULTS: Twenty-three patients were entered on this
trial. On central pathology review, 9 of them had grade 2 and 14 had grade 3
tumors. One to 24 courses (median: 1) of therapy were administered. Two partial
responses were noted (9%; 90% confidence interval 3 to 23%). Two additional
patients had short-term stable disease. With the exception of 1 case of venous
thrombosis, the toxicity profile was mild. Median durations of progression-free
survival and overall survival are 1 and 6 months, respectively. CONCLUSIONS:
Anastrozole has minimal activity in an unselected population of patients with
recurrent endometrial cancer. Copyright 2000 Academic Press.
Publication Types:
Clinical Trial
Clinical Trial, Phase II
Multicenter Study
PMID: 10926805 [PubMed - indexed for MEDLINE]
59: J Mol Endocrinol 2000 Aug;25(1):35-42
Estrogen biosynthesis in endometriosis: molecular basis and clinical relevance.
Bulun SE, Zeitoun KM, Takayama K, Sasano H.
Departments of Obstetrics and Gynecology and Molecular Genetics, University of
Illinois at Chicago, 820 S. Wood St. M/C 808, Illinois 60612, USA.
[email protected]
Conversion of C(19) steroids to estrogens is catalyzed by aromatase in human
ovary, placenta and extraglandular tissues such as adipose tissue, skin and the
brain. Aromatase activity is not detectable in normal endometrium. In contrast,
aromatase is expressed aberrantly in endometriosis and is stimulated by
prostaglandin E(2) (PGE(2)).( )This results in local production of estrogen,
which induces PGE(2) formation and establishes a positive feedback cycle.
Another abnormality in endometriosis, i.e. deficient hydroxysteroid
dehydrogenase (17beta-HSD) type 2 expression, impairs the inactivation of
estradiol to estrone. These molecular aberrations collectively favor
accumulation of increasing quantities of estradiol and PGE(2 )in endometriosis.
The clinical relevance of these findings was exemplified by the successful
treatment of an unusually aggressive case of postmenopausal endometriosis using
an aromatase inhibitor.
Publication Types:
Review
Review, Tutorial
PMID: 10915216 [PubMed - indexed for MEDLINE]
60: Cancer Chemother Pharmacol 2000;46(1):35-9
Effects of the aromatase inhibitor anastrozole on serum oestrogens in Japanese
and Caucasian women.
Dowsett M, Donaldson K, Tsuboi M, Wong J, Yates R.
Department of Academic Biochemistry, Royal Marsden Hospital, London, UK.
[email protected]
PURPOSE: Substantial differences in plasma oestrogen disposition have been
reported between Japanese and Caucasian women, but there are currently few data
available on the relative endocrinological effects of aromatase inhibitors in
these two groups. Hence, the effects of the nonsteroidal aromatase inhibitor
anastrozole on serum oestrogen concentrations were compared in 24 healthy
postmenopausal Japanese women and 24 healthy postmenopausal Caucasian women.
METHODS: Anastrozole, 1 mg/day, was given once daily for 16 days. Serum
oestradiol and oestrone sulphate levels were measured on three consecutive days
beginning 2 days before the first dose, and on a further three consecutive days
beginning on the penultimate day of dosing. Trough concentrations of anastrozole
(measured 24 h after dosing) were also determined during the same periods.
RESULTS: There were no substantial differences in plasma oestrogen
concentrations between the Japanese and Caucasian women at baseline. On average,
anastrozole suppressed serum oestradiol and oestrone sulphate levels by
approximately 87% and 93%, respectively, for both Japanese and Caucasian women,
and minimum plasma anastrozole concentrations at steady-state (anastrozole
C(min)) were also similar in both groups. Statistical analysis of serum
oestradiol and serum oestrone sulphate levels, and plasma anastrozole C(min)
showed that there were no statistically significant differences between the
Japanese and Caucasian women. CONCLUSION: Neither the pharmacodynamic effects of
anastrozole on serum oestrogens nor the pharmacokinetics of anastrozole differ
between postmenopausal Japanese and Caucasian women. Hence, these findings
suggest that the therapeutic benefits of anastrozole in Caucasians will be
predictive of the drug's effect in Japanese women and support the use of
anastrozole in postmenopausal Japanese women with breast cancer.
PMID: 10912575 [PubMed - indexed for MEDLINE]
61: J Clin Endocrinol Metab 2000 Jul;85(7):2370-7
Comment in:
J Clin Endocrinol Metab. 2001 Apr;86(4):1836-8
Estrogen suppression in males: metabolic effects.
Mauras N, O'Brien KO, Klein KO, Hayes V.
Nemours Research Programs at the Nemours Children's Clinic, Jacksonville,
Florida 32207, USA. [email protected]
We have shown that testosterone (T) deficiency per se is associated with marked
catabolic effects on protein, calcium metabolism, and body composition in men
independent of changes in GH or insulin-like growth factor I production. It is
not clear,,however, whether estrogens have a major role in whole body anabolism
in males. We investigated the metabolic effects of selective estrogen
suppression in the male using a potent aromatase inhibitor, Arimidex
(Anastrozole). First, a dose-response study of 12 males (mean age, 16.1 +/- 0.3
yr) was conducted, and blood withdrawn at baseline and after 10 days of oral
Arimidex given as two different doses (either 0.5 or 1 mg) in random order with
a 14-day washout in between. A sensitive estradiol (E2) assay showed an
approximately 50% decrease in E2 concentrations with either of the two doses;
hence, a 1-mg dose was selected for other studies. Subsequently, eight males
(aged 15-22 yr; four adults and four late pubertal) had isotopic infusions of
[(13)C]leucine and (42)Ca/(44)Ca, indirect calorimetry, dual energy x-ray
absorptiometry, isokinetic dynamometry, and growth factors measurements
performed before and after 10 weeks of daily doses of Arimidex. Contrary to the
effects of T withdrawal, there were no significant changes in body composition
(body mass index, fat mass, and fat-free mass) after estrogen suppression or in
rates of protein synthesis or degradation; carbohydrate, lipid, or protein
oxidation; muscle strength; calcium kinetics; or bone growth factors
concentrations. However, E2 concentrations decreased 48% (P = 0.006), with no
significant change in mean and peak GH concentrations, but with an 18% decrease
in plasma insulin-like growth factor I concentrations. There was a 58% increase
in serum T (P = 0.0001), sex hormone-binding globulin did not change, whereas LH
and FSH concentrations increased (P < 0.02, both). Serum bone markers,
osteocalcin and bone alkaline phosphatase concentrations, and rates of bone
calcium deposition and resorption did not change. In conclusion, these data
suggest that in the male 1) estrogens do not contribute significantly to the
changes in body composition and protein synthesis observed with changing
androgen levels; 2) estrogen is a main regulator of the gonadal-pituitary
feedback for the gonadotropin axis; and 3) this level of aromatase inhibition
does not negatively impact either kinetically measured rates of bone calcium
turnover or indirect markers of bone calcium turnover, at least in the short
term. Further studies will provide valuable information on whether timed
aromatase inhibition can be useful in increasing the height potential of
pubertal boys with profound growth retardation without the confounding negative
effects of gonadal androgen suppression.
Publication Types:
Clinical Trial
PMID: 10902781 [PubMed - indexed for MEDLINE]
62: Clin Cancer Res 2000 Jun;6(6):2229-35
The effects of neoadjuvant anastrozole (Arimidex) on tumor volume in
postmenopausal women with breast cancer: a randomized, double-blind,
single-center study.
Dixon JM, Renshaw L, Bellamy C, Stuart M, Hoctin-Boes G, Miller WR.
Edinburgh Breast Unit, Western General Hospital, Edinburgh, Scotland, United
Kingdom.
Anastrozole, an orally active, nonsteroidal aromatase inhibitor, was evaluated
in a randomized, double-blind, single-center study to determine its efficacy as
neoadjuvant therapy in postmenopausal women with newly diagnosed, estrogen
receptor-rich, locally advanced or large (>3 cm), operable breast cancers.
Twenty-four eligible patients were recruited into the study and received either
1 mg (n = 12) or 10 mg (n = 12) of anastrozole daily over a 3-month period.
Tumor volumes were estimated clinically, by using caliper measurements and
ultrasound (at baseline and after 1, 2, and 3 months' treatment) and by
mammography (at baseline and after 3 months). Tumor volume was also measured in
surgical specimens. Twenty-one patients were classified as T2, two patients as
T3, and one patient as T4B at baseline. Three patients had clinical evidence of
lymph node involvement. When considering the difference between the volume as
measured by each assessment and the actual pathological volume, the
interquartile range and the difference between the maximum and minimum values
were smaller for ultrasound when compared with those measured with calipers and
mammography. Therefore, of the three clinical assessments of tumor volume used
in this study, the data suggest that ultrasound may be the most accurate. The
median reductions in tumor volumes as measured by ultrasound for those patients
with a measurable 12-week assessment were 80.5 and 69.6% for anastrozole (1 and
10 mg, respectively) after 12 weeks of treatment and 75.5% when both doses were
grouped together. Moreover, of these patients, 11 of 12 given 1 mg and 7 of 11
given 10 mg of anastrozole were found on ultrasound to have a >50% reduction in
tumor volume after 12 weeks of treatment. Of the 17 patients who would have
required a mastectomy at initiation of treatment, 15 were suitable for breast
conservation after anastrozole treatment. These results suggest that anastrozole
is highly effective as neoadjuvant therapy in postmenopausal women with estrogen
receptor-rich, large, operable breast cancer. Future studies comparing
anastrozole with tamoxifen as a neoadjuvant treatment should be considered.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 10873072 [PubMed - indexed for MEDLINE]
63: J Steroid Biochem Mol Biol 2000 Apr;72(5):259-64
A novel HPLC-RIA method for the simultaneous detection of estrone, estradiol and
estrone sulphate levels in breast cancer tissue.
Geisler J, Berntsen H, Lonning PE.
Department of Oncology, Haukeland University Hospital, N-5021, Bergen, Norway.
Estrogen deprivation is an effective approach for treatment of hormone sensitive
breast cancer. While much is known about plasma estrogen levels with respect to
castration in premenopausal women and use of aromatase inhibitors in
postmenopausal women, currently there is increasing interest in intra-tumour
estrogen production. However, knowledge about alterations in intra-tumour
estrogen levels is limited, mainly due to methodological problems with
measurements of estrogen fractions in tissue samples. Here we describe a new
method for simultaneous measurement of the three main estrogen fractions,
estrone (E(1)), estradiol (E(2)) and estrone sulphate (E(1)S) in breast tumour
tissue. Following incubation with -labelled estrogen standards, crude fractions
were separated by ether extraction. The E(1)S fraction was hydrolysed with
sulphatase followed by eluation on a Sephadex column. High pressure liquid
chromatography (HPLC) was used to purify the individual estrogen fractions prior
to RIA analysis. Estrone and E(1)S were converted into E(2), and all three
estrogen fractions were finally measured by the same highly sensitive and
specific radioimmunoassay using
estradiol-6-(O-carboxymethyl)-oximino-2-(2--iodo-histamine) as a ligand.
Although several purification steps were used, the internal recovery values for
tritiated estrogens were found to be 25-50% for E(1) and E(2) and 15-30% for
E(1)S. The detection limit of this method was 4.3 fmol/g tissue for E(2), 19.8
fmol/g tissue for E(1) and 11.9 fmol/g E(1)S, respectively. Using tissue from
locally advanced breast cancers (n = 14), we found median levels of E(1), E(2)
and E(1)S to be 283.8 fmol/g tissue (range 19.8-547.5), 554.1 fmol/g
(9.5-3024.2) and 209.4 fmol/g (11.9-753.4), respectively. The method described
here is a promising tool to study intra-tumour estrogen fractions in breast
tissue biopsies.
PMID: 10822015 [PubMed - indexed for MEDLINE]
64: Tumori 1999 Nov-Dec;85(6):A19-25
[Anastrozolo: intracellular anti-aromatase activity and pharmacologic
interactions. Satellite Symposium AIOM 1999 - Roma].
[Article in Italian]
Longo F, Mansueto G.
Publication Types:
Congresses
PMID: 10774583 [PubMed - indexed for MEDLINE]
65: Crit Rev Oncol Hematol 2000 Feb;33(2):137-42
Steroidal aromatase inhibitors in elderly patients.
Bajetta E, Zilembo N, Bichisao E, Pozzi P, Toffolatti L.
Division of Medical Oncology, Istituto Nazionale per lo Studio e la Cura dei
Tumori, Milan, Italy.
The choice of treatment for elderly breast cancer patients needs particular care
because the presence of physiological functional impairments can modify the drug
bioavailability in an unpredictable manner. Hormonal treatment remains one of
the choices and, although tamoxifen has proved to be effective in any setting,
the use of selective aromatase inhibitors is arousing. Depending on their
chemical structure, aromatase inhibitors are either steroidal (such as
exemestane and formestane) or non-steroidal (such as letrozole, vorozole and
anastrozole). Formestane has been studied in elderly patients with breast cancer
and has been found to induce an overall response rate of 51% (95% CI, 35-67%).
The drug suppresses estradiol (E2) levels, and changes in other hormones (FSH,
LH and SHBG) are observed, but with poor clinical significance, thus confirming
its selectivity and potency. Formestane has also been demonstrated to be as
effective as tamoxifen. Exemestane and non-steroidal aromatase inhibitors appear
to be very promising drugs.
Publication Types:
Review
Review, Tutorial
PMID: 10737375 [PubMed - indexed for MEDLINE]
66: Endocr Relat Cancer 1999 Mar;6(1):75-92
Use of aromatase inhibitors in breast carcinoma.
Santen RJ, Harvey HA.
Department of Medicine, University of Virginia Health Sciences Center,
Charlottesville 22908, USA.
Aromatase, a cytochrome P-450 enzyme that catalyzes the conversion of androgens
to estrogens, is the major mechanism of estrogen synthesis in the
post-menopausal woman. We review some of the recent scientific advances which
shed light on the biologic significance, physiology, expression and regulation
of aromatase in breast tissue. Inhibition of aromatase, the terminal step in
estrogen biosynthesis, provides a way of treating hormone-dependent breast
cancer in older patients. Aminoglutethimide was the first widely used aromatase
inhibitor but had several clinical drawbacks. Newer agents are considerably more
selective, more potent, less toxic and easier to use in the clinical setting.
This article reviews the clinical data supporting the use of the potent, oral
competitive aromatase inhibitors anastrozole, letrozole and vorozole and the
irreversible inhibitors 4-OH androstenedione and exemestane. The more potent
compounds inhibit both peripheral and intra-tumoral aromatase. We discuss the
evidence supporting the notion that aromatase inhibitors lack cross-resistance
with antiestrogens and suggest that the newer, more potent compounds may have a
particular application in breast cancer treatment in a setting of adaptive
hypersensitivity to estrogens. Currently available aromatase inhibitors are safe
and effective in the management of hormone-dependent breast cancer in
post-menopausal women failing antiestrogen therapy and should now be used before
progestational agents. There is abundant evidence to support testing these
compounds as first-line hormonal therapy for metastatic breast cancer as well as
part of adjuvant regimens in older patients and quite possibly in
chemoprevention trials of breast cancer.
Publication Types:
Review
Review, Academic
PMID: 10732791 [PubMed - indexed for MEDLINE]
67: Endocr Relat Cancer 1999 Jun;6(2):259-63
Aromatase inhibitors and their use in the sequential setting.
Coombes RC, Harper-Wynne C, Dowsett M.
Cancer Research Campaign, Department of Cancer Medicine, Imperial College School
of Medicine, Charing Cross Hospital, London, UK.
Over the past decade several novel aromatase inhibitors have been introduced
into clinical practice. The discovery of these drugs followed on from the
observation that the main mechanism of action of aminogluthemide was via
inhibition of the enzyme aromatase thereby reducing peripheral levels of
oestradiol in postmenopausal patients. The second-generation drug,
4-hydroxyandrostenedione (formestane), was introduced in 1990 and although its
use was limited by its need to be given parenterally it was found to be a
well-tolerated form of endocrine therapy. Third-generation inhibitors include
vorozole, letrozole, anastrozole and exemestane, the former three being
non-steroidal inhibitors, the latter being a steroidal inhibitor. All are
capable of inhibiting aromatase action by >95% compared with 80% in the case of
4-hydroxyandrostenedione. The sequential use of different generations of
aromatase inhibitors in the same patients is discussed. Studies suggest that an
optimal sequence of these compounds may well result in longer remission in
patients with hormone receptor positive tumours.
Publication Types:
Review
Review, Tutorial
PMID: 10731118 [PubMed - indexed for MEDLINE]
68: Endocr Relat Cancer 1999 Jun;6(2):245-9
Aromatase inhibitors: a dose-response effect?
Smith IE.
Section of Medicine, Royal Marsden Hospital and Institute of Cancer Research,
London, UK.
Publication Types:
Review
Review, Tutorial
PMID: 10731116 [PubMed - indexed for MEDLINE]
69: Endocr Relat Cancer 1999 Jun;6(2):231-4
Use of aromatase inhibitors in the adjuvant treatment of breast cancer.
Baum M.
Institute of Surgical Studies, University College London, UK.
The value of endocrine treatment of early breast cancer has been illustrated by
the antioestrogen, tamoxifen, which has now been available for nearly 30 years.
However, if the recognised side effects and pharmacological properties of
tamoxifen are taken into consideration, it is possible that other endocrine
treatments that are now available can provide equal or superior efficacy, along
with improved tolerability. One such group of agents is the aromatase inhibitors
specifically the new-generation triazole aromatase inhibitors, such as
anastrozole and letrozole, which have both shown tolerability and efficacy
advantages over standard treatments in postmenopausal women with advanced breast
cancer. There are convincing reasons why the new generation of aromatase
inhibitors have advantages over tamoxifen. For instance, from their agonist
properties, the effects on the endometrium and tumour stimulation seen with
tamoxifen would not be expected, nor would the visual disturbances that have
been associated with the triphenylethylene compounds, including tamoxifen. A
number of aromatase inhibitors, for instance, anastrozole, letrozole and
exemestane, are currently being investigated for treatment of early breast
cancer. The results of the trials of aromatase inhibitors and tamoxifen will, in
the next few years, define whether or not the new-generation aromatase
inhibitors have a role to play in the treatment of postmenopausal women with
early breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 10731114 [PubMed - indexed for MEDLINE]
70: Endocr Relat Cancer 1999 Jun;6(2):227-30
Lessons from the use of aromatase inhibitors in the neoadjuvant setting.
Dixon JM, Love CD, Renshaw L, Bellamy C, Cameron DA, Miller WR, Leonard RC.
Edinburgh Breast Unit, Western General Hospital, UK.
Postmenopausal patients with oestrogen receptor-positive locally advanced T4b,
N0-1, M0 and large operable breast cancers T2>3 cm, T3, T4, N0-1 and M0 have
been treated with 2.5 mg letrozole (12 patients), 10 mg letrozole (12 patients),
1 or 10 mg anastrozole (24 patients) and 20 mg tamoxifen (65 patients). There
was no apparent difference in response rate between 2.5 and 10 mg letrozole.
Only 17 patients with anastrozole have so far completed the 3-month treatment
period. Median clinical, mammographic and ultrasound reductions in tumour
volumes for patients treated with letrozole were 81% (95% confidence interval
(CI) 66-88), 77% (95% CI 64-82) and 81% (95% CI 69-86) respectively and for
anastrozole, values were 87% (95% CI 59-97), 73% (95% CI 58-82) and 64% (95% CI
52-76) respectively. This compares with a median reduction in tumour volume for
tamoxifen-treated patients as assessed by ultrasound of 48% (95% CI 27-48).
There were seven complete clinical responses (CR), sixteen patients who achieved
50% or greater reduction in tumour volume (PR) and one no change (NC) for
letrozole and four CRs, twelve PRs and one progressive disease for anastrozole.
Best radiological responses were one CR, twenty PRs and three NCs for letrozole
and one CR, fifteen PRs and one NC for anastrozole. This study has shown that
the new aromatase inhibitors, letrozole and anastrozole, are highly effective
agents in the neoadjuvant setting and they should now be compared with tamoxifen
as first-line treatment in a randomised study.
Publication Types:
Review
Review, Tutorial
PMID: 10731113 [PubMed - indexed for MEDLINE]
71: Endocr Relat Cancer 1999 Jun;6(2):219-25
Role of aromatase inhibitors in advanced breast cancer.
Buzdar AU.
Department of Medical Oncology, The University of Texas, MD Anderson University
Cancer Center, Houston 77030, USA.
A number of potent and selective non-steroidal aromatase inhibitors are now
available for treatment of advanced breast cancer in postmenopausal women, of
which anastrozole and letrozole, in particular, represent a significant
advantage over the earlier agents in terms of both efficacy and tolerability.
These agents are rapidly becoming established as the second-line therapy of
choice in postmenopausal women with advanced disease, progressing on tamoxifen,
and data on their efficacy as first-line treatment compared with tamoxifen will
be available in the near future. Exemestane, a new, steroidal aromatase
inhibitor which potentially lacks cross-resistance with non-steroidal agents is
still in clinical development. The full potential of the new-generation
aromatase inhibitors in the treatment of breast cancer is currently being
investigated in a large program of clinical trials evaluating their use as
adjuvant treatment following surgery in postmenopausal patients with early
disease.
Publication Types:
Review
Review, Tutorial
PMID: 10731112 [PubMed - indexed for MEDLINE]
72: Endocr Relat Cancer 1999 Jun;6(2):205-10
Aromatase inhibitors and their antitumor effects in model systems.
Brodie A, Lu Q, Liu Y, Long B.
Department of Pharmacology and Experimental Therapeutics, and Greenebaum Cancer
Center, School of Medicine, University of Maryland, Baltimore 21201, USA.
The potential of aromatase (estrogen synthetase) within the breast to provide a
significant source of estrogen mediating tumor proliferation is suggested by
studies reporting 4- to 6-fold higher estrogen levels in tumors than in plasma
of postmenopausal patients with breast cancer. Recent studies in our laboratory
have identified aromatase and its mRNA in tumor epithelial cells using
immunocytochemistry and in situ hybridization. In addition, significant
aromatase activity, which was stimulated 7-fold by dexamethasone, was measured
in metastatic cells isolated from a breast cancer patient. Increase in
proliferation, as measured by proliferating cell nuclear antigen immunostaining
in tumor sections and by thymidine incorporation into DNA in response to
testosterone, was observed in histocultures of breast cancer samples. This
latter effect could be inhibited by 4-hydroxyandrostenedione. These results
imply that intratumoral aromatase has functional significance and may be an
important target for successful inhibitor treatment of breast cancer patients.
To investigate treatment strategies with aromatase inhibitors and antiestrogens,
we developed an intratumoral aromatase model to simulate the hormone responsive
postmenopausal breast cancer patient. Tumors of estrogen receptor positive human
breast carcinoma cells (MCF-7) transfected with the human aromatase gene are
grown in ovariectomized nude mice. These cells synthesize sufficient estrogen to
stimulate tumor formation. We have utilized this model to investigate the
effects on tumor growth of the antiestrogens, tamoxifen and ICI 182780, and the
aromatase inhibitors, letrozole and anastrozole (arimidex), alone and in
combination. Both the aromatase inhibitors and the antiestrogens were effective
in suppressing tumor growth. However, letrozole was significantly more effective
than the antiestrogens. When the aromatase inhibitors were combined with the
antiestrogen, tamoxifen, tumor growth was suppressed to about the same extent as
with the aromatase inhibitors alone. Furthermore, the results do not suggest any
benefit from combining tamoxifen with the pure antiestrogen, ICI 182780. Thus
sequential use of these agents is likely to be more advantageous to the patient
in terms of longer duration of effective treatment.
PMID: 10731110 [PubMed - indexed for MEDLINE]
73: Endocr Relat Cancer 1999 Jun;6(2):187-95
Biology of aromatase inhibitors: pharmacology/endocrinology within the breast.
Miller WR.
Breast Research Unit, Western General Hospital, Edinburgh, UK.
Both mammary adipose tissue and breast cancers have the ability to aromatize
androgens into oestrogens. Such potential may maintain the growth of
hormone-dependent tumours. It has therefore been important to determine the
effects of new aromatase inhibitors such as formestane, exemestane, anastrozole
and letrozole on oestrogen biosynthesis and concentrations of endogenous
hormones within the breast. Studies based on in vitro incubations of breast
cancer and cultures of mammary adipose tissue fibroblasts demonstrate that these
drugs are highly effective inhibitors, with IC50 values ranging between 1 and 50
nM (although the relative efficacy varies between tissues and test systems).
Despite this potential, in vitro incubations of breast tissues from patients
treated with type II inhibitors such as aminoglutethimide and letrozole can
display paradoxically high aromatase activity; this appears to be caused by the
reversible nature of the inhibition, coupled with induction/stabilization of the
aromatase enzyme. To assess in situ effects within the breast, postmenopausal
women with large primary breast cancers have been treated neoadjuvantly with
aromatase inhibitors using a protocol that included (i) breast biopsy before
treatment, (ii) definitive surgery after 3 months of treatment and (iii)
infusion of [3H]androstenedione and [14C]oestrone in the 18 h immediately before
biopsy and surgery. With this study design, it has been shown that drugs such as
letrozole profoundly inhibit in situ aromatase activity and reduce endogenous
oestrogens within the breast.
PMID: 10731108 [PubMed - indexed for MEDLINE]
74: Endocr Relat Cancer 1999 Jun;6(2):181-5
Drug and hormone interactions of aromatase inhibitors.
Dowsett M.
Academic Department of Biochemistry, The Royal Marsden NHS Trust, London, UK.
The clinical development of aromatase inhibitors has been largely confined to
postmenopausal breast cancer patients and strongly guided by pharmacological
data. Comparative oestrogen suppression has been helpful in circumstances in
which at least one of the comparitors has caused substantially non-maximal
aromatase inhibition. However, the triazole inhibitors, letrozole and
anastrozole, and the steroidal inhibitor, exemestane, all cause >95% inhibition.
Comparisons between these drugs therefore require more sensitive approaches such
as the direct measurement of enzyme activity by isotopic means. None of these
three agents has significant effects on other endocrine pathways at its
clinically applied doses. Pharmacokinetic analyses of the combination of
tamoxifen and letrozole have revealed that these drugs interact, resulting in
letrozole concentrations approximately 35-40% lower than when letrozole is used
alone.
Publication Types:
Review
Review, Tutorial
PMID: 10731107 [PubMed - indexed for MEDLINE]
75: Breast Cancer Res Treat 1999 Nov;58(2):157-62
Static disease on anastrozole provides similar benefit as objective response in
patients with advanced breast cancer.
Robertson JF, Howell A, Buzdar A, von Euler M, Lee D.
Department of Surgery, City Hospital, Nottingham, UK.
[email protected]
BACKGROUND: This paper reports on the clinical relevance of durable static
disease (SD) (> or = 24 weeks) in breast cancer patients treated with the
aromatase inhibitor anastrozole. PATIENTS AND METHODS: All patients were part of
two prospective, randomised, multicentre studies in postmenopausal women with
advanced disease in which megestrol acetate was compared with anastrozole 1 mg.
Survival from initiation of treatment was analysed by the response type, i.e.,
complete response (CR)/partial response (PR), static disease (SD) (> or = 24
weeks), or progressive disease (PD), achieved on therapy. RESULTS: Median
survival with anastrozole 1 mg was similar between patients who obtained CR/PR
and SD (> or = 24 weeks). Similarly, no difference in survival was observed in
patients treated with megestrol acetate who achieved CR/PR and SD. With both
treatments patients with CR/PR and SD had improved survival over those patients
with PD within 24 weeks. There was no difference between treatment arms for
patients showing PD within 24 weeks. CONCLUSIONS: These data confirm that
durable SD (> or = 24 weeks) is a clinically useful remission criterion in
postmenopausal women with advanced breast cancer with predictive value for
overall survival. It also confirms the value of this endpoint with anastrozole,
a new generation aromatase inhibitor.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 10674881 [PubMed - indexed for MEDLINE]
76: J Endocrinol 2000 Feb;164(2):225-38
Effect of chronic administration of an aromatase inhibitor to adult male rats on
pituitary and testicular function and fertility.
Turner KJ, Morley M, Atanassova N, Swanston ID, Sharpe RM.
MRC Reproductive Biology Unit, Centre for Reproductive Biology, 37 Chalmers
Street, Edinburgh EH3 9EW, Scotland, UK. [email protected]
The aim of the present study was to evaluate the effects of the administration
of a potent non-steroidal aromatase inhibitor, anastrozole, on male reproductive
function in adult rats. As anastrozole was to be administered via the drinking
water, a preliminary study was undertaken in female rats and showed that this
route of administration was effective in causing a major decrease in uterine
weight (P<0.02). In an initial study in male adult rats, anastrozole (100 mg/l
or 400 mg/l) was administered via the drinking water for a period of 9 weeks.
Treatment with either dose resulted in a significant increase ( approximately
10%) in testis weight and increase in plasma FSH concentrations (P<0.01)
throughout the 9 weeks. Mating was altered in both groups of anastrozole-treated
rats, as they failed to produce copulatory plugs. Histological evaluation of the
testes from anastrozole-treated rats revealed that spermatogenesis was grossly
normal. In a more detailed study, adult rats were treated with 200 mg/l
anastrozole via the drinking water for periods ranging from 2 weeks to 1 year.
Plasma FSH and testosterone concentrations were increased significantly
(P<0.001) during the first 19 weeks of treatment. However, LH concentrations
were increased only at 19 weeks (P<0.001) in anastrozole-treated rats, and this
coincided with a further increase in circulating and intratesticular
testosterone concentrations (P<0.05). No consistent change in inhibin-B
concentrations was observed during the study. Suppression of plasma oestradiol
concentrations could not be demonstrated in anastrozole-treated animals, but
oestradiol concentrations in testicular interstitial fluid were reduced by 18%
(P<0.01). Mating was again inhibited by anastrozole treatment, but could be
restored by s.c. injection of oestrogen, enabling demonstration that rats
treated for 10 weeks or 9 months were still fertile. Testis weight was increased
by 19% and 6% after treatment for 19 weeks and 1 year, respectively. Body weight
was significantly decreased (P<0.01) by 19 weeks of anastrozole treatment; after
1 year the animals appeared to have less fat as indicated by a 27% decrease in
the weight of the gonadal fat pad. The majority of anastrozole-treated animals
had testes with normal spermatogenesis but, occasionally, seminiferous tubules
showed abnormal loss of germ cells or contained only Sertoli cells. Ten percent
of anastrozole-treated animals had testes that appeared to contain only Sertoli
cells, and one rat had 'giant' testes in which the tubule lumens were severely
dilated. Morphometric analysis of the normal testes at 19 weeks showed no
difference in the number of Sertoli cells or germ cells, or the percentage
volumes of the seminiferous epithelium, tubule lumens and interstitium between
control and anastrozole-treated rats. On the basis of the present findings,
oestrogen appears to be involved in the regulation of FSH secretion and
testosterone production, and is also essential for normal mating behaviour in
male rats. Furthermore, these data suggest that the brain and the
hypothalamo-pituitary axis are considerably more susceptible than is the testis
to the effects of an aromatase inhibitor. Anastrozole treatment has resulted in
a model of brain oestrogen insufficiency.
PMID: 10657858 [PubMed - indexed for MEDLINE]
77: J Appl Toxicol 2000 Jan-Feb;20(1):35-47
The peripubertal male rat assay as an alternative to the Hershberger castrated
male rat assay for the detection of anti-androgens, oestrogens and metabolic
modulators.
Ashby J, Lefevre PA.
AstraZeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire
SK10 4TJ, UK. [email protected]
A range of chemicals with various levels of activity as actual or potential
endocrine disrupters have been evaluated for activity in the peripubertal male
rat assay. The chemicals studied included anti-androgens (vinclozolin),
cyproterone acetate, flutamide, 2, 2-bis(4-chlorophenyl)-1,1-dichloroethylene
(DDE), metabolic modulators (anastrazole, finasteride, ketoconazole) and
oestrogens (butyl benzyl phthalate (BBP), methoxychlor, bisphenol A (BPA),
diethylstilboestrol (DES)), the suspected anti-androgen dibutyl phthalate (DBP)
and the non-oestrogen fenitrothion. Dosing extended over postnatal days (pnd)
22-35, 36-50, 36-55 and 22-35, with recovery to pnd 55 or 22-55. The endpoints
studied were changes in the weights of testes, epididymides, seminal vesicles
and prostate. Changes in body weight and the weights of the liver and kidney
were also monitored. In some experiments changes in the day of prepuce
separation (PPS) were also determined. Only BBP and BPA were inactive in all the
assays conducted. Changes in the weight of reproductive tissues provided a
sensitive indicator of activity for the remaining chemicals with the exception
of DDE, for which higher dose levels could have been used. However, none of the
curtailed periods of exposure were able to detect all of the agents. Diethyl
stilboestrol, and to a lesser extent DBP and DDE, delayed PPS when exposure
occurred over the period pnd 22-55. A complex dependence of the day of PPS on
the period of exposure and the body weight of the test animals was observed, and
caution is recommended when assessing this endpoint in the presence of
reductions in body weight. It is concluded that reproductive tissue weight
changes in the peripubertal male have shown sensitivity to a range of
biochemical modulators, oestrogens and anti-androgens, and that as such the
assay warrants further evaluation. Measurement of delays in PPS may be of value
in cases of large delays, but delays of 1-2 days will be difficult to interpret
with confidence. The present results are discussed within the context of the
sexually mature male rat assay described by O'Connor and the castrated male rat
assay described by Hershberger, both of which are the subject of current
international study. It is concluded that a decision on the usefulness of the
peripubertal male rat assay must await the generation of further data on each of
these three assays. There is an urgent need for international agreement on a
list of reference endocrine disrupters and their active dose levels, with which
to validate individual endocrine disruption assays and batteries of assays.
Copyright 2000 John Wiley & Sons, Ltd.
PMID: 10641015 [PubMed - indexed for MEDLINE]
78: Ann Surg Oncol 1999 Dec;6(8 Suppl):14S-16S
Future directions in endocrine treatment of advanced breast cancer.
Bland KI.
PMID: 10619455 [PubMed - indexed for MEDLINE]
79: Ann Surg Oncol 1999 Dec;6(8 Suppl):12S-13S
Safety and tolerability of endocrine therapies used in the treatment of advanced
breast cancer.
Bland KI, Buzdar AU.
PMID: 10619454 [PubMed - indexed for MEDLINE]
80: Ann Surg Oncol 1999 Dec;6(8 Suppl):8S-11S
Critique of survival update analysis from two phase III anastrozole clinical
trials.
Buzdar AU.
Publication Types:
Clinical Trial
Clinical Trial, Phase III
Randomized Controlled Trial
PMID: 10619453 [PubMed - indexed for MEDLINE]
81: Breast Cancer Res Treat 1999 Sep;57(2):183-92
The effect of combining aromatase inhibitors with antiestrogens on tumor growth
in a nude mouse model for breast cancer.
Lu Q, Liu Y, Long BJ, Grigoryev D, Gimbel M, Brodie A.
Department of Pharmacology and Experimental Therapeutics, University of
Maryland, School of Medicine, Baltimore 21201, USA.
We have previously established a model for postmenopausal, hormone-dependent
breast cancer in nude mice which is responsive to both antiestrogens and
aromatase inhibitors. In this model, MCF-7 human breast carcinoma cells
transfected with the aromatase gene (MCF-7CA) synthesize sufficient estrogen to
form tumors in ovariectomized nude mice. In the present study we used this
intratumoral aromatase model to investigate the effects on tumor growth of the
new nonsteroidal aromatase inhibitors letrozole (CGS 20,267) and anastrozole (ZD
1033) and the antiestrogens tamoxifen (ICI 47,474) and faslodex (ICI 182,780).
Furthermore, we determined whether the inhibition of estrogen synthesis together
with inhibition of estrogen action would be more effective in controlling breast
tumor growth. The results of our studies indicate that the aromatase inhibitors
anastrozole and letrozole, as well as the new pure antiestrogen faslodex, have
potent antitumor effects in the mouse model. In the treatment of mice with
mammary tumors, letrozole was more effective in suppressing tumor growth than
anastrozole. This was consistent with the Ki values of these inhibitors against
placental aromatase and the IC50 values in cell culture (MCF-7CA), which
indicated the greater potency of letrozole as an aromatase inhibitor. Letrozole
also had greater antitumor effects than tamoxifen and faslodex. The antitumor
effect of letrozole was substantial, making it difficult to detect any
additional effect on the tumors when letrozole was combined with the
antiestrogens. However, the combined treatment of anastrozole + tamoxifen and
anastrozole + faslodex also did not increase efficacy compared to the aromatase
inhibitor alone. In addition, combining the two antiestrogens did not suppress
tumor growth more effectively than faslodex alone. Our results show that
treatment with the combinations of aromatase inhibitors with either tamoxifen or
faslodex are not more effective in blocking estrogen stimulation of tumor growth
than the aromatase inhibitors alone.
PMID: 10598045 [PubMed - indexed for MEDLINE]
82: Ann Oncol 1999 Oct;10(10):1219-25
A randomized, open, parallel-group trial to compare the endocrine effects of
oral anastrozole (Arimidex) with intramuscular formestane in postmenopausal
women with advanced breast cancer.
Vorobiof DA, Kleeberg UR, Perez-Carrion R, Dodwell DJ, Robertson JF, Calvo L,
Dowsett M, Clack G.
Sandton Oncology Centre, South Africa.
BACKGROUND: This study provides a direct randomized comparison of a
new-generation, non-steroidal aromatase inhibitor, anastrozole (Arimidex), with
a steroidal aromatase inhibitor (formestane) with respect to oestrogen
(oestradiol, oestrone, and oestrone sulphate) suppression and tolerability.
PATIENTS AND METHODS: Sixty postmenopausal women with advanced breast cancer
were randomized to receive either anastrozole 1 mg once daily orally (n = 29),
or formestane 250 mg once every two weeks by intramuscular injection (n = 31).
Treatment was continued until progression of disease or withdrawal from the
study. The primary endpoints of this study were oestradiol suppression and
tolerability. The secondary endpoints included oestrone and oestrone sulphate
suppression. All laboratory analyses were conducted 'blind' of the randomized
drug treatment. RESULTS: Anastrozole produced a greater and more consistent
suppression of oestradiol levels compared with formestane. Based on two- and
four-week measurements, the mean fall from baseline (pre-dose) in oestradiol
level was 79% and 58% in the anastrozole and formestane groups, respectively (P
= 0.0001). After four weeks of treatment, oestrone and oestrone sulphate levels
were also suppressed to a greater extent by anastrozole compared with formestane
(oestrone: 85% versus 67%, respectively, P = 0.0043; oestrone sulphate: 92%
versus 67%, respectively, P = 0.0007). No statistical differences were seen
between the two drugs in the incidence of adverse events. CONCLUSIONS:
Anastrozole provides a more consistent and significantly more effective
suppression of oestradiol compared with formestane. Similar results were
observed for oestrone and oestrone sulphate. The clinical significance of these
differences in total oestrogen suppression remains to be established.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 10586340 [PubMed - indexed for MEDLINE]
83: Drugs Aging 1999 Oct;15(4):271-83
Aromatase inhibitors in the treatment of postmenopausal breast cancer.
Bajetta E, Zilembo N, Bichisao E.
Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
[email protected]
Anastrozole, letrozole and vorozole are new aromatase inhibitors with a
nonsteroidal structure (NSS), and have been demonstrated to be highly effective
and better tolerated than standard endocrine therapy with megestrol (megestrol
acetate) and aminoglutethimide (AG). These agents are very potent and selective:
all of them are capable of suppressing estrone (E1) and estradiol (E2) to the
limit of sensitivity methods, and plasma estrone sulfate (E1S) levels are also
suppressed. However, the fact that this potency has not led to any greater
clinical efficacy, and that there is no relationship between estrogen
suppression and clinical response, suggests that aromatase inhibitors may have
additional mechanisms of action. A number of international, multicentre clinical
trials have compared anastrozole, letrozole and vorozole with megestrol 160
mg/day or AG 500 mg/day plus hydrocortisone in patients with advanced breast
cancer. Letrozole proved to be significantly more effective than megestrol but
anastrozole had a greater effect on survival than either agent. However,
letrozole therapy led to longer survival than that observed in patients treated
with AG. The activity of vorozole was similar to that of megestrol and AG. These
results have raised a number of questions. The first is how should the clinical
results be evaluated, given that 'disease stabilisation lasting > or =6 months'
has been considered a response? The second is how should these drugs be used,
and whether there is a rationale for using them in combination or sequentially
in the treatment of patients with advanced breast cancer? Finally, is the
possible effect of formestane and vorozole on intratumoral aromatase an
alternative or concomitant mechanism of action? Anastrozole, letrozole and
vorozole will be compared with tamoxifen in postmenopausal patients with breast
cancer in adjuvant and primary settings. However, we feel that concomitant
biological and clinical studies should also be carried out in order to clarify
the properties of these drugs and avoid possible risks for patients over time.
Publication Types:
Review
Review, Tutorial
PMID: 10582774 [PubMed - indexed for MEDLINE]
84: Bull Cancer 1999 Oct;86(10):821-7
[Aromatase inhibitors].
[Article in French]
Feutrie ML, Bonneterre J.
Hopital civil d'Armentieres, 112, rue Sadi-Carnot, 59285 Armentieres.
Aromatase inhibitors used in breast cancer, are drugs that inhibit the
transformation of androstenedione and testosterone, respectively in estradiol
and estrone. Two classes have been described: steroidal inhibitors which act
competitively and irreversibly and non steroidal inhibitors which block the P
450 cytochrome. The first one is aminoglutethimide which has an adrenal effect
on 11, 18 and 21 hydroxylase. Rogletimide, less powerful and less specific is a
aminoglutethimide analogue. The response rates obtained with formestane is not
different. The clinical development has been stopped due to a lack of
specificity. Letrozole, vorozole, exemestane and anastrozole are more powerful
and more specific. Letrozole and vorozole are at least as efficient and better
tolerated than aminoglutethimide. Anastrozole, letrozole and vorozole are at
least as efficient as megestrol acetate and better tolerated in advanced breast
cancer patients receiving a second line hormone therapy.
Publication Types:
Review
Review, Tutorial
PMID: 10572233 [PubMed - indexed for MEDLINE]
85: Prostate 1999 Dec 1;41(4):224-32
5alpha-reductase isozymes and aromatase are differentially expressed and active
in the androgen-independent human prostate cancer cell lines DU145 and PC3.
Negri-Cesi P, Colciago A, Poletti A, Motta M.
Center for Endocrinological Oncology, Department of Endocrinology, University of
Milan, Milan, Italy. [email protected]
BACKGROUND: The presence and possible role of androgen-metabolizing enzymes in
androgen-independent prostate carcinoma (CaP) are still unclear. The aim of the
present study was: 1) to evaluate the pattern of androgen metabolism (relative
production of 5alpha-reduced vs. 17-keto androgens); and 2) to analyze whether
one or both the two known 5alpha-reductase isoforms (5alpha-R1 and 5alpha-R2)
and the aromatase (Aro) are expressed and active in this pathology. METHODS: Two
different cell lines (DU145 and PC3) were used as a model of
androgen-independent human CaP. In these cells, the expression of the two
5alpha-Rs and of Aro were evaluated by reverse transcription-polymerase chain
reaction (RT-PCR) and Southern blot, using specific sets of oligoprimers and of
[(32)P]-labeled oligoprobes; the enzymatic activities of 5alpha-R and of Aro
were evaluated by radioenzymatic methods. The pH optimum for the activity of the
two 5alpha-Rs was assessed in cell homogenates at different pH (from 3.5-8),
using substrate concentrations similar either to 5alpha-R1 or to 5alpha-R2 Kms.
RESULTS: The two CaP cell lines DU145 and PC3, although unresponsive to
androgens, possess the enzymatic machinery involved in the metabolism of this
class of hormonal steroids: 5alpha-Rs, which allow their transformation into
5alpha-reduced steroids (5alpha-dihydrotestosterone, DHT, and
5alpha-androstandione, 5alpha-A), and 17beta-hydroxysteroid-oxidoreductase
(17beta-HSD), which interconverts testosterone (T) and androstenedione (ADIONE);
however, the two cell lines show differences in the rate of formation of these
metabolites. Furthermore, two cell lines expressed the type 1 isoform of
5alpha-R, but only DU145 cells also possess 5alpha-R2. Aro is expressed and
active in DU145 as well as in PC3 cells. CONCLUSIONS: The present findings
suggest that T might still be indirectly active in androgen-unresponsive CaP
through its local conversion into estrogens by the action of Aro; the biological
role played by the two 5alpha-Rs in androgen-independent CaP deserves further
investigation. Copyright 1999 Wiley-Liss, Inc.
PMID: 10544295 [PubMed - indexed for MEDLINE]
86: Am J Clin Oncol 1999 Oct;22(5):529-32
Tamoxifen-induced thrombocytopenia.
Yao JC, Thomakos N, McLaughlin P, Buchholz TA, Kudelka AP.
Division of Medicine, The University of Texas M.D. Anderson Cancer Center,
Houston 77030, USA.
Thrombocytopenia (platelet count < 100,000/microl) is a rare side effect of
tamoxifen (Nolvadex). We report a case of thrombocytopenia that developed 6
months after tamoxifen was given as an adjuvant treatment for breast cancer. The
patient received no concurrent cytotoxic chemotherapy or radiation therapy. The
thrombocytopenia resolved after the tamoxifen was stopped, reappeared promptly
when the tamoxifen was restarted, and resolved again after the second
withdrawal, at which time anastrozole (Arimidex) was substituted for the
tamoxifen. The patient's platelet count remained normal for more than 6 months
thereafter.
Publication Types:
Review
Review, Tutorial
PMID: 10521073 [PubMed - indexed for MEDLINE]
87: Drug Saf 1999 Oct;21(4):297-309
Risks and benefits of aromatase inhibitors in postmenopausal breast cancer.
Michaud LB, Buzdar AU.
Division of Pharmacy, The University of Texas M.D. Anderson Cancer Center,
Houston 77030, USA.
Aromatase inhibitors were first reported in the early 1970s and have been used
to treat breast cancer since that time. Until recently, essentially the only
agent available in this class was aminoglutethimide, a nonspecific inhibitor
with multiple adverse effects and drug interactions. Selective and potent
aromatase inhibitors are now available (formestane, exemestane, fadrozole,
anastrozole and letrozole), and we review the risks and benefits of these agents
in order to assist clinicians in making treatment decisions. Formestane is an
injectable steroidal aromatase inhibitor with significant activity against
metastatic breast cancer. It has been shown to have similar efficacy and
superior tolerability compared with megestrol, and is similar to tamoxifen in
the metastatic setting. Exemestane is an oral steroidal aromatase inhibitor. It
has been shown to be effective third-line therapy after tamoxifen and megestrol
in postmenopausal patients with metastatic breast cancer. All the nonsteroidal
(imidazole/triazole) aromatase inhibitors are orally available. Fadrozole has
similar activity to megestrol and tamoxifen in the setting of metastasis, but
has been shown in phase II trials to inhibit cortisol and aldosterone
production. Anastrozole and letrozole have similar toxicity profiles. Compared
with megestrol, anastrozole improves overall survival and has superior
tolerability. Letrozole is superior to megestrol and aminoglutethimide in terms
of overall survival and time to progression, and is also better tolerated.
Although there is a strong rationale for using these agents in the treatment of
breast cancer, the information presently available is insufficient to recommend
any one agent over another. Direct comparative studies are lacking, and
comparing agents across studies is limited by many biases and may not be valid.
Formestane is only available as an injection and exemestane is not commercially
available in many countries, making these agents more difficult to recommend
over the other 3 agents. Fadrozole is less potent and less selective in
inhibiting aromatase than letrozole. The efficacies of fadrozole, megestrol and
tamoxifen appear to be similar; however, comparative data show no advantage of
fadrozole over letrozole. Anastrozole and letrozole are generally considered to
be similar agents. The clinical future of the selective aromatase inhibitors is
promising, and these agents may change the way postmenopausal breast cancer is
treated at all stages of the disease.
Publication Types:
Review
Review, Tutorial
PMID: 10514021 [PubMed - indexed for MEDLINE]
88: Eur J Cancer 1999 May;35(5):744-6
Anastrozole shows evidence of activity in postmenopausal patients who have
responded or stabilised on formestane therapy.
Harper-Wynne C, Coombes RC.
Department of Cancer Medicine, Imperial College School of Medicine, Charing
Cross Hospital, London, U.K.
Formestane (Lentaron) and anastrozole (Arimidex) are in clinical use as
second-line treatments for advanced breast cancer. Current practice is often to
use an aromatase inhibitor only once before switching to third-line agents such
as progestins. There are few clinical data on the sequential use of aromatase
inhibitors. We therefore decided to study the clinical effects of anastrozole in
postmenopausal patients with advanced breast cancer who had already received
formestane. 21 patients were recruited. When receiving formestane 2/21 (10%)
achieved a partial response (UICC criteria) and 10/21 (48%) stable disease. Of
these 12 patients, 9 achieved further stable disease on anastrozole (78%; 7/9
oestrogen receptor positive). 4 of 9 patients who progressed on formestane also
stabilised on anastrozole, of whom 3 had oestrogen receptor positive breast
carcinomas. The explanation of this second stabilisation may relate to a further
fall in oestradiol levels. We feel these results are of interest and warrant
further clinical investigation.
Publication Types:
Clinical Trial
PMID: 10505035 [PubMed - indexed for MEDLINE]
89: Breast Cancer Res Treat 1999 May;55(2):189-99
Assessment of quality of life in women undergoing hormonal therapy for breast
cancer: validation of an endocrine symptom subscale for the FACT-B.
Fallowfield LJ, Leaity SK, Howell A, Benson S, Cella D.
CRC Psychosocial Oncology Group, Department of Oncology, University College
London Medical School, UK. [email protected]
Existing quality of life instruments do not include adequate items to measure
the side effects and putative benefits of hormonal treatments given in breast
cancer. We report the development and validation of an 18 item endocrine
subscale (ES) to accompany a standardised breast cancer quality of life measure,
the Functional Assessment of Cancer Therapy (FACT-B). The FACT-ES (FACT-B plus
ES) was tested initially on 268 women with breast cancer receiving endocrine
treatments. Alpha coefficients for all subscales demonstrated good internal
consistency (range alpha = 0.65-0.87). Test-retest reliability of the ES
indicated good stability (r = 0.93, p < 0.001). Advanced breast cancer patients'
quality of life was high, showing the efficacy of endocrine therapy, but women
with primary disease reported better physical, social, and functional well-being
and fewer breast cancer concerns. Most frequently reported symptoms were loss of
sexual interest (31%), weight gain (25%), and hot flushes (24%). Significant
differences were found between treatment groups for hot flushes and vaginal
dryness. Two assessments of the instrument's responsiveness to change were made;
32 women in a clinical trial of endocrine therapy and 18 women without breast
cancer taking HRT completed the FACT-ES at baseline, 4, 8, and 12 weeks. Trial
patients reported significantly more symptoms at 8 and 12 weeks than at
baseline. Women taking HRT reported significantly fewer or less severe symptoms
than at baseline. In conclusion the FACT-ES has acceptable validity and
reliability and is sensitive to clinically significant change, making it
suitable for clinical trials of endocrine therapy.
PMID: 10481946 [PubMed - indexed for MEDLINE]
90: Neth J Med 1999 Aug;55(2):50-8
New aromatase inhibitors for the treatment of advanced breast cancer in
postmenopausal women.
de Jong PC, Blijham GH.
Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The
Netherlands.
Inhibition of the enzyme aromatase, the rate limiting step in estrogen
production, is an effective endocrine treatment of advanced postmenopausal
breast cancer. Recently, several new aromatase inhibitors have been developed to
improve efficacy and reduce toxicity compared to the prototype aromatase
inhibitor aminoglutethimide. Aromatase inhibitors can be divided into two types.
The first are the non-steroidal inhibitors that have a mechanism of action
similar to aminoglutethimide. The second are the steroidal inhibitors that
function as a false substrate for aromatase. Of the non-steroidal aromatase
inhibitors, two drugs, anastrozole and letrozole, have recently been registered
for the second line endocrine treatment of advanced postmenopausal breast cancer
after failure on tamoxifen. The phase III studies of these drugs indicate at
least equal efficacy compared to current second line treatment with
aminoglutethimide or megestrol acetate. Their toxicity profile, however, is much
more favourable. This makes them the drugs of choice for the second line
endocrine treatment of advanced breast cancer in postmenopausal patients, who
failed during adjuvant or first line treatment with tamoxifen. Of the steroidal
aromatase inhibitors, the orally active drug exemestane is still in phase III
clinical study; the registration is expected in 1999.
Publication Types:
Review
Review, Tutorial
PMID: 10474272 [PubMed - indexed for MEDLINE]
91: Drugs 1999 Aug;58(2):233-55
Comprehensive pharmacology and clinical efficacy of aromatase inhibitors.
Njar VC, Brodie AM.
Department of Pharmacology and Experimental Therapeutics, School of Medicine,
University of Maryland, Baltimore 21201, USA.
The goal of hormone therapy is to deprive breast tumours of estrogens, since
estrogens have been implicated in the development or progression of tumours.
This can be accomplished by the use of antiestrogens that block estrogen action
or by inhibiting aromatase, the enzyme that catalyses the final and
rate-limiting step in estrogen biosynthesis. A number of steroidal and
nonsteroidal compounds have been developed as aromatase inhibitors. This review
highlights the valuable role that a few of these aromatase inhibitors have
played, and continue to play, in the treatment of breast cancer. Following
background information regarding the biochemistry of aromatase, the rationale
for its inhibition, and an outline of the test systems for evaluating and
characterising aromatase inhibitors, the discussion focuses on the new
generation of aromatase inhibitors that are in clinical trials or clinically
available. Specifically, it discusses the pharmacology and clinical efficacy of
formestane, exemestane, rogletimide, fadrozole, vorozole, anastrozole and
letrozole. The role of these agents as the optimal second-line agents (after
tamoxifen) for the treatment of advanced breast cancer has been established;
their prospects in other clinical settings and as potential breast cancer
chemopreventives are warranted but are yet to be fully determined.
Publication Types:
Review
Review, Academic
PMID: 10473018 [PubMed - indexed for MEDLINE]
92: J Steroid Biochem Mol Biol 1999 Apr-Jun;69(1-6):205-10
Aromatase and its inhibitors.
Brodie A, Lu Q, Long B.
Department of Pharmacology and Experimental Therapeutics, School of Medicine,
University of Maryland, Baltimore 21201, USA. [email protected]
Inhibitors of aromatase (estrogen synthetase) have been developed as treatment
for postmenopausal breast cancer. Both steroidal substrate analogs, type I
inhibitors, which inactivate the enzyme and non-steroidal competitive
reversible, type II inhibitors, are now available. 4-hydroxyandrostenedione
(4-OHA), the first selective aromatase inhibitor, has been shown to reduce serum
estrogen concentrations and cause complete and partial responses in
approximately 25% of patients with hormone responsive disease who have relapsed
from previous endocrine treatment. Letrozole (CGS 20, 269) and anastrozole (ZN
1033) have been recently approved for treatment. Both suppress serum estrogen
levels to the limit of assay detection. Letrozole has been shown to be
significantly superior to megace in overall response rates and time to treatment
failure, whereas anastrozole was found to improve survival in comparison to
megace. Both were better tolerated than the latter. The potential of aromatase
within the breast as a significant source of estrogen mediating tumor
proliferation and which might determine the outcome of inhibitor treatment was
explored. Using immunocytochemistry and in situ hybridization, aromatase and
mRNAarom was detected mainly in the epithelial cells of the terminal ductal
lobular units (TDLU) of the normal breast and also in breast tumor epithelial
cells as well as some stromal cells. Increase in proliferation, measured by
increased thymidine incorporation into DNA and by PCNA immunostaining in
response to testosterone was observed in histocultures of breast cancer samples.
This effect could be inhibited by 4-OHA and implies that intratumoral aromatase
has functional significance. An intratumoral aromatase model in the
ovariectomized nude mouse was developed which simulated the hormone responsive
postmenopausal breast cancer patient. This model also allows evaluation of the
efficacy of aromatase inhibitors and antiestrogens in tumors of estrogen
receptor positive, human breast carcinoma cells transfected with the human
aromatase gene. Thus, the cells synthesized estrogen which stimulated tumor
formation. Both aromatase inhibitors and antiestrogens were effective in
suppressing tumor growth in this model. However, letrozole was more effective
than tamoxifen. When the aromatase inhibitors were combined with tamoxifen,
tumor growth was suppressed to about the same extent as with the aromatase
inhibitors alone. Thus, there was no additive or synergistic effects of
combining tamoxifen with aromatase inhibitors. This suggests that sequential
treatment with these agents is likely to be more beneficial to the patient in
terms of longer response to treatment.
Publication Types:
Review
Review, Tutorial
PMID: 10418994 [PubMed - indexed for MEDLINE]
93: Biol Reprod 1999 Aug;61(2):388-92
Mitogenic and antioxidant mechanisms of estradiol action in preovulatory ovine
follicles: relevance to luteal function.
Lund SA, Murdoch J, Van Kirk EA, Murdoch WJ.
Department of Animal Science, University of Wyoming, Laramie, Wyoming 82071,
USA.
The objectives of this investigation were to determine the intrafollicular
mechanisms and physiological consequences of estradiol actions in preovulatory
ovine follicles. Acute suppression of estradiol production in proestrous ewes by
an aromatase inhibitor (Arimidex) was associated with follicular lipid
peroxidation, testosterone accumulation, and a granulosa cell deficiency
(decreased proliferation/increased apoptosis). Estradiol-17beta stimulated
granulosa proliferating cell nuclear antigen (PCNA) and protected cells from
oxidative (H(2)O(2)) stress-induced apoptosis in vitro; the PCNA, but not the
antiapoptotic response, was negated by the transcriptional inhibitor actinomycin
D. Thus, it appears that genomic/mitotic and cytoprotective (oxygen-scavenging)
modes of estradiol action operate in preovulatory follicles. Luteal (large
steroidogenic cell) function was diminished following ovulation induction of
estradiol-deficient follicles. It is suggested that inadequate exposure of the
preovulatory follicle to estradiol caused the granulosa lutein insufficiency.
PMID: 10411516 [PubMed - indexed for MEDLINE]
94: Ann Oncol 1999 Apr;10(4):377-84
The third-generation non-steroidal aromatase inhibitors: a review of their
clinical benefits in the second-line hormonal treatment of advanced breast
cancer.
Hamilton A, Piccart M.
Institut Jules Bordet, Brussels, Belgium.
Three new aromatase inhibitors have recently completed phase III evaluation as
treatment of metastatic breast cancer in post-menopausal women whose disease has
progressed despite tamoxifen therapy: anastrozole (ARIMIDEX, Zeneca), letrozole
(FEMARA, Novartis) and vorozole (RIVIZOR, Janssen). All belong to the third
generation of non-steroidal aromatase inhibitors, and each is superior to
previous generations in terms of potency and selectivity. The trials that have
been performed compare each agent to megestrol acetate, and letrozole and
vorozole to aminoglutethimide. Although the studies are not directly comparable
due to differing study designs and patient populations, it has been demonstrated
each of these drugs provides single agent, once-daily, oral palliation of
hormone-responsive, post-menopausal metastatic breast cancer. Letrozole is
clearly more effective than megestrol acetate, and anastrozole and vorozole are
possibly so. All three are better tolerated than the progestin, particularly in
terms of weight gain. Both letrozole and vorozole are significantly more
effective, and better tolerated than aminoglutethimide. Overall, this most
recent generation of aromatase inhibitors is a clear improvement on our current
standard second-line therapies. In 1999, tamoxifen remains the first choice in
the hormonal therapy of breast cancer. Following tamoxifen failure, the optimal
second-line hormonal therapy remains undefined, but aminoglutethimide and
megestrol acetate are no longer optimal therapy in this setting. The
third-generation non-steroidal aromatase inhibitors must now be compared to each
other, to the steroidal aromatase inhibitors, to the pure anti-oestrogens, and
to tamoxifen.
Publication Types:
Review
Review, Academic
PMID: 10370778 [PubMed - indexed for MEDLINE]
95: Toxicol Sci 1998 Nov;46(1):61-74
Ex vivo and in vitro testis and ovary explants: utility for identifying steroid
biosynthesis inhibitors and comparison to a Tier I screening battery.
Powlin SS, Cook JC, Novak S, O'Connor JC.
DuPont Haskell Laboratory for Toxicology and Industrial Medicine, Newark,
Delaware 19714, USA.
Testis and ovary explants have been proposed as in vitro screens for identifying
potential inhibitors of steroid biosynthesis. The goals of the current study
were to optimize the conditions of the two assays, to characterize these assays
using several compounds with well-defined endocrine activity, and to compare the
responses from the explant assays with an in vivo male battery currently
undergoing validation using the Crl:CD BR rat in order to evaluate their utility
as test systems for screening unknown compounds for possible steroid
biosynthesis inhibition activity. There were two components to the testis/ovary
assays: ex vivo and in vitro. The ex vivo component used testes/ovaries from
animals dosed with the test compounds in vivo, and the in vitro component used
testes/ovaries from control animals. For the testis assays, decapsulated testis
explants (50 mg) were placed into glass scintillation vials, +/-1.0 IU/ml hCG
for 3 h in a shaking water bath (34 degrees C). Following the incubation period,
medium was removed, centrifuged, and frozen until assayed for hormone
concentrations. A similar procedure was used for the ovary explant assay except
that each ovary was incubated separately. The testis explants were evaluated
using the following compounds: ketoconazole (KETO), a testosterone biosynthesis
inhibitor; aminoglutethimide (AG) (only in vitro) and anastrozole (ANA),
aromatase inhibitors; finasteride (FIN), a 5alpha-reductase inhibitor;
17beta-estradiol (17beta-E2), an estrogen receptor agonist; flutamide (FLUT), an
androgen receptor antagonist; ICI-182,780 (ICI), an estrogen receptor
antagonist; haloperidol (HALO), a D2 receptor antagonist; and reserpine (RES), a
dopamine depletor. In the ovary assay, AG (only in vitro), ANA, ICI, and HALO
(only in vitro) were evaluated. Addition of fetal calf serum to the medium
allowed measurement of estradiol (E2) in the testis assay, but production was
not inhibited by ANA or AG. In the ovary explant assay, only AG was identified
as inhibiting E2 production in vitro. Hence, both the testis and ovary explant
assays appear to have limited utility for detecting aromatase inhibitors.
Screening of these nine diverse endocrine-active compounds resulted in all of
them being identified as altering the endocrine system when assessed by ex vivo
and in vitro testis explants. Using only the in vitro assessment with the
criteria of steroid biosynthesis inhibition, four of nine compounds were
correctly identified in the testis explant assay (17beta-E2, KETO, FLUT, and
HALO). The predictability of both the in vitro and ex vivo ovary assay was 50%,
suggesting a 50% false positive or negative rate with unknown compounds.
However, of the seven compounds assessed to date (17beta-E2, ICI, ANA, KETO,
FLUT, HALO, and RES), all were correctly identified using an in vivo male
battery, which also has the capability to detect other endocrine activities.
Therefore, the testis and ovary explant assay would not be necessary if one were
using an in vivo male battery, since this screen would identify steroid
biosynthesis inhibitors and would also identify several other endocrine
activities. Because of the difficulties in assessing cytotoxicity and the high
false positive/negative rates, the ovary and testis explant assays are not
useful as routine screening procedures for detecting steroid biosynthesis
inhibitors; however, they may have utility in confirming in vivo findings.
PMID: 9928669 [PubMed - indexed for MEDLINE]
96: Toxicol Sci 1998 Nov;46(1):45-60
An ongoing validation of a Tier I screening battery for detecting
endocrine-active compounds (EACs).
O'Connor JC, Cook JC, Slone TW, Makovec GT, Frame SR, Davis LG.
DuPont Haskell Laboratory for Toxicology and Industrial Medicine, Newark,
Delaware 19714, USA.
After previously examining an estrogen receptor agonist (17beta-estradiol),
several additional compounds have been evaluated in a Tier I screening battery
for detecting endocrine-active compounds (EACs): an estrogen receptor antagonist
(ICI-182,780, ICI), an androgen receptor antagonist (flutamide, FLUT), a
testosterone biosynthesis inhibitor (ketoconazole, KETO), a 5alpha-reductase
inhibitor (finasteride, FIN), and an aromatase inhibitor (anastrozole, ANA). The
Tier I battery incorporates two short-term in vivo tests (a 5-day ovariectomized
female battery and a 15-day intact male battery) and an in vitro yeast
transactivation system (YTS). The Tier I battery is designed to identify
compounds that have the potential to act as agonists or antagonists to the
estrogen, androgen, progesterone, or dopamine receptors, steroid biosynthesis
inhibitors (aromatase, 5alpha-reductase, and testosterone biosynthesis), or
compounds that alter thyroid function. ICI administration decreased uterine
estrogen and progesterone receptor number in the female battery, increased serum
follicle-stimulating hormone (FSH) levels and caused spermatid retention in the
male battery, and activated gene transcription in the YTS containing the
estrogen receptor. FLUT administration increased uterine stromal cell
proliferation in the female battery and decreased weights for all
androgen-dependent tissues, induced Leydig cell hyperplasia, and caused hormonal
alterations (increased testosterone (T), estradiol (E2), dihydrotestosterone
(DHT), luteinizing hormone (LH), and FSH) in the male battery, and competed for
binding to the androgen receptor in the YTS competition assay. In the male
battery KETO decreased weights for all androgen-dependent tissues, caused
hormonal alterations (decreased T and DHT and increased LH and FSH), and induced
spermatid retention. FIN decreased seminal vesicle and accessory sex gland (ASG)
unit weight and caused hormonal alterations (decreased DHT and increased LH, and
PRL) in the male battery. KETO was judged not to affect any of the endpoints in
the female battery. ANA decreased ASG unit weight and serum E2 levels in the
male battery. Using the responses obtained for all the endpoints in the Tier I
battery, a distinct "fingerprint" was produced for each type of endocrine
activity against which compounds with unknown activity can be compared. These
data demonstrate that the described Tier I battery is useful for identifying
EACs.
PMID: 9928668 [PubMed - indexed for MEDLINE]
97: Recent Results Cancer Res 1998;152:453-70
Italian Breast Cancer Adjuvant Chemo-Hormone Therapy Cooperative Group Trials.
GROCTA Trials.
Boccardo F, Rubagotti A, Amoroso D, Mesiti M, Pacini P, Gallo L, Sismondi P,
Giai M, Genta F, Mustacchi G, Agostara B, Bolognesi A, Villa E, Schieppati G,
Ausili Cefaro GP, Bellantone R, Farris A, Sassi M, Patrone F.
Servizio di Oncologia Medica II, Istituto Nazionale per la Ricerca sul Cancro di
Genova, Italy.
The first GROCTA trial compared 5-year tamoxifen treatment to ten chemotherapy
cycles in a group of 504 pre-/post-menopausal, node-positive, ER-positive breast
cancer patients. This study also included an arm combining tamoxifen with
chemotherapy. Fifteen-year results showed no difference between tamoxifen and
tamoxifen plus chemotherapy, while both treatments were significantly superior
to chemotherapy alone. A confirmatory study (GROCTA 02) was performed in 244
pre-/perimenopausal patients by comparing 5 years of tamoxifen treatment (plus 2
years of goserelin) to six CMF cycles. No difference has emerged so far between
the tamoxifen and CMF arms at a median follow-up time of 62 months.
Post-menopausal women were scheduled to receive 3 years of tamoxifen treatment
and then to be randomly allocated to further 2 years of tamoxifen or to 2 years
of low-dose aminoglutethimide (GROCTA 04B). So far 662 patients have been
entered, 375 of whom have been randomized to tamoxifen (n = 188) or
aminoglutethimide (n = 187). Preliminary results (median follow-up time 32
months) show no major difference in patients' outcome. A new trial (ITA trial)
with a similar design but employing anastrozole in place of aminoglutethimide
has been activated in 1998. The GROCTA 03 study investigated the potential
superiority of alternating adjuvant chemotherapy over standard CMF. This study,
which included 107 node-positive ER-negative pre-menopausal women, was
prematurely closed because more patients allocated to the triple alternated
chemotherapy appeared to have relapsed and died at the first interim analysis.
The use of high-dose chemotherapy (HDC) was explored by the GROCTA 06 trial
which included 53 patients with ten or more involved nodes and a maximum age of
55 years. These patients were scheduled to receive three standard CEF cycles
followed by one cycle of HDC (cyclophosphamide 5 g/m2; etoposide 1.5 g/m2;
cisplatin 150 mg/m2) without any form of bone marrow rescue. This HDC program
proved to be feasible but was not superior to CMF-based chemotherapy we had
previously employed in a comparable group of patients in previous GROCTA trials.
These findings prompted us to explore new HDC programmes with the use of
peripheral stem cell support and in addition the possible value of new drugs
such as Taxol and vinorelbine. New-generation trials will also explore the value
of new prognostic indicators such as tumor proliferative activity, which are
prospectively used to allocate patients to different treatment options.
Publication Types:
Clinical Trial
Randomized Controlled Trial
Review
Review, Tutorial
PMID: 9928580 [PubMed - indexed for MEDLINE]
98: Recent Results Cancer Res 1998;152:277-84
Aromatase inhibitors and their use in the adjuvant setting.
Coombes RC.
Department of Cancer Medicine, Imperial College School of Medicine, Charing
Cross Hospital, London, UK.
Over the past decade several novel aromatase inhibitors have been introduced
into clinical practice. The discovery of these drugs followed on from the
observation that the main mechanism of action of aminoglutethemide was via
inhibition of the enzyme aromatase, thereby reducing peripheral levels of
estradiol in post-menopausal patients. The second-generation drug
4-hydroxyandrostenedione was introduced in 1990, and although its use was
limited by its need to be given parenterally, it was found to be a
well-tolerated form of endocrine therapy. The third-generation inhibitors
include vorozole, letrozole, anastrozole and exemestane, the former three being
non-steroidal inhibitors, the latter being a steroidal inhibitor. All these
compounds are capable of reducing estrogen levels to within 5%-10% of baseline
levels compared with 20%-30% base line levels in the case of
4-hydroxyandrostenedione. Studies are currently in progress to determine the
value of these third-generation aromatase inhibitors in the adjuvant setting.
These studies include head-to-head comparison of aromatase inhibitor with
tamoxifen, sequential aromatase inhibitor after tamoxifen and first-line
aromatase inhibitor followed by adjuvant tamoxifen. Current issues revolve
around the toxicity of these compounds in terms of effects on the cardiovascular
system and bone.
Publication Types:
Review
Review, Tutorial
PMID: 9928565 [PubMed - indexed for MEDLINE]
99: Presse Med 1998 Dec 12;27(39):2049-54
[Breast cancer: new therapeutic strategies].
[Article in French]
Espie M.
Hopital St Louis, Centre des Maladies du Sein, Paris. [email protected]
NEED FOR NEW CHEMOTHERAPY AGENTS: Metastasic breast cancer is an excellent model
for studying anticancer agents: chemotherapy or hormonotherapy or compounds
modifying the organism's response. If no adjuvant treatment is given after
locoregional treatment of breast cancer, metastasis will develop within 10 years
in 30% of the patients free of initial nodal invasion and within 5 years in 50%
of the patients with initial nodal invasion. ADJUVANT TREATMENTS: Hormonotherapy
and chemotherapy reduce mortality due to breast cancer by 10%. New adjuvant
agents have been recently introduced. Taxans (docetaxel, paclitaxel) are the
most active molecules since antracyclines. New aromataase inhibitors include
letrozole and anastrozole. Their efficacy has been demonstrated in phase II and
phase III trials, allowing their experimentation as adjuvant treatments.
Publication Types:
Clinical Trial
Clinical Trial, Phase II
Clinical Trial, Phase III
Randomized Controlled Trial
PMID: 9893697 [PubMed - indexed for MEDLINE]
100: Br J Cancer 1999 Jan;79(2):311-5
The effect of anastrozole on the pharmacokinetics of tamoxifen in
post-menopausal women with early breast cancer.
Dowsett M, Tobias JS, Howell A, Blackman GM, Welch H, King N, Ponzone R, von
Euler M, Baum M.
Academic Department of Biochemistry, Royal Marsden Hospital, London, UK.
Thirty-four post-menopausal women with early breast cancer who had received 20
mg tamoxifen once daily as adjuvant therapy for at least 10 weeks participated
in a randomized, double-blind, parallel-group, multicentre trial. The primary
aim of the trial was to determine the effect of anastrozole upon tamoxifen
pharmacokinetics, with secondary aims of assessing the tolerability of the two
drugs in combination and whether or not tamoxifen had any effect upon the
oestradiol suppression seen with anastrozole. Patients were randomized to
receive either 1 mg anastrozole (16 patients) or matching placebo (18 patients)
once daily on a double-blind basis for 28 days. No significant difference (P =
0.919) was observed in serum tamoxifen concentrations between the anastrozole
and placebo groups during the trial. The serum concentration of oestradiol was
significantly suppressed (P < 0.0001) in patients co-administered anastrozole
compared with placebo in the presence of tamoxifen, confirming that anastrozole
remained an effective suppressant of oestradiol in the presence of tamoxifen.
The combination of tamoxifen and anastrozole was well tolerated, with very
little difference in side-effects reported between anastrozole and placebo. In
conclusion, the results of this study confirm that anastrozole does not affect
the pharmacokinetics of tamoxifen when the two drugs are given in combination to
post-menopausal women with early breast cancer. In addition, the oestradiol
suppressant effects of anastrozole appear unaffected by tamoxifen.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 9888474 [PubMed - indexed for MEDLINE]
101: Endocrinology 1999 Jan;140(1):273-9
Macrophage colony stimulating-factor transcripts are differentially regulated in
rat bone-marrow by gender hormones.
Lea CK, Sarma U, Flanagan AM.
Department of Histopathology, Imperial College School of Science, Technology and
Medicine at St. Mary's, London, United Kingdom.
There are at least three forms of macrophage colony-stimulating factor (M-CSF),
a cytokine that is critical for osteoclast formation; and evidence exists that
the membrane-bound form is involved in this process. We wished to test the
hypothesis that the expression of the membrane form of M-CSF is modulated by the
presence of gender steroids. This was achieved by analyzing M-CSF messenger RNA
and protein in the bone-marrow of estrogen- and androgen-replete, and -deficient
female rats. We found that the 1.4-kb M-CSF transcript was not detected in
sham-operated rats but that the 4.6-kb transcript was expressed in abundance. In
contrast, these transcripts were differentially expressed in ovariectomized
rats, and this effect was reversed by 17beta-estradiol treatment. Administration
of androstenedione to ovariectomized rats, so that androstenedione plasma levels
were restored to just below that in sham-operated rats, also suppressed the
expression of the 1.4-kb M-CSF transcript. This effect was abrogated by
antiandrogen treatment, indicating that this was an androgen-mediated effect.
The membrane-bound protein was detected in the bone-marrow of sham-operated rats
and was elevated post ovariectomy, whereas ovariectomy had no effect on the
soluble isoform. Our data support the hypothesis that the membrane form of M-CSF
is modulated by gender hormones and that this isoform is involved in the
estrogen- and androgen-mediated effects on the skeleton.
PMID: 9886835 [PubMed - indexed for MEDLINE]
102: J Steroid Biochem Mol Biol 1998 Nov;67(4):293-304
The steroidal antiestrogen ICI 182,780 is an inhibitor of cellular aromatase
activity.
Long BJ, Tilghman SL, Yue W, Thiantanawat A, Grigoryev DN, Brodie AM.
Department of Pharmacology and Experimental Therapeutics, The University of
Maryland School of Medicine, Baltimore 21201, USA.
Two types of endocrine therapy that have been successfully applied to patients
with hormone-dependent breast cancer are the non-steroidal antiestrogen
tamoxifen, and inhibitors of aromatase, the enzyme that synthesizes estrogens.
The major drawback with tamoxifen is that it acts as a partial estrogen-agonist
and this is believed to mediate, at least in part, acquired tumor resistance to
the drug as well as endometrial hyperplasia and carcinoma in some patients. The
newer and more potent antiestrogen ICI 182,780 is a steroidal molecule that is
devoid of estrogenic activity. We now report that ICI 182,780 is also an
inhibitor of aromatase activity in fibroblasts isolated from the normal human
breast as well as other carcinoma cell lines that express aromatase (MCF-7Ca
breast cancer and JEG-3 choriocarcinoma). ICI 182,780 (1 microM) did not affect
aromatase activity levels in human placental microsomes and only inhibited
aromatase activity in each of the cell lines following a prolonged incubation
period. In the fibroblasts, inhibition of aromatase activity by ICI 182,780 was
shown to be time and dose-dependent. In contrast, tamoxifen and 17beta-estradiol
were shown to have no effect on aromatase activity levels. ICI 182,780 inhibited
aromatase activity levels with IC50 values of 16.80 nM in MCF-7Ca cells, 125.50
nM in JEG-3 cells and 386.1 nM in breast fibroblasts. These values were compared
to those for known aromatase inhibitors, and in each of the cell lines the order
of potency was letrozole>4-OHA>anastrozole>ICI 182,780. The inhibition of
aromatase activity by ICI 182,780 was sustained even after the antiestrogen was
removed from the cells indicating that ICI 182,780 may be remaining bound to the
enzyme. Although ICI 182,780 had no effect on the proliferation of the
fibroblasts, or JEG-3 cells, it significantly inhibited the growth of MCF-7Ca
cells. This growth inhibition appeared to be due to the antiestrogenic activity
of ICI 182,780 and not to its aromatase inhibiting effects. ICI 182,780 did not
inhibit aromatase activity by down-regulating levels of the aromatase
transcript. These results show that in addition to being a potent antiestrogen,
ICI 182,780 is also an inhibitor of cellular aromatase activity, and suggest
that by interfering with the actions of estrogen by two distinct mechanisms, ICI
182,780 may be a suitable drug for treating patients with hormone-dependent
breast cancer.
PMID: 9883986 [PubMed - indexed for MEDLINE]
103: Drugs 1998 Dec;56(6):1125-40
Letrozole. A review of its use in postmenopausal women with advanced breast
cancer.
Lamb HM, Adkins JC.
Adis International Limited, Auckland, New Zealand. [email protected]
Letrozole is an oral reversible nonsteroidal aromatase inhibitor. Clinical
tracer studies show that it inhibits peripheral aromatase by over 98% and
suppresses blood and urinary estrogen levels by over 95% after 2 weeks of
treatment in postmenopausal women. Letrozole also significantly inhibits
intratumoral aromatase in vivo. The action of letrozole appears to be selective
for aromatase; long term administration did not affect basal levels of 17
alpha-hydroxyprogesterone or aldosterone, although slight decreases in cortisol
levels were observed in 2 studies, these did not appear to be clinically
significant. In 2 phase IIb/III trials, letrozole 2.5 mg/day achieved objective
response rates of 19.5 and 23.6% which were sustained for a median duration of
24 and 33 months, respectively. The median duration of response compared
favourably with both comparator agents, aminoglutethimide and megestrol (15 and
18 months, respectively), as did objective response rates (12.4 and 16.4%).
Letrozole 2.5 mg/day was associated with an increase in median survival time of
8 and 3 months compared with aminoglutethimide and megestrol, respectively.
According to analyses of overall function, letrozole 2.5 mg/day was
significantly superior to both comparators with respect to duration of response
and aminoglutethimide with respect to survival. Letrozole has a good short term
tolerability profile. The adverse events reported most commonly in association
with letrozole 2.5 mg/day in the 2 phase IIb/III trials were headache (1.1 and
7%), nausea (6 and 10.3%), fatigue (3.2 and 5%), hot flushes (4.9 and 5%) and
peripheral oedema (6%). Events were usually mild to moderate in severity;
adverse events necessitated discontinuation of treatment in 3% of letrozole 2.5
mg/day recipients. CONCLUSIONS: Letrozole, in common with vorozole and
anastrozole, offers greater selectivity and potency of aromatase inhibition than
the prototype aromatase inhibitor, aminoglutethimide, and can be administered
once daily. Available clinical data suggest that letrozole achieves a
significantly longer duration of response than megestrol and aminoglutethimide
and longer overall survival than aminoglutethimide. However, direct comparisons
are required to distinguish between the newer aromatase inhibitors. For this
reason, letrozole should be recommended as a second-line treatment in
postmenopausal women with advanced breast cancer whose disease has progressed on
or failed to respond to antiestrogen therapy.
Publication Types:
Review
Review, Tutorial
PMID: 9878997 [PubMed - indexed for MEDLINE]
104: Drugs Aging 1998 Oct;13(4):321-32
Anastrozole. A review of its use in the management of postmenopausal women with
advanced breast cancer.
Wiseman LR, Adkins JC.
Adis International Limited, Auckland, New Zealand. [email protected]
Anastrozole is a new oral nonsteroidal aromatase inhibitor indicated for the
second-line endocrine treatment of postmenopausal women with advanced breast
cancer. In postmenopausal women, anastrozole significantly reduces plasma
estrogen levels; maximal suppression is achieved at dosages > or = 1 mg/day and
levels remain suppressed during long term therapy. In two phase III clinical
trials, anastrozole 1 or 10 mg/day showed similar clinical efficacy to that of
oral megestrol (megestrol acetate) 160 mg/day in postmenopausal women with
advanced breast cancer. Primary end-points [including time to disease
progression (120 to 170 days) and overall response rates (complete and partial
response and stable disease lasting > or = 24 weeks: 29 to 37%)] and secondary
end-points [time to treatment failure (115 to 168 days) and duration of response
(257 to 261 days)] did not differ significantly between treatment groups.
However, a significant survival advantage was observed in patients treated with
anastrozole 1 mg/day compared with megestrol in a follow-up combined analysis of
patients enrolled in both studies (median time to death 26.7 vs 22.5 months).
Quality of life parameters were generally improved to a similar extent in all
treatment groups. Anastrozole is generally well tolerated in the majority of
patients, the most common adverse events being gastrointestinal (GI)
disturbances (incidence 29 to 33%). These events are generally mild or moderate
and transient. Other adverse events reported with anastrozole include headache
(< or = 18%), asthenia (< or = 16%), pain (< or = 15%), hot flushes and bone
pain (both < or = 12%), back pain and dyspnoea (both < or = 11%) and peripheral
oedema (< or = 9%). GI disturbance tended to be more common with anastrozole
than megestrol, particularly at the 10 mg/day dosage; however, compared with
megestrol, anastrozole is less frequently associated with weight gain.
CONCLUSIONS: Anastrozole, with its apparent survival advantage versus megestrol
(demonstrated in a combined analysis of phase III studies), convenient once
daily oral administration and acceptable short term tolerability profile, is a
second-line treatment option for postmenopausal patients with
tamoxifenrefractory advanced breast cancer. The results of ongoing comparative
trials with tamoxifen will determine the relative efficacy of anastrozole as
first-line endocrine therapy for advanced breast cancer and as adjuvant therapy
for early disease. In addition, direct comparative studies are required to
determine the efficacy of anastrozole relative to that of other oral aromatase
inhibitors such as letrozole and vorozole.
Publication Types:
Review
Review, Tutorial
PMID: 9805213 [PubMed - indexed for MEDLINE]
105: Breast Cancer Res Treat 1998 Jul;50(1):63-71
The effects of aromatase inhibitors and antiestrogens in the nude mouse model.
Lu Q, Yue W, Wang J, Liu Y, Long B, Brodie A.
Department of Pharmacology & Experimental Therapeutics, and Greenbaum Cancer
Center, School of Medicine, University of Maryland, Baltimore 21201, USA.
The effects of antiestrogens, tamoxifen and ICI 182,780, and aromatase
inhibitors, arimidex (anastrozole ZD1033) and letrozole (CGS 20,267), on the
growth of tumors were studied in nude mice. In this model, estrogen dependent
MCF-7 human breast cancer cells stably transfected with the aromatase gene were
inoculated in four sites per mouse. Sufficient estrogen is produced from
aromatization of androstenedione supplement (0.1 mg/mouse/day) by the cells to
stimulate their proliferation, tumor formation, and maintain the uterus similar
to that of the intact mouse. Once the tumors reached a measurable size, the mice
were injected with antiestrogen or inhibitor for 35-56 days. Tumor volumes were
measured weekly. At autopsy, the tumors were removed, cleaned, and weighed.
Statistical data was determined from tumor weights. Both antiestrogens were
effective in reducing tumor growth in these mice. Tamoxifen appears to be more
effective than ICI 182,780, although the former stimulated the uterine weight
whereas the pure antiestrogen did not. However, both aromatase inhibitors were
more effective than the antiestrogens. Tumor regression was observed with
letrozole. Thus, after-treatment tumor weights were less than those of a group
of mice at the start of treatment. The aromatase inhibitors also reduced the
weight of the uterus, suggesting that these compounds, as well as the pure
antiestrogen, may not cause endometrial proliferation, unlike tamoxifen. These
aromatase inhibitors may not only benefit patients who have relapsed from
tamoxifen, but may be more effective in patients as first line agents for
suppressing the effects of estrogen.
PMID: 9802621 [PubMed - indexed for MEDLINE]
106: Breast Cancer Res Treat 1998;49 Suppl 1:S53-7; discussion S73-7
Pharmacological and clinical profile of anastrozole.
Lonning PE, Geisler J, Dowsett M.
Department of Oncology, Haukeland University Hospital Bergen, Norway.
Anastrozole (Arimidex,
2,-2[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-met
hyl)propiononitrile) is a novel, potent aromatase inhibitor belonging to the
triazole class. In vitro and in vivo animal studies have revealed the drug to be
a potent inhibitor of the aromatase enzyme with no inhibitory activity versus
other enzymes involved in steroid synthesis. The drug is a potent suppressor of
plasma estrogens in healthy male and postmenopausal female volunteers as well as
postmenopausal breast cancer patients, and anastrozole administered as 1 mg or
10 mg daily has been shown to inhibit in vivo aromatization by 96.7 and 98.1%,
respectively. Two large, randomized studies revealed anastrozole to cause
objective response rates and stable disease comparable to what was achieved with
megestrol acetate but with a lower incidence of side effects. While follow-up
results have not revealed any significant difference in time to relapse between
the drug regimens, they have revealed an improved survival among patients
treated with anastrozole 1 mg compared to megestrol acetate 160 mg daily.
Further follow-up is required to finally decide whether there may be a survival
benefit also among patients treated with anastrozole 10 mg daily and to evaluate
whether the improvement in survival is associated with an improved disease-free
survival as would be anticipated.
Publication Types:
Review
Review, Tutorial
PMID: 9797018 [PubMed - indexed for MEDLINE]
107: Breast Cancer Res Treat 1998;49 Suppl 1:S39-44; discussion S73-7
Theoretical considerations for the ideal aromatase inhibitor.
Dowsett M.
Royal Marsden Hospital, London, UK. [email protected]
A definition of the theoretical components of an ideal aromatase inhibitor is
developed, one aspect of which is completeness of enzyme inhibition. The three
triazole inhibitors, letrozole, vorozole and anastrozole all inhibit whole body
aromatisation by > 96% at their clinically used doses and vorozole and letrozole
were more effective in Phase III clinical trials than aminoglutethimide (250 mg
bd) which achieves < 90% inhibition. The possibility is considered that the
apparent small differences between the triazoles may be associated with
differences in clinical effectiveness. These new compounds merit consideration
for studies of breast cancer prevention.
Publication Types:
Review
Review, Tutorial
PMID: 9797016 [PubMed - indexed for MEDLINE]
108: Prostate 1998 Oct 1;37(2):70-6
Effect of dual inhibition of 5-alpha-reductase and aromatase on spontaneously
developed canine prostatic hypertrophy.
Suzuki K, Okazaki H, Ono Y, Kurokawa K, Suzuki T, Onuma E, Takanashi H, Mamiya
Y, Yamanaka H.
Department of Urology, Gunma University School of Medicine, Maebashi, Japan.
[email protected]
BACKGROUND: Our aim was to assess the effect of dual inhibition of
5-alpha-reductase and aromatase on prostate glands. METHODS: We investigated the
morphological changes in the prostate gland and the changes in the hormonal
environment after administration of finasteride and arimidex to intact canine
specimens. The study consisted of four groups: a 5-alpha-reductase only group
(5RI only, n = 5); a 5RI plus aromatase-inhibitor combination group (5RI + ARI
combination, n = 5); a BPH control group (n = 3); and a castration control group
(n = 3). Finasteride (1 mg/kg/day) and the same dose of arimidex were orally
administered for 80 days. RESULTS: In the 5RI group, a significant decrease in
the serum dihydrotestosterone (DHT) level was found, and prostatic volume was
significantly decreased. However, significant increases in serum testosterone
(T) and DHT levels were observed, with a concomitant increase in prostatic
volume in the 5RI + ARI combination group. Morphometric analysis showed that
histopathological findings in the 5RI + ARI combination group were similar to
those in the BPH control group. CONCLUSIONS: Dual inhibition of
5-alpha-reductase and aromatase resulted in a significant increase in prostate
volume, accompanied by a 3-10-fold increase in serum testosterone levels and a
significant increase in testicular volume.
PMID: 9759700 [PubMed - indexed for MEDLINE]
109: Br J Cancer 1998 Sep;78 Suppl 4:12-5
Aromatase inhibitors and their future role in post-menopausal women with early
breast cancer.
Lonning PE.
Department of Therapeutic Oncology and Radiophysics, Haukeland University
Hospital, Bergen, Norway.
Anastrozole is the first aromatase inhibitor to show a significant survival
advantage over megestrol acetate in post-menopausal women with advanced breast
cancer. The rationale for extending the use of aromatase inhibitors to the
treatment of early breast cancer is based on the efficacy observed in the
advanced setting, combined with good tolerability and a convenient dosing
regimen. Furthermore, oestrogen deprivation by ovarian ablation (similar to
oestrogen antagonism with tamoxifen) is already established as an effective
adjuvant treatment in premenopausal women with modality breast cancer.
Anastrozole produces a profound suppression of plasma oestrogen levels which is
greater than that obtained with earlier aromatase inhibitors (formestane,
aminoglutethimide) or megestrol acetate. This could account for the differences
in clinical efficacy seen between anastrozole and megestrol acetate. In terms of
benefits over other endocrine agents, anastrozole causes significantly less
weight gain than megestrol acetate; it does not have the partial agonist
activity of tamoxifen, and is unlikely to lead to tumour stimulation in patients
resistant to tamoxifen or to exert proliferative effects on the endometrium. The
lack of oestrogen agonist activity, however, may possibly have detrimental
effects on bone mineral density and blood lipid profile. Current clinical trials
are investigating the efficacy and safety of anastrozole in the early breast
cancer setting. The results of these trials will help to determine whether
anastrozole has any benefits over tamoxifen, the current treatment of choice in
post-menopausal women with early breast cancer.
PMID: 9741783 [PubMed - indexed for MEDLINE]
110: Br J Cancer 1998 Sep;78 Suppl 4:1-4
Tamoxifen--the treatment of choice. Why look for alternatives?
Baum M.
University College London Hospital, UK.
Tamoxifen is currently established as the endocrine treatment of choice in
breast cancer. In advanced breast cancer, response rates of up to 60% in women
with oestrogen receptor (ER)-positive tumours have been reported. In early
breast cancer, tamoxifen can produce significant benefits, both statistically
and clinically, in terms of reduction in relative risk of relapse or death in
all patient subgroups (i.e. ER status, aged < or > 50 years) except
premenopausal women with ER-negative tumours. The major benefit, however, is
seen in women over 50 years old with ER-positive tumours. The results of
randomized trials suggest that the optimum duration of tamoxifen therapy is at
least 5 years. Two large pragmatic trials (aTTom and ATLAS) are under way to
determine whether additional benefit can be gained from continuing tamoxifen
treatment beyond 5 years. Recent data also suggest possible synergism between
tamoxifen and chemotherapy in the treatment of early breast cancer in
post-menopausal women. Other benefits of tamoxifen treatment include reduction
in the risk of developing contralateral breast cancer. Included among the
non-breast cancer benefits of tamoxifen are reduced risk of cardiovascular
disease and protection against bone loss in post-menopausal women. These
benefits must be weighed against the possible increased incidence of endometrial
cancer. Notwithstanding its undoubted success, there is a need for agents to
improve upon tamoxifen. Newer agents, such as the luteinizing hormone-releasing
hormone analogue goserelin and the new-generation aromatase inhibitors, such as
anastrozole, will add new life to the search for an improved endocrine therapy
for early breast cancer.
PMID: 9741780 [PubMed - indexed for MEDLINE]
111: Cancer 1998 Sep 15;83(6):1142-52
Erratum in:
Cancer 1999 Feb 15;85(4):1010
Anastrozole versus megestrol acetate in the treatment of postmenopausal women
with advanced breast carcinoma: results of a survival update based on a combined
analysis of data from two mature phase III trials. Arimidex Study Group.
Buzdar AU, Jonat W, Howell A, Jones SE, Blomqvist CP, Vogel CL, Eiermann W,
Wolter JM, Steinberg M, Webster A, Lee D.
Department of Breast Medical Oncology, the University of Texas M.D. Anderson
Cancer Center, Houston 77030, USA.
BACKGROUND: This report presents the results of a survival update based on the
combined data from two studies that compared the efficacy and tolerability of
anastrozole (1 or 10 mg once daily), a selective, nonsteroidal aromatase
inhibitor administered orally, and megestrol acetate (40 mg 4 times daily) in
the treatment of postmenopausal women with advanced breast carcinoma whose
disease had progressed after treatment with tamoxifen. METHODS: Two randomized,
parallel-group, multicenter trials were conducted, involving a total of 764
patients. The two trials were identical in design; both were double blind for
anastrozole and open label for megestrol acetate. Overview analyses were
conducted with the intent of strengthening the interpretation of results from
each trial. The median follow-up duration for this survival update was 31
months. RESULTS: At the clinical dose of 1 mg daily, anastrozole demonstrated a
statistically significant survival advantage over megestrol acetate, with a
hazard ratio of 0.78 (P < 0.025)(0.60 < 97.5% confidence interval [CI] <1.0).
The 1 mg anastrozole group also had a longer median time to death (26.7 months)
compared with 22.5 months for the megestrol acetate group. The 10 mg anastrozole
group also had a survival benefit over the megestrol acetate group, with a
hazard ratio of 0.83 (P=0.09, not significant)(0.64 < 97.5% CI < 1.1). Higher
2-year survival rates were observed for both anastrozole treatment groups than
for the megestrol acetate group (56.1%, 54.6%, and 46.3% for the groups given 1
mg anastrozole, 10 mg anastrozole, and megestrol acetate, respectively).
CONCLUSIONS: This combined analysis of two trials of postmenopausal patients
with advanced breast carcinoma has clearly demonstrated that, after disease
progression with tamoxifen, treatment with anastrozole 1 mg once daily results
in a statistically and clinically significant advantage over a standard
treatment, megestrol acetate. This important benefit, in addition to the good
tolerability profile of anastrozole, supports the use of this drug as a valuable
new treatment option for this patient population.
Publication Types:
Clinical Trial
Clinical Trial, Phase III
Multicenter Study
Randomized Controlled Trial
PMID: 9740079 [PubMed - indexed for MEDLINE]
112: Cancer Invest 1998;16(6):385-90
Anastrozole (Arimidex), a new aromatase inhibitor for advanced breast cancer:
mechanism of action and role in management.
Hortobagyi GN, Buzdar AU.
Department of Breast Medical Oncology, University of Texas M.D. Anderson Cancer
Center, Houston, USA.
Publication Types:
Review
Review, Tutorial
PMID: 9679529 [PubMed - indexed for MEDLINE]
113: Schweiz Rundsch Med Prax 1998 Apr 22;87(17):584-8
[Aromatase inhibitors--new possibilities in treatment of breast carcinoma].
[Article in German]
Friedrichs K, Janicke F.
Frauenklinik und Poliklinik, Universitats-Krankenhaus Eppendorf, Hamburg.
Aromatase inhibition is now an acknowledged second line treatment modality for
advanced breast cancer in postmenopausal women. Aminoglutethimide is an
inhibitor of adrenal steroid biosynthesis and blocks the conversion of
cholesterol to pregnenolone, and therefore reduces levels of adrenal androgens,
which are a source of estrogens in both premenopausal and postmenopausal women.
Aminoglutethimide has produced antitumor response rates of 35% in unselected
patients, most of whom have undergone prior therapy with either chemotherapy or
hormonal manipulation. As is true of other hormonal responses, high response
rates of up to 70% are observed in patients who are ER and/or PR positive. The
reason why these drugs are currently used after tamoxifen is mainly due to the
side effects of aminoglutethimide, which impairs the mineralocorticoid and
glucocorticoid synthesis. New, less toxic compounds appear, which block the
conversion of androstenedione to estrone and efficiently suppress plasma
estrogen levels., e.g. formestane, anastrozole and letrozole. Aromatase
inhibitors are now being compared to tamoxifen as first-line endocrine treatment
in relapsing patients. If these trials confirm a similar or better response rate
to new aromatase inhibitors compared to tamoxifen, the time will come to study
them as the first line adjuvant treatment in non-metastatic disease.
Publication Types:
Review
Review, Tutorial
PMID: 9623325 [PubMed - indexed for MEDLINE]
114: Tumori 1998 Jan-Feb;84(1):45-7
Clinical efficacy of the aromatase inhibitor anastrozole in relation to
prolactin secretion in heavily pretreated metastatic breast cancer.
Barni S, Lissoni P, Meregalli S, Ardizzoia A, Mengo S, Musco F, Merlini D,
Tancini G.
Division of Oncological Radiotherapy, Ospedale S. Gerardo, Monza (Milan), Italy.
AIMS AND BACKGROUND: It is known that the aromatase inhibitors may act by
decreasing estrogen levels. Moreover, it is known that estrogens may stimulate
the release of prolactin (PRL), which is a growth factor for breast cancer. This
phase II study was performed to evaluate the effects of the novel aromatase
inhibitor anastrozole on PRL secretion in metastatic breast cancer and the
possible influence of PRL pretreatment levels on the efficacy of therapy.
METHODS: The study involved 14 pretreated metastatic breast cancer patients with
a poor clinical status. Anastrozole was given orally once a day at 1 mg/day for
at least 2 months. To evaluate PRL secretion, venous blood samples were
collected before treatment and at 1-monthly intervals during treatment. RESULTS:
The clinical response consisted of partial response (PR) in 2, stable disease
(SD) in 5 and progressive disease (PD) in the remaining 7 patients. Abnormally
high pretreatment levels of PRL were seen in 5/14 (36%) patients. Progressing
patients showed significantly higher pretreatment levels of PRL than those who
achieved PR or SD. None of the patients with high PRL pretreatment levels showed
a decline in PRL levels on treatment with anastrozole. CONCLUSIONS: This
preliminary study suggests that anastrozole has no inhibitory effect on PRL
secretion in metastatic breast cancer and that the evidence of abnormally
elevated concentrations of PRL prior to therapy is generally associated with a
lack of efficacy.
Publication Types:
Clinical Trial
Clinical Trial, Phase II
PMID: 9619713 [PubMed - indexed for MEDLINE]
115: Minerva Ginecol 1998 Mar;50(3):51-63
[Current status and prospectives of aromatase inhibitors in the treatment of
advanced breast cancer].
[Article in Italian]
Boccardo F.
Servizio di Oncologia Medica II, Istituto Nazionale per la Ricerca sul Cancro,
Genova.
Endocrine therapy represents one of the most effective instruments for the
palliative and adjuvant treatment of breast cancer, in particular in
postmenopausal patients. While tamoxifen still forms the treatment of choice
during the adjuvant phase and the first-line treatment during the metastatic
phase, aromatase inhibitors undoubtedly represent the treatment of choice for
patients who do not respond to antiestrogen treatment. These drugs represent a
heterogeneous family of compounds able to provide more or less selective
inhibition of aromatases by forming an irreversible bond with the catalytic site
of the enzymatic complex (type I inhibitors) or using a competitive mechanism
(type II inhibitors). Among the type I drugs, 4-hydroxyandrostenedione and
hexamestane are those that probably attract greatest clinical interest. These
drugs can significantly reduce the circulating levels of estrone and estradiol,
and have been shown to be active in 20% of patients pretreated with tamoxifen.
Moreover, hexamestane was also effective in patients pretreated with type II
inhibitors, of which the parent drug is aminoglutethimide. This drug is still
used in the second and third-line treatment of breast cancer but, since it
causes collateral effects in a substantial percentage of patients, above all
when used at higher doses in combination with hydrocortisone, it will soon be
replaced by second and third generation inhibitors, like letrozole, fadrozole,
vorozole and anastrozole. These drugs have been shown to be significantly more
active than aminoglutethimide, both in vitro and in vivo, and above all more
selective. In particular, even at high doses anastrozole has not been found to
interfere with steroidogenesis at a corticoadrenal level. Moreover, anastrozole
has been shown to be very active even at relatively modest doses given in a
single daily dose. Two recent controlled studies, including a total of over 600
patients, recently demonstrated that, if used in second line in patients who no
longer responded to adjuvant or palliative tamoxifen therapy, anastrozole is
just as effective but probably better tolerated than megestrol acetate. Studies
are now in progress or are currently being launched to evaluate the possible
value of anastrozole and other third generation inhibitors both as first-line
treatment and as adjuvant treatment as an alternative or in combination with
tamoxifen.
Publication Types:
Review
Review Literature
PMID: 9595916 [PubMed - indexed for MEDLINE]
116: Oncology (Huntingt) 1998 Mar;12(3 Suppl 5):36-40
Preclinical studies using the intratumoral aromatase model for postmenopausal
breast cancer.
Brodie A, Lu Q, Liu Y, Long B, Wang JP, Yue W.
Department of Pharmacology, School of Medicine, University of Maryland,
Baltimore, USA.
To determine the most effective strategies for the treatment of postmenopausal
hormone dependent breast cancer, we recently developed a model system in nude
mice. In this model, estrogen receptor-positive human breast cancer cells
(MCF-7) stably transfected with the aromatase gene are inoculated into
ovariectomized, immunosuppressed (nude) mice. These cells synthesize sufficient
estrogen from androgen substrate to stimulate their proliferation and the
development of tumors. Moreover, estrogen secreted by the tumor cells maintains
uterine weight comparable to that of the intact mouse. In the present study, we
employed this model to investigate the effects of the aromatase inhibitor,
letrozole (CGS 20267 [Femara]) on mammary tumor growth and on the uterus. We
also used this model to predict the effects of combining two aromatase
inhibitors, letrozole and anastrozole (Arimidex), with the antiestrogen
tamoxifen (Nolvadex). Letrozole was found to be a highly potent inhibitor of
tumor proliferation and more effective than tamoxifen. No stimulation of uterine
growth was observed with the aromatase inhibitors. However, the combination of
letrozole or anastrozole and tamoxifen was no more effective than either
aromatase inhibitor alone. The agonistic effect of tamoxifen on the uterus was
observed when it was given alone and when combined with the aromatase
inhibitors. Furthermore, letrozole had the most potent antitumor activity when
compared to other aromatase inhibitors and antiestrogens. No additional benefit
was observed by combining these agents with tamoxifen over treatment with
aromatase inhibitors alone.
PMID: 9556790 [PubMed - indexed for MEDLINE]
117: Oncology (Huntingt) 1998 Mar;12(3 Suppl 5):32-5
Emerging role of aromatase inhibitors in the treatment of breast cancer.
Harvey HA.
Section of Hematology-Oncology, Hershey Medical Center, Penn State Geissinger
Health Systems, Hershey, Pennsylvania, USA.
The new generation of potent steroidal and nonsteroidal inhibitors of the enzyme
aromatase act by decreasing estrogen production throughout the body in
postmenopausal women. The most potent of these agents may also inhibit estrogen
synthesis within metastatic breast cancer tissue. The newly developed, orally
administered, nonsteroidal competitive inhibitors, such as anastrozole
(Arimidex), letrozole (Femara), and vorozole (Rizivor), are a thousand times
more potent inhibitors of aromatase than is aminoglutethimide. Furthermore,
these agents are highly selective. In several large randomized trials, the new
inhibitors produced similar response rates as megestrol acetate (160 mg/d) in
postmenopausal women with hormone-dependent breast cancer, but showed a trend
toward improved response duration and survival. They also produced less weight
gain and fewer cardiovascular and thromboembolic side effects. In addition,
letrozole proved superior to aminoglutethimide in another randomized trial. Both
anastrozole (1.0 mg/d) and letrozole (2.5 mg/d) have now been approved as
second-line treatment for hormone-dependent breast cancer in postmenopausal
women in whom disease has progressed following tamoxifen treatment. Either drug
should replace the routine use of megestrol acetate in this setting. Ongoing
clinical studies are comparing anastrozole and letrozole to antiestrogens as
first-line endocrine therapy for metastatic breast cancer. Other trials will
study the possible roles of these compounds as adjuvant therapy and
chemoprevention for breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 9556789 [PubMed - indexed for MEDLINE]
118: Fertil Steril 1998 Apr;69(4):709-13
Comment in:
Fertil Steril. 1998 Dec;70(6):1183-4
Treatment of severe postmenopausal endometriosis with an aromatase inhibitor.
Takayama K, Zeitoun K, Gunby RT, Sasano H, Carr BR, Bulun SE.
Cecil H. and Ida Green Center for Reproductive Biology Sciences and Department
of Obstetrics and Gynecology, University of Texas Southwestern Medical Center,
Dallas 75235-9051, USA.
OBJECTIVE: To treat an unusually aggressive case of recurrent postmenopausal
endometriosis. DESIGN: Case report. SETTING: University of Texas Southwestern
Medical Center (Dallas, Texas). PATIENT(S): A 57-year-old woman who presented
with recurrent severe endometriosis after hysterectomy and bilateral
salpingo-oophorectomy. INTERVENTION(S): Oral administration of anastrozole (an
aromatase inhibitor) (1 mg/d) and elemental calcium (1.5 g/d) for 9 months.
Alendronate (a nonestrogenic inhibitor of bone resorption), 10 mg/d, was added
to this regimen. MAIN OUTCOME MEASURE(S): Reduction in size of endometriotic
lesion, pain relief, tissue levels of aromatase P450 messenger RNA, bone
density. RESULT(S): Circulating levels of estradiol-17beta were reduced to
approximately 50% of the baseline value after the onset of treatment with
anastrozole. Pain rapidly decreased and completely disappeared after the 2nd
month of treatment. The 30 x 30 x 20-mm bright red polypoid vaginal lesion was
reduced to a 3-mm gray tissue by the end of 9 months of treatment. Markedly high
pretreatment levels of aromatase P450 messenger RNA in the endometriotic tissue
became undetectable in a specimen obtained from a repeated biopsy after 6 months
of treatment. Bone density of lumbar spine decreased by 6.2% after 9 months of
treatment. CONCLUSION(S): This is the first description of the use of an
aromatase inhibitor in the treatment of endometriosis. The short-term results
were extraordinarily successful in elimination of pain and near-complete
eradication of implants associated with severe endometriosis not responsive to
other therapy. We conclude that the recently developed potent aromatase
inhibitors are candidate drugs in the treatment of endometriosis that is
resistant to standard regimens.
PMID: 9548162 [PubMed - indexed for MEDLINE]
119: Internist (Berl) 1997 Mar;38(3 Suppl Selektive):1-16
[Two new therapeutic principles in the management of breast cancer and
colorectal cancer: selective oral aromatase inhibition and thymidilate synthase
inhibition].
[Article in German]
PMID: 9541667 [PubMed - indexed for MEDLINE]
120: Am J Clin Oncol 1998 Apr;21(2):161-6
Anastrozole: a new addition to the armamentarium against advanced breast cancer.
Buzdar AU.
Department of Breast Medical Oncology, The University of Texas, M.D. Anderson
Cancer Center, Houston 77030, USA.
Estrogen manipulation represents an effective treatment for advanced breast
cancer in postmenopausal women with estrogen-receptor positive disease. The
antiestrogen agent, tamoxifen, is the first choice for advanced breast cancer in
postmenopausal women due to its efficacy and lack of significant side effects.
As with all cancer treatments, however, cancer may recur after initial treatment
with tamoxifen, and the limitations of currently available alternative hormonal
therapies in terms of tolerability and convenience of administration underscore
the need for new agents. Anastrozole is a new, highly selective, nonsteroidal
aromatase inhibitor capable of maximal estrogen depletion with fewer side
effects than other hormonal therapies. Anastrozole is administered in a
convenient, once-daily oral dosing regimen and does not require steroid
replacement therapy. In two multicenter clinical trials, anastrozole was as
effective as megestrol acetate for the treatment of advanced breast cancer in
postmenopausal women who progressed after tamoxifen therapy, based on objective
response rates and time to objective progression of disease. In addition, the
drug did not produce the weight gain observed with megestrol acetate therapy.
Anastrozole is an effective endocrine agent in the treatment of advanced breast
cancer in postmenopausal women.
Publication Types:
Review
Review, Tutorial
PMID: 9537204 [PubMed - indexed for MEDLINE]
121: Am J Health Syst Pharm 1998 Mar 1;55(5):445-52
Anastrozole: a selective aromatase inhibitor for the treatment of breast cancer.
Higa GM, alKhouri N.
School of Pharmacy, Mary Babb Randolph Cancer Center, West Virginia University,
Morgantown 26506-9520, USA.
The role of anastrozole, a new selective aromatase inhibitor, in treating
hormone-responsive metastatic breast cancer is discussed. Treatment options for
hormone-dependent breast cancer focus on interfering with the endocrine system
in an attempt to modify the effects of estrogen. Tamoxifen is the drug of choice
for primary endocrine therapy, but there is a need for agents with similar or
greater efficacy and better tolerability. Anastrozole inhibits the conversion of
androgens to estrogens by aromatase. Bioavailability studies have demonstrated
almost complete absorption of anastrozole after oral administration. The drug's
terminal half-life after multiple doses is 50 hours. Anastrozole is cleared
principally by the liver. Clinical trials comparing anastrozole with megestrol
acetate demonstrated no significant differences in clinical efficacy, although a
follow-up study revealed a longer median overall survival rate in patients
receiving anastrozole. The drug is well tolerated. Among the most frequently
reported adverse effects are asthenia, hot flashes, headache, and back pain. The
recommended dosage is 1 mg daily. The average wholesale cost of month's supply
of anastrozole is $187.20, compared with approximately $100 for generic
megestrol acetate or aminoglutethimide plus hydrocortisone. Although anastrozole
will likely become the preferred second-line agent in the treatment of
postmenopausal breast cancer in patients with disease progression after
tamoxifen therapy, it is not a therapeutic alternative to aminoglutethimide on
the basis of approved indications. Anastrozole and other aromatase inhibitors
may have multiple applications in treating hormone-responsive breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 9522927 [PubMed - indexed for MEDLINE]
122: Am J Physiol 1998 Feb;274(2 Pt 1):E328-35
Physiological plasma levels of androgens reduce bone loss in the ovariectomized
rat.
Lea CK, Flanagan AM.
Department of Histopathology, Imperial College School of Medicine at St. Mary's,
London, United Kingdom.
The effect of androstenedione (ADIONE) slow-release pellets on cancellous bone
volume (BV/TV) at the tibial metaphysis was investigated in ovariectomized (OVX)
rats at various times from 21 to 180 days. Plasma levels of ADIONE and
testosterone (T) in OVX rats were significantly reduced at 21 days and were
restored close to levels in the sham rats with the 1.5-mg ADIONE pellet. OVX
animals with and without ADIONE pellets resulted in close to a 50% reduction in
BV/TV, by day 21. By day 180, OVX rats had only approximately 5% BV/TV, whereas
that in ADIONE-treated OVX rats was significantly greater at approximately 12%.
The reduced BV/TV was associated with increased bone resorption and formation.
In a separate 90-day experiment, we found that the antiandrogen, Casodex,
abrogated the ADIONE-induced skeletal-protective effect in OVX rats, whereas the
antiaromatase, Arimidex, had no effect. This provides evidence that ADIONE
protects against the development of osteopenia in the estrogen-deficient rat and
mediates its effect through androgens and not estrogens.
PMID: 9486166 [PubMed - indexed for MEDLINE]
123: Cancer Epidemiol Biomarkers Prev 1998 Jan;7(1):65-78
Aromatase inhibitors as potential cancer chemopreventives.
Kelloff GJ, Lubet RA, Lieberman R, Eisenhauer K, Steele VE, Crowell JA, Hawk ET,
Boone CW, Sigman CC.
Chemoprevention Branch, Division of Cancer Prevention and Control, National
Cancer Institute, Bethesda, Maryland 20852, USA.
Epidemiological and experimental evidence strongly supports a role for estrogens
in the development and growth of breast tumors. A role for estrogen in prostate
neoplasia has also been postulated. Therefore, one chemopreventive strategy for
breast and prostate cancers is to decrease estrogen production. This can be
accomplished by inhibiting aromatase, the enzyme that catalyzes the final,
rate-limiting step in estrogen biosynthesis. The use of aromatase inhibitors is
of clinical interest for cancer therapy, and selective, potent aromatase
inhibitors have been developed. Several of these agents have demonstrated
chemopreventive efficacy in animal models. The rationale for the use of
aromatase inhibitors as chemopreventives and identification of inhibitors to
serve as potential chemopreventive agents are the subjects of this review. After
background information regarding aromatase is presented, the data for each
inhibitor are summarized separately. The discussion focuses on those inhibitors
that are clinically available or in clinical trials, including:
aminoglutethimide (Cytadren), rogletimide, fadrozole hydrochloride, liarozole
hydrochloride, anastrozole (Arimidex), letrozole, vorozole, formestane,
exemestane, and atamestane. On the basis of results from preclinical studies,
aromatase inhibitors may be promising agents for clinical trials in populations
at high risk for developing estrogen-dependent cancers. Total suppression of
aromatase may have adverse effects, as is evident in postmenopausal women
(increased osteoporosis, cardiovascular disease, and urogenital atrophy).
However, on the basis of preclinical studies of chemopreventive efficacy and
chemotherapeutic applications of aromatase inhibitors showing dose-response
efficacy, it may be possible to obtain chemopreventive effects without total
suppression of aromatase and circulating estrogen levels. Suppressing local
estrogen production may be an alternative strategy, as suggested by the
discovery of a unique transcriptional promoter of aromatase gene expression,
I.4, in breast adipose tissue. The development of drugs that target this
promoter region may be possible.
Publication Types:
Review
Review, Tutorial
PMID: 9456245 [PubMed - indexed for MEDLINE]
124: Tumori 1997 Sep-Oct;83(5):874-6
[ECCO 9 -- Future trends in endocrine therapy of breast cancer].
[Article in Italian]
Publication Types:
Congresses
News
PMID: 9446251 [PubMed - indexed for MEDLINE]
125: Regul Toxicol Pharmacol 1997 Dec;26(3):330-7
The weanling male rat as an assay for endocrine disruption: preliminary
observations.
Ashby J, Lefevre PA.
Zeneca Central Toxicological Laboratory, Macclesfield, Cheshire, United Kingdom.
Kelce and Wilson (J. Mol. Med. 75, 198-207, 1997) have suggested that dosing
chemicals to newly weaned male rats for 1 month may yield a useful assay for
antiandrogens. This suggestion was supported by reference to unpublished data on
the antiandrogen vinclozolin which indicated reductions in the weight of
accessory sex organs. The necessity for dosing during the full approximately 30
days of the protocol was not justified. An evaluation of this protocol has
commenced by the dosing of vinclozolin, cyproterone acetate, and anastrozole
daily to newly weaned male rats for 3, 7, or 14 days. No changes were observed
in accessory sex organs when vinclozolin or anastrozole was dosed for 3 days.
Significant changes were observed in the absolute and relative weight of all of
the sex accessory organs for rats dosed for 7 or 14 days with cyproterone
acetate. The effects produced by vinclozolin and anastrozole when dosed for 7 or
14 days varied according to the duration of exposure with the main effects on
the accessory sex organs being seen after 14 days of dosing. The effects
produced after 7 days of dosing with vinclozolin or anastrozole in arachis oil
had resolved 10 days after the last of the seven doses. Data are presented using
either hydroxy propyl methyoxycellulose (HPMC) or arachis oil as vehicle, the
former being recommended for general use. These preliminary results are
encouraging, and the evaluation of the second 2 weeks of the suggested 30-day
protocol is proceeding. Concurrent control data indicate that the relative
weight of the liver, testes, and epididymides increases over the first 14 days
post-weaning, while those of the kidney, the seminal vesicles, and prostate
decrease. These changes in relative tissue weight were much less than the
increase in relative weight of the uterus observed in female animals at puberty.
That indicates that successful use of a final version of this assay will depend
on access to inhouse control tissue weight data and the use of appropriate
animal group sizes. These preliminary data are presented to reduce duplication
of effort in this rapidly expanding area of toxicology.
PMID: 9441923 [PubMed - indexed for MEDLINE]
126: Cancer Pract 1997 Nov-Dec;5(6):391-3
Anastrozole. An effective, second-line hormonal treatment for advanced breast
cancer.
Camp-Sorrell D.
University of Alabama, Birmingham Hospital, USA.
Because advanced breast cancer is not curable, the goal of treatment is to
prolong survival yet maintain an acceptable quality of life. Anastrozole offers
another option for second-line hormonal therapy in postmenopausal women with
advanced breast cancer. This recently approved selective aromatase inhibitor is
as efficacious as other available hormonal therapies for this indication and
appears to offer an advantage with regard to adverse effects and ease of
administration.
Publication Types:
Review
Review, Tutorial
PMID: 9397709 [PubMed - indexed for MEDLINE]
127: Oncology 1997;54 Suppl 2:27-31
The role of selective non-steroidal aromatase inhibitors in future treatment
strategies.
Blamey RW.
Professorial Unit of Surgery, City Hospital, Nottingham, UK.
The major role of endocrine therapy in the treatment of early and advanced
breast cancer should not be forgotten as an increasing number of new and
potentially more exciting agents are introduced. Endocrine therapy generally has
a more powerful effect than cytotoxic therapy in the treatment of breast cancer.
Alternatives to tamoxifen, such as anastrozole (Arimidex), are now being
considered, both in advanced disease and as adjuvant therapy, whether as single
agents or in combination. Anastrozole has a low side-effect profile and is
becoming a drug of choice for second-line therapy in postmenopausal women with
advanced breast cancer. The present use of anastrozole in postmenopausal women
with advanced breast cancer includes second-line treatment after tamoxifen and
first-line treatment after tamoxifen has been used as an adjuvant treatment. It
may also be used when tamoxifen is not tolerated. The future potential of
anastrozole is currently being investigated in a programme of clinical trials in
postmenopausal women, including first-line treatment of advanced disease and as
an adjuvant treatment for early breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 9394858 [PubMed - indexed for MEDLINE]
128: Oncology 1997;54 Suppl 2:19-22
A randomised comparison of oestrogen suppression with anastrozole and formestane
in postmenopausal patients with advanced breast cancer.
Kleeberg UR, Dowsett M, Carrion RP, Dodwell DJ, Vorobiof DA, Aparicio LA,
Robertson JF.
The relative efficacy and tolerability of the aromatase inhibitors anastrozole
(Arimidex) and formestane are assessed in a direct comparative trial in
postmenopausal women with advanced breast cancer. Final results are available
and reported here only for oestradiol suppression. Patients were randomised to
receive either oral anastrozole, 1 mg once daily, or formestane, 250 mg every 2
weeks intramuscularly. In the anastrozole group, mean serum oestradiol levels
fell from 32.1 pmol/l at baseline to 6.5 pmol/l at week 1, and similar levels of
suppression were maintained over the next 3 weeks. In the formestane group, mean
serum oestradiol levels fell from 31.0 pmol/l at baseline to 9.5 pmol/l at the
week 1 assessment. In this group, serum oestradiol levels tended to rise by the
2- and 4-week measurements, i.e. immediately before the next injection was due.
Based on the 2- and 4-week measurements, the mean falls in oestradiol levels
were 79 and 58% in the anastrozole and formestane groups, respectively (p =
0.0001). More effective and consistent suppression of oestradiol was achieved
with anastrozole at the therapeutic dose of 1 mg once daily, orally, than with
formestane at the standard dose of 250 mg every 2 weeks, intramuscularly.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 9394856 [PubMed - indexed for MEDLINE]
129: Oncology 1997;54 Suppl 2:15-8
Clinical overview of anastrozole--a new selective oral aromatase inhibitor.
Jonat W.
Gynaecology and Obstetrics Clinic, University of Kiel, Germany.
The efficacy and tolerability of the new selective aromatase inhibitor,
anastrozole (Arimidex), was compared with megestrol acetate in the treatment of
advanced breast cancer in postmenopausal women. In two independent prospective
randomised trials, patients who progressed after prior tamoxifen therapy
received anastrozole 1 or 10 mg once daily, or megestrol acetate, 40 mg q.i.d.
The two studies were designed to allow the data to be combined to increase the
statistical power of the analyses. It is the data from these combined analyses
that are considered in further detail. After 6 months of follow-up, the
proportion of patients gaining clinical benefit (complete response + partial
response + stable disease > or = 24 weeks) was approximately one third of
patients in all three groups. No significant difference was observed between
either dose of anastrozole and megestrol acetate in the time to disease
progression (130-153 days). All three treatments were generally well tolerated,
but significantly more patients on megestrol acetate gained weight, and the
weight gain in this group continued up to at least 9 months of follow-up. At a
12-month update of tolerability, of the commonly observed adverse events, a
greater than 2-fold difference between treatment arms was observed for
hypertension, weight gain, dyspnoea, vaginal haemorrhage, sweating and diarrhoea
(all higher on megestrol acetate except for diarrhoea). Anastrozole is effective
and well tolerated and on the basis of these data, 1 mg once daily is the
recommended clinical dose in postmenopausal women with advanced breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 9394855 [PubMed - indexed for MEDLINE]
130: Oncology 1997;54 Suppl 2:11-4
Anastrozole--a new generation in aromatase inhibition: clinical pharmacology.
Dowsett M, Lonning PE.
Department of Academic Biochemistry, Royal Marsden Hospital, London, UK.
Use of the aromatase inhibitor aminoglutethimide is limited by its lack of
selectivity for aromatase and its toxicity. Newer agents are more selective, but
do not always offer improved inhibition of aromatase. Indirect comparison of
their activity in inhibiting aromatase and suppressing plasma oestrogens
indicates that aminoglutethimide, rogletimide, formestane, and fadrozole
inhibited aromatase activity by 74-91%, with reported falls in oestradiol level
of 58-76%. In contrast, the new-generation oral once-daily aromatase inhibitors
anastrozole (Arimidex) and letrozole were of a similar activity, inhibiting
aromatase activity by over 96%, with a concomitant fall in oestradiol and
oestrone levels of at least 80%. Anastrozole at the recommended clinical dose of
1 mg daily also suppressed oestrone sulphate levels by 93.5%; activity with
anastrozole 10 mg daily was not statistically significantly different. The new
generation of aromatase inhibitors, as typified by anastrozole, thus offers
effective and convenient aromatase inhibition which correlates well with
decreases in the levels of plasma oestrogens.
Publication Types:
Review
Review, Tutorial
PMID: 9394854 [PubMed - indexed for MEDLINE]
131: Oncology 1997;54 Suppl 2:6-10
The relevance of preclinical models to the treatment of postmenopausal breast
cancer.
Dukes M.
Cancer Metabolism Endocrine Department, Zeneca Pharmaceuticals, Macclesfield,
UK.
The predictive value of test results in animals when selecting a compound for
potential therapeutic human use depends upon the relevance of the animal model
to the human disease and the comparative pharmacokinetics of the compound in
animals and man. The development of the aromatase inhibitor, anastrozole
(Arimidex), illustrates the importance of these factors. In postmenopausal women
with breast cancer, aromatase activity in the peripheral tissues is the main
source of oestrogen for tumour growth. Only one form of the human enzyme is
known, which is not subject to strong feedback control. Inhibition of aromatase
therefore simply reduces oestrogen production. This situation is mimicked by
assays of acute inhibition of ovulation in rats, chronic inhibition of
androstenedione-induced uterine hypertrophy in sexually immature rats, and
chronic inhibition of peripheral aromatase in monkeys. In all these assays,
maximum anastrozole activity was consistently achieved at an oral dose of about
0.1 mg/kg, and the clearance half-life of 7-16 h indicated that once-daily
dosing would be possible in humans. The clearance half-life in postmenopausal
women is about 50 h, and with once-daily dosing the dose of anastrozole required
for maximal inhibition is 1 mg/day. The rat 7,12-dimethylbenzanthracene tumour
model, in contrast, is supported by ovarian oestrogen and chronic inhibition
provokes positive feedback loops that try to restore oestrogen production,
masculinise the animals and decrease the clearance half-life of anastrozole.
Higher doses (10 mg/kg) of anastrozole are therefore needed. Variations in the
dose of aromatase inhibitor required in different models, therefore, can be
explained in terms of pharmacokinetics and do not reflect the effectiveness of
anastrozole as an aromatase inhibitor.
Publication Types:
Review
Review, Tutorial
PMID: 9394853 [PubMed - indexed for MEDLINE]
132: Oncology (Huntingt) 1997 Nov;11(11):1697-703; discussion 1707-8
Anastrozole: a new selective nonsteroidal aromatase inhibitor.
Goss PE, Tye LM.
Department of Hematology/Oncology, Toronto Hospital, Canada.
Aromatase (estrogen synthetase) is the enzyme complex responsible for the final
step in estrogen synthesis--the conversion of androstenedione and testosterone
to estrone and estradiol, respectively. Inhibitors of this enzyme have been
shown to be clinically effective in the treatment of advanced breast cancer in
postmenopausal women, in whom the major source of estrogen production derives
from aromatization of adrenal androgens in peripheral tissues, such as muscle,
liver, and fat. The most widely used aromatase inhibitor has been
aminoglutethimide; however, it is nonselective and also inhibits
adrenocorticosteroid synthesis, necessitating hydrocortisone supplementation.
Aminoglutethimide is also associated with frequent and troublesome side effects.
Formestane, the first selective aromatase inhibitor to be developed, has an
improved safety profile and selectivity, but its use has been limited somewhat
by its inconvenient administration via intramuscular injection. In this article,
the preclinical and clinical data published to date on the new third-generation
aromatase inhibitor anastrozole (Arimidex) are presented in the context of
current endocrine therapies. Future applications of aromatase inhibitors, both
as monotherapy and in combination with other endocrine therapies, are discussed.
The use of aromatase inhibitors in advanced disease, the adjuvant setting, and
as possible chemopreventive agents are examined.
Publication Types:
Review
Review, Tutorial
PMID: 9394367 [PubMed - indexed for MEDLINE]
133: J Chromatogr B Biomed Sci Appl 1997 Oct 24;700(1-2):131-8
Validated assay for the quantification of anastrozole in human plasma by
capillary gas chromatography-63Ni electron capture detection.
Bock MJ, Bara I, LeDonne N, Martz A, Dyroff M.
Zeneca Pharmaceuticals, Wilmington, DE 19850-5437, USA.
An assay was developed for the quantification of anastrozole
[2,2'-[5-(1H-1,2,4-triazol-1-ymethyl)-1,3-phenylene]bis(2-++
+methylpropiononitrile)] in human plasma using liquid-liquid extraction.
Anastrozole and an internal standard were chromatographed and detected by gas
chromatography with electron capture detection, using a combination
temperature-pressure program. The range of the assay is 3 to 100 ng/ml.
Anastrozole was quantified by comparing its peak area to that of an internal
standard. A cross-validation of this assay was also successfully performed
between several laboratories.
Publication Types:
Clinical Trial
PMID: 9390722 [PubMed - indexed for MEDLINE]
134: Breast Cancer Res Treat 1997 Sep;45(3):219-24
Predictors of response to second-line endocrine therapy for breast cancer.
Cheung KL, Willsher PC, Pinder SE, Ellis IO, Elston CW, Nicholson RI, Blamey RW,
Robertson JF.
City Hospital, Nottingham, UK.
This study reports on factors predicting response to second-line endocrine
therapy in 250 patients with breast cancer for which they were assessable for
response by the International Union Against Cancer (UICC) criteria. Clinical
details relating to first-line endocrine therapy were available for all
patients. We have not included in this study patients who received first-line
endocrine therapy but did not or have not yet proceeded to second-line hormone
therapy--e.g. died from rapidly progressive disease, started chemotherapy for
rapidly progressive disease, or remained in long-term remission on first-line
endocrine therapy. One hundred and fifty nine patients (72%) achieved remission
(objective response and static disease [OR + SD]) on first-line endocrine
therapy with a median duration of 19 months. For second-line endocrine therapy
the remission rate was 53% (132/225) with a median duration of 15 months. Tumour
grade and oestrogen receptor status of the primary tumour were shown to be
independent predictors of response to second-line endocrine therapy while
response to first-line endocrine therapy was a predictor of the duration of
response to second-line endocrine therapy. In the sub-group of patients who
showed OR or SD to both first and second-line therapies, there was no
correlation between the time to progression (TTP) on first and second-line
therapies.
PMID: 9386865 [PubMed - indexed for MEDLINE]
135: J Surg Oncol 1997 Nov;66(3):215-20
Use of aromatase inhibitors in postmenopausal women with advanced breast cancer.
Roseman BJ, Buzdar AU, Singletary SE.
Department of Surgical Oncology, University of Texas M.D. Anderson Cancer
Center, Houston 77030, USA.
Surgeons have been involved in the management of metastatic breast cancer since
the technique of ovarian ablation was introduced in 1896. However, as newer
hormonal and chemotherapeutic regimens were developed, drug therapy gradually
replaced surgery as the preferred treatment for metastatic breast cancer. Thus,
management of metastatic breast cancer has largely shifted from surgeons to
medical oncologists. Advances in hormonal pharmacology have placed hormonal
therapy alongside surgery and radiation therapy as a standard treatment option
for women with advanced breast cancer. The purpose of this article is to update
surgeons on the current use of hormonal agents for treatment of advanced breast
cancer in postmenopausal women, and to review the aromatase inhibitors, a new
line of hormonal agents for the treatment of advanced breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 9369969 [PubMed - indexed for MEDLINE]
136: J Steroid Biochem Mol Biol 1997 Apr;61(3-6):255-60
Plasma estrogen suppression with aromatase inhibitors evaluated by a novel,
sensitive assay for estrone sulphate.
Lonning PE, Geisler J, Johannessen DC, Ekse D.
Department of Oncology, Haukeland University Hospital, Bergen, Norway.
Aromatase inhibition is a well-defined treatment option for postmenopausal
breast cancer. Although several aromatase inhibitors such as aminoglutethimide,
formestane and fadrozole have been found to inhibit in vivo aromatization by
>85%, previous studies reported plasma estrogen levels to be sustained at
approximately 20-50% of their control level during treatment with these drugs.
The discrepancy could be due to lack of sensitivity or non-specific
crossreactions in the radioimmunoassay (RIA) methods. Mean plasma levels of
estrone (E1) and estradiol (E2) in postmenopausal women are approximately 80 and
20 pmol/l, respectively; on the contrary, mean plasma levels of the estrogen
conjugate estrone sulphate (E1S) are approximately 4-500 pmol/l. Most RIA
methods for plasma E2 and E1 measurements have sensitivity limits in the range
of 2-3 and 7-10 pmol/l, respectively; accordingly, the suppression of plasma
estrogens by more than 80-90% will produce hormone values below the sensitivity
limit of the method in many patients. Recently, we developed a new method to
determine plasma E1S. This assay has a sensitivity limit of 2.7 pmol/l. In
theory, this method may allow the determination of plasma E1S levels suppressed
to less than 2% of control values in the majority of patients. Using this
method, we found different aromatase inhibitors such as formestane,
aminoglutethimide, formestane and aminoglutethimide administered in concert or
anastrozole to suppress plasma E1S levels down to 24, 13, 7 and 4%,
respectively. The suppression of plasma E1S evaluated with this method thus
approaches the percentage aromatase inhibition measured with tracer studies.
PMID: 9365198 [PubMed - indexed for MEDLINE]
137: J Steroid Biochem Mol Biol 1997 Apr;61(3-6):145-9
ARIMIDEX: a potent and selective aromatase inhibitor for the treatment of
advanced breast cancer.
Buzdar AU, Jonat W, Howell A, Plourde PV.
M.D. Anderson Cancer Center, University of Texas, Houston 77030, U.S.A.
Aromatase inhibitors have been available for a number of years and their ability
to reduce circulating estradiol levels has been shown to produce clinical
benefit in women with advanced breast cancer. Until recently, the only
commercially available aromatase inhibitor was aminoglutethimide. Although
aminoglutethimide has been shown to be efficacious in the treatment of advanced
breast cancer, it does cause significant toxicity and requires the use of
concomitant hydrocortisone therapy. Anastrozole is one of a new class of potent
aromatase inhibitors able to suppress estradiol to the limit of detection of
sensitive assays without suppressing adrenal steroidal synthesis. Two large
clinical trials (n = 764) conducted in the U.S.A. and in Europe evaluated two
doses of anastrozole, 1 and 10 mg a day, compared to megesterol acetate, 40 mg
four times a day, in postmenopausal women who had progressed while on tamoxifen.
Response rates and time to progression with anastrozole were similar to those of
megesterol acetate. Objective responses (CR + PR) were 10.3%, 8.9% and 7.9% in
the 1 and 10 mg of anastrozole and megesterol acetate treatment groups,
respectively. Another 25.2%, 22.6% and 26.1% had stable disease for over 24
weeks on 1, 10 mg anastrozole and megesterol acetate, respectively. Anastrozole
and megesterol acetate were well tolerated; however, more patients had
significant weight gain on megesterol acetate than with anastrozole treatment.
The weight gain seen with megesterol acetate continued to increase over time.
Anastrozole has a better therapeutic index (fewer side-effects) and has recently
been approved by the FDA and a number of other regulatory agencies around the
world for the treatment of advanced breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 9365184 [PubMed - indexed for MEDLINE]
138: Cancer 1997 Oct 15;80(8 Suppl):1646-51
Issues concerning the role of chemotherapy and hormonal therapy of bone
metastases from breast carcinoma.
Harvey HA.
Division of Hematology-Oncology, The Milton S. Hershey Medical Center,
Pennsylvania 17033, USA.
A significant percentage (50-70%) of patients with metastatic breast carcinoma
(MBC) will have disease involving the bony skeleton. Clonal selection mediated
by parathyroid hormone-related protein and other factors may explain the high
incidence of osseous metastases in MBC. The presence of specific growth factors
and cytokines in the microenvironment of bone may contribute to the successful
establishment and growth of metastatic lesions and also might determine response
or resistance of these lesions to chemotherapy or hormonal therapy. Osteolytic
bone lesions in MBC frequently give rise to serious clinical problems including
bone pain, pathologic fracture, hypercalcemia, and neurologic complications. MBC
often is treated with systemic chemotherapy or hormonal therapy. The purpose of
this article was to review the recent published literature describing the impact
of systemic chemotherapy and hormonal therapy of MBC on the response of bone
lesions and their clinical course and complications. Evaluating the response of
bone lesions can be problematic and may be complicated by the phenomenon of
"tumor flare" that may be observed with either chemotherapy or hormonal therapy.
Use of the International Union Against Cancer criteria for the response of bone
lesions is recommended. Several studies report objective responses (20-60%) of
lytic bone metastases to standard combination chemotherapy regimens such as
cyclophosphamide, methotrexate, and 5-fluorouracil and cyclophosphamide,
doxorubicin, and 5-fluorouracil, mitoxantrone and 5-FU, newer combinations, and
single agents including paclitaxel and docitaxel but responses to vinorelbine
may be less frequent. Complete responses of bone lesions to chemotherapy are
rare but partial responses and disease stabilization can lead to long term
patient benefit. A series from the M. D. Anderson Cancer Center of patients with
bone metastases treated with 5-FU, doxorubicin, and cyclophosphamide
chemotherapy reported a median duration of response of 14 months. In a recent
multicenter study of 195 patients with lytic lesions from MBC treated with
chemotherapy, the objective response rate (complete response + partial response)
in bone was 18% and 65% of the patients developed at least 1 morbid skeletal
event with a median onset of 7.0 months from the start of chemotherapy.
Hormone-dependent breast carcinoma has a proclivity to metastasize to bone. In
earlier studies comparing aminoglutethimide or medroxyprogesterone acetate with
tamoxifen, a higher response rate of bone metastases was observed for the first
two agents. However, in more recent studies comparing newer aromatase
inhibitors, such as anastrozole, fadrozole, and letrozole, with megestrol
acetate, there were no significant differences in rates of response in bone.
Patients with MBC with bony lesions respond to both chemotherapy and hormonal
therapy and can have a prolonged survival. Therefore such patients are in a more
favorable position to benefit from adjunctive supportive therapy such as
bisphosphonates intended to reduce skeletal morbidity.
Publication Types:
Review
Review, Tutorial
PMID: 9362431 [PubMed - indexed for MEDLINE]
139: Cancer Lett 1997 Sep 16;118(1):21-8
A novel in vitro and in vivo breast cancer model for testing inhibitors of
estrogen biosynthesis and its action using mammary tumor cells with an activated
int-5/aromatase gene.
Tekmal RR, Durgam VR.
Department of Gynecology and Obstetrics and Winship Cancer Center, Emory
University School of Medicine, Atlanta, GA 30322-4710, USA. [email protected]
We recently showed that the cellular gene int-5/aromatase in BALB/c mammary
alveolar hyperplastic nodule (D2 HAN/D2 tumor cells) is activated as a result of
mouse mammary tumor virus integration within the 3' untranslated region of the
aromatase gene. In the present study, we evaluated the effect of various
aromatase inhibitors on androstenedione-mediated tumor cell growth. Also, we
compared the effect of the non-steroidal aromatase inhibitor (CGS 16949A) on the
inhibition of tumor growth. Our results show that D2 tumor cells respond well to
various aromatase inhibitors and antiestrogens. We examined the usefulness of
this model by using D2 tumor cells to simulate postmenopausal breast cancer
employing both in vitro cell culture and in vivo ovariectomized (OVX) nude
mouse. Unlike DMBA-induced tumors or other models, D2 tumor cells form very
rapid tumors within a few days in intact mice or OVX nude mice with
androstenedione supplementation and respond well to an aromatase inhibitor. This
model with its known mechanism of aromatase activation should be useful for
studying the role of intra-tumoral estrogen in mammary cancer, for evaluating
the effects of aromatase inhibitors and antiestrogens, and for comparing breast
cancer treatments.
PMID: 9310256 [PubMed - indexed for MEDLINE]
140: Drugs Aging 1997 Sep;11(3):245-50; discussion 251-2
Vorozole.
Wiseman LR, Spencer CM.
Adis International Limited, Auckland, New Zealand. [email protected]
Vorozole is a triazole derivative which binds to the cytochrome P450 moiety of
aromatase, thus causing reversible inhibition of the enzyme. Plasma estradiol
levels are reduced by about 90% in postmenopausal women treated with vorozole.
Phase II clinical studies found vorozole to be an effective agent for the
treatment of postmenopausal women with advanced breast cancer, achieving
objective responses in up to 35% of patients. In 2 large phase III studies,
vorozole 2.5 mg/day demonstrated favourable clinical efficacy compared with
aminoglutethimide and megestrol. Vorozole improved patients' quality of life to
a greater extent than aminoglutethimide. Clinical trials to date indicate that
the tolerability of vorozole is better than that of aminoglutethimide. Vorozole
also appears to be at least as well tolerated as megestrol (although
inappropriate bodyweight gain is more common in megestrol recipients). The most
common adverse events with vorozole are hot flushes, and nausea, which are
generally mild in severity.
Publication Types:
Review
Review, Tutorial
PMID: 9303282 [PubMed - indexed for MEDLINE]
141: Ann Oncol 1997 Jul;8(7):631-2
Aromatase inhibitors come of age.
Dowsett M.
Publication Types:
Editorial
PMID: 9296213 [PubMed - indexed for MEDLINE]
142: Drug Ther Bull 1997 Jul;35(7):55-6
New aromatase inhibitors for breast cancer.
Anastrozole (Arimidex-Zeneca) and letrozole (Femara-Novartis) are the first
selective, oral, non-steroidal aromatase inhibitors. They are licensed for the
treatment of advanced breast cancer in postmenopausal women where tamoxifen or
other anti-oestrogen therapy has failed. The manufacturers of both drugs claim
that their products are more effective, less toxic and better tolerated than the
progestogen megestrol acetate, the standard therapy in this clinical situation.
We assess these claims.
Publication Types:
Review
Review, Tutorial
PMID: 9282426 [PubMed - indexed for MEDLINE]
143: Mol Endocrinol 1997 Jun;11(7):917-27
Fetal death in mice lacking 5alpha-reductase type 1 caused by estrogen excess.
Mahendroo MS, Cala KM, Landrum DP, Russell DW.
Department of Molecular Genetics, University of Texas Southwestern Medical
Center, Dallas 75235-9046, USA.
Female mice deficient in steroid 5alpha-reductase type 1 have a decreased litter
size. The average litter in homozygous deficient females is 2.7 pups vs. 8.0
pups in wild type controls. Oogenesis, fertilization, implantation, and
placental morphology appear normal in the mutant animals. Fetal loss occurs
between gestation days 10.75 and 11.0 commensurate with a midpregnancy surge in
placental androgen production and an induction of 5alpha-reductase type 1
expression in the decidua of wild type mice. Plasma levels of androstenedione
and testosterone are 2- to 3-fold higher on gestation day 9, and estradiol
levels are chronically elevated by 2- to 3-fold throughout early and
midgestation in the knockout mice. Administration of an estrogen receptor
antagonist or inhibitors of aromatase reverse the high rate of fetal death in
the mutant mice, and estradiol treatment of wild type pregnant mice causes fetal
wastage. The results suggest that in the deficient mice, a failure to
5alpha-reduce androgens leads to their conversion to estrogens, which in turn
causes fetal death in midgestation. These findings indicate that the
5alpha-reduction of androgens in female animals plays a crucial role in guarding
against estrogen toxicity during pregnancy.
PMID: 9178751 [PubMed - indexed for MEDLINE]
144: Drug Metab Dispos 1997 May;25(5):598-602
Inhibition of human drug metabolizing cytochromes P450 by anastrozole, a potent
and selective inhibitor of aromatase.
Grimm SW, Dyroff MC.
Drug Disposition and Metabolism Department, Zeneca Pharmaceuticals, Wilmington,
DE 19850, USA.
Anastrozole (2,2'[5(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]-
bis(2-methylproprionitrile)) is a potent third-generation inhibitor of
aromatase, currently marketed as a treatment for postmenopausal women with
advanced breast cancer. While its potency and selectivity for inhibition of
estrogen synthesis has been established in both preclinical and clinical
studies, this study used in vitro methods to examine the effects of anastrozole
on several drug metabolizing CYP enzymes found in human liver. Human liver
microsomes were co-incubated with anastrozole and probe substrates for CYP1A2
(phenacetin), CYP2A6 (coumarin), CYP2C9 (tolbutamide), CYP2D6
(dextromethorphan), and CYP3A (nifedipine). The formation of the CYP-specific
metabolites following co-incubation with various anastrozole concentrations was
determined to establish IC50 and Ki values for these enzymes. While anastrozole
did not inhibit CYP2A6 and CYP2D6 activities at concentrations below 500 microM,
this compound inhibited CYP1A2, CYP2C9, and CYP3A activities with Ki values of
8, 10, and 10 microM, respectively. Dixon plots used to determine the Ki values
for the inhibition of CYP1A2 and CYP3A activities by anastrozole were biphasic,
indicating additional lower affinity Ki values. Major metabolites of anastrozole
did not retain the ability to inhibit the metabolism of nifedipine (CYP3A). The
results of this study indicate that, although anastrozole can inhibit CYP1A2,
2C9, and 3A-mediated catalytic activities, this compound would not be expected
to cause clinically significant interactions with other CYP-metabolized drugs at
physiologically relevant concentrations achieved during therapy with Arimidex
(Zeneca, Ltd., Macclesfield, UK) 1-mg.
PMID: 9152599 [PubMed - indexed for MEDLINE]
145: Nurse Pract 1997 Mar;22(3):195-6, 201-2
Role of new selective aromatase inhibitor in therapy for metastatic breast
cancer in postmenopausal women.
Hannaford M.
Anastrozole offers a new option for many postmenopausal women with metastatic
breast cancer who no longer respond to antiestrogen therapy. It has a lower side
effect profile for weight gain and peripheral edema and equivalent efficacy to
the current second-line therapy, megestrol acetate, which may improve quality of
life. Due to its selectivity and lack of clinically significant effects on
cortisol metabolism, it does not have the toxicity problems of other aromatase
inhibiting agents such as aminoglutethimide. Long-term studies are needed to
adequately evaluate the impact of this degree of estrogen suppression on
cardiovascular and bone mass risk factors [12]. Cost of therapy will certainly
have an impact on the choice of second-line endocrine therapy in those with
limited income sources and lack of prescription coverage. In summary, there is
likely to be an increased use of nonsteroidal aromatase inhibitor agents for
second-line hormonal therapy of breast cancer. Due to increased length of
survival, these individuals will not be seen exclusively by oncologists; their
care will be shared with their primary care provider [21]. Providers must have
an understanding of these agents and their potential impact on the long-term
health care of the individual in order to provide knowledgeable and
comprehensive care.
Publication Types:
News
PMID: 9078523 [PubMed - indexed for MEDLINE]
146: Cancer 1997 Feb 15;79(4):730-9
A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and
selective aromatase inhibitor, with megestrol acetate in postmenopausal women
with advanced breast carcinoma. Arimidex Study Group.
Buzdar AU, Jones SE, Vogel CL, Wolter J, Plourde P, Webster A.
Department of Medical Oncology, M.D. Anderson Cancer Center, University of Texas
Medical Center, Houston 77030, USA.
BACKGROUND: Anastrozole is a new oral aromatase inhibitor with highly potent and
selective activity for the aromatase enzyme. In a Phase III trial, the efficacy
and tolerability of anastrozole, given in doses of 1 and 10 mg orally once
daily, and megestrol acetate, given in doses of 40 mg orally 4 times daily, were
compared in 386 postmenopausal women with advanced breast carcinoma who
progressed after tamoxifen therapy. METHODS: The trial was randomized, double
blind for anastrozole, open label for megestrol acetate, parallel group, and
multicenter. Patients were randomly assigned to receive anastrozole, 1 mg (n =
128); anastrozole, 10 mg (n = 130); or megestrol acetate (n = 128). The primary
efficacy measures were time to progression and tumor response; secondary
measures were time to treatment failure, duration of response, quality of life,
and time to death. RESULTS: With a median duration of follow-up of 6 months,
there was no statistical evidence of a difference between either 1 or 10 mg
doses of anastrozole and megestrol acetate for any efficacy endpoint. According
to rigid response criteria, 10%, 6%, and 6% of patients in the anastrozole 1 mg,
anastrozole 10 mg, and megestrol acetate groups, respectively, had an objective
response (complete response or partial response) and 27%, 24%, and 30% of
patients in the respective groups had stable disease for a duration of 24 weeks
or longer. Quality-of-life assessments revealed that anastrozole in a 1-mg dose
was associated with better physical scores and anastrozole in a 10-mg dose with
better psychologic scores than megestrol acetate. Both anastrozole and megestrol
acetate were generally well tolerated. Among anticipated adverse events,
gastrointestinal disturbance was more common among patients in the anastrozole
groups, whereas weight gain occurred more frequently among patients in the
megestrol acetate groups. Weight increases of 5% or more and 10% or more were
more common among megestrol acetate-treated patients; moreover, patients in this
group continued to gain weight over time. CONCLUSIONS: Anastrozole, given in
doses of 1 and 10 mg once daily, represents a well tolerated and effective
therapeutic option for the treatment of postmenopausal women with advanced
breast carcinoma who progress after tamoxifen treatment.
Publication Types:
Clinical Trial
Clinical Trial, Phase III
Multicenter Study
Randomized Controlled Trial
PMID: 9024711 [PubMed - indexed for MEDLINE]
147: Br J Cancer 1996 Oct;74(8):1286-91
Influence of anastrozole (Arimidex), a selective, non-steroidal aromatase
inhibitor, on in vivo aromatisation and plasma oestrogen levels in
postmenopausal women with breast cancer.
Geisler J, King N, Dowsett M, Ottestad L, Lundgren S, Walton P, Kormeset PO,
Lonning PE.
Department of Oncology, Haukeland University Hospital, Bergen, Norway.
The effect of anastrozole ('Arimidex', ZD1033), a new, selective, non-steroidal
aromatase inhibitor on in vivo aromatisation and plasma oestrogen levels was
evaluated in post-menopausal women with breast cancer. Twelve patients
progressing after treatment with tamoxifen were randomised to receive
anastrozole 1 mg or 10 mg once daily for a 28 day period in a double-blinded
crossover design. In vivo aromatisation and plasma oestrogen levels were
determined before commencing treatment and at the end of each 4-week period.
Treatment with anastrozole 1 and 10 mg reduced the percentage aromatisation from
2.25% to 0.074% and 0.043% (mean suppression of 96.7% and 98.1% from baseline)
and suppressed plasma levels of oestrone, oestradiol and oestrone sulphate by >
or = 86.5%, > or = 83.5% and > or = 93.5% respectively, irrespective of dose.
Notably, several patients had their oestrone and oestradiol values suppressed
beneath the sensitivity limit of the assays. In conclusion, anastrozole was
found to be highly effective in inhibiting in vivo aromatisation with no
difference in efficacy between the two drug doses. Contrary to previous studies
on other aromatase inhibitors, this study revealed an internal consistency
between the percentage aromatase inhibition and suppression of plasma oestrone
sulphate.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 8883419 [PubMed - indexed for MEDLINE]
148: Tumori 1996 Sep-Oct;82(5):417-22
Novel non-steroidal aromatase inhibitors: are there new perspectives in the
treatment of breast cancer?
Bajetta E, Celio L, Buzzoni R, Bichisao E.
Division of Medical Oncology B, Istituto Nazionale per lo Studio e la Cura dei
Tumori, Milan, Italy.
Breast cancer is the most common malignant neoplasm affecting women in Western
countries, and most new cases are manifested during the postmenopausal period.
The clinical results obtained with aminoglutethimide, and later with formestane,
have established aromatase inhibition as one of the major therapeutic options in
hormone-dependent advanced disease. Nevertheless, the lack of specificity of
aminoglutethimide and the less than optimal oral activity of formestane soon led
to further efforts to find a potent, highly selective, orally active,
side-effect-free aromatase inhibitor for use in postmenopausal women with
advanced breast cancer. Here we review the available data on three new,
competitive non-steroidal aromatase inhibitors--letrozole, vorozole and
anastrozole--which are approaching the point of detailed pharmacologic and
clinical evaluation. Preliminary data have confirmed the high potency and
selectivity of these endocrine agents, but their antitumor activity still
remains to be completely defined. Challenges given by these novel aromatase
inhibitors are discussed taking into account the biologic implications related
to their mechanism of action and their future use in the management of breast
cancer.
Publication Types:
Review
Review, Tutorial
PMID: 9063515 [PubMed - indexed for MEDLINE]
149: Semin Oncol 1996 Aug;23(4 Suppl 9):28-32
Aromatase inhibitors in metastatic breast cancer.
Buzdar AU, Plourde PV, Hortobagyi GN.
Department of Breast Medical Oncology, The University of Texas, M.D. Anderson
Cancer Center, Houston 77030, USA.
Inhibition of estrogen production or actions provides an effective therapy for
patients with hormone-dependent breast cancer. A number of approaches to
accomplishing these goals are available, and each has its own advantages and
disadvantages. Aromatase inhibitors are capable of lowering estrogen levels in
postmenopausal women whose estrogen production is not ovarian. Aromatase, the
enzyme that converts androgens to estrogens, is one of a series of related P-450
enzymes involved in the production of steroid hormones. Because of the
similarity of the P-450 enzymes, selectivity is important; nonselective
aromatase inhibitors, such as aminoglutethimide, can affect enzymes controlling
the production of other steroids and lead to significant side effects. Recently,
a number of newer aromatase inhibitors have been synthesized and are in
preclinical or clinical development. In early 1996, anastrozole became available
for clinical use in the United States and in a number of other countries. In
phase I studies, anastrozole was shown to be highly selective and inhibited
estrogen production in postmenopausal patients to levels below the detection
threshold of the assay. Another aromatase inhibitor in advanced development is
fadrozole. In this review we present briefly the available clinical data on
fadrozole and anastrozole.
PMID: 8824462 [PubMed - indexed for MEDLINE]
150: Semin Oncol 1996 Aug;23(4 Suppl 9):10-20
Aromatase inhibitors and breast cancer.
Brodie AM, Njar VC.
Department of Pharmacology and Experimental Therapeutics, School of Medicine,
University of Maryland, Baltimore 21201, USA.
Selective aromatase inhibitors cause regression of breast carcinomas by reducing
estrogen production via inhibition of the enzyme aromatase (estrogen
synthetase). A higher incidence of hormone-dependent breast cancer occurs in
postmenopausal women than in younger women. Thus, total estrogen blockade is
more likely to be achieved with systemic (pharmacologic) methods than by
surgical removal of endocrine glands. At the present time, breast cancer
patients with hormone-dependent disease usually receive the antiestrogen
tamoxifen as first-line treatment. Although tamoxifen is effective initially,
patients develop resistance to the drug, which results in disease progression.
Aromatase inhibitors acting by a different mechanism from tamoxifen are
effective in some of these patients. There is also the potential that aromatase
inhibitors could be more effective as first-line treatment. Formestane,
4-hydroxyandrostenedione, the first approved aromatase inhibitor, is proving to
be useful in postmenopausal breast cancer patients with advanced disease.
Recently, anastrozole, a nonsteroidal agent, has been approved in the United
States. Other very potent aromatase inhibitors are under development. Aromatase
inhibitors as a new class of well-tolerated agents are now becoming available
for improving the treatment of breast cancer patients.
Publication Types:
Review
Review, Academic
PMID: 8824460 [PubMed - indexed for MEDLINE]
151: Med Lett Drugs Ther 1996 Jul 5;38(978):61-2
Anastrozole for metastatic breast cancer.
PMID: 8668098 [PubMed - indexed for MEDLINE]
152: J Steroid Biochem Mol Biol 1996 Jul;58(4):439-45
The preclinical pharmacology of "Arimidex" (anastrozole; ZD1033)--a potent,
selective aromatase inhibitor.
Dukes M, Edwards PN, Large M, Smith IK, Boyle T.
Zeneca Pharmaceuticals, Alderly Park, Macclesfield, U.K.
Anastrozole is a comparatively simple, achiral benzyltriazole derivative,
2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-++
+methylpropiononitrile), that inhibits human placental aromatase with an IC50 of
15 nM and elicits maximal activity in vivo in rats (inhibition of ovulation and
androstenedione-induced uterine hypertrophy) and monkeys (lowering of plasma
oestradiol) at 0.1 mg/kg p.o. At 30 times this dose, anastrozole does not
elevate plasma 11-deoxycorticosterone in monkeys, and at 100 times this dose,
does not affect plasma aldosterone levels or Na+/K+ excretion in rats, plasma K+
concentrations in dogs, or cause adrenal hypertrophy in rats or dogs. It
therefore has no discernible effect on adrenocorticoid hormone synthesis in vivo
at very large multiples of its maximally effective aromatase-inhibiting dose. At
similar large multiples in rats it displays no oestrogenic, anti-oestrogenic,
androgenic, anti-androgenic, progestogenic, glucocorticoid, antiglucocorticoid
or mineralocorticoid activity. Anastrozole is thus a potent and highly selective
aromatase inhibitor, with no intrinsic hormonal activities--a pharmacological
profile particularly suitable for the treatment of breast cancer.
PMID: 8903429 [PubMed - indexed for MEDLINE]
153: J Clin Oncol 1996 Jul;14(7):2000-11
Anastrozole, a potent and selective aromatase inhibitor, versus megestrol
acetate in postmenopausal women with advanced breast cancer: results of overview
analysis of two phase III trials. Arimidex Study Group.
Buzdar A, Jonat W, Howell A, Jones SE, Blomqvist C, Vogel CL, Eiermann W, Wolter
JM, Azab M, Webster A, Plourde PV.
M.D. Anderson Cancer Center, University of Texas, Houston, Department of Breast
Medical Oncology 77030, USA. [email protected]
PURPOSE: To compare the efficacy and tolerability of anastrozole (1 and 10 mg
once daily), a selective, oral, nonsteroidal aromatase inhibitor, and megestrol
acetate (40 mg four times daily), in postmenopausal women who progressed
following tamoxifen treatment. PATIENTS AND METHODS: Two randomized,
double-blind for anastrozole, open-label for megestrol acetate, parallel-group,
multicenter trials were conducted in 764 patients. Because both trials were
identical in design, an analysis of the combined results was performed to
strengthen interpretation of results from each trial. RESULTS: The median
follow-up duration was approximately 6 months. The estimated progression hazards
ratios were 0.97 (97.5% confidence interval [CI], 0.75 to 1.24) for anastrozole
1 mg versus megestrol acetate and 0.92 (97.5% CI, 0.71 to 1.19) for anastrozole
10 mg versus megestrol acetate. The overall median time to progression was
approximately 21 weeks. Approximately one third of patients in each group
benefited from treatment. Twenty-seven patients (10.3%) in the anastrozole 1-mg
group, 22 (8.9%) in the anastrozole 10-mg group, and 20 (7.9%) in the megestrol
acetate group had a complete or partial response, and 66 (25.1%), 56 (22.6%),
and 66 (26.1%) patients, respectively, had stable disease for > or = 24 weeks.
For all end points, individual trial results were similar to the results of the
combined analysis. Anastrozole and megestrol acetate were well tolerated.
Gastrointestinal disturbance was more common among patients in the anastrozole
groups than the megestrol acetate group; the difference between the anastrozole
10 mg and megestrol acetate groups was significant (P = .005). Significantly
fewer patients in the anastrozole 1-mg (P < .0001) and 10-mg (P < .002) groups
had weight gain than in the megestrol acetate group. More than 30% of megestrol
acetate-treated patients had weight gain > or = 5%, and 10% of patients had
weight gain > or = 10%. Patients who received megestrol acetate continued to
gain weight over time. CONCLUSION: Anastrozole, 1 and 10 mg once daily, is well
tolerated and as effective as megestrol acetate in the treatment of
postmenopausal women with advanced breast cancer who progressed following
tamoxifen treatment. Moreover, anastrozole therapy avoids the weight gain
associated with megestrol acetate treatment.
Publication Types:
Clinical Trial
Clinical Trial, Phase III
Multicenter Study
Randomized Controlled Trial
PMID: 8683230 [PubMed - indexed for MEDLINE]
154: Eur J Cancer 1996 Mar;32A(3):404-12
Comment in:
Eur J Cancer. 1996 Mar;32A(3):393-5
A randomised trial comparing two doses of the new selective aromatase inhibitor
anastrozole (Arimidex) with megestrol acetate in postmenopausal patients with
advanced breast cancer.
Jonat W, Howell A, Blomqvist C, Eiermann W, Winblad G, Tyrrell C, Mauriac L,
Roche H, Lundgren S, Hellmund R, Azab M.
University Women's Hospital, Eppendorf, Hamburg, Germany.
The aim of this study was to compare the efficacy and tolerability of the new
aromatase inhibitor 'ARIMIDEX' (anastrozole) with megestrol acetate in the
treatment of advanced breast cancer in postmenopausal women. Anastrozole is a
new potent and highly selective non-steroidal aromatase inhibitor. We conducted
a prospective randomised trial comparing two doses of anastrozole (1 and 10 mg
orally once daily) with megestrol acetate (40 mg orally four times daily) in
postmenopausal patients with advanced breast cancer who progressed after prior
tamoxifen therapy. All patients were analysed for efficacy as randomised
(intention to treat) and for tolerability as per treatment received. Of the 378
patients who entered the study, 135 were randomised to anastrozole 1 mg, 118 to
anastrozole 10 mg, and 125 patients to megestrol acetate. After a median
follow-up of 192 days, response rate which included complete response, partial
response and patients who had disease stabilisation for 6 months or more was 34%
for anastrozole 1 mg, 33.9% for anastrozole 10 mg and 32.8% for megestrol
acetate. There were no statistically significant differences between either dose
of anastrozole and megestrol acetate in terms of objective response rate, time
to objective progression of disease or time to treatment failure. The three
treatments were generally well tolerated, but more patients on megestrol acetate
reported weight gain, oedema and dyspnoea as adverse events while more patients
on anastrozole reported gastro-intestinal disorders, usually in the form of mild
transient nausea. Patients on anastrozole did not report higher incidences of
oestrogen withdrawal symptoms. Anastrozole is an effective and well tolerated
treatment for postmenopausal patients with advanced breast cancer. The higher 10
mg dose did not result in additional clinical benefit, but was well tolerated
reflecting the good therapeutic margin with anastrozole. Based on this data,
anastrozole 1 mg should be the recommended therapeutic dose.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 8814682 [PubMed - indexed for MEDLINE]
155: Eur J Cancer 1996 Mar;32A(3):393-5
Comment on:
Eur J Cancer. 1996 Mar;32A(3):404-12
New aromatase inhibitors: more selectivity, less toxicity, unfortunately, the
same activity.
Castiglione-Gertsch M.
Publication Types:
Comment
Editorial
PMID: 8814679 [PubMed - indexed for MEDLINE]
156: Br J Cancer 1996 Feb;73(4):543-8
Arimidex (ZD1033): a selective, potent inhibitor of aromatase in postmenopausal
female volunteers.
Yates RA, Dowsett M, Fisher GV, Selen A, Wyld PJ.
Zeneca Pharmaceuticals, Macclesfield, UK.
Two multiple-dose studies were conducted in healthy post-menopausal female
volunteers to investigate the pharmacokinetics and effects on endocrinology of
Arimidex (ZD1033). Volunteers in the first trial were dosed with 3 mg of ZD1033
daily over 10 days to assess the effects on endocrinology of ZD1033 and
establish a pharmacokinetic profile. In the second trial volunteers received 14
daily doses of either 0.5 or 1.0 mg of ZD1033 to assess the pharmacokinetics of
ZD1033 and the effects of low doses of ZD1033 on serum oestradiol
concentrations. Following multiple dosing a significant reduction in the
concentration of serum oestradiol of approximately 80% of baseline was obtained
with all three doses; no recovery in oestradiol was apparent for up to 144 h
after the last dose. There was no overall difference in the level of oestradiol
suppression between the 0.5 or 1.0 mg doses of ZD1033. However, comparison of
the number of volunteers with oestradiol concentrations below the limits of
detection of the assay, 24 h after the last dose of ZD1033, suggested that 1.0
mg was the minimal dose required for maximal suppression of oestradiol. No
significant effect was recorded on serum concentrations of gonadotrophins over
the dosing period. Serum concentrations of a range of adrenal steroids were not
affected by administration of ZD1033; furthermore, steroid response to standard
adrenocorticotrophic hormone (ACTH) challenge was unimpaired by ZD1033. Together
these data demonstrate the potency, tolerability and selectivity of ZD1033. The
pharmacokinetic profile of ZD1033 supports its use as a once-daily treatment
given orally.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 8595172 [PubMed - indexed for MEDLINE]
157: J Steroid Biochem Mol Biol 1995 Jun;53(1-6):175-9
ARIMIDEX: a new oral, once-a-day aromatase inhibitor.
Plourde PV, Dyroff M, Dowsett M, Demers L, Yates R, Webster A.
ZENECA Pharmaceuticals, Wilmington, DE 19897, USA.
ARIMIDEX is a potent and selective aromatase inhibitor undergoing evaluation as
a treatment for postmenopausal women with advanced breast cancer. Studies
examining the pharmacology of ARIMIDEX were conducted in both animals and
humans. In animals, ARIMIDEX elicits maximal aromatase suppressive activity at a
dose of approx. 0.1 mg/kg, does not alter adrenal steroid hormone biosynthesis,
and at a dose of 1 mg/kg, has no other pharmacologic effects other than
aromatase inhibition. In this overview, the pharmacodynamic, pharmacokinetic,
and safety profiles of single and multiple daily doses of ARIMIDEX are reported
in humans. Daily doses of 1-10 mg of ARIMIDEX suppressed estradiol levels to the
maximum degree measurable using sensitive estrogen assays. ARIMIDEX had no
clinically significant effects on the response of cortisol and aldosterone to
ACTH stimulation. Absorption of ARIMIDEX was rapid, with maximum plasma
concentrations occurring within 2 h after oral administration. Plasma
concentrations of ARIMIDEX rose with increasing doses of the drug. The
elimination half-life of ARIMIDEX in humans ranged from 30 to 60 h. Consistent
with the long plasma half-life, steady state plasma concentrations were 3-4-fold
higher than plasma concentrations observed after single administration of 1, 3,
5, or 10 mg doses. Long term treatment of breast cancer patients with 10 mg/day
has continued in 17 patients without an escape of estradiol suppression.
Previously, these patients had received on average 2.6 systemic treatments for
breast cancer and had significant metastatic disease. Three of the 17 patients
continued ARIMIDEX treatment for 20 months and beyond. Given the number of
previous treatments and tumor burden at the start of treatment, the response to
ARIMIDEX treatment is encouraging. Phase III studies are now underway to assess
the efficacy and safety of ARIMIDEX in the treatment of advanced breast cancer.
Publication Types:
Clinical Trial
Review
Review, Tutorial
PMID: 7626450 [PubMed - indexed for MEDLINE]
158: Breast Cancer Res Treat 1994;30(1):103-11
Arimidex: a potent and selective fourth-generation aromatase inhibitor.
Plourde PV, Dyroff M, Dukes M.
Zeneca Pharmaceuticals Group, Zeneca Inc., Wilmington, Delaware 19897.
Arimidex is a potent and selective aromatase inhibitor undergoing evaluation as
a treatment for postmenopausal women with advanced breast cancer. Studies to
determine the pharmacology of Arimidex were conducted in both animals and
humans. In animals, Arimidex was selective for the aromatase enzyme, elicited
maximal activity at about 0.1 mg/kg, did not interfere with steroid hormones
produced by the adrenal glands, and, at a dose of 1 mg/kg, had no detectable
pharmacologic activity other than aromatase inhibition. Absorption of ZD1033,
the active component of Arimidex, was rapid and virtually complete after oral
administration to animals. ZD1033 was extensively metabolized in animals after
oral administration; the metabolites were excreted predominantly in urine. The
pharmacodynamic, pharmacokinetic, and safety profiles of single and multiple
daily doses of Arimidex were determined in humans. Doses of 1 to 10 mg of
Arimidex suppressed estradiol to the maximum degree measurable. Arimidex had no
clinically significant effects on key enzymes that regulate cortisol and
aldosterone biosynthesis. Absorption of ZD1033 was rapid, with maximum plasma
concentrations occurring within 2 hours after oral administration. Plasma
concentrations of ZD1033 rose with increasing doses of Arimidex. The elimination
half-life of ZD1033 in humans ranged from 30 to 60 hours. Urinary excretion
accounted for a small percentage of each dose. A 3- to 4-fold accumulation of
ZD1033 in plasma occurred after daily administration of 3-, 5-, or 10-mg doses.
Arimidex was well tolerated. Phase III studies are under way to determine the
efficacy and safety of Arimidex in postmenopausal women with advanced breast
cancer.
PMID: 7949201 [PubMed - indexed for MEDLINE]
1: Cancer 2001 Oct 15;92(8):2095-101
Use of the aromatase inhibitor anastrozole in the treatment of patients with
advanced prostate carcinoma.
Santen RJ, Petroni GR, Fisch MJ, Myers CE, Theodorescu D, Cohen RB.
Department of Medicine, University of Virginia Health System, Charlottesville,
Virginia.
BACKGROUND: Men with prostate carcinoma initially respond to therapies designed
to inhibit androgen secretion or block its action. Later, the tumors in these
patients become refractory to androgen-related therapies. Therefore, additional
hormonal maneuvers that would benefit these men currently are needed. Reports of
androgen receptor mutations and historic clinical observations raised the
hypothesis that estrogens might be involved in the proliferation of
androgen-refractory prostate carcinoma. METHODS: To explore this hypothesis, 14
men with advanced prostate carcinoma that was refractory to medical or surgical
orchiectomy and antiandrogens were entered into a clinical Phase II trial
involving suppression of estrogens. After complete evaluation, each patient
received 1 mg daily of the third-generation aromatase inhibitor anastrozole
until disease progression. Follow-up included serial determinations of prostate
specific antigen (PSA), measurements of evaluable lesions, and assessment of
intensity of pain. RESULTS: No patient experienced an objective response or
disease stabilization as measured by PSA level or the greatest dimension of the
lesion. Minimal improvement of bone pain was reported in two patients receiving
intensive analgesic medication. CONCLUSIONS: It was concluded that the
dependence of androgen-insensitive prostate carcinoma on estrogens for
proliferation is uncommon and that aromatase inhibitors may not have a place in
the treatment of prostate carcinoma at this stage of the disease. Copyright 2001
American Cancer Society.
PMID: 11596025 [PubMed - in process]
2: Clin Cancer Res 2001 Sep;7(9):2620-35
Advances in aromatase inhibition: clinical efficacy and tolerability in the
treatment of breast cancer.
Buzdar A, Howell A.
Department of Breast Medical Oncology, M. D., Anderson Cancer Center, University
of Texas, Houston, 77030, USA.
Publication Types:
Review
Review, Tutorial
PMID: 11555572 [PubMed - indexed for MEDLINE]
3: Am J Ther 2001 Sep-Oct;8(5):333-44
Aromatase, aromatase inhibitors, and breast cancer.
Brueggemeier RW.
Medicinal Chemistry and Pharmacognosy, College of Pharmacy, and Hormones and
Cancer Program, Comprehensive Cancer Center, The Ohio State University,
Columbus, OH 43210, USA. [email protected]
Estrogens are involved in numerous physiologic processes and have crucial roles
in particular disease states, such as mammary carcinomas. Estradiol, the most
potent endogenous estrogen, is biosynthesized from androgens by the cytochrome
P-450 enzyme complex called aromatase. Aromatase is found in breast tissue, and
the importance of intratumoral aromatase and local estrogen production is being
unraveled. Inhibition of aromatase is an important approach for reducing growth
stimulatory effects of estrogens in hormone-dependent breast cancer. Effective
aromatase inhibitors have been developed as therapeutic agents for controlling
estrogen-dependent breast cancer. Investigations into the development of
aromatase inhibitors began in the 1970s and have expanded greatly in the past
three decades. Competitive aromatase inhibitors are molecules that compete with
the substrate androstenedione for noncovalent binding to the active site of the
enzyme to decrease the amount of product formed. Steroidal inhibitors that have
been developed to date build on the basic androstenedione nucleus and
incorporate chemical substituents at varying positions on the steroid. The
structure-activity relationships for steroidal inhibitors have become more
refined in the past decade, and only some modifications can be made to the
steroid and still keep its affinity for aromatase. Nonsteroidal aromatase
inhibitors can be divided into three classes: aminoglutethimide-like molecules,
imidazole/triazole derivatives, and flavonoid analogs. Mechanism-based aromatase
inhibitors are inhibitors that mimic the substrate, are converted by the enzyme
to a reactive intermediate, and result in the inactivation of aromatase.
Aromatase inhibitors, both steroidal and nonsteroidal, have shown clinical
efficacy for the treatment of breast cancer. The initial nonselective nature of
nonsteroidal inhibitors such as aminoglutethimide has been greatly reduced in
the later generations of inhibitors, anastrozole and letrozole. Mechanism-based
steroidal inhibitors such as 4-hydroxyandrostenedione and exemestane produce
prolonged aromatase inhibition in patients. The potent and selective
third-generation aromatase inhibitors anastrozole, letrozole, and exemestane are
approved for clinical use as second-line endocrine therapy in postmenopausal
patients failing antiestrogen therapy alone or multiple hormonal therapies.
Publication Types:
Review
Review, Tutorial
PMID: 11550075 [PubMed - indexed for MEDLINE]
4: Oncology (Huntingt) 2001 Aug;15(8):965-72; discussion 972, 977-9
Nonsteroidal and steroidal aromatase inhibitors in breast cancer.
Hamilton A, Volm M.
Kaplan Comprehensive Cancer Center, New York University, School of Medicine, New
York 10016, USA. [email protected]
Anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are
members of the third generation of aromatase inhibitors that has now replaced
aminoglutethimide (Cytadren), the progestins, and tamoxifen (Nolvadex) as the
hormonal therapy of choice in estrogen-receptor-positive, postmenopausal,
metastatic breast cancer. This article will review the role of aromatase in the
pathogenesis of breast cancer and the results of recent studies that have
established the role of its inhibitors in estrogen-receptor-positive breast
cancer. We will also briefly outline the rationale and design of ongoing
studies.
PMID: 11548977 [PubMed - in process]
5: Tumori 2001 May-Jun;87(3):A6-14
[Evolvement of hormone therapy for breast cancer. Florence, March 14, 2001].
[Article in Italian]
Longo F, Mansueto G.
Oncologia Medica, Policlinico Umberto I, Roma.
Publication Types:
Congresses
PMID: 11505951 [PubMed - indexed for MEDLINE]
6: Br J Cancer 2001 Aug 3;85(3):317-24
Pharmacokinetics of anastrozole and tamoxifen alone, and in combination, during
adjuvant endocrine therapy for early breast cancer in postmenopausal women: a
sub-protocol of the 'Arimidex and tamoxifen alone or in combination' (ATAC)
trial.
ATAC Trialists' Group.
CRC and UCL Cancer Trials Centre, University College London, Stephenson House,
158-160 N Gower Street, London, NW1 2ND, UK.
The ATAC trial evaluates in a randomized, double-blind design, Arimidextrade
mark (anastrozole) alone or in combination with tamoxifen, relative to tamoxifen
alone as 5-year adjuvant treatment in postmenopausal women with early breast
cancer. Patients included in the pharmacokinetic (PK) sub-protocol had been in
ATAC for > or =3 months, taking their medication in the morning and were 100%
compliant for the preceding 14 days. Blood samples were collected 24 +/- 4 h
after last dose. Trough (C(min)) plasma concentrations of anastrozole, tamoxifen
and desmethyltamoxifen (DMT) were measured by validated methods. The PK results
were based on a total of 347 patients (131 anastrozole (1 mg o.d.), 111
tamoxifen (20 mg o.d.), 105 anastrozole and tamoxifen (1 and 20 mg o.d.
respectively)). The geometric mean steady-state trough plasma concentrations of
tamoxifen and DMT were statistically equivalent in patients receiving tamoxifen
alone or in combination with anastrozole: geometric mean tamoxifen = 94.8 ng
ml(-1)and 95.3 ng ml(-1)in tamoxifen alone and combination groups, respectively;
geometric mean DMT = 265.1 and 277.6 ng ml(-1)in the tamoxifen and anastrozole
and tamoxifen groups, respectively. The geometric mean anastrozole levels were
27% lower (90% Cl 20-33%;P< 0.001) in the presence of tamoxifen than with
anastrozole alone. Baseline plasma oestradiol levels were not obtained in the PK
sub-protocol, however, such information was available from a similar ATAC
sub-protocol, which evaluated bone mineral density. Mean oestradiol levels were
21.3, 19.3, and 21.6 pmol l(-1)prior to treatment and 3.7, 20.9 and 3.6 pmol
l(-1)after 3 months in the anastrozole, tamoxifen, and combination groups,
respectively (n = 167). On-treatment values were below the detection limit (3
pmol l(-1)) in 43.6 and 38.5% of the anastrozole alone and anastrozole in
combination with tamoxifen groups, respectively. As a result of (a) the lack of
effect of anastrozole on tamoxifen and DMT levels and (b) the observed fall in
blood anastrozole levels having no significant effect on oestradiol suppression
by anastrozole, we conclude that the observed reduction in anastrozole levels by
tamoxifen is unlikely to be of clinical significance when anastrozole and
tamoxifen are administered together. Copyright 2001 Cancer Research Campaign.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 11487258 [PubMed - indexed for MEDLINE]
7: Gan To Kagaku Ryoho 2001 Jul;28(7):909-16
[Endocrine therapy for advanced or recurrent breast cancer].
[Article in Japanese]
Sonoo H, Kurebayashi J.
Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577
Matsushima, Kurashiki 701-0192, Japan.
Endocrine therapy of advanced or recurrent breast cancer was described. The
presence of ER or PgR in primary breast tumors is the best-established marker
for response to endocrine therapy. However, ER-positive breast tumors
overexpressing EGF-R and/or HER-2 (Erb B2) are resistant to endocrine therapy.
Recently it was suggested that an elevated level of the circulating
extracellular domain of HER-2 could be a predictor for poor response to
endocrine therapy. LH-RH agonist is used as a first-line therapy for
premenopausal patients. And LH-RH agonist plus tamoxifen (TAM) has shown a
higher response rate and more prolonged survival than LH-RH agonist or TAM
alone. As two new aromatase inhibitors, anastrozole (ANA) and letrozole, have
shown an equal or higher response rate and a prolonged time to progression than
TAM as a first-line therapy, these could be used as a first-line therapy instead
of TAM. In a cross-over trial of ANA and TAM, the response rate of ANA after TAM
failure was equal to that of TAM after ANA failure. As these drugs showed an
equal or higher response rate and longer survival than progestin in TAM
resistant cases, these drugs could also used as a second-line therapy. In
addition, the trend of recent studies regarding the mechanisms of hormone
resistance is also described.
Publication Types:
Review
Review, Tutorial
PMID: 11478139 [PubMed - indexed for MEDLINE]
8: Gan To Kagaku Ryoho 2001 Jul;28(7):892-901
[Developments of hormonal agents for breast cancer].
[Article in Japanese]
Tominaga T.
Breast Cancer Center Toyosu Hospital, Showa University School of Medicine,
4-1-18 Toyosu, Koto-ku, Tokyo 135-8577, Japan.
Endocrine therapy for breast cancer, which began with ovariectomy, has a history
of more than 100 years. Tamoxifen has been an epoch-making drug during the late
20th century. Recently LHRH analogues which work as downregulators of estrogen
production and many aromatase inhibitors (AI), both non-steroidal and steroidal
have been developed in Japan. Fadrozole was the only AI until anastrozole was
approved a few months ago. Letrozole was shown to be a better AI than fadrozole
by prospective randomized double blind examination; however, it is not licenced
yet. The reason is that the appropriate dosage is not identical to that of
Western countries. We have reached a time when order-made medicine should take
into consideration such differences as race and individuality.
Publication Types:
Review
Review, Tutorial
PMID: 11478137 [PubMed - indexed for MEDLINE]
9: Br J Clin Pharmacol 2001 May;51(5):429-35
The effect of anastrozole on the single-dose pharmacokinetics and anticoagulant
activity of warfarin in healthy volunteers.
Yates RA, Wong J, Seiberling M, Merz M, Marz W, Nauck M.
AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK.
AIMS: The aims of this study were to determine the effects of the nonsteroidal,
selective aromatase inhibitor, anastrozole, at steady-state concentrations, on
the pharmacokinetics and pharmacodynamics of warfarin, and to assess whether or
not anastrozole alone has any anticoagulant activity. METHODS: This was a
randomized, double-blind, placebo-controlled, two-way crossover trial conducted
at a single centre. The study comprised two treatment periods of 11 days,
separated by a 3 week washout. Healthy male volunteers (n = 16, median age 28.5
years) were randomized to receive either anastrozole (7 mg loading dose on day
1, followed by 1 mg daily on days 2-11) in the first treatment period and
placebo in the second treatment period, or vice versa. In addition to their
randomized treatment, all volunteers received a single dose of 25 mg warfarin on
day 3 of each treatment period. Blood samples for pharmacokinetic and
pharmacodynamic assessment were taken at frequent intervals during each
treatment period. The safety of volunteers was monitored throughout the study.
RESULTS: Administration of anastrozole resulted in no clinically significant
changes in the pharmacokinetics of either R- or S-warfarin compared with placebo
for AUC (ng ml-1 h) (glsmean, R-warfarin; anastrozole 93619.9, placebo 91127.91,
95%CI 0.988-1.068; S-warfarin; anastrozole 57129.21, placebo 55676.34, 95%CI
0.979-1.076), CL/F (ml min-1) (glsmean, R-warfarin; anastrozole 2.23, placebo
2.29, 95%CI 0.937-1.012; S-warfarin; anastrozole 3.65, placebo 3.74, 95%CI
0.929-1.021) and t1/2 (h) (lsmean, R-warfarin; anastrozole 55.40, placebo 55.15,
95%CI-2.083-2.592; S-warfarin; anastrozole 39.38, placebo 40.98,
95%CI-6.189-2.996). In addition, anastrozole had no clinically significant
effect on the pharmacodynamic effects of warfarin, as assessed 240 h after
warfarin dosing by measurement of prothrombin time (s) (glsmean, anastrozole
11.56, placebo 11.31, 95%CI 0.987-1.059), thrombin time (s) (glsmean,
anastrozole 19.06, placebo 18.75, 95%CI 0.980-1.054) activated partial
thromboplastin time (s) (glsmean, anastrozole 29.94, placebo 29.74, 95%CI
0.968-1.047) and factor VII (%) (glsmean, anastrozole 97.81, placebo 107.26,
95%CI 0.821-1.012). Anastrozole alone had no effect on these indicators of the
clotting process. CONCLUSIONS: Overall, there was no evidence to suggest that
anastrozole has any clinically relevant effects on the pharmacokinetics of
warfarin. Anastrozole had no effect on clotting mechanisms or on the
pharmacodynamic activity of warfarin, as assessed by prothrombin time, thrombin
time, activated partial thromboplastin time, and factor VII.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 11422000 [PubMed - indexed for MEDLINE]
10: Semin Oncol 2001 Jun;28(3):291-304
Endocrine therapy in the treatment of metastatic breast cancer.
Buzdar AU.
Department of Breast Medical Oncology, M.D. Anderson Cancer Center, 1515
Holcombe Blvd., Houston, TX 77037, USA.
The goals of treating patients with metastatic breast cancer are to prolong
survival, slow or halt disease progression, and enhance the patient's quality of
life. In patients with estrogen receptor (ER)-positive cancers that are not
progressing rapidly, endocrine therapy is generally the first treatment option.
If a patient initially responds to an endocrine agent and then progresses,
another endocrine agent may still provide benefit. Tamoxifen has been used as
first-line therapy for metastatic breast cancer for many years. Until recently,
no other endocrine agent has shown superiority to tamoxifen in this setting. The
nonsteroidal aromatase inhibitors, anastrozole and letrozole, have been widely
accepted as second-line therapy after failure of tamoxifen; they have replaced
megestrol acetate in this setting. Recently, anastrozole was shown to have at
least equivalent efficacy and a superior side effect profile compared with
tamoxifen for treating postmenopausal women in the first-line setting. Thus,
this aromatase inhibitor has become a viable option for first-line therapy in
postmenopausal women. Trials of letrozole in this setting are nearing
completion. Exemestane has been shown to be an effective second-line agent and
to have at least some efficacy as a third-line agent even after failure of a
nonsteroidal aromatase inhibitor. Results are anxiously awaited from trials of
new endocrine agents including the first member of a new class of endocrine
agent, the estrogen-receptor downregulator class. Semin Oncol 28:291-304.
Copyright 2001 by W.B. Saunders Company.
Publication Types:
Review
Review, Tutorial
PMID: 11402439 [PubMed - indexed for MEDLINE]
11: Drugs 2001;61(6):807-13; discussion 814
Fulvestrant.
Curran M, Wiseman L.
Adis International Limited, Mairangi Bay, Auckland, New Zealand.
[email protected]
Fulvestrant is a 7alpha-alkylsulphinyl analogue of estradiol that competes with
endogenous estrogen for binding to the estrogen receptor. Once bound to the
receptor, fulvestrant attenuates receptor dimerisation, effecting a rapid
degradation of the estrogen receptor protein and inhibition of transcription.
Fulvestrant is a potent inhibitor of the growth of human breast cancer cells in
vitro and in vivo. It has demonstrated pure anti-estrogenic activity in animal
systems. Intramuscular fulvestrant 250 mg once a month was as effective as the
oral aromatase inhibitor anastrozole 1 mg/day in 2 phase III trials in
postmenopausal women with advanced breast cancer who had received prior
endocrine therapy. Median time to disease progression (the primary end-point)
with fulvestrant and anastrozole was 5.4 and 3.4 months (North American trial)
and 5.5 and 5.1 months (European trial). The median duration of response was
19.3 and 10.5 months (North American trial) and 14.3 and 14.0 months (European
trial). The most common adverse events with fulvestrant are gastrointestinal
disturbances and hot flushes. Fulvestrant showed similar tolerability to
anastrozole in 2 phase III trials.
Publication Types:
Review
Review, Tutorial
PMID: 11398912 [PubMed - indexed for MEDLINE]
12: Strahlenther Onkol 2001 May;177(5):273-4
[Aromatase inhibitors: anastrozole versus tamoxifen as first-ine therapy for
advanced postmenopausal breast cancer].
[Article in German]
Bergmann L.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 11398617 [PubMed - indexed for MEDLINE]
13: J Clin Endocrinol Metab 2001 Jun;86(6):2869-74
The effect of aromatase inhibition on sex steroids, gonadotropins, and markers
of bone turnover in older men.
Taxel P, Kennedy DG, Fall PM, Willard AK, Clive JM, Raisz LG.
Division of Endocrinology and Metabolism, Center on Aging, University of
Connecticut Health Center, Farmington, Connecticut 06030-1317, USA.
[email protected]
There is evidence that estrogen decreases bone turnover in men as well as women.
We therefore hypothesized that older men would show increased bone resorption in
response to inhibition of the aromatase enzyme, which converts androgens to
estrogen. Fifteen eugonadal men over 65 yr were treated for 9 weeks with 2.0
mg/day of anastrozole, an aromatase inhibitor. After 9 weeks of treatment, there
were significant decreases in estradiol, estrone, and sex hormone-binding
globulin levels by 29%, 73%, and 16%, respectively, and total testosterone
increased significantly by 56%. Despite the limited decrease of estrogen and the
increase in testosterone, C-telopeptide of type 1 collagen showed a progressive
significant increase of 11%, 24%, and 33% (P for trend = 0.033) above baseline
at 3, 6, and 9 weeks, respectively. N-telopeptide of type 1 collagen values were
highly correlated with C-telopeptide of type 1 collagen, but the change in
N-telopeptide of type 1 collagen was not statistically significant.
Bone-specific alkaline phosphatase and N-terminal type I procollagen peptides
showed significant decreases of 8% and 11% of baseline at 9 weeks. Osteocalcin
decreased significantly by 30% at 18 weeks. We conclude that aromatase
inhibition can reduce estrogen levels in older men, but this effect is limited,
perhaps because of feedback stimulation of testosterone production, and that
endogenous estrogen derived from aromatization of testosterone plays a role in
bone metabolism of older men by limiting the rate of bone resorption.
PMID: 11397902 [PubMed - indexed for MEDLINE]
14: J Clin Endocrinol Metab 2001 Jun;86(6):2600-6
Aromatization mediates testosterone's short-term feedback restraint of 24-hour
endogenously driven and acute exogenous gonadotropin-releasing
hormone-stimulated luteinizing hormone and follicle-stimulating hormone
secretion in young men.
Schnorr JA, Bray MJ, Veldhuis JD.
Division of Endocrinology, Department of Internal Medicine, General Clinical
Research Center, Center for Biomathematical Technology, University of Virginia
School of Medicine, Charlottesville, Virginia 22908, USA.
The present clinical study examines the neuroregulatory hypothesis that feedback
restraint of LH and FSH secretion by testosterone requires in vivo
aromatization. To test this postulate, we prospectively and randomly assigned 47
healthy young men to 1 of 5 parallel short-term (5-day) double-blind
interventions with: 1) placebo; 2) high-dose ketoconazole (KTCZ, 400 mg orally 4
times daily) to block both Leydig-cell and adrenal steroidogenesis; 3) KTCZ and
transdermal testosterone delivery (7.5 mg daily); 4) KTCZ and transdermal
estradiol (0.05 mg daily); or 5) KTCZ, testosterone, and the selective and
potent aromatase inhibitor, anastrazole (5 mg orally twice daily). Blood was
sampled every 10 min for 27 h on the last day of intervention to quantitate 24-h
mean spontaneous and 3-h post-GnRH-stimulated (100 ng/kg iv bolus) LH and FSH
release. KTCZ administration lowered the serum total testosterone concentration
markedly from (mean +/- SEM) 423 +/- 57 ng/dL (15 +/- 2.0 nmo/L) during placebo
ingestion to 58 +/- 8.6 ng/dL (2.0 +/- 0.3 nmol/L) (P < 10(-3)). Transdermal
androgen addback along with KTCZ blockade increased testosterone levels to 607
+/- 57 ng/dL (21 +/- 2.0 nmol/L). KTCZ exposure alone drove a 3-fold increase in
serum LH concentrations (P < 10(-3)) and a 2.5-fold rise in FSH secretion (P =
0.015), as assessed by high-specificity immunoradiometric assays. Concomitant
transdermal testosterone (or estradiol) delivery repressed the elevated
secretion of both LH and FSH to mid-normal baseline values. A 3-fold
administration of anastrazole, KTCZ, and testosterone completely opposed
exogenous testosterone's suppression of 24-h LH and FSH secretion. Anastrazole
coadministration likewise abolished testosterone-dependent inhibition of 3-h
GnRH-stimulated LH and FSH release. In summary, assuming the specificity of
anastrazole's inhibition of aromatase activity, we conclude that circulating
testosterone in healthy men curtails endogenously driven as well as exogenous
GnRH-stimulated LH and FSH secretion conditional on its in vivo aromatization.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 11397860 [PubMed - indexed for MEDLINE]
15: Oncology (Huntingt) 2001 May;15(5 Suppl 7):28-34
Aromatase inhibition and antiestrogen therapy in early breast cancer treatment
and chemoprevention.
Ingle JN.
Mayo Clinic, Rochester, Minnesota, USA. [email protected]
The aromatase inhibitors represent an important class of hormonal agents for the
management of breast cancer. The third-generation aromatase inhibitors have
replaced megestrol acetate as second-line hormonal therapy in advanced breast
cancer, and large clinical trials are maturing to establish their efficacy
relative to tamoxifen (Nolvadex) in the first-line metastatic setting. The
increased potency, increased specificity, and established efficacy of aromatase
inhibitors in advanced breast cancer have provided the rationale for a large
number of randomized trials in the adjuvant setting evaluating anastrozole
(Arimidex), exemestane (Aromasin), and letrozole (Femara). These trials are
addressing the value of these agents in sequence with, instead of, and in
combination with tamoxifen. The relationship between estrogen exposure and
breast cancer risk has long been accepted and traditionally related to
estrogen-receptor-mediated events. The emergence of the estrogen genotoxicity
hypothesis as a mechanism for breast cancer carcinogenesis provides additional
rationale for considering aromatase inhibitors in the chemoprevention setting.
PMID: 11396362 [PubMed - in process]
16: J Steroid Biochem Mol Biol 2001 Jan-Mar;76(1-5):199-202
Intracellular aromatase and its relevance to the pharmacological efficacy of
aromatase inhibitors.
Bhatnagar AS, Brodie AM, Long BJ, Evans DB, Miller WR.
Novartis Pharma AG, CH-4002, Basel, Switzerland.
An important feature of the pharmacological profile of aromatase inhibitors is
the ability of the various inhibitors to inhibit intracellular aromatase. It is
now well documented that a large proportion of breast tumors express their own
aromatase. This intratumoral aromatase produces estrogen in situ and therefore
may contribute significantly to the amount of estrogen to which the cell is
exposed. Thus it is not only important that aromatase inhibitors potently
inhibit the peripheral production of estrogen and eliminate the external supply
of estrogen to the tumor cell, but that they in addition potently inhibit
intratumoral aromatase and prevent the tumor cell from making its own estrogen
within the cell. To study the inhibition of intracellular aromatase we have
compared the aromatase-inhibiting potency of the non-steroidal aromatase
inhibitors, letrozole, anastrozole and fadrozole in a variety of model cellular
endocrine and tumor systems which contain aromatase. We have used hamsters
ovarian tissue fragments, adipose tissue fibroblasts from normal human breast,
the MCF-7Ca human breast cancer cell line transfected with the human aromatase
gene and the JEG-3 human choriocarcinoma cell line. Although letrozole and
anastrozole are approximately equipotent in a cell-free aromatase system (human
placental microsomes), letrozole is consistently 10-30 times more potent than
anastrozole in inhibiting intracellular aromatase in intact rodent cells, normal
human adipose fibroblasts and human cancer cell lines. Whether these differences
between letrozole and anastrozole are seen in the clinical setting will have to
await the results of clinical trials which are currently in progress.
PMID: 11384878 [PubMed - indexed for MEDLINE]
17: Vopr Onkol 2001;47(2):195-9
[Modern approaches to hormone therapy of breast cancer as a reflection of
pathogenesis of the disease].
[Article in Russian]
Semiglazov VP.
N.N. Petrov Research Institute of Oncology, Ministry of Health of the RF, St.
Petersburg.
Experimental and epidemiological studies have pointed to a major role of
estrogens in the pathogenesis of human breast cancer. The Oxford meta-analysis
(1998) once again confirmed the efficacy of antiestrogens (tamoxifen) as
adjuvant therapy. We need to know whether the new non-steroid antiestrogens
(idoxifen, droloxifen and TAT-59) and selective estrogen receptor modulator
(raloxifen), whith preclinical characteristics better than those of tamoxifen
will be more efficient clinically. Large-scale trials to compare the new drugs
with tamoxifen are under way. Faslodex, a pure antiestrogen, looks highly
promising, too. Zoladex, a luteinising hormone-releasing hormone agonist, is
looking as a better choice than ovariectomy or irradiation of the pelvis for
ovarian ablation in premenopausal breast cancer. New aromatase inhibitors are
more efficient than progestins and much safer than aminoglutethimide. It has
been shown recently that these inhibitors keep metastatic breast cancer at bay
longer, and with longer survival. The non-steroid inhibitors (anastrozole and
letrozole) and the steroid oral drug exemestane are undergoing clinical trials
as means of adjuvant treatment of breast cancer. The trial of arimidex and
tamoxifen administered alone or in combination (ATAC) is unique since it is
using a combination of tamoxifen and an aromatase inhibitor (anastrozole). New
methods of endocrine therapy have resulted in less toxic and more convenient
procedures. Also, longer therapeutic effects and survival are becoming more
apparent.
PMID: 11383456 [PubMed - indexed for MEDLINE]
18: J Clin Oncol 2001 May 15;19(10):2767
Aromatase inhibitors and arthralgia.
Donnellan PP, Douglas SL, Cameron DA, Leonard RC.
Publication Types:
Letter
PMID: 11352973 [PubMed - indexed for MEDLINE]
19: Clin Cancer Res 2001 May;7(5):1230-6
Influence of neoadjuvant anastrozole (Arimidex) on intratumoral estrogen levels
and proliferation markers in patients with locally advanced breast cancer.
Geisler J, Detre S, Berntsen H, Ottestad L, Lindtjorn B, Dowsett M, Einstein
Lonning P.
Department of Oncology, Haukeland University Hospital, N-5021 Bergen, Norway.
Anastrozole (Arimidex) is a novel, selective, and potent aromatase inhibitor
used for the treatment of postmenopausal breast cancer. The drug has been shown
to inhibit in vivo aromatization by 96--97% and to suppress plasma estrogen
levels by 84--94%. However, the effects of anastrozole on intratumoral estrogen
levels have not been studied. Here we report the effects of neoadjuvant
treatment with anastrozole on intratumoral levels of estrone (E(1)), estradiol
(E(2)), and estrone sulfate (E(1)S), measured by a highly sensitive RIA
following a multistep purification procedure involving high-pressure liquid
chromatography. Tumor tissue was obtained prior to treatment and after 15 weeks
on therapy with anastrozole (1 mg once daily) from 12 postmenopausal women with
locally advanced breast cancer (T(3)--T(4) and/or N(2)). Pretreatment tissue
levels of E(2), E(1), and E(1)S were 217.9 (69.8--679.9), 173.6 (83.9--358.9),
and 80.7 (31.4--207.3) fmol/g tissue (geometric mean values with 95% confidence
interval, respectively). Treatment with anastrozole suppressed tissue E(2),
E(1), and E(1)S levels by 89.0% (73.2--95.5%), 83.4% (63.2--92.5%), and 72.9%
(47.3--86.1%), respectively, compared with baseline levels, with no significant
difference between responders and nonresponders. Plasma levels of E(2), E(1),
and E(1)S were suppressed by 86.1, 83.9, and 94.2%, respectively. Anastrozole
caused a decrease in the immunoexpression of the proliferation markers Ki67 and
pS2 in all of the patients, with a trend for a more profound suppression in
those achieving an objective response. The mean percentage of apoptotic cells
was found to be decreased in responders and increased in nonresponders after 15
weeks of anastrozole therapy. Our results reveal anastrozole to cause a
significant suppression of tissue estrogen levels and to influence the biology
of primary estrogen receptor-positive breast cancers in postmenopausal women.
Publication Types:
Clinical Trial
PMID: 11350888 [PubMed - indexed for MEDLINE]
20: Breast J 1999 May;5(3):176-181
Efficacy of Anastrozole in a Consecutive Series of Advanced Breast Cancer
Patients Treated with Multiple Prior Chemotherapies and Endocrine Agents: M. D.
Anderson Cancer Center Experience.
Knoche AJ, Michaud LB, Buzdar AU.
University of Texas M. D. Anderson Cancer Center, Houston, Texas.
Anastrozole is a highly selective, nonsteroidal aromatase inhibitor approved by
the U.S. Food and Drug Administration (FDA) in January 1996 for the treatment of
advanced breast cancer in postmenopausal women with disease progression
following tamoxifen therapy. To date, information on anastrozole's use has been
limited to breast cancer patients with minimal prior therapy. The purpose of
this review was to determine, in clinical practice, the benefits of anastrozole
in advanced breast cancer patients treated with multiple prior cytotoxic and
endocrine therapies. This was a retrospective review of a consecutive series of
117 patients who received anastrozole after marketing in January 1996. As this
was not a prospective study, rigorous response criteria could not be applied.
Responses were categorized as improvement in disease (ID), stable disease (SD),
or progressive disease (PD). One hundred eight patients were evaluable for
response with a median age of 61 years and the number of prior therapies ranging
from one to nine. Response, defined as improvement of disease or stable disease
>/=8 weeks, was seen in 59% of patients. Patients with three or more prior
endocrine therapies demonstrated a 61% response (ID + SD) and patients with
ER-negative tumors demonstrated 50% response. Patients with prior
aminoglutethamide therapy exhibited similar response rates to the overall group.
One male patient received anastrozole without benefit. This data determines the
activity of anastrozole even in heavily pretreated patients and suggests that
patients who have tumors that are ER-negative may also benefit from anastrozole
therapy.
PMID: 11348281 [PubMed - as supplied by publisher]
21: J Clin Oncol 2001 May 1;19(9):2580; discussion 2580-2
Is anastrozole superior to tamoxifen as first-line therapy for advanced breast
cancer?
Costa SD, Kaufmann M.
Publication Types:
Letter
PMID: 11331346 [PubMed - indexed for MEDLINE]
22: J Clin Oncol 2001 May 1;19(9):2579-80; discussion 2580-2
Is anastrozole superior to tamoxifen as first-line therapy for advanced breast
cancer?
Tonkin K.
Publication Types:
Letter
PMID: 11331344 [PubMed - indexed for MEDLINE]
23: J Clin Oncol 2001 May 1;19(9):2578; discussion 2580-2
Is anastrozole superior to tamoxifen as first-line therapy for advanced breast
cancer?
Copur MS, Ledakis P, Bolton M, Norvell M, Muhvic J.
Publication Types:
Letter
PMID: 11331343 [PubMed - indexed for MEDLINE]
24: J Clin Oncol 2001 May 1;19(9):2578-9; discussion 2580-2
Is anastrozole superior to tamoxifen as first-line therapy for advanced breast
cancer?
Bagley CM Jr, Rowbotham RK.
Publication Types:
Letter
PMID: 11331342 [PubMed - indexed for MEDLINE]
25: J Clin Oncol 2001 May 1;19(9):2578; discussion 2580-2
Is anastrozole superior to tamoxifen as first-line therapy for advanced breast
cancer?
Panasci LC.
Publication Types:
Letter
PMID: 11331341 [PubMed - indexed for MEDLINE]
26: Gan To Kagaku Ryoho 2001 Apr;28(4):549-60
[Development of a novel aromatase inhibitor, anastrozole (Arimidex)--its basic
and clinical studies].
[Article in Japanese]
Tsukagoshi S.
Cancer Institute, Japanese Foundation for Cancer Research.
Anastrozole (JAN), developed by Zeneca UK (presently AstraZeneca UK), is a new
aromatase inhibitor which belongs to triazole. Anastrozole shows selective
aromatase inhibition and negligible effects on other steroid hormone
biosyntheses. The daily dose of 3 mg/kg anastrozole inhibited the growth of DMBA
mammary tumours significantly. Anastrozole inhibited the tumor growth at 5
micrograms/mouse/day (s.c.) in androstenedione-treated ovariectomized nude mice
inoculated with MCF-7CA cells transfected with aromatase gene. In the Japanese
Phase IIa study, the response rate was 27.8% (10/36) in the 0.5 mg group, and
38.2% (13/34) in the 1 mg group. The most common adverse drug reactions were
leucopenia in the 0.5 mg group, and LDH increased and leucopenia in the 1 mg
group. There were no early deaths, other serious adverse events, or adverse drug
reactions of grade 3 or above in this trial; anastrozole was well tolerated. In
the Japanese Phase IIb study, the response rates were 33.3% (117/351 patients)
and 32.8% (114/348 patients) for anastrozole and tamoxifen, respectively,
showing non-inferiority of anastrozole. The median time to disease progression
(TTP) was 251 days and 252 days for anastrozole and tamoxifen, respectively.
Group comparison using a Cox regression model revealed non-inferiority of
anastrozole. Therefore, anastrozole was found to be at least as effective as
tamoxifen (in the response rate and TTP). In US study compared anastrozole with
tamoxifen, TTP with anastrozole is a significantly longer than that of tamoxifen
(p = 0.005, two-sides). Anastrozole has shown to be at least as effective as
tamoxifen, standard endocrine therapy for breast cancer, with good safety
profiles. Thus, anastrozole is a promising first-line endocrine therapy in the
treatment of postmenopausal breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 11329794 [PubMed - indexed for MEDLINE]
27: Tumori 2000 Nov-Dec;86(6):A13-8
[National Conference of Medical Oncology. Controversies in the treatment of
breast cancer. Genova, October 28, 2000].
[Article in Italian]
Longo F.
Publication Types:
Congresses
PMID: 11271674 [PubMed - indexed for MEDLINE]
28: Curr Med Res Opin 2001;16(4):276-84
The Twenty-third Annual San Antonio Breast Cancer Symposium.
Mokbel K.
St George's Hospital, Blackshaw Road, London SW17 0QT, UK.
[email protected]
This paper reviews the recent Twenty-third Annual San Antonio Breast Cancer
Symposium. A total of 580 studies were presented either orally or as posters.
Two phase III multi-centre clinical trials found that fulvestrant (Falsodex),
given as a once-monthly intramuscular injection (250 mg), was well-tolerated and
at least as good as anastrozole (1 mg) in postmenopausal women with advanced
breast cancer that had progressed or recurred on prior endocrine therapy.
Another phase III randomised trial found that letrozole (2.5 mg daily) was
superior to tamoxifen as a neoadjuvant therapy in postmenopausal women with ER-
and/or PgR-positive breast cancer unsuitable for breast-conserving surgery. In a
phase III study, capecitabine (Xeloda) was found to be well-tolerated and able
to improve survival by three months when added to Taxotere. Cutting edge data on
microarray gene profiling in breast cancer were presented. The potential role of
this new technology in predicting outcome and selecting therapy was discussed.
Furthermore, its limitations and the need for validation were highlighted. The
role of new diagnostic tools, such as fibre-optic ductoscopy (FDS) and
microcatheters to obtain ductal cells, was discussed. Finally, the worldwide
overview was presented.
Publication Types:
Congresses
PMID: 11268712 [PubMed - indexed for MEDLINE]
29: Bull Cancer 2000 Dec;87 Spec No:31-39
[Aromatase inhibitors: a review of clinical trials].
[Article in French]
Kerbrat P, Lefeuvre C.
Departement d'oncologie medicale, Centre Eugene-Marquis, rue de la
Bataille-Flandres-Dunkerque, CS 44229, 35042 Rennes Cedex, France.
To increase the therapeutic index of second line hormonal treatment of breast
cancer, new aromatase inhibitors have been synthetized; they belong to two
groups: type I (formestane and exemestane) are steroidal irreversible and
specific inhibitors, type II (anastrozole, letrozole and vorozole) are non
steroidal reversible inhibitors, interfering with the aromatase heme. Several
phase II and III trials demonstrated that these drugs are, at least, as active
as aminoglutethimid or progestins in second line treatment, and are less toxic.
Recently, an identical activity have been observed for anastrozole and tamoxifen
in first line. In metastatic and adjuvant settings, large trials are ongoing to
clarify the exact value of these drugs.
Publication Types:
Review
Review Literature
PMID: 11250606 [PubMed - indexed for MEDLINE]
30: Bull Cancer 2000 Dec;87 Spec No:23-29
[Aromatase inhibitors: pharmacological aspects].
[Article in French]
de Cremoux P.
Laboratoire de physiopathologie et de pharmacologie, Institut Curie, 26, rue
d'Ulm, 75248 Paris Cedex 05, France.
Selective new aromatase inhibitors are a new class of agents that are of
considerable interest in the treatment of hormone-dependent breast cancer in
postmenopausal women. Aromatase is an enzymic complex that catalyses the
conversion of the adrenal androgens androstenedione and testosterone to estrone.
In postmenopausal women, the process of peripheral aromatisation accounts for
the majority of circulating estrogens. The selective inhibition of estrogen
production by aromatase inhibitors is an efficient strategy for breast cancer
treatment. These compounds are classified as irreversible inhibitors of
aromatase (type I), and comprise steroidal compounds. Reversible inhibitors of
aromatase, which comprises non-steroidal compounds are type II aromatase
inhibitors. Second and third generation aromatase inhibitors are considerably
more potent and more specific in their ability to inhibit aromatase, as compared
with first generation compounds (aminoglutethimide).
Publication Types:
Review
Review Literature
PMID: 11250605 [PubMed - indexed for MEDLINE]
31: Bull Cancer 2000 Dec;87 Spec No:7-22
[Preclinical evaluation of aromatase inhibitors antitumor activity].
[Article in French]
Auvray P, Bichat F, Genne P.
Oncodesign Biotechnology, Parc technologique de la Toison-d'Or, 28, rue de
Broglie, 21000 Dijon, France.
Aromatase is an enzymatic complex responsible for the conversion of androgens
into estrogens; these hormones are important in development, reproduction, but
also in the growth of estrogen-dependent cancer. This enzyme is present in
60-70% of the breast cancer. The aromatase inhibitors are important drugs in the
breast cancer treatment of postmenopausal women. In order to study their in vivo
activity, animal models have been developed, e.g. rat with tumour induced by
7,12-dimethylbenz[a]anthracene, PMSG-primed immature rat or athymic nude mice
with aromatase transfected MCF-7 xenograft. In this review, we were interested
in preclinical results obtained with both classes: steroidal and nonsteroidal
inhibitors. The former group, as substrate analogs formestane or exemestane, are
irreversible, selective and long-lasting inhibitors of aromatase. The
nonsteroidal molecules, such as letrozole or anastrozole, are reversible
inhibitors with high affinity. Finally, knowledge of the enzyme active site,
with molecular modeling and site-directed mutagenesis, could be useful to
develop new inhibitor families, more specific and potent in vivo.
Publication Types:
Review
Review Literature
PMID: 11250604 [PubMed - indexed for MEDLINE]
32: Mol Reprod Dev 2001 Apr;58(4):417-23
Estrogenic upregulation of DNA polymerase beta in oocytes of preovulatory ovine
follicles.
Murdoch WJ, Van Kirk EA.
Department of Animal Science, University of Wyoming, Laramie, Wyoming.
The basic premise of this investigation was that local hormonal control of
stockpiling of the base excision repair polymerase (poly) beta within oocytes of
preovulatory follicles occurs as a function of cytoplasmic maturation. There was
an increase in immunoreactive poly beta in sectioned oocytes of preovulatory
ovine follicles during a 12-36-hour interval following the onset of
prostaglandin (PG) F2alpha-induced (Day 14 of the estrous cycle) luteal
regression; this response was not observed in subordinate (nonovulatory)
follicles. Accumulation of poly beta in oocytes at 36 hr after PGF2alpha was
negated by treatment of ewes at 12 hr with the aromatase inhibitor Arimidex or
an ovulatory dose of GnRH (which, via surge gonadotropin stimulation, acutely
downregulates the proestrous rise in follicular estrogen biosynthesis).
Estradiol-17beta stimulated poly beta expression (transcriptional control) in
oocytes of explanted (12 hr after PGF2alpha) follicles (24-hour incubation). We
suggest that a critical period of estrogen amplification in the preovulatory
follicle underscores the capacity of its oocyte to efficiently repair DNA and
therefore reconcile spontaneous infidelities in genomic integrity that
inevitably occur during preimplantation embryogenesis.
PMID: 11241778 [PubMed - indexed for MEDLINE]
33: Nippon Rinsho 2001 Jan;59 Suppl 1:157-60
[Endometriosis and aromatase inhibitor].
[Article in Japanese]
Takayama K, Bulun SE.
Yamagata Prefectural Central Hospital.
Publication Types:
Review
Review, Tutorial
PMID: 11235156 [PubMed - indexed for MEDLINE]
34: J Clin Endocrinol Metab 2001 Jan;86(1):53-8
Differential regulation of gonadotropin secretion by testosterone in the human
male: absence of a negative feedback effect of testosterone on
follicle-stimulating hormone secretion.
Hayes FJ, DeCruz S, Seminara SB, Boepple PA, Crowley WF Jr.
Reproductive Endocrine Unit of the Department of Medicine and National Center
for Infertility Research, Massachusetts General Hospital, Boston, Massachusetts
02114, USA. [email protected]
Studies of sex steroid regulation of gonadotropin secretion in the human male
have focused primarily on the respective site(s) of negative feedback of
testosterone (T) and estradiol (E(2)). The use of pharmacological doses of sex
steroids in these studies has precluded conclusions about the relative roles of
T and E(2) in gonadotropin feedback. Thus, the aims of the present study were to
1) determine the relative contributions of T vs. E(2) to the sex steroid
component of gonadotropin regulation, and 2) distinguish the feedback effects of
T that that are direct (i.e. mediated by the androgen receptor) vs. indirect
(mediated by aromatization to E(2)). Two experimental interventions were used:
1) inhibition of aromatization by a selective aromatase inhibitor to examine the
impact of selective E(2) withdrawal; and 2) acute medical castration to examine
the effect of ablating both T and E(2). Sixteen normal (NL) men (mean age, 30.5
+/- 2.2 yr) were studied. Nine NL subjects were treated with the aromatase
inhibitor, anastrozole (10 mg, orally, daily, for 5 days). Twelve NL men
underwent medical castration with ketoconazole (1-g loading dose followed by 400
mg, orally, four times a day for 5 days). Ketoconazole-treated subjects received
concomitant treatment with dexamethasone (0.5 mg twice daily) to prevent the
development of adrenal insufficiency. Single blood samples were drawn daily
between 0800-1000 h. To ensure that dexamethasone was not altering the
gonadotropin response to sex steroid ablation by a direct pituitary effect, five
GnRH-deficient men (mean age, 37.6 +/- 3.9 yr) underwent GnRH dose-response
studies at baseline and after treatment with dexamethasone (0.5 mg twice daily).
Aromatase blockade caused significant lowering of E(2) (33 +/- 3 to 14 +/- 1
pg/mL; P: < 0.0005) with a corresponding increase in T levels (563 +/- 42 to 817
+/- 81 ng/dL; P: < 0.05). Treatment with ketoconazole resulted in equivalent
suppression of E(2) (41 +/- 4 to 14 +/- 1 pg/mL; P: < 0.0005), but also induced
castrate levels of T (491 +/- 28 to 40 +/- 3 ng/dL; P: < 0.0005). Both treatment
regimens were associated with a significant increase in gonadotropin levels. For
LH, the percent increase in serum levels after castration was almost 3-fold
greater than that seen after selective E(2) withdrawal (275 +/- 23% with
ketoconazole vs. 95.6 +/- 21% with anastrozole; P: < 0.005). Despite the
divergent changes in T levels with these two maneuvers (a marked decrease after
ketoconazole and a significant increase with anastrozole), the percent rise in
FSH levels was similar in the two protocols (91 +/- 6% vs. 71 +/- 7%,
respectively; P: = NS). Inhibin B levels were unchanged after selective E(2)
withdrawal (156 +/- 23 vs. 176 +/- 19 pg/mL), but decreased slightly with
ketoconazole (156 +/- 15 to 131 +/- 11 pg/mL; P: < 0.05). In contrast to the
effects of glucocorticoid administration on gonadotropin secretion in women, no
significant changes were observed in the GnRH-deficient men treated with
dexamethasone in terms of mean LH levels (19.8 +/- 3.2 vs. 23.3 +/- 5.4 IU/L),
mean LH pulse amplitude after GnRH (16.0 +/- 2.5 vs. 19.0 +/- 5.1 IU/L), or mean
FSH levels (8.0 +/- 1.9 vs. 9.2 +/- 2.4 IU/L, pre vs. post). These studies
provide evidence of differential regulation of gonadotropin secretion by T in
the human male. T exerts both direct and indirect feedback on LH secretion,
whereas its effects on FSH appear to be mediated largely by aromatization to
E(2). From these data we conclude that in terms of sex steroid feedback, E(2) is
the predominant regulator of FSH secretion in the human male.
PMID: 11231978 [PubMed - indexed for MEDLINE]
35: J Endocrinol Invest 2000 Dec;23(11):721-3
Delayed closure of epiphyseal cartilages induced by the aromatase inhibitor
anastrozole. Would it help short children grow up?
Faglia G, Arosio M, Porretti S.
Institute of Endocrine Sciences, Ospedale Maggiore IRCCS, University of Milan,
Italy. [email protected]
Estrogens locally generated from androgen precursors due to the action of
aromatase play a main role in epiphyseal cartilage fusion. Treatment with an
aromatase inhibitor (anastrozole, 1 mg/day for 3 yr) in a boy previously
operated on for a hamartoma causing precocious puberty and presenting with
advanced bone maturation and nearly fused epiphyseal cartilages, slowed
cartilage fusion consenting a higher final stature than expected (164.4 cm vs
158.4 cm). It is suggested that treatment with aromatase inhibitors, alone or in
combination with rh-GH, may also be useful in children with constitutional short
stature in order to delay epiphyseal closure and improve the final height.
PMID: 11194703 [PubMed - indexed for MEDLINE]
36: Oncologist 2001;6(1):4-11
Drug approval summaries: arsenic trioxide, tamoxifen citrate, anastrazole,
paclitaxel, bexarotene.
Cohen MH, Hirschfeld S, Flamm Honig S, Ibrahim A, Johnson JR, O'Leary JJ, White
RM, Williams GA, Pazdur R.
Division of Oncology Drug Products, Center for Drug Evaluation and Research,
U.S. Food and Drug Administration, Rockville, Maryland 20852, USA.
[email protected]
This report summarizes information on drugs recently approved by the Food and
Drug Administration, Office of Drug Evaluation I, Division of Oncology Drug
Products. Five applications supporting new claims will be discussed: Trisenox
(arsenic trioxide) for induction of remission and consolidation in patients with
acute promyelocytic leukemia who are refractory to, or have relapsed from,
retinoid and anthracycline chemotherapy, and whose disease is characterized by
the presence of the t(15;17) translocation or PML/RAR-alpha gene expression;
Nolvadex (tamoxifen citrate) in women with ductal carcinoma in situ, following
breast surgery and radiation, to reduce the risk of invasive breast cancer;
Arimidex (anastrazole) for first-line treatment of postmenopausal women with
hormone receptor positive or hormone receptor unknown locally advanced or
metastatic breast cancer; Taxol (paclitaxel), 175 mg/m(2) by 3 h infusion in
combination with cisplatin for first-line treatment of advanced ovarian cancer;
and Targretin gel (bexarotene) for the topical treatment of cutaneous lesions in
patients with stage IA and IB cutaneous T-cell lymphoma who have not tolerated
other therapies or who have refractory or persistent disease. Information
provided includes rationale for drug development, study design, efficacy and
safety results, and pertinent literature references.
PMID: 11161223 [PubMed - indexed for MEDLINE]
37: J Clin Oncol 2001 Feb 1;19(3):881-94
Aromatase inhibitors in the treatment and prevention of breast cancer.
Goss PE, Strasser K.
Division of Hematology/Oncology, Princess Margaret Hospital, Toronto, Ontario,
Canada. [email protected]
PURPOSE: The purpose of this article is to provide an overview of the current
clinical status and possible future applications of aromatase inhibitors in
breast cancer. METHODS: A review of the literature on the third-generation
aromatase inhibitors was conducted. Some data that have been presented but not
published are included. In addition, the designs of ongoing trials with
aromatase inhibitors are outlined and the implications of possible results
discussed. RESULTS: All of the third-generation oral aromatase
inhibitors--letrozole, anastrozole, and vorozole (nonsteroidal, type II) and
exemestane (steroidal, type I)--have now been tested in phase III trials as
second-line treatment of postmenopausal hormone-dependent breast cancer. They
have shown clear superiority compared with the conventional therapies and are
therefore considered established second-line hormonal agents. Currently, they
are being tested as first-line therapy in the metastatic, adjuvant, and
neoadjuvant settings. Preliminary results suggest that the inhibitors might
displace tamoxifen as first-line treatment, but further studies are needed to
determine this. CONCLUSION: The role of aromatase inhibitors in premenopausal
breast cancer and in combination with chemotherapy and other anticancer
treatments are areas of future exploration. The ongoing adjuvant trials will
provide important data on the long-term safety of aromatase inhibitors, which
will help to determine their suitability for use as chemopreventives in healthy
women at risk of developing breast cancer.
Publication Types:
Review
Review Literature
PMID: 11157042 [PubMed - indexed for MEDLINE]
38: Ann Oncol 2000 Nov;11(11):1371-3
Clinical trials in cancer: what makes for a successful study?
Tobias JS, Baum M, Thornton H.
Publication Types:
Editorial
PMID: 11142473 [PubMed - indexed for MEDLINE]
39: Toxicol Lett 2001 Jan 3;118(3):165-9
The uterotrophic activity of nonylphenol in the rat is not mediated by aromatase
enzyme induction.
Odum J, Tinwell H, Van Miller J, Joiner R, Ashby J.
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, SK10 4TJ,
Cheshire, UK.
p-Nonylphenol (NP) is weakly estrogenic to rodents and to some species of fish.
All evidence to date has indicated that the estrogenic effects of NP are due to
the interaction of NP with the estrogen receptor. Recent findings of increased
plasma estradiol in fish exposed to NP have, however, led to the proposal of an
alternative mechanism for NP-induced estrogenicity in this species, possibly via
induction of aromatase enzymes. In the present studies, this hypothesis was
investigated in rats using the aromatase inhibitor anastrozole. The results
indicated that the uterotrophic action of NP, as with estradiol used as a
positive control, is mediated directly by its interaction with uterine ER,
rather than an indirect effect via aromatase enzyme induction. Circulating
levels of estradiol were unchanged after NP treatment and the aromatase
inhibitor anastrozole failed to inhibit NP-induced uterine growth. These results
are consistent with previous published data on NP in rodents.
PMID: 11137323 [PubMed - indexed for MEDLINE]
40: Anticancer Drugs 2000 Oct;11(9):701-6
Survival in patients with metastatic breast cancer: analysis of randomized
studies comparing oral aromatase inhibitors versus megestrol.
Messori A, Cattel F, Trippoli S, Vaiani M.
Laboratorio SIFO di Farmacoeconomia, Centro Informazione Farmaci, Azienda
Ospedaliera Careggi, Florence, Italy. [email protected]
In patients with metastatic breast cancer, second-line therapy with aromatase
inhibitors can improve survival in comparison with megestrol. We conducted a
meta-analysis to assess the effectiveness of aromatase inhibitors versus
megestrol. After a Medline search, three trials (evaluating letrozole,
anastrozole or exemestane versus megestrol) were included in the survival
meta-analysis. Our methodology retrieved patient-level information on survival.
In comparison with megestrol, aromatase inhibitors prolonged survival at levels
of statistical significance (relative death risk for oral aromatase
inhibitors=0.79, 95% confidence interval 0.69-0.91; p=0.0011). A lifetime
analysis of the pooled survival curves of aromatase inhibitors versus megestrol
found a mean survival gain of 4.1 months per patient. Aromatase inhibitors
confer a significant survival benefit to patients with metastatic breast cancer
as compared with megestrol. A preliminary calculation of the cost per life year
gained shows that the pharmacoeconomic profile of these drugs is favorable.
Publication Types:
Meta-Analysis
PMID: 11129731 [PubMed - indexed for MEDLINE]
41: J Clin Oncol 2000 Dec 15;18(24):4109
Clarification of anastrozole/megestrol acetate trial program design.
Howell A.
Publication Types:
Letter
PMID: 11118472 [PubMed - indexed for MEDLINE]
42: Breast Cancer 2000;7(4):345-9
Endocrine options for breast cancer treatment: looking beyond tamoxifen.
Watanabe T, Sonoo H.
Department of Internal Medicine, National Cancer Center Hospital, 5-1-1 Tsukiji,
Chuo-ku, Tokyo 104-0045, Japan.
PMID: 11114863 [PubMed - indexed for MEDLINE]
43: Oncology 2000;59 Suppl 1:19-23
Gonadotropins stimulate growth of MCF-7 human breast cancer cells by promoting
intracellular conversion of adrenal androgens to estrogens.
Tanaka Y, Kuwabara K, Okazaki T, Fujita T, Oizumi I, Kaiho S, Ogata E.
Third Department of Internal Medicine, National Defense Medical College,
Tokorozawa, Saitama, Japan. [email protected]
Estrogen receptor (ER)-positive breast cancers initially respond well to
estrogen ablation treatment but finally acquire refractoriness, the phenomenon
that is a major clinical problem. Because some breast cancers synthesize
estradiol (E(2)) and E(2) synthesis is regulated by gonadotropins in normal
ovaries, and because circulating gonadotropins are elevated in postmenopausal
women and during estrogen ablation treatment, we hypothesized that gonadotropins
might modulate estrogen synthesis/metabolism in breast cancer tissue as well. To
test this possibility, MCF-7 cells were treated with dehydroepiandrosterone
(DHEA) or human chorionic gonadotropin (hCG; approximately LH), each alone or in
combination. Cell growth (3-day treatment) was assayed by the MTT method and
estrogen synthesis (24-hour treatment) was measured using the ERE-luciferase
reporter system. First, MCF-7 cell growth was stimulated by DHEA in a
concentration-dependent manner with a maximal effect at 10(-4) M. Although hCG
alone did not have a significant proliferative effect, hCG significantly and
dose dependently stimulated MCF-7 cell growth in the presence of a submaximal
concentration of DHEA (10(-7 )M). This stimulatory effect of DHEA and hCG was
blocked by a pure antiestrogen ICI182,780 and an aromatase inhibitor, arimidex.
Using MCF-7 cells transfected with the ERE-luciferase reporter system, hCG
treatment was shown to increase ERE-mediated transcription. These results
indicate that MCF-7 cells intrinsically converted DHEA into E(2) upon hCG
stimulation, then grew their own cells DHEA- and hCG-dependently. We conclude
that gonadotropins can act on breast cancer cells and accelerate conversion of
DHEA into estrogens, thereby stimulating growth of estrogen-dependent tumor
cells. This phenomenon, at least in part, could explain: (1) an increased tissue
concentration of E(2) in postmenopausal breast cancer; (2) acquisition of
hormone refractoriness during estrogen ablation treatment, and (3) the
effectiveness of GnRH antagonist/superagonist in some postmenopausal breast
cancer patients. Copyright 2000 S. Karger AG, Basel
PMID: 11096352 [PubMed - indexed for MEDLINE]
44: J Clin Oncol 2000 Nov 15;18(22):3758-67
Anastrozole is superior to tamoxifen as first-line therapy for advanced breast
cancer in postmenopausal women: results of a North American multicenter
randomized trial. Arimidex Study Group.
Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, Steinberg M,
Webster A, von Euler M.
Cancer-Cross Institute, Edmonton, Alberta, Canada. jean-marc.nabholtz@bcom
PURPOSE: The efficacy and tolerability of anastrozole (Arimidex; AstraZeneca,
Wilmington, DE, and Macclesfield, United Kingdom) and tamoxifen were compared as
first-line therapy for advanced breast cancer in 353 postmenopausal women.
PATIENTS AND METHODS: The randomized, double-blind, multicenter study was
designed to evaluate anastrozole 1 mg once daily relative to tamoxifen 20 mg
once daily in patients with hormone receptor-positive tumors or tumors of
unknown receptor status who were eligible for endocrine therapy. Primary end
points were objective response (OR), defined as complete (CR) or partial (PR)
response, time to progression (TTP), and tolerability. RESULTS: Anastrozole was
as effective as tamoxifen in terms of OR (21% v 17% of patients, respectively),
with clinical benefit (CR + PR + stabilization > or = 24 weeks) observed in 59%
of patients on anastrozole and 46% on tamoxifen (two-sided P =.0098,
retrospective analysis). Anastrozole had a significant advantage over tamoxifen
in terms of TTP (median TTP of 11.1 and 5.6 months for anastrozole and
tamoxifen, respectively; two-sided P =.005). The tamoxifen:anastrozole hazards
ratio was 1.44 (lower one-sided 95% confidence limit, 1.16). Both treatments
were well tolerated. However, thromboembolic events and vaginal bleeding were
reported in fewer patients who received anastrozole compared with those who
received tamoxifen (4.1% v 8.2% [thromboembolic events] and 1.2% v 3.8% [vaginal
bleeding], respectively). CONCLUSION: Anastrozole satisfied the predefined
criteria for equivalence to tamoxifen. Furthermore, we observed both a
significant increase in TTP and a lower incidence of thromboembolic events and
vaginal bleeding with anastrozole. These findings indicate that anastrozole
should be considered as first-line therapy for postmenopausal women with
advanced breast cancer.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 11078488 [PubMed - indexed for MEDLINE]
45: J Clin Oncol 2000 Nov 15;18(22):3748-57
Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in
668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group
Efficacy and Tolerability study.
Bonneterre J, Thurlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P,
Vergote I, Webster A, Steinberg M, von Euler M.
Centre Oscar Lambret, Lille, France. [email protected]
PURPOSE: To compare the efficacy and tolerability of anastrozole (Arimidex;
AstraZeneca, Wilmington, DE, and Macclesfield, United Kingdom) with that of
tamoxifen as first-line therapy for advanced breast cancer (ABC) in
postmenopausal women. PATIENTS AND METHODS: This randomized, double-blind,
multicenter study evaluated the efficacy of anastrozole 1 mg once daily relative
to tamoxifen 20 mg once daily in patients with tumors that were hormone
receptor-positive or of unknown receptor status who were eligible for endocrine
therapy. The primary end points were time to progression (TTP), objective
response (OR), and tolerability. RESULTS: A total of 668 patients (340 in the
anastrozole arm and 328 in the tamoxifen arm) were randomized to treatment and
followed-up for a median of 19 months. Median TTP was similar for both
treatments (8.2 months in patients who received anastrozole and 8.3 months in
patients who received tamoxifen). The tamoxifen:anastrozole hazards ratio was
0.99 (lower one-sided 95% confidence limit, 0.86), demonstrating that
anastrozole was at least equivalent to tamoxifen. Anastrozole was also as
effective as tamoxifen in terms of OR (32.9% of anastrozole and 32.6% of
tamoxifen patients achieved a complete response [CR] or partial response [PR]).
Clinical benefit (CR + PR + stabilization of > or = 24 weeks) rates were 56.2%
and 55.5% for patients receiving anastrozole and tamoxifen, respectively. Both
treatments were well tolerated. However, incidences of thromboembolic events and
vaginal bleeding were reported in fewer patients treated with anastrozole than
with tamoxifen (4.8% v 7.3% [thromboembolic events] and 1.2% v 2.4% [vaginal
bleeding], respectively). CONCLUSION: Anastrozole satisfied the predefined
criteria for equivalence to tamoxifen. Together with the lower observed
incidence of thromboembolic events and vaginal bleeding, these findings indicate
that anastrozole should be considered as first-line therapy for postmenopausal
women with ABC.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 11078487 [PubMed - indexed for MEDLINE]
46: Eur J Cancer 2000 Sep;36 Suppl 4:S84-5
Randomised study of anastrozole versus tamoxifen as first-line therapy for
advanced breast cancer in postmenopausal women.
Vergote I, Bonneterre J, Thurlimann B, Robertson J, Krzakowski M, Mauriac L,
Koralewski L, Webster A, Steinberg M, von Euler M.
Department Gynaecological Oncology, University Hospitals Leuven, Herestraat 49,
B3000, Leuven, Belgium. [email protected]
A total of 668 patients (340 anastrozole and 328 tamoxifen) were randomised in a
double-blind, double-dummy multicentre study. Anastrozole was given in a dose of
1 mg once daily and compared with tamoxifen 20 mg daily in postmenopausal
patients with tumours that were hormone-receptor positive or of unknown receptor
status. The efficacy and tolerability of anastrozole was compared with that of
tamoxifen as first-line therapy for advanced breast cancer. The median time to
progression was similar for both treatments (8.2 months in anastrozole patients
and 8.3 months in tamoxifen patients). Anastrozole was also as effective as
tamoxifen in terms of objective response-rate with 33% in the anastrozole group
and 32.6% in the tamoxifen group achieving a complete or partial response. Both
treatments were well tolerated. However, incidences of thromboembolic events and
vaginal bleeding were reported in fewer patients treated with anastrozole than
with tamoxifen. In conclusion, these findings indicate that anastrozole can be
considered as first-line therapy for postmenopausal women with advanced breast
cancer.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 11056332 [PubMed - indexed for MEDLINE]
47: Eur J Cancer 2000 Sep;36 Suppl 4:S82-4
An overview of the use of non-steroidal aromatase inhibitors in the treatment of
breast cancer.
Buzdar A.
Department of Medical Oncology, The University of Texas - MD University Cancer
Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
[email protected]
A number of potent and selective non-steroidal aromatase inhibitors are now
available for the treatment of advanced breast cancer in postmenopausal women.
In particular, anastrozole represents a significant advantage over earlier
agents, such as aminoglutethimide and formestane, in terms of both efficacy and
tolerability. These agents are now established as the second-line therapy of
choice in postmenopausal women with advanced disease progressing on tamoxifen
and, furthermore, data are now available on the efficacy and tolerability of
anastrozole as first-line treatment of advanced breast cancer compared with
tamoxifen. The full potential of the new-generation aromatase inhibitors in the
treatment of breast cancer is currently being investigated in a large programme
of clinical trials, including evaluation as neoadjuvant treatment in
postmenopausal women with newly-diagnosed locally-advanced or large operable
breast cancers, as first-line treatment of advanced breast cancer in
postmenopausal women. Aromatase inhibitors have been available for over 20
years; the ability of these compounds to reduce circulating oestradiol levels
has been shown to produce clinical benefit in postmenopausal women with advanced
breast cancer. Early aromatase inhibitors, however, such as aminoglutethimide
and formestane, were not specific for the aromatase enzyme and resulted in
significant side-effects.
PMID: 11056331 [PubMed - indexed for MEDLINE]
48: Eur J Cancer 2000 Sep;36 Suppl 4:S81-2
Clinico-pharmacological aspects of different hormone treatments.
Lonning PE.
Department of Oncology, Haukeland University Hospital, N-5021, Bergen, Norway.
[email protected]
During the last decade, several new drugs and classes of drugs have become
available for breast cancer treatment. Thus, in addition to tamoxifen we have
got several new selective oestrogen receptor modulators (SERMs) with a partially
different pharmacological profile. The first generation aromatase inhibitor,
aminoglutethimide, has been replaced by more potent and less toxic inhibitors
belonging to the triazole class (anastrozole and letrozole) and, more recently,
the steroidal aromatase inactivator exemestane [1-3]. These drugs have all
revealed a better toxicity profile and, in general, an improved antitumour
activity, compared with conventional therapy. Faslodex, the first representative
of the so-called 'pure' oestrogen antagonists, has shown beneficial effects in
patients resistant to tamoxifen [4].
PMID: 11056330 [PubMed - indexed for MEDLINE]
49: Eur J Cancer 2000 Sep;36 Suppl 4:112-3
Apoptosis and anti-apoptosis in oestrogen-receptor negative endometrial cancer
cells in response to anastrozole, 4-hydroxytamoxifen and medroxyprogesterone
acetate
Morsi HM, Leers MP, Nap M, Bjorklund V V, El Kabarity H, Jaeger W.
Department of Obstetrics and Gynaecology, Ain Shams University, Cairo, Egypt.
PMID: 11056358 [PubMed - as supplied by publisher]
50: Anticancer Drugs 2000 Aug;11(7):591-601
Cost-utility analysis of second-line hormonal therapy in advanced breast cancer:
a comparison of two aromatase inhibitors to megestrol acetate.
Dranitsaris G, Leung P, Mather J, Oza A.
Department of Pharmacy, Ontario Cancer Institute/Princess Margaret Hospital,
Toronto, Canada. [email protected]
Randomized trials comparing the aromatase inhibitors, anastrozole and letrozole,
to megestrol acetate (MA) in postmenopausal women with advanced breast cancer
demonstrated that both agents are better tolerated than MA with comparable
efficacy. In addition, one trial revealed that tumor response and time to
treatment failure were significantly better with letrozole. Since oncologists
are faced with a choice between three agents with at least comparable efficacy
but different toxicity profiles and cost, a cost-utility analysis was conducted
to quantify these differences and to determine if the new agents are more
cost-effective than MA. In the absence of a randomized three-arm trial, a
decision model was developed to simulate the most common therapeutic outcomes.
The clinical data were obtained from an overview analysis of randomized trials.
Total hospital resource consumption was collected from 87 patients with advanced
disease that had failed second-line hormonal therapy. Utility estimates were
obtained from interviewing a random sample of 25 women from the general public
and 25 female health care professionals using the Time Trade-Off technique. The
model suggested a similar duration of quality-adjusted progression-free survival
between drugs (letrozole 150 days, anastrozole 153 days and MA 146 days).
Letrozole had an overall cost of Can$2949 per patient which was comparable to MA
at Can$2966 per patient. In contrast, anastrozole was slightly more costly than
MA at $Can3149 per patient, respectively. The analysis revealed that letrozole
has comparable overall costs relative to MA while providing at least equivalent
quality-adjusted progression-free survival. These outcomes were largely related
to its higher tumor response rate, which translated to a lower proportion of
patients requiring chemotherapy. Anastrozole was slightly more costly than MA
and did not demonstrate superiority in quality-adjusted progression-free
survival in this palliative setting.
PMID: 11036964 [PubMed - indexed for MEDLINE]
51: Int J Oncol 2000 Nov;17(5):1037-41
New aromatase inhibitors in the treatment of advanced breast cancer.
Crucitta E, Lorusso V, Attolico M, Sambiasi D, Mazzei A, De Lena M.
Operative Unit of Medical Oncology, Oncology Institute of Bari, Bari, Italy.
New aromatase inhibitors are an exciting treatment option for postmenopausal
women with hormone sensitive breast cancer. They have been shown to reduce
tumors in a significant number of patients, and exhibit definite antitumor
activity at a relatively low daily dose, and are highly potent, highly
selective, and well-tolerated. Results from recent clinical phase III studies
have confirmed their efficacy and the key role they have in the therapy for
advanced breast cancer in postmenopausal women. The agents available for
clinical use are: letrozole, anastrozole, and exemestane. These drugs have
demonstrated high activity in women failing tamoxifen in locally advanced or
metastatic disease. This communication reviews the clinical use of aromatase
inhibitors, particularly in second and first line hormonal treatment of advanced
breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 11029510 [PubMed - indexed for MEDLINE]
52: Nippon Rinsho 2000 Apr;58 Suppl:322-7
[Aromatase inhibitors for treatment of advanced breast cancers].
[Article in Japanese]
Sonoo H.
Department of Breast & Thyroid Surgery, Kawasaki Medical School.
Publication Types:
Review
Review, Tutorial
PMID: 11026013 [PubMed - indexed for MEDLINE]
53: Rev Med Suisse Romande 2000 Jun;120(6):495-500
[Aromatase inhibitors in the treatment of breast cancer].
[Article in French]
Perey L.
Centre pluridisciplinaire d'oncologie, Lausanne.
PMID: 11014093 [PubMed - indexed for MEDLINE]
54: J Clin Endocrinol Metab 2000 Sep;85(9):3027-35
Comment in:
J Clin Endocrinol Metab. 2000 Sep;85(9):3024-6
Aromatase inhibition in the human male reveals a hypothalamic site of estrogen
feedback.
Hayes FJ, Seminara SB, Decruz S, Boepple PA, Crowley WF Jr.
Department of Medicine and National Center for Infertility Research,
Massachusetts General Hospital, Boston 02114, USA. [email protected]
The preponderance of evidence states that, in adult men, estradiol (E2) inhibits
LH secretion by decreasing pulse amplitude and responsiveness to GnRH consistent
with a pituitary site of action. However, this conclusion is based on studies
that employed pharmacologic doses of sex steroids, used nonselective aromatase
inhibitors, and/or were performed in normal (NL) men, a model in which
endogenous counterregulatory adaptations to physiologic perturbations confound
interpretation of the results. In addition, studies in which estrogen
antagonists were administered to NL men demonstrated an increase in LH pulse
frequency, suggesting a potential additional hypothalamic site of E2 feedback.
To reconcile these conflicting data, we used a selective aromatase inhibitor,
anastrozole, to examine the impact of E2 suppression on the
hypothalamic-pituitary axis in the male. Parallel studies of NL men and men with
idiopathic hypogonadotropic hypogonadism (IHH), whose pituitary-gonadal axis had
been normalized with long-term GnRH therapy, were performed to permit precise
localization of the site of E2 feedback. In this so-called tandem model, a
hypothalamic site of action of sex steroids can thus be inferred whenever there
is a difference in the gonadotropin responses of NL and IHH men to alterations
in their sex steroid milieu. A selective GnRH antagonist was also used to
provide a semiquantitative estimate of endogenous GnRH secretion before and
after E2 suppression. Fourteen NL men and seven IHH men were studied. In Exp 1,
nine NL and seven IHH men received anastrozole (10 mg/day po x 7 days). Blood
samples were drawn daily between 0800 and 1000 h in the NL men and immediately
before a GnRH bolus dose in the IHH men. In Exp 2, blood was drawn (every 10 min
x 12 h) from nine NL men at baseline and on day 7 of anastrozole. In a subset of
five NL men, 5 microg/kg of the Nal-Glu GnRH antagonist was administered on
completion of frequent blood sampling, then sampling continued every 20 min for
a further 8 h. Anastrozole suppressed E2 equivalently in the NL (136 +/- 10 to
52 +/-2 pmol/L, P < 0.005) and IHH men (118 +/- 23 to 60 +/- 5 pmol/L, P <
0.005). Testosterone levels rose significantly (P < 0.005), with a mean increase
of 53 +/- 6% in NL vs. 56 +/- 7% in IHH men. Despite these similar changes in
sex steroids, the increase in gonadotropins was greater in NL than in IHH men
(100 +/- 9 vs. 58 +/- 6% for LH, P = 0.07; and 85 +/- 6 vs. 41 +/- 4% for FSH, P
< 0.002). Frequent sampling studies in the NL men demonstrated that this rise in
mean LH levels, after aromatase blockade, reflected an increase in both LH pulse
frequency (10.2 +/- 0.9 to 14.0 +/- 1.0 pulses/24 h, P < 0.05) and pulse
amplitude (5.7 +/- 0.7 to 8.4 +/- 0.7 IU/L, P < 0.001). Percent LH inhibition
after acute GnRH receptor blockade was similar at baseline and after E2
suppression (69.2 +/- 2.4 vs. 70 +/- 1.9%), suggesting that there was no change
in the quantity of endogenous GnRH secreted. From these data, we conclude that
in the human male, estrogen has dual sites of negative feedback, acting at the
hypothalamus to decrease GnRH pulse frequency and at the pituitary to decrease
responsiveness to GnRH.
Publication Types:
Clinical Trial
PMID: 10999781 [PubMed - indexed for MEDLINE]
55: Cancer 2000 Aug 15;89(4):817-25
Erratum in:
Cancer 2001 Jan 15;91(2):455
ICI 182,780 (Faslodex): development of a novel, "pure" antiestrogen.
Howell A, Osborne CK, Morris C, Wakeling AE.
Department of Medical Oncology, Christie Hospital National Health Service Trust,
Manchester, United Kingdom.
BACKGROUND: The nonsteroidal antiestrogen tamoxifen is well established as an
effective treatment for patients with breast carcinoma, both for the treatment
of metastatic disease and as an adjuvant to surgery for patients with primary
breast carcinoma. In addition to exerting antagonistic effects on the estrogen
receptor, tamoxifen and its derivatives act as partial agonists on certain
tissues. These agonistic effects, for example, endometrial stimulation and
stimulation of tumor growth after previous response to tamoxifen, may limit
their clinical efficacy. ICI 182,780 (Faslodex) from AstraZeneca (Cheshire,
United Kingdom) is a novel, steroidal estrogen antagonist that was designed to
be devoid of estrogen agonist activity in preclinical models. METHODS: ICI
182,780 was tested in a large number of in vitro and in vivo preclinical models,
and its value was assessed clinically when administered before surgery for
breast carcinoma and hysterectomy for benign conditions and after failure of
tamoxifen in patients with advanced breast carcinoma. RESULTS: All data
indicated that ICI 182,780 is devoid of agonist activity in preclinical models
and in clinical trials. It inhibits growth of the breast and endometrium. In
animal models, it does not cross the blood-brain barrier and appears to be
neutral with respect to lipids and bone. ICI 182,780 down-regulates the estrogen
receptor and is active in tamoxifen-resistant breast carcinoma. In a small,
Phase II study, durable responses were seen: Phase III clinical trials are in
progress comparing ICI 182,780 with anastrozole and tamoxifen in the treatment
of patients with advanced breast carcinoma. CONCLUSIONS: ICI 182,780
specifically down-regulates the estrogen receptor and, thus, represents the
first of a new class of therapeutic agents. In this report, the authors present
the current evidence that distinguishes ICI 182,780 from tamoxifen and related
nonsteroidal compounds and establishes ICI 182,780 as the first in a new class
of therapeutic agents. Copyright 2000 American Cancer Society.
PMID: 10951345 [PubMed - indexed for MEDLINE]
56: Gan To Kagaku Ryoho 2000 Jul;27(8):1225-32
[Chemo/endocrine therapy for breast cancer patients].
[Article in Japanese]
Ikeda T, Masamura S, Matsui A, Hohjoh T, Kawaguchi M, Takayama S, Tokura H,
Mitsui Y, Fujiwara K, Kitajima M.
Dept. of Surgery, Keio University School of Medicine.
Standard adjuvant chemo/endocrine therapy for breast cancer patient is based
upon St. Gallen's consensus 1998. Recent development in the field of adjuvant
chemo/endocrine therapy is an usage of LH-RH analogue with tamoxifen for
premenopausal hormone receptor positive women, and also an emerging role of
taxans. Orally given 5-FU derivatives may work in adjuvant settings. The third
generation aromatase inhibitors have established their role in second line
hormone therapy for the advanced or recurrent breast cancer patients. High dose
chemotherapy should not be used in outside clinical trials.
Publication Types:
Review
Review, Tutorial
PMID: 10945021 [PubMed - indexed for MEDLINE]
57: Tumori 2000 May-Jun;86(3):A3
[In Europe Anastrozole approved for first-line treatment of advanced breast
cancer in postmenopausal patients].
[Article in Italian]
Publication Types:
News
PMID: 10939612 [PubMed - indexed for MEDLINE]
58: Gynecol Oncol 2000 Aug;78(2):212-6
A phase II trial of anastrozole in advanced recurrent or persistent endometrial
carcinoma: a Gynecologic Oncology Group study.
Rose PG, Brunetto VL, VanLe L, Bell J, Walker JL, Lee RB.
Department of Obstetrics and Gynecology, University Hospital of Cleveland, Ohio,
44106, USA.
BACKGROUND: Some endometrial cancers are hormonally dependent. A principal
source of circulating estrogen is conversion of adrenal androstenedione by
aromatase. Anastrozole (Arimidex) is an oral nonsteroidal aromatase inhibitor
which is active in recurrent breast cancer. This Phase II study was undertaken
to evaluate anastrozole in recurrent endometrial carcinoma. METHODS: Patients
with advanced or recurrent endometrial cancer not curable with either surgery or
radiation therapy and with measurable disease, a GOG (Zubrod) performance status
of < or = 2, no more than one prior hormonal therapy regimen, and no prior
chemotherapy were eligible. Anastrozole was administered at a dose of 1 mg/day
orally for at least 28 days. RESULTS: Twenty-three patients were entered on this
trial. On central pathology review, 9 of them had grade 2 and 14 had grade 3
tumors. One to 24 courses (median: 1) of therapy were administered. Two partial
responses were noted (9%; 90% confidence interval 3 to 23%). Two additional
patients had short-term stable disease. With the exception of 1 case of venous
thrombosis, the toxicity profile was mild. Median durations of progression-free
survival and overall survival are 1 and 6 months, respectively. CONCLUSIONS:
Anastrozole has minimal activity in an unselected population of patients with
recurrent endometrial cancer. Copyright 2000 Academic Press.
Publication Types:
Clinical Trial
Clinical Trial, Phase II
Multicenter Study
PMID: 10926805 [PubMed - indexed for MEDLINE]
59: J Mol Endocrinol 2000 Aug;25(1):35-42
Estrogen biosynthesis in endometriosis: molecular basis and clinical relevance.
Bulun SE, Zeitoun KM, Takayama K, Sasano H.
Departments of Obstetrics and Gynecology and Molecular Genetics, University of
Illinois at Chicago, 820 S. Wood St. M/C 808, Illinois 60612, USA.
[email protected]
Conversion of C(19) steroids to estrogens is catalyzed by aromatase in human
ovary, placenta and extraglandular tissues such as adipose tissue, skin and the
brain. Aromatase activity is not detectable in normal endometrium. In contrast,
aromatase is expressed aberrantly in endometriosis and is stimulated by
prostaglandin E(2) (PGE(2)).( )This results in local production of estrogen,
which induces PGE(2) formation and establishes a positive feedback cycle.
Another abnormality in endometriosis, i.e. deficient hydroxysteroid
dehydrogenase (17beta-HSD) type 2 expression, impairs the inactivation of
estradiol to estrone. These molecular aberrations collectively favor
accumulation of increasing quantities of estradiol and PGE(2 )in endometriosis.
The clinical relevance of these findings was exemplified by the successful
treatment of an unusually aggressive case of postmenopausal endometriosis using
an aromatase inhibitor.
Publication Types:
Review
Review, Tutorial
PMID: 10915216 [PubMed - indexed for MEDLINE]
60: Cancer Chemother Pharmacol 2000;46(1):35-9
Effects of the aromatase inhibitor anastrozole on serum oestrogens in Japanese
and Caucasian women.
Dowsett M, Donaldson K, Tsuboi M, Wong J, Yates R.
Department of Academic Biochemistry, Royal Marsden Hospital, London, UK.
[email protected]
PURPOSE: Substantial differences in plasma oestrogen disposition have been
reported between Japanese and Caucasian women, but there are currently few data
available on the relative endocrinological effects of aromatase inhibitors in
these two groups. Hence, the effects of the nonsteroidal aromatase inhibitor
anastrozole on serum oestrogen concentrations were compared in 24 healthy
postmenopausal Japanese women and 24 healthy postmenopausal Caucasian women.
METHODS: Anastrozole, 1 mg/day, was given once daily for 16 days. Serum
oestradiol and oestrone sulphate levels were measured on three consecutive days
beginning 2 days before the first dose, and on a further three consecutive days
beginning on the penultimate day of dosing. Trough concentrations of anastrozole
(measured 24 h after dosing) were also determined during the same periods.
RESULTS: There were no substantial differences in plasma oestrogen
concentrations between the Japanese and Caucasian women at baseline. On average,
anastrozole suppressed serum oestradiol and oestrone sulphate levels by
approximately 87% and 93%, respectively, for both Japanese and Caucasian women,
and minimum plasma anastrozole concentrations at steady-state (anastrozole
C(min)) were also similar in both groups. Statistical analysis of serum
oestradiol and serum oestrone sulphate levels, and plasma anastrozole C(min)
showed that there were no statistically significant differences between the
Japanese and Caucasian women. CONCLUSION: Neither the pharmacodynamic effects of
anastrozole on serum oestrogens nor the pharmacokinetics of anastrozole differ
between postmenopausal Japanese and Caucasian women. Hence, these findings
suggest that the therapeutic benefits of anastrozole in Caucasians will be
predictive of the drug's effect in Japanese women and support the use of
anastrozole in postmenopausal Japanese women with breast cancer.
PMID: 10912575 [PubMed - indexed for MEDLINE]
61: J Clin Endocrinol Metab 2000 Jul;85(7):2370-7
Comment in:
J Clin Endocrinol Metab. 2001 Apr;86(4):1836-8
Estrogen suppression in males: metabolic effects.
Mauras N, O'Brien KO, Klein KO, Hayes V.
Nemours Research Programs at the Nemours Children's Clinic, Jacksonville,
Florida 32207, USA. [email protected]
We have shown that testosterone (T) deficiency per se is associated with marked
catabolic effects on protein, calcium metabolism, and body composition in men
independent of changes in GH or insulin-like growth factor I production. It is
not clear,,however, whether estrogens have a major role in whole body anabolism
in males. We investigated the metabolic effects of selective estrogen
suppression in the male using a potent aromatase inhibitor, Arimidex
(Anastrozole). First, a dose-response study of 12 males (mean age, 16.1 +/- 0.3
yr) was conducted, and blood withdrawn at baseline and after 10 days of oral
Arimidex given as two different doses (either 0.5 or 1 mg) in random order with
a 14-day washout in between. A sensitive estradiol (E2) assay showed an
approximately 50% decrease in E2 concentrations with either of the two doses;
hence, a 1-mg dose was selected for other studies. Subsequently, eight males
(aged 15-22 yr; four adults and four late pubertal) had isotopic infusions of
[(13)C]leucine and (42)Ca/(44)Ca, indirect calorimetry, dual energy x-ray
absorptiometry, isokinetic dynamometry, and growth factors measurements
performed before and after 10 weeks of daily doses of Arimidex. Contrary to the
effects of T withdrawal, there were no significant changes in body composition
(body mass index, fat mass, and fat-free mass) after estrogen suppression or in
rates of protein synthesis or degradation; carbohydrate, lipid, or protein
oxidation; muscle strength; calcium kinetics; or bone growth factors
concentrations. However, E2 concentrations decreased 48% (P = 0.006), with no
significant change in mean and peak GH concentrations, but with an 18% decrease
in plasma insulin-like growth factor I concentrations. There was a 58% increase
in serum T (P = 0.0001), sex hormone-binding globulin did not change, whereas LH
and FSH concentrations increased (P < 0.02, both). Serum bone markers,
osteocalcin and bone alkaline phosphatase concentrations, and rates of bone
calcium deposition and resorption did not change. In conclusion, these data
suggest that in the male 1) estrogens do not contribute significantly to the
changes in body composition and protein synthesis observed with changing
androgen levels; 2) estrogen is a main regulator of the gonadal-pituitary
feedback for the gonadotropin axis; and 3) this level of aromatase inhibition
does not negatively impact either kinetically measured rates of bone calcium
turnover or indirect markers of bone calcium turnover, at least in the short
term. Further studies will provide valuable information on whether timed
aromatase inhibition can be useful in increasing the height potential of
pubertal boys with profound growth retardation without the confounding negative
effects of gonadal androgen suppression.
Publication Types:
Clinical Trial
PMID: 10902781 [PubMed - indexed for MEDLINE]
62: Clin Cancer Res 2000 Jun;6(6):2229-35
The effects of neoadjuvant anastrozole (Arimidex) on tumor volume in
postmenopausal women with breast cancer: a randomized, double-blind,
single-center study.
Dixon JM, Renshaw L, Bellamy C, Stuart M, Hoctin-Boes G, Miller WR.
Edinburgh Breast Unit, Western General Hospital, Edinburgh, Scotland, United
Kingdom.
Anastrozole, an orally active, nonsteroidal aromatase inhibitor, was evaluated
in a randomized, double-blind, single-center study to determine its efficacy as
neoadjuvant therapy in postmenopausal women with newly diagnosed, estrogen
receptor-rich, locally advanced or large (>3 cm), operable breast cancers.
Twenty-four eligible patients were recruited into the study and received either
1 mg (n = 12) or 10 mg (n = 12) of anastrozole daily over a 3-month period.
Tumor volumes were estimated clinically, by using caliper measurements and
ultrasound (at baseline and after 1, 2, and 3 months' treatment) and by
mammography (at baseline and after 3 months). Tumor volume was also measured in
surgical specimens. Twenty-one patients were classified as T2, two patients as
T3, and one patient as T4B at baseline. Three patients had clinical evidence of
lymph node involvement. When considering the difference between the volume as
measured by each assessment and the actual pathological volume, the
interquartile range and the difference between the maximum and minimum values
were smaller for ultrasound when compared with those measured with calipers and
mammography. Therefore, of the three clinical assessments of tumor volume used
in this study, the data suggest that ultrasound may be the most accurate. The
median reductions in tumor volumes as measured by ultrasound for those patients
with a measurable 12-week assessment were 80.5 and 69.6% for anastrozole (1 and
10 mg, respectively) after 12 weeks of treatment and 75.5% when both doses were
grouped together. Moreover, of these patients, 11 of 12 given 1 mg and 7 of 11
given 10 mg of anastrozole were found on ultrasound to have a >50% reduction in
tumor volume after 12 weeks of treatment. Of the 17 patients who would have
required a mastectomy at initiation of treatment, 15 were suitable for breast
conservation after anastrozole treatment. These results suggest that anastrozole
is highly effective as neoadjuvant therapy in postmenopausal women with estrogen
receptor-rich, large, operable breast cancer. Future studies comparing
anastrozole with tamoxifen as a neoadjuvant treatment should be considered.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 10873072 [PubMed - indexed for MEDLINE]
63: J Steroid Biochem Mol Biol 2000 Apr;72(5):259-64
A novel HPLC-RIA method for the simultaneous detection of estrone, estradiol and
estrone sulphate levels in breast cancer tissue.
Geisler J, Berntsen H, Lonning PE.
Department of Oncology, Haukeland University Hospital, N-5021, Bergen, Norway.
Estrogen deprivation is an effective approach for treatment of hormone sensitive
breast cancer. While much is known about plasma estrogen levels with respect to
castration in premenopausal women and use of aromatase inhibitors in
postmenopausal women, currently there is increasing interest in intra-tumour
estrogen production. However, knowledge about alterations in intra-tumour
estrogen levels is limited, mainly due to methodological problems with
measurements of estrogen fractions in tissue samples. Here we describe a new
method for simultaneous measurement of the three main estrogen fractions,
estrone (E(1)), estradiol (E(2)) and estrone sulphate (E(1)S) in breast tumour
tissue. Following incubation with -labelled estrogen standards, crude fractions
were separated by ether extraction. The E(1)S fraction was hydrolysed with
sulphatase followed by eluation on a Sephadex column. High pressure liquid
chromatography (HPLC) was used to purify the individual estrogen fractions prior
to RIA analysis. Estrone and E(1)S were converted into E(2), and all three
estrogen fractions were finally measured by the same highly sensitive and
specific radioimmunoassay using
estradiol-6-(O-carboxymethyl)-oximino-2-(2--iodo-histamine) as a ligand.
Although several purification steps were used, the internal recovery values for
tritiated estrogens were found to be 25-50% for E(1) and E(2) and 15-30% for
E(1)S. The detection limit of this method was 4.3 fmol/g tissue for E(2), 19.8
fmol/g tissue for E(1) and 11.9 fmol/g E(1)S, respectively. Using tissue from
locally advanced breast cancers (n = 14), we found median levels of E(1), E(2)
and E(1)S to be 283.8 fmol/g tissue (range 19.8-547.5), 554.1 fmol/g
(9.5-3024.2) and 209.4 fmol/g (11.9-753.4), respectively. The method described
here is a promising tool to study intra-tumour estrogen fractions in breast
tissue biopsies.
PMID: 10822015 [PubMed - indexed for MEDLINE]
64: Tumori 1999 Nov-Dec;85(6):A19-25
[Anastrozolo: intracellular anti-aromatase activity and pharmacologic
interactions. Satellite Symposium AIOM 1999 - Roma].
[Article in Italian]
Longo F, Mansueto G.
Publication Types:
Congresses
PMID: 10774583 [PubMed - indexed for MEDLINE]
65: Crit Rev Oncol Hematol 2000 Feb;33(2):137-42
Steroidal aromatase inhibitors in elderly patients.
Bajetta E, Zilembo N, Bichisao E, Pozzi P, Toffolatti L.
Division of Medical Oncology, Istituto Nazionale per lo Studio e la Cura dei
Tumori, Milan, Italy.
The choice of treatment for elderly breast cancer patients needs particular care
because the presence of physiological functional impairments can modify the drug
bioavailability in an unpredictable manner. Hormonal treatment remains one of
the choices and, although tamoxifen has proved to be effective in any setting,
the use of selective aromatase inhibitors is arousing. Depending on their
chemical structure, aromatase inhibitors are either steroidal (such as
exemestane and formestane) or non-steroidal (such as letrozole, vorozole and
anastrozole). Formestane has been studied in elderly patients with breast cancer
and has been found to induce an overall response rate of 51% (95% CI, 35-67%).
The drug suppresses estradiol (E2) levels, and changes in other hormones (FSH,
LH and SHBG) are observed, but with poor clinical significance, thus confirming
its selectivity and potency. Formestane has also been demonstrated to be as
effective as tamoxifen. Exemestane and non-steroidal aromatase inhibitors appear
to be very promising drugs.
Publication Types:
Review
Review, Tutorial
PMID: 10737375 [PubMed - indexed for MEDLINE]
66: Endocr Relat Cancer 1999 Mar;6(1):75-92
Use of aromatase inhibitors in breast carcinoma.
Santen RJ, Harvey HA.
Department of Medicine, University of Virginia Health Sciences Center,
Charlottesville 22908, USA.
Aromatase, a cytochrome P-450 enzyme that catalyzes the conversion of androgens
to estrogens, is the major mechanism of estrogen synthesis in the
post-menopausal woman. We review some of the recent scientific advances which
shed light on the biologic significance, physiology, expression and regulation
of aromatase in breast tissue. Inhibition of aromatase, the terminal step in
estrogen biosynthesis, provides a way of treating hormone-dependent breast
cancer in older patients. Aminoglutethimide was the first widely used aromatase
inhibitor but had several clinical drawbacks. Newer agents are considerably more
selective, more potent, less toxic and easier to use in the clinical setting.
This article reviews the clinical data supporting the use of the potent, oral
competitive aromatase inhibitors anastrozole, letrozole and vorozole and the
irreversible inhibitors 4-OH androstenedione and exemestane. The more potent
compounds inhibit both peripheral and intra-tumoral aromatase. We discuss the
evidence supporting the notion that aromatase inhibitors lack cross-resistance
with antiestrogens and suggest that the newer, more potent compounds may have a
particular application in breast cancer treatment in a setting of adaptive
hypersensitivity to estrogens. Currently available aromatase inhibitors are safe
and effective in the management of hormone-dependent breast cancer in
post-menopausal women failing antiestrogen therapy and should now be used before
progestational agents. There is abundant evidence to support testing these
compounds as first-line hormonal therapy for metastatic breast cancer as well as
part of adjuvant regimens in older patients and quite possibly in
chemoprevention trials of breast cancer.
Publication Types:
Review
Review, Academic
PMID: 10732791 [PubMed - indexed for MEDLINE]
67: Endocr Relat Cancer 1999 Jun;6(2):259-63
Aromatase inhibitors and their use in the sequential setting.
Coombes RC, Harper-Wynne C, Dowsett M.
Cancer Research Campaign, Department of Cancer Medicine, Imperial College School
of Medicine, Charing Cross Hospital, London, UK.
Over the past decade several novel aromatase inhibitors have been introduced
into clinical practice. The discovery of these drugs followed on from the
observation that the main mechanism of action of aminogluthemide was via
inhibition of the enzyme aromatase thereby reducing peripheral levels of
oestradiol in postmenopausal patients. The second-generation drug,
4-hydroxyandrostenedione (formestane), was introduced in 1990 and although its
use was limited by its need to be given parenterally it was found to be a
well-tolerated form of endocrine therapy. Third-generation inhibitors include
vorozole, letrozole, anastrozole and exemestane, the former three being
non-steroidal inhibitors, the latter being a steroidal inhibitor. All are
capable of inhibiting aromatase action by >95% compared with 80% in the case of
4-hydroxyandrostenedione. The sequential use of different generations of
aromatase inhibitors in the same patients is discussed. Studies suggest that an
optimal sequence of these compounds may well result in longer remission in
patients with hormone receptor positive tumours.
Publication Types:
Review
Review, Tutorial
PMID: 10731118 [PubMed - indexed for MEDLINE]
68: Endocr Relat Cancer 1999 Jun;6(2):245-9
Aromatase inhibitors: a dose-response effect?
Smith IE.
Section of Medicine, Royal Marsden Hospital and Institute of Cancer Research,
London, UK.
Publication Types:
Review
Review, Tutorial
PMID: 10731116 [PubMed - indexed for MEDLINE]
69: Endocr Relat Cancer 1999 Jun;6(2):231-4
Use of aromatase inhibitors in the adjuvant treatment of breast cancer.
Baum M.
Institute of Surgical Studies, University College London, UK.
The value of endocrine treatment of early breast cancer has been illustrated by
the antioestrogen, tamoxifen, which has now been available for nearly 30 years.
However, if the recognised side effects and pharmacological properties of
tamoxifen are taken into consideration, it is possible that other endocrine
treatments that are now available can provide equal or superior efficacy, along
with improved tolerability. One such group of agents is the aromatase inhibitors
specifically the new-generation triazole aromatase inhibitors, such as
anastrozole and letrozole, which have both shown tolerability and efficacy
advantages over standard treatments in postmenopausal women with advanced breast
cancer. There are convincing reasons why the new generation of aromatase
inhibitors have advantages over tamoxifen. For instance, from their agonist
properties, the effects on the endometrium and tumour stimulation seen with
tamoxifen would not be expected, nor would the visual disturbances that have
been associated with the triphenylethylene compounds, including tamoxifen. A
number of aromatase inhibitors, for instance, anastrozole, letrozole and
exemestane, are currently being investigated for treatment of early breast
cancer. The results of the trials of aromatase inhibitors and tamoxifen will, in
the next few years, define whether or not the new-generation aromatase
inhibitors have a role to play in the treatment of postmenopausal women with
early breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 10731114 [PubMed - indexed for MEDLINE]
70: Endocr Relat Cancer 1999 Jun;6(2):227-30
Lessons from the use of aromatase inhibitors in the neoadjuvant setting.
Dixon JM, Love CD, Renshaw L, Bellamy C, Cameron DA, Miller WR, Leonard RC.
Edinburgh Breast Unit, Western General Hospital, UK.
Postmenopausal patients with oestrogen receptor-positive locally advanced T4b,
N0-1, M0 and large operable breast cancers T2>3 cm, T3, T4, N0-1 and M0 have
been treated with 2.5 mg letrozole (12 patients), 10 mg letrozole (12 patients),
1 or 10 mg anastrozole (24 patients) and 20 mg tamoxifen (65 patients). There
was no apparent difference in response rate between 2.5 and 10 mg letrozole.
Only 17 patients with anastrozole have so far completed the 3-month treatment
period. Median clinical, mammographic and ultrasound reductions in tumour
volumes for patients treated with letrozole were 81% (95% confidence interval
(CI) 66-88), 77% (95% CI 64-82) and 81% (95% CI 69-86) respectively and for
anastrozole, values were 87% (95% CI 59-97), 73% (95% CI 58-82) and 64% (95% CI
52-76) respectively. This compares with a median reduction in tumour volume for
tamoxifen-treated patients as assessed by ultrasound of 48% (95% CI 27-48).
There were seven complete clinical responses (CR), sixteen patients who achieved
50% or greater reduction in tumour volume (PR) and one no change (NC) for
letrozole and four CRs, twelve PRs and one progressive disease for anastrozole.
Best radiological responses were one CR, twenty PRs and three NCs for letrozole
and one CR, fifteen PRs and one NC for anastrozole. This study has shown that
the new aromatase inhibitors, letrozole and anastrozole, are highly effective
agents in the neoadjuvant setting and they should now be compared with tamoxifen
as first-line treatment in a randomised study.
Publication Types:
Review
Review, Tutorial
PMID: 10731113 [PubMed - indexed for MEDLINE]
71: Endocr Relat Cancer 1999 Jun;6(2):219-25
Role of aromatase inhibitors in advanced breast cancer.
Buzdar AU.
Department of Medical Oncology, The University of Texas, MD Anderson University
Cancer Center, Houston 77030, USA.
A number of potent and selective non-steroidal aromatase inhibitors are now
available for treatment of advanced breast cancer in postmenopausal women, of
which anastrozole and letrozole, in particular, represent a significant
advantage over the earlier agents in terms of both efficacy and tolerability.
These agents are rapidly becoming established as the second-line therapy of
choice in postmenopausal women with advanced disease, progressing on tamoxifen,
and data on their efficacy as first-line treatment compared with tamoxifen will
be available in the near future. Exemestane, a new, steroidal aromatase
inhibitor which potentially lacks cross-resistance with non-steroidal agents is
still in clinical development. The full potential of the new-generation
aromatase inhibitors in the treatment of breast cancer is currently being
investigated in a large program of clinical trials evaluating their use as
adjuvant treatment following surgery in postmenopausal patients with early
disease.
Publication Types:
Review
Review, Tutorial
PMID: 10731112 [PubMed - indexed for MEDLINE]
72: Endocr Relat Cancer 1999 Jun;6(2):205-10
Aromatase inhibitors and their antitumor effects in model systems.
Brodie A, Lu Q, Liu Y, Long B.
Department of Pharmacology and Experimental Therapeutics, and Greenebaum Cancer
Center, School of Medicine, University of Maryland, Baltimore 21201, USA.
The potential of aromatase (estrogen synthetase) within the breast to provide a
significant source of estrogen mediating tumor proliferation is suggested by
studies reporting 4- to 6-fold higher estrogen levels in tumors than in plasma
of postmenopausal patients with breast cancer. Recent studies in our laboratory
have identified aromatase and its mRNA in tumor epithelial cells using
immunocytochemistry and in situ hybridization. In addition, significant
aromatase activity, which was stimulated 7-fold by dexamethasone, was measured
in metastatic cells isolated from a breast cancer patient. Increase in
proliferation, as measured by proliferating cell nuclear antigen immunostaining
in tumor sections and by thymidine incorporation into DNA in response to
testosterone, was observed in histocultures of breast cancer samples. This
latter effect could be inhibited by 4-hydroxyandrostenedione. These results
imply that intratumoral aromatase has functional significance and may be an
important target for successful inhibitor treatment of breast cancer patients.
To investigate treatment strategies with aromatase inhibitors and antiestrogens,
we developed an intratumoral aromatase model to simulate the hormone responsive
postmenopausal breast cancer patient. Tumors of estrogen receptor positive human
breast carcinoma cells (MCF-7) transfected with the human aromatase gene are
grown in ovariectomized nude mice. These cells synthesize sufficient estrogen to
stimulate tumor formation. We have utilized this model to investigate the
effects on tumor growth of the antiestrogens, tamoxifen and ICI 182780, and the
aromatase inhibitors, letrozole and anastrozole (arimidex), alone and in
combination. Both the aromatase inhibitors and the antiestrogens were effective
in suppressing tumor growth. However, letrozole was significantly more effective
than the antiestrogens. When the aromatase inhibitors were combined with the
antiestrogen, tamoxifen, tumor growth was suppressed to about the same extent as
with the aromatase inhibitors alone. Furthermore, the results do not suggest any
benefit from combining tamoxifen with the pure antiestrogen, ICI 182780. Thus
sequential use of these agents is likely to be more advantageous to the patient
in terms of longer duration of effective treatment.
PMID: 10731110 [PubMed - indexed for MEDLINE]
73: Endocr Relat Cancer 1999 Jun;6(2):187-95
Biology of aromatase inhibitors: pharmacology/endocrinology within the breast.
Miller WR.
Breast Research Unit, Western General Hospital, Edinburgh, UK.
Both mammary adipose tissue and breast cancers have the ability to aromatize
androgens into oestrogens. Such potential may maintain the growth of
hormone-dependent tumours. It has therefore been important to determine the
effects of new aromatase inhibitors such as formestane, exemestane, anastrozole
and letrozole on oestrogen biosynthesis and concentrations of endogenous
hormones within the breast. Studies based on in vitro incubations of breast
cancer and cultures of mammary adipose tissue fibroblasts demonstrate that these
drugs are highly effective inhibitors, with IC50 values ranging between 1 and 50
nM (although the relative efficacy varies between tissues and test systems).
Despite this potential, in vitro incubations of breast tissues from patients
treated with type II inhibitors such as aminoglutethimide and letrozole can
display paradoxically high aromatase activity; this appears to be caused by the
reversible nature of the inhibition, coupled with induction/stabilization of the
aromatase enzyme. To assess in situ effects within the breast, postmenopausal
women with large primary breast cancers have been treated neoadjuvantly with
aromatase inhibitors using a protocol that included (i) breast biopsy before
treatment, (ii) definitive surgery after 3 months of treatment and (iii)
infusion of [3H]androstenedione and [14C]oestrone in the 18 h immediately before
biopsy and surgery. With this study design, it has been shown that drugs such as
letrozole profoundly inhibit in situ aromatase activity and reduce endogenous
oestrogens within the breast.
PMID: 10731108 [PubMed - indexed for MEDLINE]
74: Endocr Relat Cancer 1999 Jun;6(2):181-5
Drug and hormone interactions of aromatase inhibitors.
Dowsett M.
Academic Department of Biochemistry, The Royal Marsden NHS Trust, London, UK.
The clinical development of aromatase inhibitors has been largely confined to
postmenopausal breast cancer patients and strongly guided by pharmacological
data. Comparative oestrogen suppression has been helpful in circumstances in
which at least one of the comparitors has caused substantially non-maximal
aromatase inhibition. However, the triazole inhibitors, letrozole and
anastrozole, and the steroidal inhibitor, exemestane, all cause >95% inhibition.
Comparisons between these drugs therefore require more sensitive approaches such
as the direct measurement of enzyme activity by isotopic means. None of these
three agents has significant effects on other endocrine pathways at its
clinically applied doses. Pharmacokinetic analyses of the combination of
tamoxifen and letrozole have revealed that these drugs interact, resulting in
letrozole concentrations approximately 35-40% lower than when letrozole is used
alone.
Publication Types:
Review
Review, Tutorial
PMID: 10731107 [PubMed - indexed for MEDLINE]
75: Breast Cancer Res Treat 1999 Nov;58(2):157-62
Static disease on anastrozole provides similar benefit as objective response in
patients with advanced breast cancer.
Robertson JF, Howell A, Buzdar A, von Euler M, Lee D.
Department of Surgery, City Hospital, Nottingham, UK.
[email protected]
BACKGROUND: This paper reports on the clinical relevance of durable static
disease (SD) (> or = 24 weeks) in breast cancer patients treated with the
aromatase inhibitor anastrozole. PATIENTS AND METHODS: All patients were part of
two prospective, randomised, multicentre studies in postmenopausal women with
advanced disease in which megestrol acetate was compared with anastrozole 1 mg.
Survival from initiation of treatment was analysed by the response type, i.e.,
complete response (CR)/partial response (PR), static disease (SD) (> or = 24
weeks), or progressive disease (PD), achieved on therapy. RESULTS: Median
survival with anastrozole 1 mg was similar between patients who obtained CR/PR
and SD (> or = 24 weeks). Similarly, no difference in survival was observed in
patients treated with megestrol acetate who achieved CR/PR and SD. With both
treatments patients with CR/PR and SD had improved survival over those patients
with PD within 24 weeks. There was no difference between treatment arms for
patients showing PD within 24 weeks. CONCLUSIONS: These data confirm that
durable SD (> or = 24 weeks) is a clinically useful remission criterion in
postmenopausal women with advanced breast cancer with predictive value for
overall survival. It also confirms the value of this endpoint with anastrozole,
a new generation aromatase inhibitor.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 10674881 [PubMed - indexed for MEDLINE]
76: J Endocrinol 2000 Feb;164(2):225-38
Effect of chronic administration of an aromatase inhibitor to adult male rats on
pituitary and testicular function and fertility.
Turner KJ, Morley M, Atanassova N, Swanston ID, Sharpe RM.
MRC Reproductive Biology Unit, Centre for Reproductive Biology, 37 Chalmers
Street, Edinburgh EH3 9EW, Scotland, UK. [email protected]
The aim of the present study was to evaluate the effects of the administration
of a potent non-steroidal aromatase inhibitor, anastrozole, on male reproductive
function in adult rats. As anastrozole was to be administered via the drinking
water, a preliminary study was undertaken in female rats and showed that this
route of administration was effective in causing a major decrease in uterine
weight (P<0.02). In an initial study in male adult rats, anastrozole (100 mg/l
or 400 mg/l) was administered via the drinking water for a period of 9 weeks.
Treatment with either dose resulted in a significant increase ( approximately
10%) in testis weight and increase in plasma FSH concentrations (P<0.01)
throughout the 9 weeks. Mating was altered in both groups of anastrozole-treated
rats, as they failed to produce copulatory plugs. Histological evaluation of the
testes from anastrozole-treated rats revealed that spermatogenesis was grossly
normal. In a more detailed study, adult rats were treated with 200 mg/l
anastrozole via the drinking water for periods ranging from 2 weeks to 1 year.
Plasma FSH and testosterone concentrations were increased significantly
(P<0.001) during the first 19 weeks of treatment. However, LH concentrations
were increased only at 19 weeks (P<0.001) in anastrozole-treated rats, and this
coincided with a further increase in circulating and intratesticular
testosterone concentrations (P<0.05). No consistent change in inhibin-B
concentrations was observed during the study. Suppression of plasma oestradiol
concentrations could not be demonstrated in anastrozole-treated animals, but
oestradiol concentrations in testicular interstitial fluid were reduced by 18%
(P<0.01). Mating was again inhibited by anastrozole treatment, but could be
restored by s.c. injection of oestrogen, enabling demonstration that rats
treated for 10 weeks or 9 months were still fertile. Testis weight was increased
by 19% and 6% after treatment for 19 weeks and 1 year, respectively. Body weight
was significantly decreased (P<0.01) by 19 weeks of anastrozole treatment; after
1 year the animals appeared to have less fat as indicated by a 27% decrease in
the weight of the gonadal fat pad. The majority of anastrozole-treated animals
had testes with normal spermatogenesis but, occasionally, seminiferous tubules
showed abnormal loss of germ cells or contained only Sertoli cells. Ten percent
of anastrozole-treated animals had testes that appeared to contain only Sertoli
cells, and one rat had 'giant' testes in which the tubule lumens were severely
dilated. Morphometric analysis of the normal testes at 19 weeks showed no
difference in the number of Sertoli cells or germ cells, or the percentage
volumes of the seminiferous epithelium, tubule lumens and interstitium between
control and anastrozole-treated rats. On the basis of the present findings,
oestrogen appears to be involved in the regulation of FSH secretion and
testosterone production, and is also essential for normal mating behaviour in
male rats. Furthermore, these data suggest that the brain and the
hypothalamo-pituitary axis are considerably more susceptible than is the testis
to the effects of an aromatase inhibitor. Anastrozole treatment has resulted in
a model of brain oestrogen insufficiency.
PMID: 10657858 [PubMed - indexed for MEDLINE]
77: J Appl Toxicol 2000 Jan-Feb;20(1):35-47
The peripubertal male rat assay as an alternative to the Hershberger castrated
male rat assay for the detection of anti-androgens, oestrogens and metabolic
modulators.
Ashby J, Lefevre PA.
AstraZeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire
SK10 4TJ, UK. [email protected]
A range of chemicals with various levels of activity as actual or potential
endocrine disrupters have been evaluated for activity in the peripubertal male
rat assay. The chemicals studied included anti-androgens (vinclozolin),
cyproterone acetate, flutamide, 2, 2-bis(4-chlorophenyl)-1,1-dichloroethylene
(DDE), metabolic modulators (anastrazole, finasteride, ketoconazole) and
oestrogens (butyl benzyl phthalate (BBP), methoxychlor, bisphenol A (BPA),
diethylstilboestrol (DES)), the suspected anti-androgen dibutyl phthalate (DBP)
and the non-oestrogen fenitrothion. Dosing extended over postnatal days (pnd)
22-35, 36-50, 36-55 and 22-35, with recovery to pnd 55 or 22-55. The endpoints
studied were changes in the weights of testes, epididymides, seminal vesicles
and prostate. Changes in body weight and the weights of the liver and kidney
were also monitored. In some experiments changes in the day of prepuce
separation (PPS) were also determined. Only BBP and BPA were inactive in all the
assays conducted. Changes in the weight of reproductive tissues provided a
sensitive indicator of activity for the remaining chemicals with the exception
of DDE, for which higher dose levels could have been used. However, none of the
curtailed periods of exposure were able to detect all of the agents. Diethyl
stilboestrol, and to a lesser extent DBP and DDE, delayed PPS when exposure
occurred over the period pnd 22-55. A complex dependence of the day of PPS on
the period of exposure and the body weight of the test animals was observed, and
caution is recommended when assessing this endpoint in the presence of
reductions in body weight. It is concluded that reproductive tissue weight
changes in the peripubertal male have shown sensitivity to a range of
biochemical modulators, oestrogens and anti-androgens, and that as such the
assay warrants further evaluation. Measurement of delays in PPS may be of value
in cases of large delays, but delays of 1-2 days will be difficult to interpret
with confidence. The present results are discussed within the context of the
sexually mature male rat assay described by O'Connor and the castrated male rat
assay described by Hershberger, both of which are the subject of current
international study. It is concluded that a decision on the usefulness of the
peripubertal male rat assay must await the generation of further data on each of
these three assays. There is an urgent need for international agreement on a
list of reference endocrine disrupters and their active dose levels, with which
to validate individual endocrine disruption assays and batteries of assays.
Copyright 2000 John Wiley & Sons, Ltd.
PMID: 10641015 [PubMed - indexed for MEDLINE]
78: Ann Surg Oncol 1999 Dec;6(8 Suppl):14S-16S
Future directions in endocrine treatment of advanced breast cancer.
Bland KI.
PMID: 10619455 [PubMed - indexed for MEDLINE]
79: Ann Surg Oncol 1999 Dec;6(8 Suppl):12S-13S
Safety and tolerability of endocrine therapies used in the treatment of advanced
breast cancer.
Bland KI, Buzdar AU.
PMID: 10619454 [PubMed - indexed for MEDLINE]
80: Ann Surg Oncol 1999 Dec;6(8 Suppl):8S-11S
Critique of survival update analysis from two phase III anastrozole clinical
trials.
Buzdar AU.
Publication Types:
Clinical Trial
Clinical Trial, Phase III
Randomized Controlled Trial
PMID: 10619453 [PubMed - indexed for MEDLINE]
81: Breast Cancer Res Treat 1999 Sep;57(2):183-92
The effect of combining aromatase inhibitors with antiestrogens on tumor growth
in a nude mouse model for breast cancer.
Lu Q, Liu Y, Long BJ, Grigoryev D, Gimbel M, Brodie A.
Department of Pharmacology and Experimental Therapeutics, University of
Maryland, School of Medicine, Baltimore 21201, USA.
We have previously established a model for postmenopausal, hormone-dependent
breast cancer in nude mice which is responsive to both antiestrogens and
aromatase inhibitors. In this model, MCF-7 human breast carcinoma cells
transfected with the aromatase gene (MCF-7CA) synthesize sufficient estrogen to
form tumors in ovariectomized nude mice. In the present study we used this
intratumoral aromatase model to investigate the effects on tumor growth of the
new nonsteroidal aromatase inhibitors letrozole (CGS 20,267) and anastrozole (ZD
1033) and the antiestrogens tamoxifen (ICI 47,474) and faslodex (ICI 182,780).
Furthermore, we determined whether the inhibition of estrogen synthesis together
with inhibition of estrogen action would be more effective in controlling breast
tumor growth. The results of our studies indicate that the aromatase inhibitors
anastrozole and letrozole, as well as the new pure antiestrogen faslodex, have
potent antitumor effects in the mouse model. In the treatment of mice with
mammary tumors, letrozole was more effective in suppressing tumor growth than
anastrozole. This was consistent with the Ki values of these inhibitors against
placental aromatase and the IC50 values in cell culture (MCF-7CA), which
indicated the greater potency of letrozole as an aromatase inhibitor. Letrozole
also had greater antitumor effects than tamoxifen and faslodex. The antitumor
effect of letrozole was substantial, making it difficult to detect any
additional effect on the tumors when letrozole was combined with the
antiestrogens. However, the combined treatment of anastrozole + tamoxifen and
anastrozole + faslodex also did not increase efficacy compared to the aromatase
inhibitor alone. In addition, combining the two antiestrogens did not suppress
tumor growth more effectively than faslodex alone. Our results show that
treatment with the combinations of aromatase inhibitors with either tamoxifen or
faslodex are not more effective in blocking estrogen stimulation of tumor growth
than the aromatase inhibitors alone.
PMID: 10598045 [PubMed - indexed for MEDLINE]
82: Ann Oncol 1999 Oct;10(10):1219-25
A randomized, open, parallel-group trial to compare the endocrine effects of
oral anastrozole (Arimidex) with intramuscular formestane in postmenopausal
women with advanced breast cancer.
Vorobiof DA, Kleeberg UR, Perez-Carrion R, Dodwell DJ, Robertson JF, Calvo L,
Dowsett M, Clack G.
Sandton Oncology Centre, South Africa.
BACKGROUND: This study provides a direct randomized comparison of a
new-generation, non-steroidal aromatase inhibitor, anastrozole (Arimidex), with
a steroidal aromatase inhibitor (formestane) with respect to oestrogen
(oestradiol, oestrone, and oestrone sulphate) suppression and tolerability.
PATIENTS AND METHODS: Sixty postmenopausal women with advanced breast cancer
were randomized to receive either anastrozole 1 mg once daily orally (n = 29),
or formestane 250 mg once every two weeks by intramuscular injection (n = 31).
Treatment was continued until progression of disease or withdrawal from the
study. The primary endpoints of this study were oestradiol suppression and
tolerability. The secondary endpoints included oestrone and oestrone sulphate
suppression. All laboratory analyses were conducted 'blind' of the randomized
drug treatment. RESULTS: Anastrozole produced a greater and more consistent
suppression of oestradiol levels compared with formestane. Based on two- and
four-week measurements, the mean fall from baseline (pre-dose) in oestradiol
level was 79% and 58% in the anastrozole and formestane groups, respectively (P
= 0.0001). After four weeks of treatment, oestrone and oestrone sulphate levels
were also suppressed to a greater extent by anastrozole compared with formestane
(oestrone: 85% versus 67%, respectively, P = 0.0043; oestrone sulphate: 92%
versus 67%, respectively, P = 0.0007). No statistical differences were seen
between the two drugs in the incidence of adverse events. CONCLUSIONS:
Anastrozole provides a more consistent and significantly more effective
suppression of oestradiol compared with formestane. Similar results were
observed for oestrone and oestrone sulphate. The clinical significance of these
differences in total oestrogen suppression remains to be established.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 10586340 [PubMed - indexed for MEDLINE]
83: Drugs Aging 1999 Oct;15(4):271-83
Aromatase inhibitors in the treatment of postmenopausal breast cancer.
Bajetta E, Zilembo N, Bichisao E.
Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
[email protected]
Anastrozole, letrozole and vorozole are new aromatase inhibitors with a
nonsteroidal structure (NSS), and have been demonstrated to be highly effective
and better tolerated than standard endocrine therapy with megestrol (megestrol
acetate) and aminoglutethimide (AG). These agents are very potent and selective:
all of them are capable of suppressing estrone (E1) and estradiol (E2) to the
limit of sensitivity methods, and plasma estrone sulfate (E1S) levels are also
suppressed. However, the fact that this potency has not led to any greater
clinical efficacy, and that there is no relationship between estrogen
suppression and clinical response, suggests that aromatase inhibitors may have
additional mechanisms of action. A number of international, multicentre clinical
trials have compared anastrozole, letrozole and vorozole with megestrol 160
mg/day or AG 500 mg/day plus hydrocortisone in patients with advanced breast
cancer. Letrozole proved to be significantly more effective than megestrol but
anastrozole had a greater effect on survival than either agent. However,
letrozole therapy led to longer survival than that observed in patients treated
with AG. The activity of vorozole was similar to that of megestrol and AG. These
results have raised a number of questions. The first is how should the clinical
results be evaluated, given that 'disease stabilisation lasting > or =6 months'
has been considered a response? The second is how should these drugs be used,
and whether there is a rationale for using them in combination or sequentially
in the treatment of patients with advanced breast cancer? Finally, is the
possible effect of formestane and vorozole on intratumoral aromatase an
alternative or concomitant mechanism of action? Anastrozole, letrozole and
vorozole will be compared with tamoxifen in postmenopausal patients with breast
cancer in adjuvant and primary settings. However, we feel that concomitant
biological and clinical studies should also be carried out in order to clarify
the properties of these drugs and avoid possible risks for patients over time.
Publication Types:
Review
Review, Tutorial
PMID: 10582774 [PubMed - indexed for MEDLINE]
84: Bull Cancer 1999 Oct;86(10):821-7
[Aromatase inhibitors].
[Article in French]
Feutrie ML, Bonneterre J.
Hopital civil d'Armentieres, 112, rue Sadi-Carnot, 59285 Armentieres.
Aromatase inhibitors used in breast cancer, are drugs that inhibit the
transformation of androstenedione and testosterone, respectively in estradiol
and estrone. Two classes have been described: steroidal inhibitors which act
competitively and irreversibly and non steroidal inhibitors which block the P
450 cytochrome. The first one is aminoglutethimide which has an adrenal effect
on 11, 18 and 21 hydroxylase. Rogletimide, less powerful and less specific is a
aminoglutethimide analogue. The response rates obtained with formestane is not
different. The clinical development has been stopped due to a lack of
specificity. Letrozole, vorozole, exemestane and anastrozole are more powerful
and more specific. Letrozole and vorozole are at least as efficient and better
tolerated than aminoglutethimide. Anastrozole, letrozole and vorozole are at
least as efficient as megestrol acetate and better tolerated in advanced breast
cancer patients receiving a second line hormone therapy.
Publication Types:
Review
Review, Tutorial
PMID: 10572233 [PubMed - indexed for MEDLINE]
85: Prostate 1999 Dec 1;41(4):224-32
5alpha-reductase isozymes and aromatase are differentially expressed and active
in the androgen-independent human prostate cancer cell lines DU145 and PC3.
Negri-Cesi P, Colciago A, Poletti A, Motta M.
Center for Endocrinological Oncology, Department of Endocrinology, University of
Milan, Milan, Italy. [email protected]
BACKGROUND: The presence and possible role of androgen-metabolizing enzymes in
androgen-independent prostate carcinoma (CaP) are still unclear. The aim of the
present study was: 1) to evaluate the pattern of androgen metabolism (relative
production of 5alpha-reduced vs. 17-keto androgens); and 2) to analyze whether
one or both the two known 5alpha-reductase isoforms (5alpha-R1 and 5alpha-R2)
and the aromatase (Aro) are expressed and active in this pathology. METHODS: Two
different cell lines (DU145 and PC3) were used as a model of
androgen-independent human CaP. In these cells, the expression of the two
5alpha-Rs and of Aro were evaluated by reverse transcription-polymerase chain
reaction (RT-PCR) and Southern blot, using specific sets of oligoprimers and of
[(32)P]-labeled oligoprobes; the enzymatic activities of 5alpha-R and of Aro
were evaluated by radioenzymatic methods. The pH optimum for the activity of the
two 5alpha-Rs was assessed in cell homogenates at different pH (from 3.5-8),
using substrate concentrations similar either to 5alpha-R1 or to 5alpha-R2 Kms.
RESULTS: The two CaP cell lines DU145 and PC3, although unresponsive to
androgens, possess the enzymatic machinery involved in the metabolism of this
class of hormonal steroids: 5alpha-Rs, which allow their transformation into
5alpha-reduced steroids (5alpha-dihydrotestosterone, DHT, and
5alpha-androstandione, 5alpha-A), and 17beta-hydroxysteroid-oxidoreductase
(17beta-HSD), which interconverts testosterone (T) and androstenedione (ADIONE);
however, the two cell lines show differences in the rate of formation of these
metabolites. Furthermore, two cell lines expressed the type 1 isoform of
5alpha-R, but only DU145 cells also possess 5alpha-R2. Aro is expressed and
active in DU145 as well as in PC3 cells. CONCLUSIONS: The present findings
suggest that T might still be indirectly active in androgen-unresponsive CaP
through its local conversion into estrogens by the action of Aro; the biological
role played by the two 5alpha-Rs in androgen-independent CaP deserves further
investigation. Copyright 1999 Wiley-Liss, Inc.
PMID: 10544295 [PubMed - indexed for MEDLINE]
86: Am J Clin Oncol 1999 Oct;22(5):529-32
Tamoxifen-induced thrombocytopenia.
Yao JC, Thomakos N, McLaughlin P, Buchholz TA, Kudelka AP.
Division of Medicine, The University of Texas M.D. Anderson Cancer Center,
Houston 77030, USA.
Thrombocytopenia (platelet count < 100,000/microl) is a rare side effect of
tamoxifen (Nolvadex). We report a case of thrombocytopenia that developed 6
months after tamoxifen was given as an adjuvant treatment for breast cancer. The
patient received no concurrent cytotoxic chemotherapy or radiation therapy. The
thrombocytopenia resolved after the tamoxifen was stopped, reappeared promptly
when the tamoxifen was restarted, and resolved again after the second
withdrawal, at which time anastrozole (Arimidex) was substituted for the
tamoxifen. The patient's platelet count remained normal for more than 6 months
thereafter.
Publication Types:
Review
Review, Tutorial
PMID: 10521073 [PubMed - indexed for MEDLINE]
87: Drug Saf 1999 Oct;21(4):297-309
Risks and benefits of aromatase inhibitors in postmenopausal breast cancer.
Michaud LB, Buzdar AU.
Division of Pharmacy, The University of Texas M.D. Anderson Cancer Center,
Houston 77030, USA.
Aromatase inhibitors were first reported in the early 1970s and have been used
to treat breast cancer since that time. Until recently, essentially the only
agent available in this class was aminoglutethimide, a nonspecific inhibitor
with multiple adverse effects and drug interactions. Selective and potent
aromatase inhibitors are now available (formestane, exemestane, fadrozole,
anastrozole and letrozole), and we review the risks and benefits of these agents
in order to assist clinicians in making treatment decisions. Formestane is an
injectable steroidal aromatase inhibitor with significant activity against
metastatic breast cancer. It has been shown to have similar efficacy and
superior tolerability compared with megestrol, and is similar to tamoxifen in
the metastatic setting. Exemestane is an oral steroidal aromatase inhibitor. It
has been shown to be effective third-line therapy after tamoxifen and megestrol
in postmenopausal patients with metastatic breast cancer. All the nonsteroidal
(imidazole/triazole) aromatase inhibitors are orally available. Fadrozole has
similar activity to megestrol and tamoxifen in the setting of metastasis, but
has been shown in phase II trials to inhibit cortisol and aldosterone
production. Anastrozole and letrozole have similar toxicity profiles. Compared
with megestrol, anastrozole improves overall survival and has superior
tolerability. Letrozole is superior to megestrol and aminoglutethimide in terms
of overall survival and time to progression, and is also better tolerated.
Although there is a strong rationale for using these agents in the treatment of
breast cancer, the information presently available is insufficient to recommend
any one agent over another. Direct comparative studies are lacking, and
comparing agents across studies is limited by many biases and may not be valid.
Formestane is only available as an injection and exemestane is not commercially
available in many countries, making these agents more difficult to recommend
over the other 3 agents. Fadrozole is less potent and less selective in
inhibiting aromatase than letrozole. The efficacies of fadrozole, megestrol and
tamoxifen appear to be similar; however, comparative data show no advantage of
fadrozole over letrozole. Anastrozole and letrozole are generally considered to
be similar agents. The clinical future of the selective aromatase inhibitors is
promising, and these agents may change the way postmenopausal breast cancer is
treated at all stages of the disease.
Publication Types:
Review
Review, Tutorial
PMID: 10514021 [PubMed - indexed for MEDLINE]
88: Eur J Cancer 1999 May;35(5):744-6
Anastrozole shows evidence of activity in postmenopausal patients who have
responded or stabilised on formestane therapy.
Harper-Wynne C, Coombes RC.
Department of Cancer Medicine, Imperial College School of Medicine, Charing
Cross Hospital, London, U.K.
Formestane (Lentaron) and anastrozole (Arimidex) are in clinical use as
second-line treatments for advanced breast cancer. Current practice is often to
use an aromatase inhibitor only once before switching to third-line agents such
as progestins. There are few clinical data on the sequential use of aromatase
inhibitors. We therefore decided to study the clinical effects of anastrozole in
postmenopausal patients with advanced breast cancer who had already received
formestane. 21 patients were recruited. When receiving formestane 2/21 (10%)
achieved a partial response (UICC criteria) and 10/21 (48%) stable disease. Of
these 12 patients, 9 achieved further stable disease on anastrozole (78%; 7/9
oestrogen receptor positive). 4 of 9 patients who progressed on formestane also
stabilised on anastrozole, of whom 3 had oestrogen receptor positive breast
carcinomas. The explanation of this second stabilisation may relate to a further
fall in oestradiol levels. We feel these results are of interest and warrant
further clinical investigation.
Publication Types:
Clinical Trial
PMID: 10505035 [PubMed - indexed for MEDLINE]
89: Breast Cancer Res Treat 1999 May;55(2):189-99
Assessment of quality of life in women undergoing hormonal therapy for breast
cancer: validation of an endocrine symptom subscale for the FACT-B.
Fallowfield LJ, Leaity SK, Howell A, Benson S, Cella D.
CRC Psychosocial Oncology Group, Department of Oncology, University College
London Medical School, UK. [email protected]
Existing quality of life instruments do not include adequate items to measure
the side effects and putative benefits of hormonal treatments given in breast
cancer. We report the development and validation of an 18 item endocrine
subscale (ES) to accompany a standardised breast cancer quality of life measure,
the Functional Assessment of Cancer Therapy (FACT-B). The FACT-ES (FACT-B plus
ES) was tested initially on 268 women with breast cancer receiving endocrine
treatments. Alpha coefficients for all subscales demonstrated good internal
consistency (range alpha = 0.65-0.87). Test-retest reliability of the ES
indicated good stability (r = 0.93, p < 0.001). Advanced breast cancer patients'
quality of life was high, showing the efficacy of endocrine therapy, but women
with primary disease reported better physical, social, and functional well-being
and fewer breast cancer concerns. Most frequently reported symptoms were loss of
sexual interest (31%), weight gain (25%), and hot flushes (24%). Significant
differences were found between treatment groups for hot flushes and vaginal
dryness. Two assessments of the instrument's responsiveness to change were made;
32 women in a clinical trial of endocrine therapy and 18 women without breast
cancer taking HRT completed the FACT-ES at baseline, 4, 8, and 12 weeks. Trial
patients reported significantly more symptoms at 8 and 12 weeks than at
baseline. Women taking HRT reported significantly fewer or less severe symptoms
than at baseline. In conclusion the FACT-ES has acceptable validity and
reliability and is sensitive to clinically significant change, making it
suitable for clinical trials of endocrine therapy.
PMID: 10481946 [PubMed - indexed for MEDLINE]
90: Neth J Med 1999 Aug;55(2):50-8
New aromatase inhibitors for the treatment of advanced breast cancer in
postmenopausal women.
de Jong PC, Blijham GH.
Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The
Netherlands.
Inhibition of the enzyme aromatase, the rate limiting step in estrogen
production, is an effective endocrine treatment of advanced postmenopausal
breast cancer. Recently, several new aromatase inhibitors have been developed to
improve efficacy and reduce toxicity compared to the prototype aromatase
inhibitor aminoglutethimide. Aromatase inhibitors can be divided into two types.
The first are the non-steroidal inhibitors that have a mechanism of action
similar to aminoglutethimide. The second are the steroidal inhibitors that
function as a false substrate for aromatase. Of the non-steroidal aromatase
inhibitors, two drugs, anastrozole and letrozole, have recently been registered
for the second line endocrine treatment of advanced postmenopausal breast cancer
after failure on tamoxifen. The phase III studies of these drugs indicate at
least equal efficacy compared to current second line treatment with
aminoglutethimide or megestrol acetate. Their toxicity profile, however, is much
more favourable. This makes them the drugs of choice for the second line
endocrine treatment of advanced breast cancer in postmenopausal patients, who
failed during adjuvant or first line treatment with tamoxifen. Of the steroidal
aromatase inhibitors, the orally active drug exemestane is still in phase III
clinical study; the registration is expected in 1999.
Publication Types:
Review
Review, Tutorial
PMID: 10474272 [PubMed - indexed for MEDLINE]
91: Drugs 1999 Aug;58(2):233-55
Comprehensive pharmacology and clinical efficacy of aromatase inhibitors.
Njar VC, Brodie AM.
Department of Pharmacology and Experimental Therapeutics, School of Medicine,
University of Maryland, Baltimore 21201, USA.
The goal of hormone therapy is to deprive breast tumours of estrogens, since
estrogens have been implicated in the development or progression of tumours.
This can be accomplished by the use of antiestrogens that block estrogen action
or by inhibiting aromatase, the enzyme that catalyses the final and
rate-limiting step in estrogen biosynthesis. A number of steroidal and
nonsteroidal compounds have been developed as aromatase inhibitors. This review
highlights the valuable role that a few of these aromatase inhibitors have
played, and continue to play, in the treatment of breast cancer. Following
background information regarding the biochemistry of aromatase, the rationale
for its inhibition, and an outline of the test systems for evaluating and
characterising aromatase inhibitors, the discussion focuses on the new
generation of aromatase inhibitors that are in clinical trials or clinically
available. Specifically, it discusses the pharmacology and clinical efficacy of
formestane, exemestane, rogletimide, fadrozole, vorozole, anastrozole and
letrozole. The role of these agents as the optimal second-line agents (after
tamoxifen) for the treatment of advanced breast cancer has been established;
their prospects in other clinical settings and as potential breast cancer
chemopreventives are warranted but are yet to be fully determined.
Publication Types:
Review
Review, Academic
PMID: 10473018 [PubMed - indexed for MEDLINE]
92: J Steroid Biochem Mol Biol 1999 Apr-Jun;69(1-6):205-10
Aromatase and its inhibitors.
Brodie A, Lu Q, Long B.
Department of Pharmacology and Experimental Therapeutics, School of Medicine,
University of Maryland, Baltimore 21201, USA. [email protected]
Inhibitors of aromatase (estrogen synthetase) have been developed as treatment
for postmenopausal breast cancer. Both steroidal substrate analogs, type I
inhibitors, which inactivate the enzyme and non-steroidal competitive
reversible, type II inhibitors, are now available. 4-hydroxyandrostenedione
(4-OHA), the first selective aromatase inhibitor, has been shown to reduce serum
estrogen concentrations and cause complete and partial responses in
approximately 25% of patients with hormone responsive disease who have relapsed
from previous endocrine treatment. Letrozole (CGS 20, 269) and anastrozole (ZN
1033) have been recently approved for treatment. Both suppress serum estrogen
levels to the limit of assay detection. Letrozole has been shown to be
significantly superior to megace in overall response rates and time to treatment
failure, whereas anastrozole was found to improve survival in comparison to
megace. Both were better tolerated than the latter. The potential of aromatase
within the breast as a significant source of estrogen mediating tumor
proliferation and which might determine the outcome of inhibitor treatment was
explored. Using immunocytochemistry and in situ hybridization, aromatase and
mRNAarom was detected mainly in the epithelial cells of the terminal ductal
lobular units (TDLU) of the normal breast and also in breast tumor epithelial
cells as well as some stromal cells. Increase in proliferation, measured by
increased thymidine incorporation into DNA and by PCNA immunostaining in
response to testosterone was observed in histocultures of breast cancer samples.
This effect could be inhibited by 4-OHA and implies that intratumoral aromatase
has functional significance. An intratumoral aromatase model in the
ovariectomized nude mouse was developed which simulated the hormone responsive
postmenopausal breast cancer patient. This model also allows evaluation of the
efficacy of aromatase inhibitors and antiestrogens in tumors of estrogen
receptor positive, human breast carcinoma cells transfected with the human
aromatase gene. Thus, the cells synthesized estrogen which stimulated tumor
formation. Both aromatase inhibitors and antiestrogens were effective in
suppressing tumor growth in this model. However, letrozole was more effective
than tamoxifen. When the aromatase inhibitors were combined with tamoxifen,
tumor growth was suppressed to about the same extent as with the aromatase
inhibitors alone. Thus, there was no additive or synergistic effects of
combining tamoxifen with aromatase inhibitors. This suggests that sequential
treatment with these agents is likely to be more beneficial to the patient in
terms of longer response to treatment.
Publication Types:
Review
Review, Tutorial
PMID: 10418994 [PubMed - indexed for MEDLINE]
93: Biol Reprod 1999 Aug;61(2):388-92
Mitogenic and antioxidant mechanisms of estradiol action in preovulatory ovine
follicles: relevance to luteal function.
Lund SA, Murdoch J, Van Kirk EA, Murdoch WJ.
Department of Animal Science, University of Wyoming, Laramie, Wyoming 82071,
USA.
The objectives of this investigation were to determine the intrafollicular
mechanisms and physiological consequences of estradiol actions in preovulatory
ovine follicles. Acute suppression of estradiol production in proestrous ewes by
an aromatase inhibitor (Arimidex) was associated with follicular lipid
peroxidation, testosterone accumulation, and a granulosa cell deficiency
(decreased proliferation/increased apoptosis). Estradiol-17beta stimulated
granulosa proliferating cell nuclear antigen (PCNA) and protected cells from
oxidative (H(2)O(2)) stress-induced apoptosis in vitro; the PCNA, but not the
antiapoptotic response, was negated by the transcriptional inhibitor actinomycin
D. Thus, it appears that genomic/mitotic and cytoprotective (oxygen-scavenging)
modes of estradiol action operate in preovulatory follicles. Luteal (large
steroidogenic cell) function was diminished following ovulation induction of
estradiol-deficient follicles. It is suggested that inadequate exposure of the
preovulatory follicle to estradiol caused the granulosa lutein insufficiency.
PMID: 10411516 [PubMed - indexed for MEDLINE]
94: Ann Oncol 1999 Apr;10(4):377-84
The third-generation non-steroidal aromatase inhibitors: a review of their
clinical benefits in the second-line hormonal treatment of advanced breast
cancer.
Hamilton A, Piccart M.
Institut Jules Bordet, Brussels, Belgium.
Three new aromatase inhibitors have recently completed phase III evaluation as
treatment of metastatic breast cancer in post-menopausal women whose disease has
progressed despite tamoxifen therapy: anastrozole (ARIMIDEX, Zeneca), letrozole
(FEMARA, Novartis) and vorozole (RIVIZOR, Janssen). All belong to the third
generation of non-steroidal aromatase inhibitors, and each is superior to
previous generations in terms of potency and selectivity. The trials that have
been performed compare each agent to megestrol acetate, and letrozole and
vorozole to aminoglutethimide. Although the studies are not directly comparable
due to differing study designs and patient populations, it has been demonstrated
each of these drugs provides single agent, once-daily, oral palliation of
hormone-responsive, post-menopausal metastatic breast cancer. Letrozole is
clearly more effective than megestrol acetate, and anastrozole and vorozole are
possibly so. All three are better tolerated than the progestin, particularly in
terms of weight gain. Both letrozole and vorozole are significantly more
effective, and better tolerated than aminoglutethimide. Overall, this most
recent generation of aromatase inhibitors is a clear improvement on our current
standard second-line therapies. In 1999, tamoxifen remains the first choice in
the hormonal therapy of breast cancer. Following tamoxifen failure, the optimal
second-line hormonal therapy remains undefined, but aminoglutethimide and
megestrol acetate are no longer optimal therapy in this setting. The
third-generation non-steroidal aromatase inhibitors must now be compared to each
other, to the steroidal aromatase inhibitors, to the pure anti-oestrogens, and
to tamoxifen.
Publication Types:
Review
Review, Academic
PMID: 10370778 [PubMed - indexed for MEDLINE]
95: Toxicol Sci 1998 Nov;46(1):61-74
Ex vivo and in vitro testis and ovary explants: utility for identifying steroid
biosynthesis inhibitors and comparison to a Tier I screening battery.
Powlin SS, Cook JC, Novak S, O'Connor JC.
DuPont Haskell Laboratory for Toxicology and Industrial Medicine, Newark,
Delaware 19714, USA.
Testis and ovary explants have been proposed as in vitro screens for identifying
potential inhibitors of steroid biosynthesis. The goals of the current study
were to optimize the conditions of the two assays, to characterize these assays
using several compounds with well-defined endocrine activity, and to compare the
responses from the explant assays with an in vivo male battery currently
undergoing validation using the Crl:CD BR rat in order to evaluate their utility
as test systems for screening unknown compounds for possible steroid
biosynthesis inhibition activity. There were two components to the testis/ovary
assays: ex vivo and in vitro. The ex vivo component used testes/ovaries from
animals dosed with the test compounds in vivo, and the in vitro component used
testes/ovaries from control animals. For the testis assays, decapsulated testis
explants (50 mg) were placed into glass scintillation vials, +/-1.0 IU/ml hCG
for 3 h in a shaking water bath (34 degrees C). Following the incubation period,
medium was removed, centrifuged, and frozen until assayed for hormone
concentrations. A similar procedure was used for the ovary explant assay except
that each ovary was incubated separately. The testis explants were evaluated
using the following compounds: ketoconazole (KETO), a testosterone biosynthesis
inhibitor; aminoglutethimide (AG) (only in vitro) and anastrozole (ANA),
aromatase inhibitors; finasteride (FIN), a 5alpha-reductase inhibitor;
17beta-estradiol (17beta-E2), an estrogen receptor agonist; flutamide (FLUT), an
androgen receptor antagonist; ICI-182,780 (ICI), an estrogen receptor
antagonist; haloperidol (HALO), a D2 receptor antagonist; and reserpine (RES), a
dopamine depletor. In the ovary assay, AG (only in vitro), ANA, ICI, and HALO
(only in vitro) were evaluated. Addition of fetal calf serum to the medium
allowed measurement of estradiol (E2) in the testis assay, but production was
not inhibited by ANA or AG. In the ovary explant assay, only AG was identified
as inhibiting E2 production in vitro. Hence, both the testis and ovary explant
assays appear to have limited utility for detecting aromatase inhibitors.
Screening of these nine diverse endocrine-active compounds resulted in all of
them being identified as altering the endocrine system when assessed by ex vivo
and in vitro testis explants. Using only the in vitro assessment with the
criteria of steroid biosynthesis inhibition, four of nine compounds were
correctly identified in the testis explant assay (17beta-E2, KETO, FLUT, and
HALO). The predictability of both the in vitro and ex vivo ovary assay was 50%,
suggesting a 50% false positive or negative rate with unknown compounds.
However, of the seven compounds assessed to date (17beta-E2, ICI, ANA, KETO,
FLUT, HALO, and RES), all were correctly identified using an in vivo male
battery, which also has the capability to detect other endocrine activities.
Therefore, the testis and ovary explant assay would not be necessary if one were
using an in vivo male battery, since this screen would identify steroid
biosynthesis inhibitors and would also identify several other endocrine
activities. Because of the difficulties in assessing cytotoxicity and the high
false positive/negative rates, the ovary and testis explant assays are not
useful as routine screening procedures for detecting steroid biosynthesis
inhibitors; however, they may have utility in confirming in vivo findings.
PMID: 9928669 [PubMed - indexed for MEDLINE]
96: Toxicol Sci 1998 Nov;46(1):45-60
An ongoing validation of a Tier I screening battery for detecting
endocrine-active compounds (EACs).
O'Connor JC, Cook JC, Slone TW, Makovec GT, Frame SR, Davis LG.
DuPont Haskell Laboratory for Toxicology and Industrial Medicine, Newark,
Delaware 19714, USA.
After previously examining an estrogen receptor agonist (17beta-estradiol),
several additional compounds have been evaluated in a Tier I screening battery
for detecting endocrine-active compounds (EACs): an estrogen receptor antagonist
(ICI-182,780, ICI), an androgen receptor antagonist (flutamide, FLUT), a
testosterone biosynthesis inhibitor (ketoconazole, KETO), a 5alpha-reductase
inhibitor (finasteride, FIN), and an aromatase inhibitor (anastrozole, ANA). The
Tier I battery incorporates two short-term in vivo tests (a 5-day ovariectomized
female battery and a 15-day intact male battery) and an in vitro yeast
transactivation system (YTS). The Tier I battery is designed to identify
compounds that have the potential to act as agonists or antagonists to the
estrogen, androgen, progesterone, or dopamine receptors, steroid biosynthesis
inhibitors (aromatase, 5alpha-reductase, and testosterone biosynthesis), or
compounds that alter thyroid function. ICI administration decreased uterine
estrogen and progesterone receptor number in the female battery, increased serum
follicle-stimulating hormone (FSH) levels and caused spermatid retention in the
male battery, and activated gene transcription in the YTS containing the
estrogen receptor. FLUT administration increased uterine stromal cell
proliferation in the female battery and decreased weights for all
androgen-dependent tissues, induced Leydig cell hyperplasia, and caused hormonal
alterations (increased testosterone (T), estradiol (E2), dihydrotestosterone
(DHT), luteinizing hormone (LH), and FSH) in the male battery, and competed for
binding to the androgen receptor in the YTS competition assay. In the male
battery KETO decreased weights for all androgen-dependent tissues, caused
hormonal alterations (decreased T and DHT and increased LH and FSH), and induced
spermatid retention. FIN decreased seminal vesicle and accessory sex gland (ASG)
unit weight and caused hormonal alterations (decreased DHT and increased LH, and
PRL) in the male battery. KETO was judged not to affect any of the endpoints in
the female battery. ANA decreased ASG unit weight and serum E2 levels in the
male battery. Using the responses obtained for all the endpoints in the Tier I
battery, a distinct "fingerprint" was produced for each type of endocrine
activity against which compounds with unknown activity can be compared. These
data demonstrate that the described Tier I battery is useful for identifying
EACs.
PMID: 9928668 [PubMed - indexed for MEDLINE]
97: Recent Results Cancer Res 1998;152:453-70
Italian Breast Cancer Adjuvant Chemo-Hormone Therapy Cooperative Group Trials.
GROCTA Trials.
Boccardo F, Rubagotti A, Amoroso D, Mesiti M, Pacini P, Gallo L, Sismondi P,
Giai M, Genta F, Mustacchi G, Agostara B, Bolognesi A, Villa E, Schieppati G,
Ausili Cefaro GP, Bellantone R, Farris A, Sassi M, Patrone F.
Servizio di Oncologia Medica II, Istituto Nazionale per la Ricerca sul Cancro di
Genova, Italy.
The first GROCTA trial compared 5-year tamoxifen treatment to ten chemotherapy
cycles in a group of 504 pre-/post-menopausal, node-positive, ER-positive breast
cancer patients. This study also included an arm combining tamoxifen with
chemotherapy. Fifteen-year results showed no difference between tamoxifen and
tamoxifen plus chemotherapy, while both treatments were significantly superior
to chemotherapy alone. A confirmatory study (GROCTA 02) was performed in 244
pre-/perimenopausal patients by comparing 5 years of tamoxifen treatment (plus 2
years of goserelin) to six CMF cycles. No difference has emerged so far between
the tamoxifen and CMF arms at a median follow-up time of 62 months.
Post-menopausal women were scheduled to receive 3 years of tamoxifen treatment
and then to be randomly allocated to further 2 years of tamoxifen or to 2 years
of low-dose aminoglutethimide (GROCTA 04B). So far 662 patients have been
entered, 375 of whom have been randomized to tamoxifen (n = 188) or
aminoglutethimide (n = 187). Preliminary results (median follow-up time 32
months) show no major difference in patients' outcome. A new trial (ITA trial)
with a similar design but employing anastrozole in place of aminoglutethimide
has been activated in 1998. The GROCTA 03 study investigated the potential
superiority of alternating adjuvant chemotherapy over standard CMF. This study,
which included 107 node-positive ER-negative pre-menopausal women, was
prematurely closed because more patients allocated to the triple alternated
chemotherapy appeared to have relapsed and died at the first interim analysis.
The use of high-dose chemotherapy (HDC) was explored by the GROCTA 06 trial
which included 53 patients with ten or more involved nodes and a maximum age of
55 years. These patients were scheduled to receive three standard CEF cycles
followed by one cycle of HDC (cyclophosphamide 5 g/m2; etoposide 1.5 g/m2;
cisplatin 150 mg/m2) without any form of bone marrow rescue. This HDC program
proved to be feasible but was not superior to CMF-based chemotherapy we had
previously employed in a comparable group of patients in previous GROCTA trials.
These findings prompted us to explore new HDC programmes with the use of
peripheral stem cell support and in addition the possible value of new drugs
such as Taxol and vinorelbine. New-generation trials will also explore the value
of new prognostic indicators such as tumor proliferative activity, which are
prospectively used to allocate patients to different treatment options.
Publication Types:
Clinical Trial
Randomized Controlled Trial
Review
Review, Tutorial
PMID: 9928580 [PubMed - indexed for MEDLINE]
98: Recent Results Cancer Res 1998;152:277-84
Aromatase inhibitors and their use in the adjuvant setting.
Coombes RC.
Department of Cancer Medicine, Imperial College School of Medicine, Charing
Cross Hospital, London, UK.
Over the past decade several novel aromatase inhibitors have been introduced
into clinical practice. The discovery of these drugs followed on from the
observation that the main mechanism of action of aminoglutethemide was via
inhibition of the enzyme aromatase, thereby reducing peripheral levels of
estradiol in post-menopausal patients. The second-generation drug
4-hydroxyandrostenedione was introduced in 1990, and although its use was
limited by its need to be given parenterally, it was found to be a
well-tolerated form of endocrine therapy. The third-generation inhibitors
include vorozole, letrozole, anastrozole and exemestane, the former three being
non-steroidal inhibitors, the latter being a steroidal inhibitor. All these
compounds are capable of reducing estrogen levels to within 5%-10% of baseline
levels compared with 20%-30% base line levels in the case of
4-hydroxyandrostenedione. Studies are currently in progress to determine the
value of these third-generation aromatase inhibitors in the adjuvant setting.
These studies include head-to-head comparison of aromatase inhibitor with
tamoxifen, sequential aromatase inhibitor after tamoxifen and first-line
aromatase inhibitor followed by adjuvant tamoxifen. Current issues revolve
around the toxicity of these compounds in terms of effects on the cardiovascular
system and bone.
Publication Types:
Review
Review, Tutorial
PMID: 9928565 [PubMed - indexed for MEDLINE]
99: Presse Med 1998 Dec 12;27(39):2049-54
[Breast cancer: new therapeutic strategies].
[Article in French]
Espie M.
Hopital St Louis, Centre des Maladies du Sein, Paris. [email protected]
NEED FOR NEW CHEMOTHERAPY AGENTS: Metastasic breast cancer is an excellent model
for studying anticancer agents: chemotherapy or hormonotherapy or compounds
modifying the organism's response. If no adjuvant treatment is given after
locoregional treatment of breast cancer, metastasis will develop within 10 years
in 30% of the patients free of initial nodal invasion and within 5 years in 50%
of the patients with initial nodal invasion. ADJUVANT TREATMENTS: Hormonotherapy
and chemotherapy reduce mortality due to breast cancer by 10%. New adjuvant
agents have been recently introduced. Taxans (docetaxel, paclitaxel) are the
most active molecules since antracyclines. New aromataase inhibitors include
letrozole and anastrozole. Their efficacy has been demonstrated in phase II and
phase III trials, allowing their experimentation as adjuvant treatments.
Publication Types:
Clinical Trial
Clinical Trial, Phase II
Clinical Trial, Phase III
Randomized Controlled Trial
PMID: 9893697 [PubMed - indexed for MEDLINE]
100: Br J Cancer 1999 Jan;79(2):311-5
The effect of anastrozole on the pharmacokinetics of tamoxifen in
post-menopausal women with early breast cancer.
Dowsett M, Tobias JS, Howell A, Blackman GM, Welch H, King N, Ponzone R, von
Euler M, Baum M.
Academic Department of Biochemistry, Royal Marsden Hospital, London, UK.
Thirty-four post-menopausal women with early breast cancer who had received 20
mg tamoxifen once daily as adjuvant therapy for at least 10 weeks participated
in a randomized, double-blind, parallel-group, multicentre trial. The primary
aim of the trial was to determine the effect of anastrozole upon tamoxifen
pharmacokinetics, with secondary aims of assessing the tolerability of the two
drugs in combination and whether or not tamoxifen had any effect upon the
oestradiol suppression seen with anastrozole. Patients were randomized to
receive either 1 mg anastrozole (16 patients) or matching placebo (18 patients)
once daily on a double-blind basis for 28 days. No significant difference (P =
0.919) was observed in serum tamoxifen concentrations between the anastrozole
and placebo groups during the trial. The serum concentration of oestradiol was
significantly suppressed (P < 0.0001) in patients co-administered anastrozole
compared with placebo in the presence of tamoxifen, confirming that anastrozole
remained an effective suppressant of oestradiol in the presence of tamoxifen.
The combination of tamoxifen and anastrozole was well tolerated, with very
little difference in side-effects reported between anastrozole and placebo. In
conclusion, the results of this study confirm that anastrozole does not affect
the pharmacokinetics of tamoxifen when the two drugs are given in combination to
post-menopausal women with early breast cancer. In addition, the oestradiol
suppressant effects of anastrozole appear unaffected by tamoxifen.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 9888474 [PubMed - indexed for MEDLINE]
101: Endocrinology 1999 Jan;140(1):273-9
Macrophage colony stimulating-factor transcripts are differentially regulated in
rat bone-marrow by gender hormones.
Lea CK, Sarma U, Flanagan AM.
Department of Histopathology, Imperial College School of Science, Technology and
Medicine at St. Mary's, London, United Kingdom.
There are at least three forms of macrophage colony-stimulating factor (M-CSF),
a cytokine that is critical for osteoclast formation; and evidence exists that
the membrane-bound form is involved in this process. We wished to test the
hypothesis that the expression of the membrane form of M-CSF is modulated by the
presence of gender steroids. This was achieved by analyzing M-CSF messenger RNA
and protein in the bone-marrow of estrogen- and androgen-replete, and -deficient
female rats. We found that the 1.4-kb M-CSF transcript was not detected in
sham-operated rats but that the 4.6-kb transcript was expressed in abundance. In
contrast, these transcripts were differentially expressed in ovariectomized
rats, and this effect was reversed by 17beta-estradiol treatment. Administration
of androstenedione to ovariectomized rats, so that androstenedione plasma levels
were restored to just below that in sham-operated rats, also suppressed the
expression of the 1.4-kb M-CSF transcript. This effect was abrogated by
antiandrogen treatment, indicating that this was an androgen-mediated effect.
The membrane-bound protein was detected in the bone-marrow of sham-operated rats
and was elevated post ovariectomy, whereas ovariectomy had no effect on the
soluble isoform. Our data support the hypothesis that the membrane form of M-CSF
is modulated by gender hormones and that this isoform is involved in the
estrogen- and androgen-mediated effects on the skeleton.
PMID: 9886835 [PubMed - indexed for MEDLINE]
102: J Steroid Biochem Mol Biol 1998 Nov;67(4):293-304
The steroidal antiestrogen ICI 182,780 is an inhibitor of cellular aromatase
activity.
Long BJ, Tilghman SL, Yue W, Thiantanawat A, Grigoryev DN, Brodie AM.
Department of Pharmacology and Experimental Therapeutics, The University of
Maryland School of Medicine, Baltimore 21201, USA.
Two types of endocrine therapy that have been successfully applied to patients
with hormone-dependent breast cancer are the non-steroidal antiestrogen
tamoxifen, and inhibitors of aromatase, the enzyme that synthesizes estrogens.
The major drawback with tamoxifen is that it acts as a partial estrogen-agonist
and this is believed to mediate, at least in part, acquired tumor resistance to
the drug as well as endometrial hyperplasia and carcinoma in some patients. The
newer and more potent antiestrogen ICI 182,780 is a steroidal molecule that is
devoid of estrogenic activity. We now report that ICI 182,780 is also an
inhibitor of aromatase activity in fibroblasts isolated from the normal human
breast as well as other carcinoma cell lines that express aromatase (MCF-7Ca
breast cancer and JEG-3 choriocarcinoma). ICI 182,780 (1 microM) did not affect
aromatase activity levels in human placental microsomes and only inhibited
aromatase activity in each of the cell lines following a prolonged incubation
period. In the fibroblasts, inhibition of aromatase activity by ICI 182,780 was
shown to be time and dose-dependent. In contrast, tamoxifen and 17beta-estradiol
were shown to have no effect on aromatase activity levels. ICI 182,780 inhibited
aromatase activity levels with IC50 values of 16.80 nM in MCF-7Ca cells, 125.50
nM in JEG-3 cells and 386.1 nM in breast fibroblasts. These values were compared
to those for known aromatase inhibitors, and in each of the cell lines the order
of potency was letrozole>4-OHA>anastrozole>ICI 182,780. The inhibition of
aromatase activity by ICI 182,780 was sustained even after the antiestrogen was
removed from the cells indicating that ICI 182,780 may be remaining bound to the
enzyme. Although ICI 182,780 had no effect on the proliferation of the
fibroblasts, or JEG-3 cells, it significantly inhibited the growth of MCF-7Ca
cells. This growth inhibition appeared to be due to the antiestrogenic activity
of ICI 182,780 and not to its aromatase inhibiting effects. ICI 182,780 did not
inhibit aromatase activity by down-regulating levels of the aromatase
transcript. These results show that in addition to being a potent antiestrogen,
ICI 182,780 is also an inhibitor of cellular aromatase activity, and suggest
that by interfering with the actions of estrogen by two distinct mechanisms, ICI
182,780 may be a suitable drug for treating patients with hormone-dependent
breast cancer.
PMID: 9883986 [PubMed - indexed for MEDLINE]
103: Drugs 1998 Dec;56(6):1125-40
Letrozole. A review of its use in postmenopausal women with advanced breast
cancer.
Lamb HM, Adkins JC.
Adis International Limited, Auckland, New Zealand. [email protected]
Letrozole is an oral reversible nonsteroidal aromatase inhibitor. Clinical
tracer studies show that it inhibits peripheral aromatase by over 98% and
suppresses blood and urinary estrogen levels by over 95% after 2 weeks of
treatment in postmenopausal women. Letrozole also significantly inhibits
intratumoral aromatase in vivo. The action of letrozole appears to be selective
for aromatase; long term administration did not affect basal levels of 17
alpha-hydroxyprogesterone or aldosterone, although slight decreases in cortisol
levels were observed in 2 studies, these did not appear to be clinically
significant. In 2 phase IIb/III trials, letrozole 2.5 mg/day achieved objective
response rates of 19.5 and 23.6% which were sustained for a median duration of
24 and 33 months, respectively. The median duration of response compared
favourably with both comparator agents, aminoglutethimide and megestrol (15 and
18 months, respectively), as did objective response rates (12.4 and 16.4%).
Letrozole 2.5 mg/day was associated with an increase in median survival time of
8 and 3 months compared with aminoglutethimide and megestrol, respectively.
According to analyses of overall function, letrozole 2.5 mg/day was
significantly superior to both comparators with respect to duration of response
and aminoglutethimide with respect to survival. Letrozole has a good short term
tolerability profile. The adverse events reported most commonly in association
with letrozole 2.5 mg/day in the 2 phase IIb/III trials were headache (1.1 and
7%), nausea (6 and 10.3%), fatigue (3.2 and 5%), hot flushes (4.9 and 5%) and
peripheral oedema (6%). Events were usually mild to moderate in severity;
adverse events necessitated discontinuation of treatment in 3% of letrozole 2.5
mg/day recipients. CONCLUSIONS: Letrozole, in common with vorozole and
anastrozole, offers greater selectivity and potency of aromatase inhibition than
the prototype aromatase inhibitor, aminoglutethimide, and can be administered
once daily. Available clinical data suggest that letrozole achieves a
significantly longer duration of response than megestrol and aminoglutethimide
and longer overall survival than aminoglutethimide. However, direct comparisons
are required to distinguish between the newer aromatase inhibitors. For this
reason, letrozole should be recommended as a second-line treatment in
postmenopausal women with advanced breast cancer whose disease has progressed on
or failed to respond to antiestrogen therapy.
Publication Types:
Review
Review, Tutorial
PMID: 9878997 [PubMed - indexed for MEDLINE]
104: Drugs Aging 1998 Oct;13(4):321-32
Anastrozole. A review of its use in the management of postmenopausal women with
advanced breast cancer.
Wiseman LR, Adkins JC.
Adis International Limited, Auckland, New Zealand. [email protected]
Anastrozole is a new oral nonsteroidal aromatase inhibitor indicated for the
second-line endocrine treatment of postmenopausal women with advanced breast
cancer. In postmenopausal women, anastrozole significantly reduces plasma
estrogen levels; maximal suppression is achieved at dosages > or = 1 mg/day and
levels remain suppressed during long term therapy. In two phase III clinical
trials, anastrozole 1 or 10 mg/day showed similar clinical efficacy to that of
oral megestrol (megestrol acetate) 160 mg/day in postmenopausal women with
advanced breast cancer. Primary end-points [including time to disease
progression (120 to 170 days) and overall response rates (complete and partial
response and stable disease lasting > or = 24 weeks: 29 to 37%)] and secondary
end-points [time to treatment failure (115 to 168 days) and duration of response
(257 to 261 days)] did not differ significantly between treatment groups.
However, a significant survival advantage was observed in patients treated with
anastrozole 1 mg/day compared with megestrol in a follow-up combined analysis of
patients enrolled in both studies (median time to death 26.7 vs 22.5 months).
Quality of life parameters were generally improved to a similar extent in all
treatment groups. Anastrozole is generally well tolerated in the majority of
patients, the most common adverse events being gastrointestinal (GI)
disturbances (incidence 29 to 33%). These events are generally mild or moderate
and transient. Other adverse events reported with anastrozole include headache
(< or = 18%), asthenia (< or = 16%), pain (< or = 15%), hot flushes and bone
pain (both < or = 12%), back pain and dyspnoea (both < or = 11%) and peripheral
oedema (< or = 9%). GI disturbance tended to be more common with anastrozole
than megestrol, particularly at the 10 mg/day dosage; however, compared with
megestrol, anastrozole is less frequently associated with weight gain.
CONCLUSIONS: Anastrozole, with its apparent survival advantage versus megestrol
(demonstrated in a combined analysis of phase III studies), convenient once
daily oral administration and acceptable short term tolerability profile, is a
second-line treatment option for postmenopausal patients with
tamoxifenrefractory advanced breast cancer. The results of ongoing comparative
trials with tamoxifen will determine the relative efficacy of anastrozole as
first-line endocrine therapy for advanced breast cancer and as adjuvant therapy
for early disease. In addition, direct comparative studies are required to
determine the efficacy of anastrozole relative to that of other oral aromatase
inhibitors such as letrozole and vorozole.
Publication Types:
Review
Review, Tutorial
PMID: 9805213 [PubMed - indexed for MEDLINE]
105: Breast Cancer Res Treat 1998 Jul;50(1):63-71
The effects of aromatase inhibitors and antiestrogens in the nude mouse model.
Lu Q, Yue W, Wang J, Liu Y, Long B, Brodie A.
Department of Pharmacology & Experimental Therapeutics, and Greenbaum Cancer
Center, School of Medicine, University of Maryland, Baltimore 21201, USA.
The effects of antiestrogens, tamoxifen and ICI 182,780, and aromatase
inhibitors, arimidex (anastrozole ZD1033) and letrozole (CGS 20,267), on the
growth of tumors were studied in nude mice. In this model, estrogen dependent
MCF-7 human breast cancer cells stably transfected with the aromatase gene were
inoculated in four sites per mouse. Sufficient estrogen is produced from
aromatization of androstenedione supplement (0.1 mg/mouse/day) by the cells to
stimulate their proliferation, tumor formation, and maintain the uterus similar
to that of the intact mouse. Once the tumors reached a measurable size, the mice
were injected with antiestrogen or inhibitor for 35-56 days. Tumor volumes were
measured weekly. At autopsy, the tumors were removed, cleaned, and weighed.
Statistical data was determined from tumor weights. Both antiestrogens were
effective in reducing tumor growth in these mice. Tamoxifen appears to be more
effective than ICI 182,780, although the former stimulated the uterine weight
whereas the pure antiestrogen did not. However, both aromatase inhibitors were
more effective than the antiestrogens. Tumor regression was observed with
letrozole. Thus, after-treatment tumor weights were less than those of a group
of mice at the start of treatment. The aromatase inhibitors also reduced the
weight of the uterus, suggesting that these compounds, as well as the pure
antiestrogen, may not cause endometrial proliferation, unlike tamoxifen. These
aromatase inhibitors may not only benefit patients who have relapsed from
tamoxifen, but may be more effective in patients as first line agents for
suppressing the effects of estrogen.
PMID: 9802621 [PubMed - indexed for MEDLINE]
106: Breast Cancer Res Treat 1998;49 Suppl 1:S53-7; discussion S73-7
Pharmacological and clinical profile of anastrozole.
Lonning PE, Geisler J, Dowsett M.
Department of Oncology, Haukeland University Hospital Bergen, Norway.
Anastrozole (Arimidex,
2,-2[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-met
hyl)propiononitrile) is a novel, potent aromatase inhibitor belonging to the
triazole class. In vitro and in vivo animal studies have revealed the drug to be
a potent inhibitor of the aromatase enzyme with no inhibitory activity versus
other enzymes involved in steroid synthesis. The drug is a potent suppressor of
plasma estrogens in healthy male and postmenopausal female volunteers as well as
postmenopausal breast cancer patients, and anastrozole administered as 1 mg or
10 mg daily has been shown to inhibit in vivo aromatization by 96.7 and 98.1%,
respectively. Two large, randomized studies revealed anastrozole to cause
objective response rates and stable disease comparable to what was achieved with
megestrol acetate but with a lower incidence of side effects. While follow-up
results have not revealed any significant difference in time to relapse between
the drug regimens, they have revealed an improved survival among patients
treated with anastrozole 1 mg compared to megestrol acetate 160 mg daily.
Further follow-up is required to finally decide whether there may be a survival
benefit also among patients treated with anastrozole 10 mg daily and to evaluate
whether the improvement in survival is associated with an improved disease-free
survival as would be anticipated.
Publication Types:
Review
Review, Tutorial
PMID: 9797018 [PubMed - indexed for MEDLINE]
107: Breast Cancer Res Treat 1998;49 Suppl 1:S39-44; discussion S73-7
Theoretical considerations for the ideal aromatase inhibitor.
Dowsett M.
Royal Marsden Hospital, London, UK. [email protected]
A definition of the theoretical components of an ideal aromatase inhibitor is
developed, one aspect of which is completeness of enzyme inhibition. The three
triazole inhibitors, letrozole, vorozole and anastrozole all inhibit whole body
aromatisation by > 96% at their clinically used doses and vorozole and letrozole
were more effective in Phase III clinical trials than aminoglutethimide (250 mg
bd) which achieves < 90% inhibition. The possibility is considered that the
apparent small differences between the triazoles may be associated with
differences in clinical effectiveness. These new compounds merit consideration
for studies of breast cancer prevention.
Publication Types:
Review
Review, Tutorial
PMID: 9797016 [PubMed - indexed for MEDLINE]
108: Prostate 1998 Oct 1;37(2):70-6
Effect of dual inhibition of 5-alpha-reductase and aromatase on spontaneously
developed canine prostatic hypertrophy.
Suzuki K, Okazaki H, Ono Y, Kurokawa K, Suzuki T, Onuma E, Takanashi H, Mamiya
Y, Yamanaka H.
Department of Urology, Gunma University School of Medicine, Maebashi, Japan.
[email protected]
BACKGROUND: Our aim was to assess the effect of dual inhibition of
5-alpha-reductase and aromatase on prostate glands. METHODS: We investigated the
morphological changes in the prostate gland and the changes in the hormonal
environment after administration of finasteride and arimidex to intact canine
specimens. The study consisted of four groups: a 5-alpha-reductase only group
(5RI only, n = 5); a 5RI plus aromatase-inhibitor combination group (5RI + ARI
combination, n = 5); a BPH control group (n = 3); and a castration control group
(n = 3). Finasteride (1 mg/kg/day) and the same dose of arimidex were orally
administered for 80 days. RESULTS: In the 5RI group, a significant decrease in
the serum dihydrotestosterone (DHT) level was found, and prostatic volume was
significantly decreased. However, significant increases in serum testosterone
(T) and DHT levels were observed, with a concomitant increase in prostatic
volume in the 5RI + ARI combination group. Morphometric analysis showed that
histopathological findings in the 5RI + ARI combination group were similar to
those in the BPH control group. CONCLUSIONS: Dual inhibition of
5-alpha-reductase and aromatase resulted in a significant increase in prostate
volume, accompanied by a 3-10-fold increase in serum testosterone levels and a
significant increase in testicular volume.
PMID: 9759700 [PubMed - indexed for MEDLINE]
109: Br J Cancer 1998 Sep;78 Suppl 4:12-5
Aromatase inhibitors and their future role in post-menopausal women with early
breast cancer.
Lonning PE.
Department of Therapeutic Oncology and Radiophysics, Haukeland University
Hospital, Bergen, Norway.
Anastrozole is the first aromatase inhibitor to show a significant survival
advantage over megestrol acetate in post-menopausal women with advanced breast
cancer. The rationale for extending the use of aromatase inhibitors to the
treatment of early breast cancer is based on the efficacy observed in the
advanced setting, combined with good tolerability and a convenient dosing
regimen. Furthermore, oestrogen deprivation by ovarian ablation (similar to
oestrogen antagonism with tamoxifen) is already established as an effective
adjuvant treatment in premenopausal women with modality breast cancer.
Anastrozole produces a profound suppression of plasma oestrogen levels which is
greater than that obtained with earlier aromatase inhibitors (formestane,
aminoglutethimide) or megestrol acetate. This could account for the differences
in clinical efficacy seen between anastrozole and megestrol acetate. In terms of
benefits over other endocrine agents, anastrozole causes significantly less
weight gain than megestrol acetate; it does not have the partial agonist
activity of tamoxifen, and is unlikely to lead to tumour stimulation in patients
resistant to tamoxifen or to exert proliferative effects on the endometrium. The
lack of oestrogen agonist activity, however, may possibly have detrimental
effects on bone mineral density and blood lipid profile. Current clinical trials
are investigating the efficacy and safety of anastrozole in the early breast
cancer setting. The results of these trials will help to determine whether
anastrozole has any benefits over tamoxifen, the current treatment of choice in
post-menopausal women with early breast cancer.
PMID: 9741783 [PubMed - indexed for MEDLINE]
110: Br J Cancer 1998 Sep;78 Suppl 4:1-4
Tamoxifen--the treatment of choice. Why look for alternatives?
Baum M.
University College London Hospital, UK.
Tamoxifen is currently established as the endocrine treatment of choice in
breast cancer. In advanced breast cancer, response rates of up to 60% in women
with oestrogen receptor (ER)-positive tumours have been reported. In early
breast cancer, tamoxifen can produce significant benefits, both statistically
and clinically, in terms of reduction in relative risk of relapse or death in
all patient subgroups (i.e. ER status, aged < or > 50 years) except
premenopausal women with ER-negative tumours. The major benefit, however, is
seen in women over 50 years old with ER-positive tumours. The results of
randomized trials suggest that the optimum duration of tamoxifen therapy is at
least 5 years. Two large pragmatic trials (aTTom and ATLAS) are under way to
determine whether additional benefit can be gained from continuing tamoxifen
treatment beyond 5 years. Recent data also suggest possible synergism between
tamoxifen and chemotherapy in the treatment of early breast cancer in
post-menopausal women. Other benefits of tamoxifen treatment include reduction
in the risk of developing contralateral breast cancer. Included among the
non-breast cancer benefits of tamoxifen are reduced risk of cardiovascular
disease and protection against bone loss in post-menopausal women. These
benefits must be weighed against the possible increased incidence of endometrial
cancer. Notwithstanding its undoubted success, there is a need for agents to
improve upon tamoxifen. Newer agents, such as the luteinizing hormone-releasing
hormone analogue goserelin and the new-generation aromatase inhibitors, such as
anastrozole, will add new life to the search for an improved endocrine therapy
for early breast cancer.
PMID: 9741780 [PubMed - indexed for MEDLINE]
111: Cancer 1998 Sep 15;83(6):1142-52
Erratum in:
Cancer 1999 Feb 15;85(4):1010
Anastrozole versus megestrol acetate in the treatment of postmenopausal women
with advanced breast carcinoma: results of a survival update based on a combined
analysis of data from two mature phase III trials. Arimidex Study Group.
Buzdar AU, Jonat W, Howell A, Jones SE, Blomqvist CP, Vogel CL, Eiermann W,
Wolter JM, Steinberg M, Webster A, Lee D.
Department of Breast Medical Oncology, the University of Texas M.D. Anderson
Cancer Center, Houston 77030, USA.
BACKGROUND: This report presents the results of a survival update based on the
combined data from two studies that compared the efficacy and tolerability of
anastrozole (1 or 10 mg once daily), a selective, nonsteroidal aromatase
inhibitor administered orally, and megestrol acetate (40 mg 4 times daily) in
the treatment of postmenopausal women with advanced breast carcinoma whose
disease had progressed after treatment with tamoxifen. METHODS: Two randomized,
parallel-group, multicenter trials were conducted, involving a total of 764
patients. The two trials were identical in design; both were double blind for
anastrozole and open label for megestrol acetate. Overview analyses were
conducted with the intent of strengthening the interpretation of results from
each trial. The median follow-up duration for this survival update was 31
months. RESULTS: At the clinical dose of 1 mg daily, anastrozole demonstrated a
statistically significant survival advantage over megestrol acetate, with a
hazard ratio of 0.78 (P < 0.025)(0.60 < 97.5% confidence interval [CI] <1.0).
The 1 mg anastrozole group also had a longer median time to death (26.7 months)
compared with 22.5 months for the megestrol acetate group. The 10 mg anastrozole
group also had a survival benefit over the megestrol acetate group, with a
hazard ratio of 0.83 (P=0.09, not significant)(0.64 < 97.5% CI < 1.1). Higher
2-year survival rates were observed for both anastrozole treatment groups than
for the megestrol acetate group (56.1%, 54.6%, and 46.3% for the groups given 1
mg anastrozole, 10 mg anastrozole, and megestrol acetate, respectively).
CONCLUSIONS: This combined analysis of two trials of postmenopausal patients
with advanced breast carcinoma has clearly demonstrated that, after disease
progression with tamoxifen, treatment with anastrozole 1 mg once daily results
in a statistically and clinically significant advantage over a standard
treatment, megestrol acetate. This important benefit, in addition to the good
tolerability profile of anastrozole, supports the use of this drug as a valuable
new treatment option for this patient population.
Publication Types:
Clinical Trial
Clinical Trial, Phase III
Multicenter Study
Randomized Controlled Trial
PMID: 9740079 [PubMed - indexed for MEDLINE]
112: Cancer Invest 1998;16(6):385-90
Anastrozole (Arimidex), a new aromatase inhibitor for advanced breast cancer:
mechanism of action and role in management.
Hortobagyi GN, Buzdar AU.
Department of Breast Medical Oncology, University of Texas M.D. Anderson Cancer
Center, Houston, USA.
Publication Types:
Review
Review, Tutorial
PMID: 9679529 [PubMed - indexed for MEDLINE]
113: Schweiz Rundsch Med Prax 1998 Apr 22;87(17):584-8
[Aromatase inhibitors--new possibilities in treatment of breast carcinoma].
[Article in German]
Friedrichs K, Janicke F.
Frauenklinik und Poliklinik, Universitats-Krankenhaus Eppendorf, Hamburg.
Aromatase inhibition is now an acknowledged second line treatment modality for
advanced breast cancer in postmenopausal women. Aminoglutethimide is an
inhibitor of adrenal steroid biosynthesis and blocks the conversion of
cholesterol to pregnenolone, and therefore reduces levels of adrenal androgens,
which are a source of estrogens in both premenopausal and postmenopausal women.
Aminoglutethimide has produced antitumor response rates of 35% in unselected
patients, most of whom have undergone prior therapy with either chemotherapy or
hormonal manipulation. As is true of other hormonal responses, high response
rates of up to 70% are observed in patients who are ER and/or PR positive. The
reason why these drugs are currently used after tamoxifen is mainly due to the
side effects of aminoglutethimide, which impairs the mineralocorticoid and
glucocorticoid synthesis. New, less toxic compounds appear, which block the
conversion of androstenedione to estrone and efficiently suppress plasma
estrogen levels., e.g. formestane, anastrozole and letrozole. Aromatase
inhibitors are now being compared to tamoxifen as first-line endocrine treatment
in relapsing patients. If these trials confirm a similar or better response rate
to new aromatase inhibitors compared to tamoxifen, the time will come to study
them as the first line adjuvant treatment in non-metastatic disease.
Publication Types:
Review
Review, Tutorial
PMID: 9623325 [PubMed - indexed for MEDLINE]
114: Tumori 1998 Jan-Feb;84(1):45-7
Clinical efficacy of the aromatase inhibitor anastrozole in relation to
prolactin secretion in heavily pretreated metastatic breast cancer.
Barni S, Lissoni P, Meregalli S, Ardizzoia A, Mengo S, Musco F, Merlini D,
Tancini G.
Division of Oncological Radiotherapy, Ospedale S. Gerardo, Monza (Milan), Italy.
AIMS AND BACKGROUND: It is known that the aromatase inhibitors may act by
decreasing estrogen levels. Moreover, it is known that estrogens may stimulate
the release of prolactin (PRL), which is a growth factor for breast cancer. This
phase II study was performed to evaluate the effects of the novel aromatase
inhibitor anastrozole on PRL secretion in metastatic breast cancer and the
possible influence of PRL pretreatment levels on the efficacy of therapy.
METHODS: The study involved 14 pretreated metastatic breast cancer patients with
a poor clinical status. Anastrozole was given orally once a day at 1 mg/day for
at least 2 months. To evaluate PRL secretion, venous blood samples were
collected before treatment and at 1-monthly intervals during treatment. RESULTS:
The clinical response consisted of partial response (PR) in 2, stable disease
(SD) in 5 and progressive disease (PD) in the remaining 7 patients. Abnormally
high pretreatment levels of PRL were seen in 5/14 (36%) patients. Progressing
patients showed significantly higher pretreatment levels of PRL than those who
achieved PR or SD. None of the patients with high PRL pretreatment levels showed
a decline in PRL levels on treatment with anastrozole. CONCLUSIONS: This
preliminary study suggests that anastrozole has no inhibitory effect on PRL
secretion in metastatic breast cancer and that the evidence of abnormally
elevated concentrations of PRL prior to therapy is generally associated with a
lack of efficacy.
Publication Types:
Clinical Trial
Clinical Trial, Phase II
PMID: 9619713 [PubMed - indexed for MEDLINE]
115: Minerva Ginecol 1998 Mar;50(3):51-63
[Current status and prospectives of aromatase inhibitors in the treatment of
advanced breast cancer].
[Article in Italian]
Boccardo F.
Servizio di Oncologia Medica II, Istituto Nazionale per la Ricerca sul Cancro,
Genova.
Endocrine therapy represents one of the most effective instruments for the
palliative and adjuvant treatment of breast cancer, in particular in
postmenopausal patients. While tamoxifen still forms the treatment of choice
during the adjuvant phase and the first-line treatment during the metastatic
phase, aromatase inhibitors undoubtedly represent the treatment of choice for
patients who do not respond to antiestrogen treatment. These drugs represent a
heterogeneous family of compounds able to provide more or less selective
inhibition of aromatases by forming an irreversible bond with the catalytic site
of the enzymatic complex (type I inhibitors) or using a competitive mechanism
(type II inhibitors). Among the type I drugs, 4-hydroxyandrostenedione and
hexamestane are those that probably attract greatest clinical interest. These
drugs can significantly reduce the circulating levels of estrone and estradiol,
and have been shown to be active in 20% of patients pretreated with tamoxifen.
Moreover, hexamestane was also effective in patients pretreated with type II
inhibitors, of which the parent drug is aminoglutethimide. This drug is still
used in the second and third-line treatment of breast cancer but, since it
causes collateral effects in a substantial percentage of patients, above all
when used at higher doses in combination with hydrocortisone, it will soon be
replaced by second and third generation inhibitors, like letrozole, fadrozole,
vorozole and anastrozole. These drugs have been shown to be significantly more
active than aminoglutethimide, both in vitro and in vivo, and above all more
selective. In particular, even at high doses anastrozole has not been found to
interfere with steroidogenesis at a corticoadrenal level. Moreover, anastrozole
has been shown to be very active even at relatively modest doses given in a
single daily dose. Two recent controlled studies, including a total of over 600
patients, recently demonstrated that, if used in second line in patients who no
longer responded to adjuvant or palliative tamoxifen therapy, anastrozole is
just as effective but probably better tolerated than megestrol acetate. Studies
are now in progress or are currently being launched to evaluate the possible
value of anastrozole and other third generation inhibitors both as first-line
treatment and as adjuvant treatment as an alternative or in combination with
tamoxifen.
Publication Types:
Review
Review Literature
PMID: 9595916 [PubMed - indexed for MEDLINE]
116: Oncology (Huntingt) 1998 Mar;12(3 Suppl 5):36-40
Preclinical studies using the intratumoral aromatase model for postmenopausal
breast cancer.
Brodie A, Lu Q, Liu Y, Long B, Wang JP, Yue W.
Department of Pharmacology, School of Medicine, University of Maryland,
Baltimore, USA.
To determine the most effective strategies for the treatment of postmenopausal
hormone dependent breast cancer, we recently developed a model system in nude
mice. In this model, estrogen receptor-positive human breast cancer cells
(MCF-7) stably transfected with the aromatase gene are inoculated into
ovariectomized, immunosuppressed (nude) mice. These cells synthesize sufficient
estrogen from androgen substrate to stimulate their proliferation and the
development of tumors. Moreover, estrogen secreted by the tumor cells maintains
uterine weight comparable to that of the intact mouse. In the present study, we
employed this model to investigate the effects of the aromatase inhibitor,
letrozole (CGS 20267 [Femara]) on mammary tumor growth and on the uterus. We
also used this model to predict the effects of combining two aromatase
inhibitors, letrozole and anastrozole (Arimidex), with the antiestrogen
tamoxifen (Nolvadex). Letrozole was found to be a highly potent inhibitor of
tumor proliferation and more effective than tamoxifen. No stimulation of uterine
growth was observed with the aromatase inhibitors. However, the combination of
letrozole or anastrozole and tamoxifen was no more effective than either
aromatase inhibitor alone. The agonistic effect of tamoxifen on the uterus was
observed when it was given alone and when combined with the aromatase
inhibitors. Furthermore, letrozole had the most potent antitumor activity when
compared to other aromatase inhibitors and antiestrogens. No additional benefit
was observed by combining these agents with tamoxifen over treatment with
aromatase inhibitors alone.
PMID: 9556790 [PubMed - indexed for MEDLINE]
117: Oncology (Huntingt) 1998 Mar;12(3 Suppl 5):32-5
Emerging role of aromatase inhibitors in the treatment of breast cancer.
Harvey HA.
Section of Hematology-Oncology, Hershey Medical Center, Penn State Geissinger
Health Systems, Hershey, Pennsylvania, USA.
The new generation of potent steroidal and nonsteroidal inhibitors of the enzyme
aromatase act by decreasing estrogen production throughout the body in
postmenopausal women. The most potent of these agents may also inhibit estrogen
synthesis within metastatic breast cancer tissue. The newly developed, orally
administered, nonsteroidal competitive inhibitors, such as anastrozole
(Arimidex), letrozole (Femara), and vorozole (Rizivor), are a thousand times
more potent inhibitors of aromatase than is aminoglutethimide. Furthermore,
these agents are highly selective. In several large randomized trials, the new
inhibitors produced similar response rates as megestrol acetate (160 mg/d) in
postmenopausal women with hormone-dependent breast cancer, but showed a trend
toward improved response duration and survival. They also produced less weight
gain and fewer cardiovascular and thromboembolic side effects. In addition,
letrozole proved superior to aminoglutethimide in another randomized trial. Both
anastrozole (1.0 mg/d) and letrozole (2.5 mg/d) have now been approved as
second-line treatment for hormone-dependent breast cancer in postmenopausal
women in whom disease has progressed following tamoxifen treatment. Either drug
should replace the routine use of megestrol acetate in this setting. Ongoing
clinical studies are comparing anastrozole and letrozole to antiestrogens as
first-line endocrine therapy for metastatic breast cancer. Other trials will
study the possible roles of these compounds as adjuvant therapy and
chemoprevention for breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 9556789 [PubMed - indexed for MEDLINE]
118: Fertil Steril 1998 Apr;69(4):709-13
Comment in:
Fertil Steril. 1998 Dec;70(6):1183-4
Treatment of severe postmenopausal endometriosis with an aromatase inhibitor.
Takayama K, Zeitoun K, Gunby RT, Sasano H, Carr BR, Bulun SE.
Cecil H. and Ida Green Center for Reproductive Biology Sciences and Department
of Obstetrics and Gynecology, University of Texas Southwestern Medical Center,
Dallas 75235-9051, USA.
OBJECTIVE: To treat an unusually aggressive case of recurrent postmenopausal
endometriosis. DESIGN: Case report. SETTING: University of Texas Southwestern
Medical Center (Dallas, Texas). PATIENT(S): A 57-year-old woman who presented
with recurrent severe endometriosis after hysterectomy and bilateral
salpingo-oophorectomy. INTERVENTION(S): Oral administration of anastrozole (an
aromatase inhibitor) (1 mg/d) and elemental calcium (1.5 g/d) for 9 months.
Alendronate (a nonestrogenic inhibitor of bone resorption), 10 mg/d, was added
to this regimen. MAIN OUTCOME MEASURE(S): Reduction in size of endometriotic
lesion, pain relief, tissue levels of aromatase P450 messenger RNA, bone
density. RESULT(S): Circulating levels of estradiol-17beta were reduced to
approximately 50% of the baseline value after the onset of treatment with
anastrozole. Pain rapidly decreased and completely disappeared after the 2nd
month of treatment. The 30 x 30 x 20-mm bright red polypoid vaginal lesion was
reduced to a 3-mm gray tissue by the end of 9 months of treatment. Markedly high
pretreatment levels of aromatase P450 messenger RNA in the endometriotic tissue
became undetectable in a specimen obtained from a repeated biopsy after 6 months
of treatment. Bone density of lumbar spine decreased by 6.2% after 9 months of
treatment. CONCLUSION(S): This is the first description of the use of an
aromatase inhibitor in the treatment of endometriosis. The short-term results
were extraordinarily successful in elimination of pain and near-complete
eradication of implants associated with severe endometriosis not responsive to
other therapy. We conclude that the recently developed potent aromatase
inhibitors are candidate drugs in the treatment of endometriosis that is
resistant to standard regimens.
PMID: 9548162 [PubMed - indexed for MEDLINE]
119: Internist (Berl) 1997 Mar;38(3 Suppl Selektive):1-16
[Two new therapeutic principles in the management of breast cancer and
colorectal cancer: selective oral aromatase inhibition and thymidilate synthase
inhibition].
[Article in German]
PMID: 9541667 [PubMed - indexed for MEDLINE]
120: Am J Clin Oncol 1998 Apr;21(2):161-6
Anastrozole: a new addition to the armamentarium against advanced breast cancer.
Buzdar AU.
Department of Breast Medical Oncology, The University of Texas, M.D. Anderson
Cancer Center, Houston 77030, USA.
Estrogen manipulation represents an effective treatment for advanced breast
cancer in postmenopausal women with estrogen-receptor positive disease. The
antiestrogen agent, tamoxifen, is the first choice for advanced breast cancer in
postmenopausal women due to its efficacy and lack of significant side effects.
As with all cancer treatments, however, cancer may recur after initial treatment
with tamoxifen, and the limitations of currently available alternative hormonal
therapies in terms of tolerability and convenience of administration underscore
the need for new agents. Anastrozole is a new, highly selective, nonsteroidal
aromatase inhibitor capable of maximal estrogen depletion with fewer side
effects than other hormonal therapies. Anastrozole is administered in a
convenient, once-daily oral dosing regimen and does not require steroid
replacement therapy. In two multicenter clinical trials, anastrozole was as
effective as megestrol acetate for the treatment of advanced breast cancer in
postmenopausal women who progressed after tamoxifen therapy, based on objective
response rates and time to objective progression of disease. In addition, the
drug did not produce the weight gain observed with megestrol acetate therapy.
Anastrozole is an effective endocrine agent in the treatment of advanced breast
cancer in postmenopausal women.
Publication Types:
Review
Review, Tutorial
PMID: 9537204 [PubMed - indexed for MEDLINE]
121: Am J Health Syst Pharm 1998 Mar 1;55(5):445-52
Anastrozole: a selective aromatase inhibitor for the treatment of breast cancer.
Higa GM, alKhouri N.
School of Pharmacy, Mary Babb Randolph Cancer Center, West Virginia University,
Morgantown 26506-9520, USA.
The role of anastrozole, a new selective aromatase inhibitor, in treating
hormone-responsive metastatic breast cancer is discussed. Treatment options for
hormone-dependent breast cancer focus on interfering with the endocrine system
in an attempt to modify the effects of estrogen. Tamoxifen is the drug of choice
for primary endocrine therapy, but there is a need for agents with similar or
greater efficacy and better tolerability. Anastrozole inhibits the conversion of
androgens to estrogens by aromatase. Bioavailability studies have demonstrated
almost complete absorption of anastrozole after oral administration. The drug's
terminal half-life after multiple doses is 50 hours. Anastrozole is cleared
principally by the liver. Clinical trials comparing anastrozole with megestrol
acetate demonstrated no significant differences in clinical efficacy, although a
follow-up study revealed a longer median overall survival rate in patients
receiving anastrozole. The drug is well tolerated. Among the most frequently
reported adverse effects are asthenia, hot flashes, headache, and back pain. The
recommended dosage is 1 mg daily. The average wholesale cost of month's supply
of anastrozole is $187.20, compared with approximately $100 for generic
megestrol acetate or aminoglutethimide plus hydrocortisone. Although anastrozole
will likely become the preferred second-line agent in the treatment of
postmenopausal breast cancer in patients with disease progression after
tamoxifen therapy, it is not a therapeutic alternative to aminoglutethimide on
the basis of approved indications. Anastrozole and other aromatase inhibitors
may have multiple applications in treating hormone-responsive breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 9522927 [PubMed - indexed for MEDLINE]
122: Am J Physiol 1998 Feb;274(2 Pt 1):E328-35
Physiological plasma levels of androgens reduce bone loss in the ovariectomized
rat.
Lea CK, Flanagan AM.
Department of Histopathology, Imperial College School of Medicine at St. Mary's,
London, United Kingdom.
The effect of androstenedione (ADIONE) slow-release pellets on cancellous bone
volume (BV/TV) at the tibial metaphysis was investigated in ovariectomized (OVX)
rats at various times from 21 to 180 days. Plasma levels of ADIONE and
testosterone (T) in OVX rats were significantly reduced at 21 days and were
restored close to levels in the sham rats with the 1.5-mg ADIONE pellet. OVX
animals with and without ADIONE pellets resulted in close to a 50% reduction in
BV/TV, by day 21. By day 180, OVX rats had only approximately 5% BV/TV, whereas
that in ADIONE-treated OVX rats was significantly greater at approximately 12%.
The reduced BV/TV was associated with increased bone resorption and formation.
In a separate 90-day experiment, we found that the antiandrogen, Casodex,
abrogated the ADIONE-induced skeletal-protective effect in OVX rats, whereas the
antiaromatase, Arimidex, had no effect. This provides evidence that ADIONE
protects against the development of osteopenia in the estrogen-deficient rat and
mediates its effect through androgens and not estrogens.
PMID: 9486166 [PubMed - indexed for MEDLINE]
123: Cancer Epidemiol Biomarkers Prev 1998 Jan;7(1):65-78
Aromatase inhibitors as potential cancer chemopreventives.
Kelloff GJ, Lubet RA, Lieberman R, Eisenhauer K, Steele VE, Crowell JA, Hawk ET,
Boone CW, Sigman CC.
Chemoprevention Branch, Division of Cancer Prevention and Control, National
Cancer Institute, Bethesda, Maryland 20852, USA.
Epidemiological and experimental evidence strongly supports a role for estrogens
in the development and growth of breast tumors. A role for estrogen in prostate
neoplasia has also been postulated. Therefore, one chemopreventive strategy for
breast and prostate cancers is to decrease estrogen production. This can be
accomplished by inhibiting aromatase, the enzyme that catalyzes the final,
rate-limiting step in estrogen biosynthesis. The use of aromatase inhibitors is
of clinical interest for cancer therapy, and selective, potent aromatase
inhibitors have been developed. Several of these agents have demonstrated
chemopreventive efficacy in animal models. The rationale for the use of
aromatase inhibitors as chemopreventives and identification of inhibitors to
serve as potential chemopreventive agents are the subjects of this review. After
background information regarding aromatase is presented, the data for each
inhibitor are summarized separately. The discussion focuses on those inhibitors
that are clinically available or in clinical trials, including:
aminoglutethimide (Cytadren), rogletimide, fadrozole hydrochloride, liarozole
hydrochloride, anastrozole (Arimidex), letrozole, vorozole, formestane,
exemestane, and atamestane. On the basis of results from preclinical studies,
aromatase inhibitors may be promising agents for clinical trials in populations
at high risk for developing estrogen-dependent cancers. Total suppression of
aromatase may have adverse effects, as is evident in postmenopausal women
(increased osteoporosis, cardiovascular disease, and urogenital atrophy).
However, on the basis of preclinical studies of chemopreventive efficacy and
chemotherapeutic applications of aromatase inhibitors showing dose-response
efficacy, it may be possible to obtain chemopreventive effects without total
suppression of aromatase and circulating estrogen levels. Suppressing local
estrogen production may be an alternative strategy, as suggested by the
discovery of a unique transcriptional promoter of aromatase gene expression,
I.4, in breast adipose tissue. The development of drugs that target this
promoter region may be possible.
Publication Types:
Review
Review, Tutorial
PMID: 9456245 [PubMed - indexed for MEDLINE]
124: Tumori 1997 Sep-Oct;83(5):874-6
[ECCO 9 -- Future trends in endocrine therapy of breast cancer].
[Article in Italian]
Publication Types:
Congresses
News
PMID: 9446251 [PubMed - indexed for MEDLINE]
125: Regul Toxicol Pharmacol 1997 Dec;26(3):330-7
The weanling male rat as an assay for endocrine disruption: preliminary
observations.
Ashby J, Lefevre PA.
Zeneca Central Toxicological Laboratory, Macclesfield, Cheshire, United Kingdom.
Kelce and Wilson (J. Mol. Med. 75, 198-207, 1997) have suggested that dosing
chemicals to newly weaned male rats for 1 month may yield a useful assay for
antiandrogens. This suggestion was supported by reference to unpublished data on
the antiandrogen vinclozolin which indicated reductions in the weight of
accessory sex organs. The necessity for dosing during the full approximately 30
days of the protocol was not justified. An evaluation of this protocol has
commenced by the dosing of vinclozolin, cyproterone acetate, and anastrozole
daily to newly weaned male rats for 3, 7, or 14 days. No changes were observed
in accessory sex organs when vinclozolin or anastrozole was dosed for 3 days.
Significant changes were observed in the absolute and relative weight of all of
the sex accessory organs for rats dosed for 7 or 14 days with cyproterone
acetate. The effects produced by vinclozolin and anastrozole when dosed for 7 or
14 days varied according to the duration of exposure with the main effects on
the accessory sex organs being seen after 14 days of dosing. The effects
produced after 7 days of dosing with vinclozolin or anastrozole in arachis oil
had resolved 10 days after the last of the seven doses. Data are presented using
either hydroxy propyl methyoxycellulose (HPMC) or arachis oil as vehicle, the
former being recommended for general use. These preliminary results are
encouraging, and the evaluation of the second 2 weeks of the suggested 30-day
protocol is proceeding. Concurrent control data indicate that the relative
weight of the liver, testes, and epididymides increases over the first 14 days
post-weaning, while those of the kidney, the seminal vesicles, and prostate
decrease. These changes in relative tissue weight were much less than the
increase in relative weight of the uterus observed in female animals at puberty.
That indicates that successful use of a final version of this assay will depend
on access to inhouse control tissue weight data and the use of appropriate
animal group sizes. These preliminary data are presented to reduce duplication
of effort in this rapidly expanding area of toxicology.
PMID: 9441923 [PubMed - indexed for MEDLINE]
126: Cancer Pract 1997 Nov-Dec;5(6):391-3
Anastrozole. An effective, second-line hormonal treatment for advanced breast
cancer.
Camp-Sorrell D.
University of Alabama, Birmingham Hospital, USA.
Because advanced breast cancer is not curable, the goal of treatment is to
prolong survival yet maintain an acceptable quality of life. Anastrozole offers
another option for second-line hormonal therapy in postmenopausal women with
advanced breast cancer. This recently approved selective aromatase inhibitor is
as efficacious as other available hormonal therapies for this indication and
appears to offer an advantage with regard to adverse effects and ease of
administration.
Publication Types:
Review
Review, Tutorial
PMID: 9397709 [PubMed - indexed for MEDLINE]
127: Oncology 1997;54 Suppl 2:27-31
The role of selective non-steroidal aromatase inhibitors in future treatment
strategies.
Blamey RW.
Professorial Unit of Surgery, City Hospital, Nottingham, UK.
The major role of endocrine therapy in the treatment of early and advanced
breast cancer should not be forgotten as an increasing number of new and
potentially more exciting agents are introduced. Endocrine therapy generally has
a more powerful effect than cytotoxic therapy in the treatment of breast cancer.
Alternatives to tamoxifen, such as anastrozole (Arimidex), are now being
considered, both in advanced disease and as adjuvant therapy, whether as single
agents or in combination. Anastrozole has a low side-effect profile and is
becoming a drug of choice for second-line therapy in postmenopausal women with
advanced breast cancer. The present use of anastrozole in postmenopausal women
with advanced breast cancer includes second-line treatment after tamoxifen and
first-line treatment after tamoxifen has been used as an adjuvant treatment. It
may also be used when tamoxifen is not tolerated. The future potential of
anastrozole is currently being investigated in a programme of clinical trials in
postmenopausal women, including first-line treatment of advanced disease and as
an adjuvant treatment for early breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 9394858 [PubMed - indexed for MEDLINE]
128: Oncology 1997;54 Suppl 2:19-22
A randomised comparison of oestrogen suppression with anastrozole and formestane
in postmenopausal patients with advanced breast cancer.
Kleeberg UR, Dowsett M, Carrion RP, Dodwell DJ, Vorobiof DA, Aparicio LA,
Robertson JF.
The relative efficacy and tolerability of the aromatase inhibitors anastrozole
(Arimidex) and formestane are assessed in a direct comparative trial in
postmenopausal women with advanced breast cancer. Final results are available
and reported here only for oestradiol suppression. Patients were randomised to
receive either oral anastrozole, 1 mg once daily, or formestane, 250 mg every 2
weeks intramuscularly. In the anastrozole group, mean serum oestradiol levels
fell from 32.1 pmol/l at baseline to 6.5 pmol/l at week 1, and similar levels of
suppression were maintained over the next 3 weeks. In the formestane group, mean
serum oestradiol levels fell from 31.0 pmol/l at baseline to 9.5 pmol/l at the
week 1 assessment. In this group, serum oestradiol levels tended to rise by the
2- and 4-week measurements, i.e. immediately before the next injection was due.
Based on the 2- and 4-week measurements, the mean falls in oestradiol levels
were 79 and 58% in the anastrozole and formestane groups, respectively (p =
0.0001). More effective and consistent suppression of oestradiol was achieved
with anastrozole at the therapeutic dose of 1 mg once daily, orally, than with
formestane at the standard dose of 250 mg every 2 weeks, intramuscularly.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 9394856 [PubMed - indexed for MEDLINE]
129: Oncology 1997;54 Suppl 2:15-8
Clinical overview of anastrozole--a new selective oral aromatase inhibitor.
Jonat W.
Gynaecology and Obstetrics Clinic, University of Kiel, Germany.
The efficacy and tolerability of the new selective aromatase inhibitor,
anastrozole (Arimidex), was compared with megestrol acetate in the treatment of
advanced breast cancer in postmenopausal women. In two independent prospective
randomised trials, patients who progressed after prior tamoxifen therapy
received anastrozole 1 or 10 mg once daily, or megestrol acetate, 40 mg q.i.d.
The two studies were designed to allow the data to be combined to increase the
statistical power of the analyses. It is the data from these combined analyses
that are considered in further detail. After 6 months of follow-up, the
proportion of patients gaining clinical benefit (complete response + partial
response + stable disease > or = 24 weeks) was approximately one third of
patients in all three groups. No significant difference was observed between
either dose of anastrozole and megestrol acetate in the time to disease
progression (130-153 days). All three treatments were generally well tolerated,
but significantly more patients on megestrol acetate gained weight, and the
weight gain in this group continued up to at least 9 months of follow-up. At a
12-month update of tolerability, of the commonly observed adverse events, a
greater than 2-fold difference between treatment arms was observed for
hypertension, weight gain, dyspnoea, vaginal haemorrhage, sweating and diarrhoea
(all higher on megestrol acetate except for diarrhoea). Anastrozole is effective
and well tolerated and on the basis of these data, 1 mg once daily is the
recommended clinical dose in postmenopausal women with advanced breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 9394855 [PubMed - indexed for MEDLINE]
130: Oncology 1997;54 Suppl 2:11-4
Anastrozole--a new generation in aromatase inhibition: clinical pharmacology.
Dowsett M, Lonning PE.
Department of Academic Biochemistry, Royal Marsden Hospital, London, UK.
Use of the aromatase inhibitor aminoglutethimide is limited by its lack of
selectivity for aromatase and its toxicity. Newer agents are more selective, but
do not always offer improved inhibition of aromatase. Indirect comparison of
their activity in inhibiting aromatase and suppressing plasma oestrogens
indicates that aminoglutethimide, rogletimide, formestane, and fadrozole
inhibited aromatase activity by 74-91%, with reported falls in oestradiol level
of 58-76%. In contrast, the new-generation oral once-daily aromatase inhibitors
anastrozole (Arimidex) and letrozole were of a similar activity, inhibiting
aromatase activity by over 96%, with a concomitant fall in oestradiol and
oestrone levels of at least 80%. Anastrozole at the recommended clinical dose of
1 mg daily also suppressed oestrone sulphate levels by 93.5%; activity with
anastrozole 10 mg daily was not statistically significantly different. The new
generation of aromatase inhibitors, as typified by anastrozole, thus offers
effective and convenient aromatase inhibition which correlates well with
decreases in the levels of plasma oestrogens.
Publication Types:
Review
Review, Tutorial
PMID: 9394854 [PubMed - indexed for MEDLINE]
131: Oncology 1997;54 Suppl 2:6-10
The relevance of preclinical models to the treatment of postmenopausal breast
cancer.
Dukes M.
Cancer Metabolism Endocrine Department, Zeneca Pharmaceuticals, Macclesfield,
UK.
The predictive value of test results in animals when selecting a compound for
potential therapeutic human use depends upon the relevance of the animal model
to the human disease and the comparative pharmacokinetics of the compound in
animals and man. The development of the aromatase inhibitor, anastrozole
(Arimidex), illustrates the importance of these factors. In postmenopausal women
with breast cancer, aromatase activity in the peripheral tissues is the main
source of oestrogen for tumour growth. Only one form of the human enzyme is
known, which is not subject to strong feedback control. Inhibition of aromatase
therefore simply reduces oestrogen production. This situation is mimicked by
assays of acute inhibition of ovulation in rats, chronic inhibition of
androstenedione-induced uterine hypertrophy in sexually immature rats, and
chronic inhibition of peripheral aromatase in monkeys. In all these assays,
maximum anastrozole activity was consistently achieved at an oral dose of about
0.1 mg/kg, and the clearance half-life of 7-16 h indicated that once-daily
dosing would be possible in humans. The clearance half-life in postmenopausal
women is about 50 h, and with once-daily dosing the dose of anastrozole required
for maximal inhibition is 1 mg/day. The rat 7,12-dimethylbenzanthracene tumour
model, in contrast, is supported by ovarian oestrogen and chronic inhibition
provokes positive feedback loops that try to restore oestrogen production,
masculinise the animals and decrease the clearance half-life of anastrozole.
Higher doses (10 mg/kg) of anastrozole are therefore needed. Variations in the
dose of aromatase inhibitor required in different models, therefore, can be
explained in terms of pharmacokinetics and do not reflect the effectiveness of
anastrozole as an aromatase inhibitor.
Publication Types:
Review
Review, Tutorial
PMID: 9394853 [PubMed - indexed for MEDLINE]
132: Oncology (Huntingt) 1997 Nov;11(11):1697-703; discussion 1707-8
Anastrozole: a new selective nonsteroidal aromatase inhibitor.
Goss PE, Tye LM.
Department of Hematology/Oncology, Toronto Hospital, Canada.
Aromatase (estrogen synthetase) is the enzyme complex responsible for the final
step in estrogen synthesis--the conversion of androstenedione and testosterone
to estrone and estradiol, respectively. Inhibitors of this enzyme have been
shown to be clinically effective in the treatment of advanced breast cancer in
postmenopausal women, in whom the major source of estrogen production derives
from aromatization of adrenal androgens in peripheral tissues, such as muscle,
liver, and fat. The most widely used aromatase inhibitor has been
aminoglutethimide; however, it is nonselective and also inhibits
adrenocorticosteroid synthesis, necessitating hydrocortisone supplementation.
Aminoglutethimide is also associated with frequent and troublesome side effects.
Formestane, the first selective aromatase inhibitor to be developed, has an
improved safety profile and selectivity, but its use has been limited somewhat
by its inconvenient administration via intramuscular injection. In this article,
the preclinical and clinical data published to date on the new third-generation
aromatase inhibitor anastrozole (Arimidex) are presented in the context of
current endocrine therapies. Future applications of aromatase inhibitors, both
as monotherapy and in combination with other endocrine therapies, are discussed.
The use of aromatase inhibitors in advanced disease, the adjuvant setting, and
as possible chemopreventive agents are examined.
Publication Types:
Review
Review, Tutorial
PMID: 9394367 [PubMed - indexed for MEDLINE]
133: J Chromatogr B Biomed Sci Appl 1997 Oct 24;700(1-2):131-8
Validated assay for the quantification of anastrozole in human plasma by
capillary gas chromatography-63Ni electron capture detection.
Bock MJ, Bara I, LeDonne N, Martz A, Dyroff M.
Zeneca Pharmaceuticals, Wilmington, DE 19850-5437, USA.
An assay was developed for the quantification of anastrozole
[2,2'-[5-(1H-1,2,4-triazol-1-ymethyl)-1,3-phenylene]bis(2-++
+methylpropiononitrile)] in human plasma using liquid-liquid extraction.
Anastrozole and an internal standard were chromatographed and detected by gas
chromatography with electron capture detection, using a combination
temperature-pressure program. The range of the assay is 3 to 100 ng/ml.
Anastrozole was quantified by comparing its peak area to that of an internal
standard. A cross-validation of this assay was also successfully performed
between several laboratories.
Publication Types:
Clinical Trial
PMID: 9390722 [PubMed - indexed for MEDLINE]
134: Breast Cancer Res Treat 1997 Sep;45(3):219-24
Predictors of response to second-line endocrine therapy for breast cancer.
Cheung KL, Willsher PC, Pinder SE, Ellis IO, Elston CW, Nicholson RI, Blamey RW,
Robertson JF.
City Hospital, Nottingham, UK.
This study reports on factors predicting response to second-line endocrine
therapy in 250 patients with breast cancer for which they were assessable for
response by the International Union Against Cancer (UICC) criteria. Clinical
details relating to first-line endocrine therapy were available for all
patients. We have not included in this study patients who received first-line
endocrine therapy but did not or have not yet proceeded to second-line hormone
therapy--e.g. died from rapidly progressive disease, started chemotherapy for
rapidly progressive disease, or remained in long-term remission on first-line
endocrine therapy. One hundred and fifty nine patients (72%) achieved remission
(objective response and static disease [OR + SD]) on first-line endocrine
therapy with a median duration of 19 months. For second-line endocrine therapy
the remission rate was 53% (132/225) with a median duration of 15 months. Tumour
grade and oestrogen receptor status of the primary tumour were shown to be
independent predictors of response to second-line endocrine therapy while
response to first-line endocrine therapy was a predictor of the duration of
response to second-line endocrine therapy. In the sub-group of patients who
showed OR or SD to both first and second-line therapies, there was no
correlation between the time to progression (TTP) on first and second-line
therapies.
PMID: 9386865 [PubMed - indexed for MEDLINE]
135: J Surg Oncol 1997 Nov;66(3):215-20
Use of aromatase inhibitors in postmenopausal women with advanced breast cancer.
Roseman BJ, Buzdar AU, Singletary SE.
Department of Surgical Oncology, University of Texas M.D. Anderson Cancer
Center, Houston 77030, USA.
Surgeons have been involved in the management of metastatic breast cancer since
the technique of ovarian ablation was introduced in 1896. However, as newer
hormonal and chemotherapeutic regimens were developed, drug therapy gradually
replaced surgery as the preferred treatment for metastatic breast cancer. Thus,
management of metastatic breast cancer has largely shifted from surgeons to
medical oncologists. Advances in hormonal pharmacology have placed hormonal
therapy alongside surgery and radiation therapy as a standard treatment option
for women with advanced breast cancer. The purpose of this article is to update
surgeons on the current use of hormonal agents for treatment of advanced breast
cancer in postmenopausal women, and to review the aromatase inhibitors, a new
line of hormonal agents for the treatment of advanced breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 9369969 [PubMed - indexed for MEDLINE]
136: J Steroid Biochem Mol Biol 1997 Apr;61(3-6):255-60
Plasma estrogen suppression with aromatase inhibitors evaluated by a novel,
sensitive assay for estrone sulphate.
Lonning PE, Geisler J, Johannessen DC, Ekse D.
Department of Oncology, Haukeland University Hospital, Bergen, Norway.
Aromatase inhibition is a well-defined treatment option for postmenopausal
breast cancer. Although several aromatase inhibitors such as aminoglutethimide,
formestane and fadrozole have been found to inhibit in vivo aromatization by
>85%, previous studies reported plasma estrogen levels to be sustained at
approximately 20-50% of their control level during treatment with these drugs.
The discrepancy could be due to lack of sensitivity or non-specific
crossreactions in the radioimmunoassay (RIA) methods. Mean plasma levels of
estrone (E1) and estradiol (E2) in postmenopausal women are approximately 80 and
20 pmol/l, respectively; on the contrary, mean plasma levels of the estrogen
conjugate estrone sulphate (E1S) are approximately 4-500 pmol/l. Most RIA
methods for plasma E2 and E1 measurements have sensitivity limits in the range
of 2-3 and 7-10 pmol/l, respectively; accordingly, the suppression of plasma
estrogens by more than 80-90% will produce hormone values below the sensitivity
limit of the method in many patients. Recently, we developed a new method to
determine plasma E1S. This assay has a sensitivity limit of 2.7 pmol/l. In
theory, this method may allow the determination of plasma E1S levels suppressed
to less than 2% of control values in the majority of patients. Using this
method, we found different aromatase inhibitors such as formestane,
aminoglutethimide, formestane and aminoglutethimide administered in concert or
anastrozole to suppress plasma E1S levels down to 24, 13, 7 and 4%,
respectively. The suppression of plasma E1S evaluated with this method thus
approaches the percentage aromatase inhibition measured with tracer studies.
PMID: 9365198 [PubMed - indexed for MEDLINE]
137: J Steroid Biochem Mol Biol 1997 Apr;61(3-6):145-9
ARIMIDEX: a potent and selective aromatase inhibitor for the treatment of
advanced breast cancer.
Buzdar AU, Jonat W, Howell A, Plourde PV.
M.D. Anderson Cancer Center, University of Texas, Houston 77030, U.S.A.
Aromatase inhibitors have been available for a number of years and their ability
to reduce circulating estradiol levels has been shown to produce clinical
benefit in women with advanced breast cancer. Until recently, the only
commercially available aromatase inhibitor was aminoglutethimide. Although
aminoglutethimide has been shown to be efficacious in the treatment of advanced
breast cancer, it does cause significant toxicity and requires the use of
concomitant hydrocortisone therapy. Anastrozole is one of a new class of potent
aromatase inhibitors able to suppress estradiol to the limit of detection of
sensitive assays without suppressing adrenal steroidal synthesis. Two large
clinical trials (n = 764) conducted in the U.S.A. and in Europe evaluated two
doses of anastrozole, 1 and 10 mg a day, compared to megesterol acetate, 40 mg
four times a day, in postmenopausal women who had progressed while on tamoxifen.
Response rates and time to progression with anastrozole were similar to those of
megesterol acetate. Objective responses (CR + PR) were 10.3%, 8.9% and 7.9% in
the 1 and 10 mg of anastrozole and megesterol acetate treatment groups,
respectively. Another 25.2%, 22.6% and 26.1% had stable disease for over 24
weeks on 1, 10 mg anastrozole and megesterol acetate, respectively. Anastrozole
and megesterol acetate were well tolerated; however, more patients had
significant weight gain on megesterol acetate than with anastrozole treatment.
The weight gain seen with megesterol acetate continued to increase over time.
Anastrozole has a better therapeutic index (fewer side-effects) and has recently
been approved by the FDA and a number of other regulatory agencies around the
world for the treatment of advanced breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 9365184 [PubMed - indexed for MEDLINE]
138: Cancer 1997 Oct 15;80(8 Suppl):1646-51
Issues concerning the role of chemotherapy and hormonal therapy of bone
metastases from breast carcinoma.
Harvey HA.
Division of Hematology-Oncology, The Milton S. Hershey Medical Center,
Pennsylvania 17033, USA.
A significant percentage (50-70%) of patients with metastatic breast carcinoma
(MBC) will have disease involving the bony skeleton. Clonal selection mediated
by parathyroid hormone-related protein and other factors may explain the high
incidence of osseous metastases in MBC. The presence of specific growth factors
and cytokines in the microenvironment of bone may contribute to the successful
establishment and growth of metastatic lesions and also might determine response
or resistance of these lesions to chemotherapy or hormonal therapy. Osteolytic
bone lesions in MBC frequently give rise to serious clinical problems including
bone pain, pathologic fracture, hypercalcemia, and neurologic complications. MBC
often is treated with systemic chemotherapy or hormonal therapy. The purpose of
this article was to review the recent published literature describing the impact
of systemic chemotherapy and hormonal therapy of MBC on the response of bone
lesions and their clinical course and complications. Evaluating the response of
bone lesions can be problematic and may be complicated by the phenomenon of
"tumor flare" that may be observed with either chemotherapy or hormonal therapy.
Use of the International Union Against Cancer criteria for the response of bone
lesions is recommended. Several studies report objective responses (20-60%) of
lytic bone metastases to standard combination chemotherapy regimens such as
cyclophosphamide, methotrexate, and 5-fluorouracil and cyclophosphamide,
doxorubicin, and 5-fluorouracil, mitoxantrone and 5-FU, newer combinations, and
single agents including paclitaxel and docitaxel but responses to vinorelbine
may be less frequent. Complete responses of bone lesions to chemotherapy are
rare but partial responses and disease stabilization can lead to long term
patient benefit. A series from the M. D. Anderson Cancer Center of patients with
bone metastases treated with 5-FU, doxorubicin, and cyclophosphamide
chemotherapy reported a median duration of response of 14 months. In a recent
multicenter study of 195 patients with lytic lesions from MBC treated with
chemotherapy, the objective response rate (complete response + partial response)
in bone was 18% and 65% of the patients developed at least 1 morbid skeletal
event with a median onset of 7.0 months from the start of chemotherapy.
Hormone-dependent breast carcinoma has a proclivity to metastasize to bone. In
earlier studies comparing aminoglutethimide or medroxyprogesterone acetate with
tamoxifen, a higher response rate of bone metastases was observed for the first
two agents. However, in more recent studies comparing newer aromatase
inhibitors, such as anastrozole, fadrozole, and letrozole, with megestrol
acetate, there were no significant differences in rates of response in bone.
Patients with MBC with bony lesions respond to both chemotherapy and hormonal
therapy and can have a prolonged survival. Therefore such patients are in a more
favorable position to benefit from adjunctive supportive therapy such as
bisphosphonates intended to reduce skeletal morbidity.
Publication Types:
Review
Review, Tutorial
PMID: 9362431 [PubMed - indexed for MEDLINE]
139: Cancer Lett 1997 Sep 16;118(1):21-8
A novel in vitro and in vivo breast cancer model for testing inhibitors of
estrogen biosynthesis and its action using mammary tumor cells with an activated
int-5/aromatase gene.
Tekmal RR, Durgam VR.
Department of Gynecology and Obstetrics and Winship Cancer Center, Emory
University School of Medicine, Atlanta, GA 30322-4710, USA. [email protected]
We recently showed that the cellular gene int-5/aromatase in BALB/c mammary
alveolar hyperplastic nodule (D2 HAN/D2 tumor cells) is activated as a result of
mouse mammary tumor virus integration within the 3' untranslated region of the
aromatase gene. In the present study, we evaluated the effect of various
aromatase inhibitors on androstenedione-mediated tumor cell growth. Also, we
compared the effect of the non-steroidal aromatase inhibitor (CGS 16949A) on the
inhibition of tumor growth. Our results show that D2 tumor cells respond well to
various aromatase inhibitors and antiestrogens. We examined the usefulness of
this model by using D2 tumor cells to simulate postmenopausal breast cancer
employing both in vitro cell culture and in vivo ovariectomized (OVX) nude
mouse. Unlike DMBA-induced tumors or other models, D2 tumor cells form very
rapid tumors within a few days in intact mice or OVX nude mice with
androstenedione supplementation and respond well to an aromatase inhibitor. This
model with its known mechanism of aromatase activation should be useful for
studying the role of intra-tumoral estrogen in mammary cancer, for evaluating
the effects of aromatase inhibitors and antiestrogens, and for comparing breast
cancer treatments.
PMID: 9310256 [PubMed - indexed for MEDLINE]
140: Drugs Aging 1997 Sep;11(3):245-50; discussion 251-2
Vorozole.
Wiseman LR, Spencer CM.
Adis International Limited, Auckland, New Zealand. [email protected]
Vorozole is a triazole derivative which binds to the cytochrome P450 moiety of
aromatase, thus causing reversible inhibition of the enzyme. Plasma estradiol
levels are reduced by about 90% in postmenopausal women treated with vorozole.
Phase II clinical studies found vorozole to be an effective agent for the
treatment of postmenopausal women with advanced breast cancer, achieving
objective responses in up to 35% of patients. In 2 large phase III studies,
vorozole 2.5 mg/day demonstrated favourable clinical efficacy compared with
aminoglutethimide and megestrol. Vorozole improved patients' quality of life to
a greater extent than aminoglutethimide. Clinical trials to date indicate that
the tolerability of vorozole is better than that of aminoglutethimide. Vorozole
also appears to be at least as well tolerated as megestrol (although
inappropriate bodyweight gain is more common in megestrol recipients). The most
common adverse events with vorozole are hot flushes, and nausea, which are
generally mild in severity.
Publication Types:
Review
Review, Tutorial
PMID: 9303282 [PubMed - indexed for MEDLINE]
141: Ann Oncol 1997 Jul;8(7):631-2
Aromatase inhibitors come of age.
Dowsett M.
Publication Types:
Editorial
PMID: 9296213 [PubMed - indexed for MEDLINE]
142: Drug Ther Bull 1997 Jul;35(7):55-6
New aromatase inhibitors for breast cancer.
Anastrozole (Arimidex-Zeneca) and letrozole (Femara-Novartis) are the first
selective, oral, non-steroidal aromatase inhibitors. They are licensed for the
treatment of advanced breast cancer in postmenopausal women where tamoxifen or
other anti-oestrogen therapy has failed. The manufacturers of both drugs claim
that their products are more effective, less toxic and better tolerated than the
progestogen megestrol acetate, the standard therapy in this clinical situation.
We assess these claims.
Publication Types:
Review
Review, Tutorial
PMID: 9282426 [PubMed - indexed for MEDLINE]
143: Mol Endocrinol 1997 Jun;11(7):917-27
Fetal death in mice lacking 5alpha-reductase type 1 caused by estrogen excess.
Mahendroo MS, Cala KM, Landrum DP, Russell DW.
Department of Molecular Genetics, University of Texas Southwestern Medical
Center, Dallas 75235-9046, USA.
Female mice deficient in steroid 5alpha-reductase type 1 have a decreased litter
size. The average litter in homozygous deficient females is 2.7 pups vs. 8.0
pups in wild type controls. Oogenesis, fertilization, implantation, and
placental morphology appear normal in the mutant animals. Fetal loss occurs
between gestation days 10.75 and 11.0 commensurate with a midpregnancy surge in
placental androgen production and an induction of 5alpha-reductase type 1
expression in the decidua of wild type mice. Plasma levels of androstenedione
and testosterone are 2- to 3-fold higher on gestation day 9, and estradiol
levels are chronically elevated by 2- to 3-fold throughout early and
midgestation in the knockout mice. Administration of an estrogen receptor
antagonist or inhibitors of aromatase reverse the high rate of fetal death in
the mutant mice, and estradiol treatment of wild type pregnant mice causes fetal
wastage. The results suggest that in the deficient mice, a failure to
5alpha-reduce androgens leads to their conversion to estrogens, which in turn
causes fetal death in midgestation. These findings indicate that the
5alpha-reduction of androgens in female animals plays a crucial role in guarding
against estrogen toxicity during pregnancy.
PMID: 9178751 [PubMed - indexed for MEDLINE]
144: Drug Metab Dispos 1997 May;25(5):598-602
Inhibition of human drug metabolizing cytochromes P450 by anastrozole, a potent
and selective inhibitor of aromatase.
Grimm SW, Dyroff MC.
Drug Disposition and Metabolism Department, Zeneca Pharmaceuticals, Wilmington,
DE 19850, USA.
Anastrozole (2,2'[5(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]-
bis(2-methylproprionitrile)) is a potent third-generation inhibitor of
aromatase, currently marketed as a treatment for postmenopausal women with
advanced breast cancer. While its potency and selectivity for inhibition of
estrogen synthesis has been established in both preclinical and clinical
studies, this study used in vitro methods to examine the effects of anastrozole
on several drug metabolizing CYP enzymes found in human liver. Human liver
microsomes were co-incubated with anastrozole and probe substrates for CYP1A2
(phenacetin), CYP2A6 (coumarin), CYP2C9 (tolbutamide), CYP2D6
(dextromethorphan), and CYP3A (nifedipine). The formation of the CYP-specific
metabolites following co-incubation with various anastrozole concentrations was
determined to establish IC50 and Ki values for these enzymes. While anastrozole
did not inhibit CYP2A6 and CYP2D6 activities at concentrations below 500 microM,
this compound inhibited CYP1A2, CYP2C9, and CYP3A activities with Ki values of
8, 10, and 10 microM, respectively. Dixon plots used to determine the Ki values
for the inhibition of CYP1A2 and CYP3A activities by anastrozole were biphasic,
indicating additional lower affinity Ki values. Major metabolites of anastrozole
did not retain the ability to inhibit the metabolism of nifedipine (CYP3A). The
results of this study indicate that, although anastrozole can inhibit CYP1A2,
2C9, and 3A-mediated catalytic activities, this compound would not be expected
to cause clinically significant interactions with other CYP-metabolized drugs at
physiologically relevant concentrations achieved during therapy with Arimidex
(Zeneca, Ltd., Macclesfield, UK) 1-mg.
PMID: 9152599 [PubMed - indexed for MEDLINE]
145: Nurse Pract 1997 Mar;22(3):195-6, 201-2
Role of new selective aromatase inhibitor in therapy for metastatic breast
cancer in postmenopausal women.
Hannaford M.
Anastrozole offers a new option for many postmenopausal women with metastatic
breast cancer who no longer respond to antiestrogen therapy. It has a lower side
effect profile for weight gain and peripheral edema and equivalent efficacy to
the current second-line therapy, megestrol acetate, which may improve quality of
life. Due to its selectivity and lack of clinically significant effects on
cortisol metabolism, it does not have the toxicity problems of other aromatase
inhibiting agents such as aminoglutethimide. Long-term studies are needed to
adequately evaluate the impact of this degree of estrogen suppression on
cardiovascular and bone mass risk factors [12]. Cost of therapy will certainly
have an impact on the choice of second-line endocrine therapy in those with
limited income sources and lack of prescription coverage. In summary, there is
likely to be an increased use of nonsteroidal aromatase inhibitor agents for
second-line hormonal therapy of breast cancer. Due to increased length of
survival, these individuals will not be seen exclusively by oncologists; their
care will be shared with their primary care provider [21]. Providers must have
an understanding of these agents and their potential impact on the long-term
health care of the individual in order to provide knowledgeable and
comprehensive care.
Publication Types:
News
PMID: 9078523 [PubMed - indexed for MEDLINE]
146: Cancer 1997 Feb 15;79(4):730-9
A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and
selective aromatase inhibitor, with megestrol acetate in postmenopausal women
with advanced breast carcinoma. Arimidex Study Group.
Buzdar AU, Jones SE, Vogel CL, Wolter J, Plourde P, Webster A.
Department of Medical Oncology, M.D. Anderson Cancer Center, University of Texas
Medical Center, Houston 77030, USA.
BACKGROUND: Anastrozole is a new oral aromatase inhibitor with highly potent and
selective activity for the aromatase enzyme. In a Phase III trial, the efficacy
and tolerability of anastrozole, given in doses of 1 and 10 mg orally once
daily, and megestrol acetate, given in doses of 40 mg orally 4 times daily, were
compared in 386 postmenopausal women with advanced breast carcinoma who
progressed after tamoxifen therapy. METHODS: The trial was randomized, double
blind for anastrozole, open label for megestrol acetate, parallel group, and
multicenter. Patients were randomly assigned to receive anastrozole, 1 mg (n =
128); anastrozole, 10 mg (n = 130); or megestrol acetate (n = 128). The primary
efficacy measures were time to progression and tumor response; secondary
measures were time to treatment failure, duration of response, quality of life,
and time to death. RESULTS: With a median duration of follow-up of 6 months,
there was no statistical evidence of a difference between either 1 or 10 mg
doses of anastrozole and megestrol acetate for any efficacy endpoint. According
to rigid response criteria, 10%, 6%, and 6% of patients in the anastrozole 1 mg,
anastrozole 10 mg, and megestrol acetate groups, respectively, had an objective
response (complete response or partial response) and 27%, 24%, and 30% of
patients in the respective groups had stable disease for a duration of 24 weeks
or longer. Quality-of-life assessments revealed that anastrozole in a 1-mg dose
was associated with better physical scores and anastrozole in a 10-mg dose with
better psychologic scores than megestrol acetate. Both anastrozole and megestrol
acetate were generally well tolerated. Among anticipated adverse events,
gastrointestinal disturbance was more common among patients in the anastrozole
groups, whereas weight gain occurred more frequently among patients in the
megestrol acetate groups. Weight increases of 5% or more and 10% or more were
more common among megestrol acetate-treated patients; moreover, patients in this
group continued to gain weight over time. CONCLUSIONS: Anastrozole, given in
doses of 1 and 10 mg once daily, represents a well tolerated and effective
therapeutic option for the treatment of postmenopausal women with advanced
breast carcinoma who progress after tamoxifen treatment.
Publication Types:
Clinical Trial
Clinical Trial, Phase III
Multicenter Study
Randomized Controlled Trial
PMID: 9024711 [PubMed - indexed for MEDLINE]
147: Br J Cancer 1996 Oct;74(8):1286-91
Influence of anastrozole (Arimidex), a selective, non-steroidal aromatase
inhibitor, on in vivo aromatisation and plasma oestrogen levels in
postmenopausal women with breast cancer.
Geisler J, King N, Dowsett M, Ottestad L, Lundgren S, Walton P, Kormeset PO,
Lonning PE.
Department of Oncology, Haukeland University Hospital, Bergen, Norway.
The effect of anastrozole ('Arimidex', ZD1033), a new, selective, non-steroidal
aromatase inhibitor on in vivo aromatisation and plasma oestrogen levels was
evaluated in post-menopausal women with breast cancer. Twelve patients
progressing after treatment with tamoxifen were randomised to receive
anastrozole 1 mg or 10 mg once daily for a 28 day period in a double-blinded
crossover design. In vivo aromatisation and plasma oestrogen levels were
determined before commencing treatment and at the end of each 4-week period.
Treatment with anastrozole 1 and 10 mg reduced the percentage aromatisation from
2.25% to 0.074% and 0.043% (mean suppression of 96.7% and 98.1% from baseline)
and suppressed plasma levels of oestrone, oestradiol and oestrone sulphate by >
or = 86.5%, > or = 83.5% and > or = 93.5% respectively, irrespective of dose.
Notably, several patients had their oestrone and oestradiol values suppressed
beneath the sensitivity limit of the assays. In conclusion, anastrozole was
found to be highly effective in inhibiting in vivo aromatisation with no
difference in efficacy between the two drug doses. Contrary to previous studies
on other aromatase inhibitors, this study revealed an internal consistency
between the percentage aromatase inhibition and suppression of plasma oestrone
sulphate.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 8883419 [PubMed - indexed for MEDLINE]
148: Tumori 1996 Sep-Oct;82(5):417-22
Novel non-steroidal aromatase inhibitors: are there new perspectives in the
treatment of breast cancer?
Bajetta E, Celio L, Buzzoni R, Bichisao E.
Division of Medical Oncology B, Istituto Nazionale per lo Studio e la Cura dei
Tumori, Milan, Italy.
Breast cancer is the most common malignant neoplasm affecting women in Western
countries, and most new cases are manifested during the postmenopausal period.
The clinical results obtained with aminoglutethimide, and later with formestane,
have established aromatase inhibition as one of the major therapeutic options in
hormone-dependent advanced disease. Nevertheless, the lack of specificity of
aminoglutethimide and the less than optimal oral activity of formestane soon led
to further efforts to find a potent, highly selective, orally active,
side-effect-free aromatase inhibitor for use in postmenopausal women with
advanced breast cancer. Here we review the available data on three new,
competitive non-steroidal aromatase inhibitors--letrozole, vorozole and
anastrozole--which are approaching the point of detailed pharmacologic and
clinical evaluation. Preliminary data have confirmed the high potency and
selectivity of these endocrine agents, but their antitumor activity still
remains to be completely defined. Challenges given by these novel aromatase
inhibitors are discussed taking into account the biologic implications related
to their mechanism of action and their future use in the management of breast
cancer.
Publication Types:
Review
Review, Tutorial
PMID: 9063515 [PubMed - indexed for MEDLINE]
149: Semin Oncol 1996 Aug;23(4 Suppl 9):28-32
Aromatase inhibitors in metastatic breast cancer.
Buzdar AU, Plourde PV, Hortobagyi GN.
Department of Breast Medical Oncology, The University of Texas, M.D. Anderson
Cancer Center, Houston 77030, USA.
Inhibition of estrogen production or actions provides an effective therapy for
patients with hormone-dependent breast cancer. A number of approaches to
accomplishing these goals are available, and each has its own advantages and
disadvantages. Aromatase inhibitors are capable of lowering estrogen levels in
postmenopausal women whose estrogen production is not ovarian. Aromatase, the
enzyme that converts androgens to estrogens, is one of a series of related P-450
enzymes involved in the production of steroid hormones. Because of the
similarity of the P-450 enzymes, selectivity is important; nonselective
aromatase inhibitors, such as aminoglutethimide, can affect enzymes controlling
the production of other steroids and lead to significant side effects. Recently,
a number of newer aromatase inhibitors have been synthesized and are in
preclinical or clinical development. In early 1996, anastrozole became available
for clinical use in the United States and in a number of other countries. In
phase I studies, anastrozole was shown to be highly selective and inhibited
estrogen production in postmenopausal patients to levels below the detection
threshold of the assay. Another aromatase inhibitor in advanced development is
fadrozole. In this review we present briefly the available clinical data on
fadrozole and anastrozole.
PMID: 8824462 [PubMed - indexed for MEDLINE]
150: Semin Oncol 1996 Aug;23(4 Suppl 9):10-20
Aromatase inhibitors and breast cancer.
Brodie AM, Njar VC.
Department of Pharmacology and Experimental Therapeutics, School of Medicine,
University of Maryland, Baltimore 21201, USA.
Selective aromatase inhibitors cause regression of breast carcinomas by reducing
estrogen production via inhibition of the enzyme aromatase (estrogen
synthetase). A higher incidence of hormone-dependent breast cancer occurs in
postmenopausal women than in younger women. Thus, total estrogen blockade is
more likely to be achieved with systemic (pharmacologic) methods than by
surgical removal of endocrine glands. At the present time, breast cancer
patients with hormone-dependent disease usually receive the antiestrogen
tamoxifen as first-line treatment. Although tamoxifen is effective initially,
patients develop resistance to the drug, which results in disease progression.
Aromatase inhibitors acting by a different mechanism from tamoxifen are
effective in some of these patients. There is also the potential that aromatase
inhibitors could be more effective as first-line treatment. Formestane,
4-hydroxyandrostenedione, the first approved aromatase inhibitor, is proving to
be useful in postmenopausal breast cancer patients with advanced disease.
Recently, anastrozole, a nonsteroidal agent, has been approved in the United
States. Other very potent aromatase inhibitors are under development. Aromatase
inhibitors as a new class of well-tolerated agents are now becoming available
for improving the treatment of breast cancer patients.
Publication Types:
Review
Review, Academic
PMID: 8824460 [PubMed - indexed for MEDLINE]
151: Med Lett Drugs Ther 1996 Jul 5;38(978):61-2
Anastrozole for metastatic breast cancer.
PMID: 8668098 [PubMed - indexed for MEDLINE]
152: J Steroid Biochem Mol Biol 1996 Jul;58(4):439-45
The preclinical pharmacology of "Arimidex" (anastrozole; ZD1033)--a potent,
selective aromatase inhibitor.
Dukes M, Edwards PN, Large M, Smith IK, Boyle T.
Zeneca Pharmaceuticals, Alderly Park, Macclesfield, U.K.
Anastrozole is a comparatively simple, achiral benzyltriazole derivative,
2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-++
+methylpropiononitrile), that inhibits human placental aromatase with an IC50 of
15 nM and elicits maximal activity in vivo in rats (inhibition of ovulation and
androstenedione-induced uterine hypertrophy) and monkeys (lowering of plasma
oestradiol) at 0.1 mg/kg p.o. At 30 times this dose, anastrozole does not
elevate plasma 11-deoxycorticosterone in monkeys, and at 100 times this dose,
does not affect plasma aldosterone levels or Na+/K+ excretion in rats, plasma K+
concentrations in dogs, or cause adrenal hypertrophy in rats or dogs. It
therefore has no discernible effect on adrenocorticoid hormone synthesis in vivo
at very large multiples of its maximally effective aromatase-inhibiting dose. At
similar large multiples in rats it displays no oestrogenic, anti-oestrogenic,
androgenic, anti-androgenic, progestogenic, glucocorticoid, antiglucocorticoid
or mineralocorticoid activity. Anastrozole is thus a potent and highly selective
aromatase inhibitor, with no intrinsic hormonal activities--a pharmacological
profile particularly suitable for the treatment of breast cancer.
PMID: 8903429 [PubMed - indexed for MEDLINE]
153: J Clin Oncol 1996 Jul;14(7):2000-11
Anastrozole, a potent and selective aromatase inhibitor, versus megestrol
acetate in postmenopausal women with advanced breast cancer: results of overview
analysis of two phase III trials. Arimidex Study Group.
Buzdar A, Jonat W, Howell A, Jones SE, Blomqvist C, Vogel CL, Eiermann W, Wolter
JM, Azab M, Webster A, Plourde PV.
M.D. Anderson Cancer Center, University of Texas, Houston, Department of Breast
Medical Oncology 77030, USA. [email protected]
PURPOSE: To compare the efficacy and tolerability of anastrozole (1 and 10 mg
once daily), a selective, oral, nonsteroidal aromatase inhibitor, and megestrol
acetate (40 mg four times daily), in postmenopausal women who progressed
following tamoxifen treatment. PATIENTS AND METHODS: Two randomized,
double-blind for anastrozole, open-label for megestrol acetate, parallel-group,
multicenter trials were conducted in 764 patients. Because both trials were
identical in design, an analysis of the combined results was performed to
strengthen interpretation of results from each trial. RESULTS: The median
follow-up duration was approximately 6 months. The estimated progression hazards
ratios were 0.97 (97.5% confidence interval [CI], 0.75 to 1.24) for anastrozole
1 mg versus megestrol acetate and 0.92 (97.5% CI, 0.71 to 1.19) for anastrozole
10 mg versus megestrol acetate. The overall median time to progression was
approximately 21 weeks. Approximately one third of patients in each group
benefited from treatment. Twenty-seven patients (10.3%) in the anastrozole 1-mg
group, 22 (8.9%) in the anastrozole 10-mg group, and 20 (7.9%) in the megestrol
acetate group had a complete or partial response, and 66 (25.1%), 56 (22.6%),
and 66 (26.1%) patients, respectively, had stable disease for > or = 24 weeks.
For all end points, individual trial results were similar to the results of the
combined analysis. Anastrozole and megestrol acetate were well tolerated.
Gastrointestinal disturbance was more common among patients in the anastrozole
groups than the megestrol acetate group; the difference between the anastrozole
10 mg and megestrol acetate groups was significant (P = .005). Significantly
fewer patients in the anastrozole 1-mg (P < .0001) and 10-mg (P < .002) groups
had weight gain than in the megestrol acetate group. More than 30% of megestrol
acetate-treated patients had weight gain > or = 5%, and 10% of patients had
weight gain > or = 10%. Patients who received megestrol acetate continued to
gain weight over time. CONCLUSION: Anastrozole, 1 and 10 mg once daily, is well
tolerated and as effective as megestrol acetate in the treatment of
postmenopausal women with advanced breast cancer who progressed following
tamoxifen treatment. Moreover, anastrozole therapy avoids the weight gain
associated with megestrol acetate treatment.
Publication Types:
Clinical Trial
Clinical Trial, Phase III
Multicenter Study
Randomized Controlled Trial
PMID: 8683230 [PubMed - indexed for MEDLINE]
154: Eur J Cancer 1996 Mar;32A(3):404-12
Comment in:
Eur J Cancer. 1996 Mar;32A(3):393-5
A randomised trial comparing two doses of the new selective aromatase inhibitor
anastrozole (Arimidex) with megestrol acetate in postmenopausal patients with
advanced breast cancer.
Jonat W, Howell A, Blomqvist C, Eiermann W, Winblad G, Tyrrell C, Mauriac L,
Roche H, Lundgren S, Hellmund R, Azab M.
University Women's Hospital, Eppendorf, Hamburg, Germany.
The aim of this study was to compare the efficacy and tolerability of the new
aromatase inhibitor 'ARIMIDEX' (anastrozole) with megestrol acetate in the
treatment of advanced breast cancer in postmenopausal women. Anastrozole is a
new potent and highly selective non-steroidal aromatase inhibitor. We conducted
a prospective randomised trial comparing two doses of anastrozole (1 and 10 mg
orally once daily) with megestrol acetate (40 mg orally four times daily) in
postmenopausal patients with advanced breast cancer who progressed after prior
tamoxifen therapy. All patients were analysed for efficacy as randomised
(intention to treat) and for tolerability as per treatment received. Of the 378
patients who entered the study, 135 were randomised to anastrozole 1 mg, 118 to
anastrozole 10 mg, and 125 patients to megestrol acetate. After a median
follow-up of 192 days, response rate which included complete response, partial
response and patients who had disease stabilisation for 6 months or more was 34%
for anastrozole 1 mg, 33.9% for anastrozole 10 mg and 32.8% for megestrol
acetate. There were no statistically significant differences between either dose
of anastrozole and megestrol acetate in terms of objective response rate, time
to objective progression of disease or time to treatment failure. The three
treatments were generally well tolerated, but more patients on megestrol acetate
reported weight gain, oedema and dyspnoea as adverse events while more patients
on anastrozole reported gastro-intestinal disorders, usually in the form of mild
transient nausea. Patients on anastrozole did not report higher incidences of
oestrogen withdrawal symptoms. Anastrozole is an effective and well tolerated
treatment for postmenopausal patients with advanced breast cancer. The higher 10
mg dose did not result in additional clinical benefit, but was well tolerated
reflecting the good therapeutic margin with anastrozole. Based on this data,
anastrozole 1 mg should be the recommended therapeutic dose.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 8814682 [PubMed - indexed for MEDLINE]
155: Eur J Cancer 1996 Mar;32A(3):393-5
Comment on:
Eur J Cancer. 1996 Mar;32A(3):404-12
New aromatase inhibitors: more selectivity, less toxicity, unfortunately, the
same activity.
Castiglione-Gertsch M.
Publication Types:
Comment
Editorial
PMID: 8814679 [PubMed - indexed for MEDLINE]
156: Br J Cancer 1996 Feb;73(4):543-8
Arimidex (ZD1033): a selective, potent inhibitor of aromatase in postmenopausal
female volunteers.
Yates RA, Dowsett M, Fisher GV, Selen A, Wyld PJ.
Zeneca Pharmaceuticals, Macclesfield, UK.
Two multiple-dose studies were conducted in healthy post-menopausal female
volunteers to investigate the pharmacokinetics and effects on endocrinology of
Arimidex (ZD1033). Volunteers in the first trial were dosed with 3 mg of ZD1033
daily over 10 days to assess the effects on endocrinology of ZD1033 and
establish a pharmacokinetic profile. In the second trial volunteers received 14
daily doses of either 0.5 or 1.0 mg of ZD1033 to assess the pharmacokinetics of
ZD1033 and the effects of low doses of ZD1033 on serum oestradiol
concentrations. Following multiple dosing a significant reduction in the
concentration of serum oestradiol of approximately 80% of baseline was obtained
with all three doses; no recovery in oestradiol was apparent for up to 144 h
after the last dose. There was no overall difference in the level of oestradiol
suppression between the 0.5 or 1.0 mg doses of ZD1033. However, comparison of
the number of volunteers with oestradiol concentrations below the limits of
detection of the assay, 24 h after the last dose of ZD1033, suggested that 1.0
mg was the minimal dose required for maximal suppression of oestradiol. No
significant effect was recorded on serum concentrations of gonadotrophins over
the dosing period. Serum concentrations of a range of adrenal steroids were not
affected by administration of ZD1033; furthermore, steroid response to standard
adrenocorticotrophic hormone (ACTH) challenge was unimpaired by ZD1033. Together
these data demonstrate the potency, tolerability and selectivity of ZD1033. The
pharmacokinetic profile of ZD1033 supports its use as a once-daily treatment
given orally.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 8595172 [PubMed - indexed for MEDLINE]
157: J Steroid Biochem Mol Biol 1995 Jun;53(1-6):175-9
ARIMIDEX: a new oral, once-a-day aromatase inhibitor.
Plourde PV, Dyroff M, Dowsett M, Demers L, Yates R, Webster A.
ZENECA Pharmaceuticals, Wilmington, DE 19897, USA.
ARIMIDEX is a potent and selective aromatase inhibitor undergoing evaluation as
a treatment for postmenopausal women with advanced breast cancer. Studies
examining the pharmacology of ARIMIDEX were conducted in both animals and
humans. In animals, ARIMIDEX elicits maximal aromatase suppressive activity at a
dose of approx. 0.1 mg/kg, does not alter adrenal steroid hormone biosynthesis,
and at a dose of 1 mg/kg, has no other pharmacologic effects other than
aromatase inhibition. In this overview, the pharmacodynamic, pharmacokinetic,
and safety profiles of single and multiple daily doses of ARIMIDEX are reported
in humans. Daily doses of 1-10 mg of ARIMIDEX suppressed estradiol levels to the
maximum degree measurable using sensitive estrogen assays. ARIMIDEX had no
clinically significant effects on the response of cortisol and aldosterone to
ACTH stimulation. Absorption of ARIMIDEX was rapid, with maximum plasma
concentrations occurring within 2 h after oral administration. Plasma
concentrations of ARIMIDEX rose with increasing doses of the drug. The
elimination half-life of ARIMIDEX in humans ranged from 30 to 60 h. Consistent
with the long plasma half-life, steady state plasma concentrations were 3-4-fold
higher than plasma concentrations observed after single administration of 1, 3,
5, or 10 mg doses. Long term treatment of breast cancer patients with 10 mg/day
has continued in 17 patients without an escape of estradiol suppression.
Previously, these patients had received on average 2.6 systemic treatments for
breast cancer and had significant metastatic disease. Three of the 17 patients
continued ARIMIDEX treatment for 20 months and beyond. Given the number of
previous treatments and tumor burden at the start of treatment, the response to
ARIMIDEX treatment is encouraging. Phase III studies are now underway to assess
the efficacy and safety of ARIMIDEX in the treatment of advanced breast cancer.
Publication Types:
Clinical Trial
Review
Review, Tutorial
PMID: 7626450 [PubMed - indexed for MEDLINE]
158: Breast Cancer Res Treat 1994;30(1):103-11
Arimidex: a potent and selective fourth-generation aromatase inhibitor.
Plourde PV, Dyroff M, Dukes M.
Zeneca Pharmaceuticals Group, Zeneca Inc., Wilmington, Delaware 19897.
Arimidex is a potent and selective aromatase inhibitor undergoing evaluation as
a treatment for postmenopausal women with advanced breast cancer. Studies to
determine the pharmacology of Arimidex were conducted in both animals and
humans. In animals, Arimidex was selective for the aromatase enzyme, elicited
maximal activity at about 0.1 mg/kg, did not interfere with steroid hormones
produced by the adrenal glands, and, at a dose of 1 mg/kg, had no detectable
pharmacologic activity other than aromatase inhibition. Absorption of ZD1033,
the active component of Arimidex, was rapid and virtually complete after oral
administration to animals. ZD1033 was extensively metabolized in animals after
oral administration; the metabolites were excreted predominantly in urine. The
pharmacodynamic, pharmacokinetic, and safety profiles of single and multiple
daily doses of Arimidex were determined in humans. Doses of 1 to 10 mg of
Arimidex suppressed estradiol to the maximum degree measurable. Arimidex had no
clinically significant effects on key enzymes that regulate cortisol and
aldosterone biosynthesis. Absorption of ZD1033 was rapid, with maximum plasma
concentrations occurring within 2 hours after oral administration. Plasma
concentrations of ZD1033 rose with increasing doses of Arimidex. The elimination
half-life of ZD1033 in humans ranged from 30 to 60 hours. Urinary excretion
accounted for a small percentage of each dose. A 3- to 4-fold accumulation of
ZD1033 in plasma occurred after daily administration of 3-, 5-, or 10-mg doses.
Arimidex was well tolerated. Phase III studies are under way to determine the
efficacy and safety of Arimidex in postmenopausal women with advanced breast
cancer.
PMID: 7949201 [PubMed - indexed for MEDLINE]
Letrozole.
1: Gan To Kagaku Ryoho 2002 May;29(5):741-9
[CGS20267 (Letrozole), a new aromatase inhibitor: late phase II study in
postmenopausal women with advanced or recurrent breast cancer (no.
2)--evaluation of efficacy and safety at the recommended clinical dose CGS20267
Study Group]
[Article in Japanese]
Kimijima I, Tominaga T, Nomizu T, Nomura Y, Takashima S, Koyama H, Sano M, Tohge
T, Ueo H, Ikeda S, Ohashi Y; CGS20267 Study Group.
Dept. of Surgery II, Fukushima Medical College.
In the first part of this late phase II study, we determined the recommended
clinical dose of CGS20267 to be 1.0 mg once daily for the treatment of
postmenopausal women with advanced or recurrent breast cancer. To further
evaluate the efficacy and safety of CGS20267 at the derived or recommended
clinical dose, 30 more patients were enrolled in the second part of the study,
and were added to the patients treated at 1.0 mg in the first part. As a result
of putting the first and second parts together, the objective response rate at
1.0 mg was found to be 38.3%, which was almost equal to that of the early phase
II study (40.7%). Drug-related adverse events occurred in 35.4% of the patients
at 1.0 mg, and all of the events were of grade 2 or lower. These results
demonstrated that CGS20267 1.0 mg once daily is effective and well tolerated in
the treatment of postmenopausal women with advanced or recurrent breast cancer.
PMID: 12040678 [PubMed - in process]
2: Gan To Kagaku Ryoho 2002 May;29(5):729-40
[CGS20267 (Letrozole), a new aromatase inhibitor: late phase II study for
postmenopausal women with advanced or recurrent breast cancer (no.
1)--investigation of recommended clinical dose CGS20267 Study Group]
[Article in Japanese]
Abe R, Tominaga T, Nomizu T, Nomura Y, Takashima S, Koyama H, Sano M, Tohge T,
Ueo H, Ikeda S, Ohashi Y; CGS20267 Study Group.
Dept. of Surgery II, Fukushima Medical College.
To determine the recommended clinical dose of CGS20267 (Letrozole), we conducted
a randomized comparative study as a late phase II study (first part) in
postmenopausal women with advanced or recurrent breast cancer. Forty-one
patients were randomly assigned to receive 0.5 mg or 1.0 mg once daily. There
were no statistically significant differences in background between the two
groups. Although there was no significant difference in the objective response
rates between the two groups, the rate was higher at 1.0 mg (44.4%) than at 0.5
mg (38.1%). We also combined these data with the results of an early phase II
study. The objective response rates (CR + PR) were 31.4% at 0.5 mg and 42.2% at
1.0 mg, and response rates consisting of CR, PR, and NC for longer than 6 months
were significantly higher at a dose of 1.0 mg (68.9%) than 0.5 mg (41.2%). Side
effects included drug-related adverse events in 36.8% at 0.5 mg and in 31.6% at
1.0 mg. All of the events were grade 2 or lower, indicating a favorable
tolerability of CGS20267. These results demonstrated that CGS20267 1.0 mg once
daily is more effective than 0.5 mg, and has comparable safety, in the treatment
of postmenopausal women with advanced or recurrent breast cancer. We conclude
the recommended clinical dose of CGS20267 should be 1.0 mg once daily.
PMID: 12040677 [PubMed - in process]
3: Clin Breast Cancer 2002 Apr;3(1):33-42
Antiaromatase agents: evolving role in adjuvant therapy.
Jones SE.
Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX
75246, USA. [email protected]
The goal of adjuvant hormonal therapy is to prevent breast cancer recurrence.
Standard therapy with tamoxifen has shown great value in the adjuvant setting;
however, its tolerability profile can render it unsuitable for some patients.
The aromatase inactivator, exemestane, and the 2 aromatase inhibitors, letrozole
and anastrozole, have been shown to be equivalent or superior to tamoxifen with
respect to multiple endpoints in patients with metastatic breast cancer. With
tolerability profiles that are similar to, and in many cases, more acceptable
than that of tamoxifen, and efficacy potentially superior to tamoxifen, studies
using the antiaromatase agents as adjuvant therapy are currently ongoing. These
trials will answer some important questions, such as the order in which adjuvant
hormonal therapies are selected to maximize efficacy, whether the antiaromatase
agents show improved tolerability, and whether combination therapy is more
effective than monotherapy.
Publication Types:
Review
Review, Tutorial
PMID: 12020394 [PubMed - indexed for MEDLINE]
4: Curr Med Res Opin 2002;18(1):26-9
Recent advances in breast cancer (the Twenty-fourth San Antonio Breast Cancer
Symposium, December, 2001).
Mokbel K, Kirkpatrick KL.
The Breast Unit, St. George's Hospital and Medical School, London, UK.
This paper reviews the Twenty-fourth Annual San Antonio Breast Cancer Symposium.
The preliminary results of the ATAC study have shown that Arimidex is superior
to tamoxifen in postmenopausal women with ER-positive early breast cancer in
terms of DFS, adverse effects and prevention of contralateral breast cancer.
However, longer follow up is required to assess the drug safety regarding bone
mineral density and cognitive function. Letrozole seems to be superior to
tamoxifen as a first-line therapy in ER-positive advanced breast cancer in
postmenopausal women. Although the incidence of acute myeloid leukaemia is
significantly increased (cumulative incidence at 5 years = 1.1%) in breast
cancer patients receiving cyclophosphamide and anthracyclines, the risk of this
complication is easily outweighed by the benefits of chemotherapy. Adjuvant
clodronate was found to be associated with a significant reduction in the
incidence of bone metastases during the treatment period. A randomised trial
comparing axillary dissection and axillary radiotherapy (RT) for early breast
cancer reported no significant difference in survival at 15 years. However,
axillary recurrence was significantly increased in the RT group. hTERT protein
expression by IHC was found to correlate significantly with breast
cancer-specific survival. There is no evidence to support the use of IHC of the
sentinel node in routine clinical practice. LCIS is currently considered as a
non-obligate precursor to breast cancer rather than just a risk factor.
PMID: 11999142 [PubMed - in process]
5: Expert Opin Pharmacother 2002 May;3(5):607-17
Letrozole in the treatment of breast cancer.
Shaw HS, Ellis MJ.
Multidisciplinary Breast Program, Duke University Medical Center, Box 3381,
Durham, NC 27710, USA. [email protected]
Over the last 30 years the role of tamoxifen in breast cancer treatment has been
progressively expanded by clinical investigation to encompass the entire
spectrum of disease from cancer chemoprevention to palliation of advanced
disease. The primacy of tamoxifen for these indications in postmenopausal women
is now under challenge by the selective aromatase inhibitors, a class of
endocrine agent that induces oestrogen deprivation rather than oestrogen
receptor blockade. This review considers the biochemical, pharmacological and
clinical properties of the nonsteroidal aromatase inhibitor letrozole. This
agent is superior to tamoxifen for the treatment of metastatic breast cancer, a
finding that suggests that letrozole may ultimately eclipse tamoxifen for other
indications, including chemoprevention. Further clinical investigation will be
necessary to establish the risks and benefits of letrozole versus tamoxifen for
each new indication, with adjuvant therapy being the next in line. The object of
this review is to provide a reference source on the biochemical, pharmacological
and clinical properties of letrozole for clinicians to consider both established
and future indications.
PMID: 11996638 [PubMed - in process]
6: J Steroid Biochem Mol Biol 2002 Apr;80(4-5):411-8
Short-term effects of anastrozole treatment on insulin-like growth factor system
in postmenopausal advanced breast cancer patients.
Ferrari L, Martinetti A, Zilembo N, Pozzi P, Buzzoni R, La Torre I, Gattinoni L,
Catena L, Vitali M, Celio L, Seregni E, Bombardieri E, Bajetta E.
Nuclear Medicine, Istituto Nazionale per lo Studio e la Cura dei Tumori of
Milan, Via G. Venezian, 1, 20133, Milan, Italy
Insulin-like growth factors (IGFs) play a fundamental role in cancer development
by acting in both an endocrinal and paracrinal manner, and hormone breast cancer
treatments affect the IGF system by modifying circulating growth factor levels.
We evaluated total IGF-1, IGF-2, IGF binding protein (IGFBP)-1 and IGFBP-3 in
the blood of 34 postmenopausal advanced breast cancer patients (median age 63
years, range 41-85) treated with anastrozole, a non-steroidal structure
aromatase inhibitor (NSS-AI). The plasma samples were obtained at baseline, and
after 2, 4, 8 and 12 weeks of treatment. The IGFs were quantitated by means of
sensitive radioimmunoassays (RIAs). IGF-1 significantly increased during
anastrozole treatment (baseline versus 12 weeks, P=0.031), IGF-2 showed a trend
towards an increase, and IGFBP-1 constantly but not significantly decreased;
IGFBP-3 did not seem to be affected at all. The anastrozole-induced changes in
IGFs and IGFBP-1 appeared to be different in the patients receiving a clinical
benefit from those observed in non-responders. We have previously shown that
letrozole (a different type of NSS-AI) modifies blood IGF-1 levels, and the
results of this study of the biological effects of anastrozole on the components
of the IGF system confirm our previous observations.
PMID: 11983488 [PubMed - in process]
7: Gan To Kagaku Ryoho 2002 Apr;29(4):551-62
[CGS 20267 (Letrozole), a new aromatase inhibitor: early phase II study for
postmenopausal women with advanced breast cancer]
[Article in Japanese]
Nomura Y, Tominaga T, Enomoto K, Aoyama H, Nakamura Y, Abe R, Sano M, Nomizu T,
Tohge T, Takashima S, Ohashi Y.
Dept. of Breast Surgery, National Kyushu Cancer Center.
A multicenter, open labeled, randomized early Phase II study for CGS 20267 was
conducted at the doses 0.5 mg once daily and 1.0 mg once daily in postmenopausal
women with advanced breast cancer. Sixty-four patients were randomly assigned to
the doses of either 0.5 mg once daily (n = 33) or 1.0 mg once daily (n = 31).
Thirty-one patients were eligible for 0.5 mg group, and 29 for 1.0 mg group. A
total of 57 patients (30 in the 0.5 mg group and 27 in the 1.0 mg group) were
eligible for the evaluation of efficacy. There were 3 CR, 5 PR, 5 stable disease
(SD: NC lasting over 24 weeks), 7 NC and 10 PD in the 0.5 mg group. The
objective response rate (ORR) was 26.7%. There were 4 CR, 7 PR, 8 SD, 3 NC and 5
PD in the 1.0 mg group. The ORR was 40.7%. A total of 57 patients (29 in the 0.5
mg group and 28 in the 1.0 mg group) were eligible for safety evaluation.
Adverse clinical events related to CGS 20267 in the 0.5 mg group were headache,
nausea, cold sweat, sleepiness and muscle ache in the lower extremities (2
patients, incidence rate 6.9%) whereas those in the 1.0 mg group were
generalized itching and generalized hot feeling (2 patients, incidence rate
7.1%). All of the adverse events were grade 1 except the generalized itching
which was grade 2. CGS 20267-related abnormalities in the laboratory tests for
the 0.5 mg group were a decrease in WBC, and increases in GOT, GPT, LDH and
gamma-GTP (5 patients, 14.3%) whereas those in the 1.0 mg group were increases
in GPT, gamma-GTP, alkaline phosphatase, and total bilirubin (1 patient, 3.6%).
The increases in GOT and GPT were grade 2, but others were grade 1. The data
show both CGS 20267 0.5 mg once daily and 1.0 mg once daily to be effective and
tolerable in the treatment of postmenopausal women with advanced breast cancer.
Publication Types:
Clinical Trial
Clinical Trial, Phase II
Multicenter Study
Randomized Controlled Trial
PMID: 11977539 [PubMed - indexed for MEDLINE]
8: Clin Breast Cancer 2000 Sep;1 Suppl 1:S68-73
Comparison of in vitro exemestane activity versus other antiaromatase agents.
Soudon J.
Pharmacell, Paris, France; [email protected]
Anastrozole, letrozole, and exemestane are the most selective and potent oral
antiaromatase agents currently available. However, in vitro and in vivo studies
comparing these agents are lacking. Anastrozole and letrozole are reversible,
competitive nonsteroidal type II inhibitors, whereas exemestane is an
irreversible steroidal type I inactivator. The study was conducted to determine
the impact of this characteristic on in vitro residual aromatase activity and
protein levels after incubation of JEG-3 cells with aminoglutethimide (a type II
inhibitor), anastrozole, exemestane, or letrozole. Aromatase activity was
measured after various incubation times with each antiaromatase agent at a
concentration 10 times higher than IC50 (concentration giving 50% inhibition).
Only exemestane induced a residual inhibition of aromatase activity after its
removal, without any change in the aromatase protein level. Aromatase activity
increased after preincubation of JEG-3 cells with either aminoglutethimide or
anastrozole without any change in the aromatase protein level. The aromatase
protein level increased rapidly when cells were incubated with letrozole and
aromatase activity inhibition disappeared immediately after removal of the drug.
The breakthrough effects in aromatase activity or protein levels observed after
treatment with reversible inhibitors may be a factor in therapeutic failure with
these agents. These results suggest a possible advantage for exemestane because
it is the only clinically available oral irreversible aromatase inactivator.
PMID: 11970753 [PubMed - in process]
9: Cancer Control 2002 Mar-Apr;9(2 Suppl):9-15
Endocrine and clinical endpoints of exemestane as neoadjuvant therapy.
Miller WR, Dixon JM.
Breast Research Unit, University of Edinburgh, Western General Hospital,
Edinburgh EH4 2XU, Scotland, UK. [email protected]
A series of in vitro and in vivo studies have been performed to establish the
endocrine and clinical endpoints of the type I anti-aromatase agent exemestane
in neoadjuvant therapy. In vitro studies demonstrated a dose-related inhibition
of aromatase activity with exemestane, even when activity was measured in a
system in which the aromatase enzyme was induced in fibroblasts preincubated
with exemestane but assayed in the absence of the drug. In contrast, type II
anti-aromatase agents (eg, aminoglutethimide, anastrozole, and letrozole) often
caused a paradoxical increase in aromatase activity when measured under similar
conditions. In vivo and in situ studies were performed in 12 postmenopausal
women with untreated large or locally advanced estrogen receptor-rich tumors.
The effect of exemestane 25 mg daily for 3 months on aromatization peripherally
and in breast cancer and surrounding normal tissue was determined. Immediately
before starting therapy, patients received an 18-hour infusion of radioactively
labeled androgen and estrogen, followed by a wedge biopsy. This procedure was
repeated after 3 months of treatment with exemestane, and the data were used to
calculate peripheral and local aromatization. Changes in tumor volume were based
on clinical examination, ultrasound, and mammography. Exemestane treatment was
associated with a marked reduction in aromatization peripherally and in
nonmalignant breast tissue in every patient and in breast tumor in all but one
patient. Median reduction in tumor volume was 85.5% for clinical examination,
82.5% for ultrasound, and 84% for mammography. Eight of 10 patients who would
have required mastectomy before treatment were able to undergo breast-conserving
surgery after treatment. Clinical benefits were accompanied by a marked
reduction in cellular proliferation and progesterone receptor expression. These
data support the use of exemestane in neoadjuvant therapy of breast cancer in
postmenopausal women.
PMID: 11965226 [PubMed - in process]
10: Cancer Control 2002 Mar-Apr;9(2 Suppl):2-8
Anti-aromatase Agents in the Treatment and Prevention of Breast Cancer.
Goss P.
Breast Cancer Prevention Program at the Princess Margaret Hospital, Toronto, ON
M5G 2M9, Canada. [email protected]
Anti-aromatase agents now have a central role in the management of breast cancer
in postmenopausal women; they are superior to megestrol acetate as second-line
therapy and to tamoxifen for initial therapy of metastatic disease. They also
are highly active as neoadjuvant therapy. Two classes of anti-aromatase agents
are available: steroidal (eg, exemestane) and nonsteroidal (eg, anastrozole,
letrozole). Although both types of agents act on the aromatase enzyme, they do
so by different mechanisms and have different effects on cellular aromatase
activity. Nonsteroidal agents are associated with increased aromatase enzyme
content and steroidal agents are associated with decreased content. The increase
in aromatase content seen with the nonsteroidal agents may in part explain the
development of resistance with these agents and the ability of the steroidal
agent exemestane to induce a response when nonsteroidal agents fail. Because the
anti-aromatase agents almost completely eliminate endogenous estrogen
production, they not only affect breast cancer tissues, but also may alter the
function of other estrogen-responsive tissues. However, preclinical data show
that the steroidal agent exemestane may actually improve bone and lipid
metabolism. In addition, no increase in clinical fracture rate has been noted in
women treated with exemestane in metastatic trials; the fracture risk has not
yet been studied following prolonged exposure in healthy women. Exemestane
associated beneficial effects on these end organs may be due to the steroidal
nature of both the parent compound and its principal metabolite,
17-hydroexemestane. Similar benefits have not been reported with nonsteroidal
antiaromatase agents. Based on their excellent activity in the metastatic
setting, anti-aromatase agents are now being evaluated in the adjuvant setting
and in pilot studies for chemoprevention. These studies will provide long-term
data in healthy women and will help to differentiate anti-aromatase agents, in
terms of their efficacy in the treatment of breast cancer and their effects on
end organs.
PMID: 11965225 [PubMed - in process]
11: Harv Womens Health Watch 2002 Apr;9(8):7
New breast cancer drugs expand treatment options.
Publication Types:
News
PMID: 11959538 [PubMed - indexed for MEDLINE]
12: Strahlenther Onkol 2002 Feb;178(2):111-3
[Superiority of letrozole compared with tamoxifen as first line therapy of
postmenopausal women with advanced breast cancer: results of a phase III study
of the International Letrozole Breast Cancer Group]
[Article in German]
Illiger HJ.
Publication Types:
Clinical Trial
Clinical Trial, Phase III
Multicenter Study
Randomized Controlled Trial
PMID: 11942036 [PubMed - indexed for MEDLINE]
13: Fertil Steril 2002 Apr;77(4):776-80
Aromatase inhibition improves ovarian response to follicle-stimulating hormone
in poor responders(1).
Mitwally MF, Casper RF.
Division of Reproductive Sciences, Department of Obstetrics and Gynecology,
Samuel Lunenfeld Research Institute and Mount Sinai Hospital, University of
Toronto, Toronto, Ontario, Canada
Objective: To examine the use of the aromatase inhibitor letrozole with FSH for
ovarian stimulation in poor responders undergoing ovarian superovulation and
IUI.Design: Observational cohort study as a prospective clinical trial in
patients with unexplained infertility and a low response to ovarian stimulation
with FSH.Setting: Two tertiary referral infertility clinics associated with the
Reproductive Sciences Division, University of Toronto.Patient(s): Twelve
patients with unexplained infertility undergoing IUI who received FSH alone in
25 prior cycles with poor response (less than three dominant
follicles).Intervention(s): Patients were offered letrozole, 2.5 mg/day from day
3-7 of the menstrual cycle with FSH (50-225 IU/day) starting on day 5-7. hCG
(10,000 IU) was given when two leading follicles were >/=2 cm followed by
IUI.Main Outcome Measure(s): Number of mature follicles (>1.8 cm), FSH dose,
endometrial thickness, and pregnancy rate.Result(s): Improved response to FSH
stimulation with letrozole co-treatment was evidenced by the significantly lower
FSH dose associated with significantly higher number of mature follicles. During
letrozole plus FSH stimulation cycles, clinical pregnancy was achieved in three
cycles (21%).Conclusion(s): In this preliminary report, we demonstrate a
potential benefit of aromatase inhibition for improving ovarian response to FSH
in poor responders.
PMID: 11937133 [PubMed - in process]
14: Drugs 2002;62(6):957-66
Tamoxifen resistant and refractory breast cancer: the value of aromatase
inhibitors.
Goss PE, Strasser K.
Breast Cancer Prevention Program, Princess Margaret Hospital, University Health
Network, Toronto, Ontario, Canada. [email protected]
Tamoxifen has dominated endocrine treatment of breast cancer for over two
decades. It is useful in metastatic breast cancer, adjuvant therapy,
preoperative treatment, ductal carcinoma-in-situ and chemoprevention. However,
breast cancer may be refractory to tamoxifen or develop resistance to it with
ongoing treatment. This resistance involves several mechanisms including
receptor mutation causing 'estrogen hypersensitivity' and an increasing agonist
effect of tamoxifen. Megestrol (megestrol acetate), in North America, and
aminoglutethimide, in Europe, have been the traditional second line therapies
after tamoxifen in advanced breast cancer. Aromatase (estrogen synthetase)
inhibitors are a logical alternative to tamoxifen to antagonise the effects of
estrogen on breast cancer. The third-generation non-steroidal aromatase
inhibitors anastrozole, letrozole and vorozole, and the steroidal inhibitor
exemestane, have been studied after tamoxifen versus either megestrol or
aminoglutethimide. They showed enhanced efficacy and significantly superior
toxicity profiles. Compliance with the inhibitors was also significantly better
than with the traditional treatments. Aromatase inhibitors have most recently
been shown to be superior to tamoxifen as initial therapy and are being
extensively tested in the adjuvant setting after, or instead of, tamoxifen.
Pilot studies of chemoprevention are also being undertaken. The aromatase
inhibitors are an important new addition to the armamentarium of breast cancer
therapy.
Publication Types:
Review
Review, Tutorial
PMID: 11929341 [PubMed - indexed for MEDLINE]
15: Clin Cancer Res 2001 Dec;7(12 Suppl):4402s-4410s; discussion 4411s-4412s
Future use of selective estrogen receptor modulators and aromatase inhibitors.
Howell A.
CRC Department of Medical Oncology, University of Manchester, Christie Hospital,
United Kingdom.
Selective estrogen receptor modulators (SERMs) may act as estrogens or
antiestrogens depending on the cell and tissue targets. The triphenylethylene
SERMs are represented by tamoxifen and toremifene and a new agent with a novel
carboxylic acid side chain (GW5638). Because of isomerization in the
triphenylethylene molecule, "fixed ring" SERMs were introduced. The major one in
development is the benzothiophene arzoxiphene (LY353381), which is now in Phase
III clinical trial versus tamoxifen. A fourth group of SERMs is based on the
estrogen molecule and comprises the so-called "pure" antiestrogen ICI 182,780
(fulvestrant, Faslodex) and a new oral analogue just entering trials, SR16234.
The steroidal aromatase inhibitors [AIs (40H androstenedione 'and exemestane)]
inactivate aromatase, whereas the triazole AIs (anastrozole and letrozole)
inhibit the enzyme via the heme prosthetic group. Thus, there are two groups of
AIs that show relative non-cross-resistance in advanced breast cancer and four
groups of SERMs that also show a high degree of non-cross-resistance. With six
different treatments and six or more clinical situations (prevention,
neoadjuvant, adjuvant, and first- and second-line treatments for advanced
disease) in which they may be used, the possible combinations of treatment are
enormous. At present, we have few clinical pointers to optimal sequence of
treatments. Now that most of the appropriate comparative trials have been
performed, it may be the time to initiate novel approaches. These include
alternating and sequential treatments, preferably with treatments changed before
overt progression occurs.
PMID: 11916232 [PubMed - in process]
16: Clin Cancer Res 2001 Dec;7(12 Suppl):4397s-4401s; discussion 4411s-4412s
Preliminary data from ongoing adjuvant aromatase inhibitor trials.
Goss P E.
Princess Margaret Hospital, Toronto, Ontario, Canada. [email protected]
With recent results showing letrozole and anastrozole to be superior to
tamoxifen as initial therapy for advanced disease, the aromatase inhibitors are
poised to establish their place in the adjuvant therapy of postmenopausal
receptor-positive breast cancer. A review of the rationale, design, and
preliminary results of the ongoing adjuvant trials that include aromatase
inhibitors will be presented, along with the ongoing or planned substudies. Two
strategies employing aromatase inhibitors after tamoxifen are being evaluated.
The MA.17 international intergroup trial is randomizing postmenopausal patients
who are disease-free after 5 years of adjuvant tamoxifen to an additional 5
years of letrozole or placebo. In a similar design, the National Surgical
Adjuvant Breast and Bowel Project (NSABP) B33 trial is randomizing this patient
population to 2 years of exemestane or placebo after the standard 5 years of
adjuvant tamoxifen. The second approach under study is the use of both aromatase
inhibitor and tamoxifen in sequence within the first 5 postoperative years. The
International Cancer Collaboration Group (ICCG) trial is comparing 2 years of
exemestane after 3 years of tamoxifen to a standard 5-year course of tamoxifen.
Similarly, the ARNO trial is comparing 5 years of tamoxifen versus 2 years of
tamoxifen followed by 3 years of anastrozole. In a four-arm study Breast
International Group/Femara-Tamoxifen (BIG/FEMTA) conducted by the BIG, one arm
contains letrozole given for 3 years after 2 years of tamoxifen. Several trials
are investigating the role of anastrozole, letrozole, or exemestane as a 5-year
adjuvant therapy to replace the standard 5 years of tamoxifen. Only the Arimidex
and Tamoxifen, Alone or in Combination (ATAC) trial is testing a 5-year
combination of tamoxifen plus an aromatase inhibitor in this setting. Companion
studies of effects on end-organs other than the breast are ongoing in a number
of these trials. Aromatase inhibitors are poised to alter the treatment paradigm
of breast cancer and hopefully improve outcome for a substantial number of
patients.
PMID: 11916231 [PubMed - in process]
17: Clin Cancer Res 2001 Dec;7(12 Suppl):4388s-4391s; discussion 4411s-4412s
Neoadjuvant endocrine therapy for breast cancer: medical perspectives.
Ellis M J.
Duke University Breast Cancer Program, Duke University Medical Center, Durham,
North Carolina 27710, USA. [email protected]
The indolent nature of estrogen-dependent breast cancer is the most important
obstacle for development of new adjuvant endocrine treatments. Clinical trials
require thousands of study participants and at least a decade of clinical
investigation. How can we be sure that a new endocrine agent warrants this
extraordinary level of investment? Traditionally, we have relied on advanced
breast cancer trials to determine which drugs are suitable for adjuvant studies.
However, with endocrine agents the high incidence of resistance in metastatic
breast cancer may mask important advances in efficacy. Recent clinical results
with the aromatase inhibitor letrozole suggest that neoadjuvant endocrine
therapy is a highly informative additional approach to consider when planning
adjuvant studies. In this report, new neoadjuvant endocrine therapy study
designs are discussed that address the following issues: (a) the scientific
opportunities afforded by gene microarray studies and other genetic technologies
to investigate the molecular basis of estrogen-dependent breast cancer; (b)
studies that address critical drug development questions as a prelude to
adjuvant studies; and (c) the conduct of randomized trials that compare
neoadjuvant chemotherapy with neoadjuvant aromatase inhibitor therapy to
establish a place for neoadjuvant endocrine therapy in routine clinical
practice.
PMID: 11916229 [PubMed - in process]
18: Clin Cancer Res 2001 Dec;7(12 Suppl):4360s-4368s; discussion 4411s-4412s
Are differences in the available aromatase inhibitors and inactivators
significant?
Johnson P E, Buzdar A.
Department of Breast Medical Oncology, The University of Texas M. D. Anderson
Cancer Center, Houston 77030, USA.
Aromatase inhibitors are endocrine agents with a different mode of action than
tamoxifen against breast tumors. In postmenopausal women, estrogen
concentrations are maintained primarily via aromatase, a cytochrome P-450 enzyme
that acts at the final step in the estrogen synthesis pathway. The first
clinically available aromatase inhibitor, aminoglutethimide, was introduced for
the second-line treatment of advanced breast cancer in the late 1970s. Despite
proven efficacy in this setting, its widespread use was limited by its overall
toxicity and its lack of selectivity for the aromatase enzyme. This led to the
search for novel, more effective, and less toxic aromatase inhibitors. As a
result, several aromatase inhibitors with a high degree of selectivity for
aromatase and improved tolerability have become clinically available for the
treatment of postmenopausal women with advanced breast cancer: (a) anastrozole;
(b) letrozole; (c) fadrozole; (d) formestane; and (e) exemestane. Of these,
formestane and exemestane are steroidal nonreversible aromatase inhibitors, also
known as aromatase inactivators, whereas fadrozole, anastrozole, and letrozole
are nonsteroidal reversible aromatase inhibitors. These agents differ in
pharmacokinetics, selectivity, and potency, although all are more selective than
aminoglutethimide. Some differences in adverse effect profile are also
noticeable between and within these two classes of agents. The clinical
significance of these differences is not yet evident but may well prove to be
relevant in the long-term adjunctive setting.
PMID: 11916226 [PubMed - in process]
19: Clin Cancer Res 2001 Dec;7(12 Suppl):4356s-4359s; discussion 4411s-4412s
The role of tamoxifen and aromatase inhibitors/inactivators in postmenopausal
patients.
Pritchard K I.
Toronto-Sunnybrook Regional Cancer Centre, University of Toronto, Ontario,
Canada. [email protected]
The traditional hormonal cascade of the 1970s and 1980s used tamoxifen followed
by megestrol acetate and subsequently by aminoglutethimide. In the 1990s,
however, three trials of third-generation aromatase inhibitors (AIs) compared
with megestrol acetate and two trials of third-generation AIs compared with
aminoglutethimide showed improved efficacy and decreased toxicity for the newer
AIs. Thus, the hormonal cascade changed in the late 1990s, to one in which
tamoxifen, followed by a third-generation AI, followed by megestrol acetate,
seemed more suitable. Now, however, several trials comparing anastrozole,
letrozole, and exemestane to tamoxifen as first-line hormonal agents for
metastatic breast cancer have shown that these drugs are at least equivalent and
perhaps superior to tamoxifen in that setting in terms of response rate and time
to progression. Results from 1021 patients randomized to receive anastrozole
versus tamoxifen showed a slightly improved overall response rate (RR; 29%
versus 26%), slightly improved clinical benefit (CB; 57% versus 52%), and a
significantly improved time to progression (TTP; 8.5 months versus 7.0 months)
in favor of anastrozole. In 907 women randomized to treatment with letrozole
versus tamoxifen, significantly improved RR (30% versus 20%), CB (49% versus
38%), and TTP (9.4 months versus 6 months) have all been shown for those treated
with letrozole. In addition, a randomized Phase II trial of 121 patients has
shown nonsignificant benefits in favor of exemestane (RR 41% versus 14%; CB 56%
versus 42%; TTP not available). To date, none of these trials has demonstrated
any overall survival benefit. Additional follow-up in regard to survival in the
trial of tamoxifen versus letrozole and an expanded Phase III trial of tamoxifen
versus exemestane are ongoing.
PMID: 11916225 [PubMed - in process]
20: Lancet Oncol 2000 Nov;1:132
Breast cancer studies challenge tamoxifen therapy.
Timms B.
Publication Types:
News
PMID: 11905647 [PubMed - indexed for MEDLINE]
21: Curr Med Res Opin 2001;17(3):217-22
Aromatase inhibitors.
Cunnick G H, Mokbel K.
St George's Breast Cancer Centre, St George's Hospital, London, UK.
The new non-steroidal and steroidal aromatase inhibitors are at least as
effective as megestrol acetate (MA) as second-line hormonal agents in
postmenopausal women with breast cancer. However, they are superior to MA in
terms of tolerability and adverse effects. Letrozole and exemestane have been
shown to be superior to MA in terms of efficacy. Furthermore, exemestane and
anastrozole demonstrated a survival advantage over MA. These drugs are therefore
considered established second-line hormonal agents. There is a growing body of
evidence supporting the role of third-generation aromatase inhibitors as
first-line therapy for ER-and/or PgR-positive advanced breast cancer in
postmenopausal women, and as a neoadjuvant therapy in postmenopausal women with
hormone receptor positive tumours unsuitable for breast conserving surgery.
Studies comparing these drugs head-to-head and with adjuvant tamoxifen are
currently in progress. The potential role of these drugs in breast cancer
prevention is worth investigating.
PMID: 11900315 [PubMed - in process]
22: J Clin Oncol 2002 Mar 15;20(6):1467-72
Elevated serum Her-2/neu level predicts decreased response to hormone therapy in
metastatic breast cancer.
Lipton A, Ali SM, Leitzel K, Demers L, Chinchilli V, Engle L, Harvey HA, Brady
C, Nalin CM, Dugan M, Carney W, Allard J.
Department of Hematology and Oncology, Penn State Milton S. Hershey Medical
Center, Hershey, Pennsylvania 17033, USA. [email protected]
PURPOSE: To determine the effect of elevation of serum HER-2/neu on response to
hormone therapy. PATIENTS AND METHODS: Seven hundred nineteen metastatic
patients with estrogen receptor-positive (ER(+)), progesterone
receptor-positive, or both or ER status unknown breast cancer were randomized in
three independent clinical trials to receive second-line hormone therapy with
either megestrol acetate or an aromatase inhibitor (fadrozole or letrozole). An
automated enzyme-linked immunosorbent assay specific for the extracellular
domain of the HER-2/neu (c-erbB-2) oncoprotein product was used to detect serum
levels. RESULTS: Two hundred nineteen patients (30%) had elevated serum
HER-2/neu protein levels, using the mean + 2 SD (15 ng/mL) from the serum of
healthy women as an upper limit. Response to treatment was available for 711
patients. The response rate (complete responses plus partial responses plus
stable disease) to endocrine therapy was 45% in 494 patients with non-elevated
and 23% in 217 patients with elevated serum HER-2/neu levels (P <.0001). Median
duration of treatment response (using the time to progression [TTP] variable for
patients who responded) was shorter in the group with elevated serum HER-2/neu
levels (11.7 months) compared with the patient group with non-elevated levels
(17.4 months). TTP, time to treatment failure, and median survival (17.2 months
v 29.6 months) were also significantly shorter in the patients with elevated
serum HER-2/neu levels (P <.0001). CONCLUSION: Patients with ER(+) and serum
HER-2/neu-positive metastatic breast cancer are less likely to respond to
hormone treatment and have a shorter duration of response than ER(+) and serum
HER-2/neu-negative patients. Their survival duration is also shorter.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 11896093 [PubMed - indexed for MEDLINE]
23: Clin Cancer Res 2002 Mar;8(3):665-9
Approval summary: letrozole in the treatment of postmenopausal women with
advanced breast cancer.
Cohen MH, Johnson JR, Li N, Chen G, Pazdur R.
Division of Oncology Drug Products (HFD-150), Center for Drug Evaluation and
Research, Food and Drug Administration, Rockville, Maryland 20857.
Letrozole (Femara; Novartis Pharmaceuticals Corp., East Hanover, NJ) is a
nonsteroidal inhibitor of aromatase enzyme complex. It inhibits the peripheral
conversion of circulating androgens to estrogens. In postmenopausal women,
letrozole decreases plasma concentrations of estradiol, estrone, and estrone
sulfate by 75-95% from baseline with maximal suppression achieved within 2-3
days of treatment initiation. Suppression is dose related, with doses of >/=0.5
mg giving estrone and estrone sulfate values that were often below assay
detection limits. At clinically used dosage, letrozole does not impair adrenal
synthesis of glucocorticoids or aldosterone. In 1998, letrozole was approved by
the United States Food and Drug Administration (FDA) for the treatment of
advanced breast cancer in postmenopausal women, with hormone receptor positive
or unknown breast cancer, who had failed one prior antiestrogen treatment (i.e.,
for "second-line" treatment). Approval was based on two randomized trials
comparing tumor RRs of patients receiving 0.5 mg of letrozole, 2.5 mg of
letrozole, and either megestrol acetate (MA) or aminoglutethimide. In the
megestrol trial, 2.5 mg/day letrozole was superior to 0.5 mg of letrozole and MA
(RRs 24, 13, and 16%, respectively), whereas in the aminoglutethimide trial,
there was no significant difference in 2.5 mg of letrozole and 0.5 mg of
letrozole RRs (20 and 17%). There was a trend toward RR superiority of 2.5 mg of
letrozole over aminoglutethimide (P = 0.06). Letrozole (2.5 mg) was the dose
chosen for comparison with tamoxifen in the first-line setting. In July 2000, a
marketing application for first-line letrozole treatment of postmenopausal women
with hormone receptor positive or hormone receptor unknown locally advanced or
metastatic breast cancer was submitted to the FDA. A single double-blind, double
dummy, randomized, and multicenter trial compared 2.5 mg of letrozole to 20 mg
of tamoxifen (456 patients/arm). Letrozole was superior to tamoxifen with regard
to time to progression (TTP) and objective response rate (RR). The median TTP
for letrozole treatment was 9.9 months [95% confidence interval (CI) 9.1-12.2]
versus 6.2 months (95% CI 5.8-8.5) for tamoxifen, P = 0.0001, hazard ratio
0.713, (95% CI 0.61-0.84). RR was 32% for letrozole versus 21% for tamoxifen
(odds ratio 1.74, 95% CI 1.29-2.34, P = 0.0003). Preliminary survival data
(survival data are still blinded) indicate that letrozole is unlikely to be
worse than tamoxifen. Both treatments were similarly tolerated. On the basis of
these results, the United States FDA approved letrozole tablets, 2.5 mg/day, for
first-line treatment of postmenopausal women with hormone receptor-positive or
hormone receptor-unknown locally advanced or metastatic breast cancer. The
manufacturer made a commitment to provide updated information on survival.
PMID: 11895893 [PubMed - in process]
24: Eur J Endocrinol 2002 Mar;146(3):339-46
The role of sex steroids in the regulation of insulin sensitivity and serum
lipid concentrations during male puberty: a prospective study with a
P450-aromatase inhibitor.
Wickman S, Saukkonen T, Dunkel L.
Hospital for Children and Adolescents, University of Helsinki, PL281, FIN-00029
HUS, Helsinki, Finland. [email protected]
OBJECTIVE: Our purpose was to study the sex steroid-mediated changes in serum
insulin and lipid concentrations in boys during puberty. DESIGN AND METHODS: We
treated boys with constitutional delay of puberty either with testosterone plus
placebo or with testosterone plus an aromatase inhibitor, letrozole, which
inhibits the conversion of androgens to oestrogens. We demonstrated previously
that during treatment with testosterone plus letrozole the increase in
testosterone concentration was more than 5-fold higher than during treatment
with testosterone plus placebo. The concentrations of 17beta-oestradiol, IGF-I
and IGF-binding protein-3 increased during testosterone-plus-placebo treatment,
but during testosterone-plus-letrozole treatment the concentrations remained
unchanged. These divergent changes in the two groups enabled us to study the
effects of sex steroids and GH on insulin sensitivity and lipid concentrations.
RESULTS: The insulin concentration in the testosterone-plus-placebo-treated
group did not change. In contrast, in the testosterone-plus-letrozole-treated
group, the concentration decreased during letrozole treatment, indicating
improved insulin sensitivity. Changes in insulin and IGF-I concentrations within
12 and 18 months were correlated. In the testosterone-plus-placebo-treated
group, the high-density lipoprotein cholesterol concentration did not change but
in the testosterone-plus-letrozole-treated group the concentration decreased.
The concentrations of low-density lipoprotein cholesterol (LDL-cholesterol) and
triglycerides did not change in either of the groups. CONCLUSIONS: The findings
indicate that androgens do not directly alter insulin sensitivity in boys during
puberty. In contrast, the observations suggest tight regulation of
glucose--insulin homeostasis by GH in boys at this stage. Furthermore, our
findings indicate that sex steroids do not significantly participate in the
regulation of serum concentrations of LDL-cholesterol or triglycerides in boys
during early and mid-puberty.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 11888840 [PubMed - indexed for MEDLINE]
25: MMW Fortschr Med 2002 Jan 31;144(5):46-8
[Aromatase inhibitors of the 3rd generation. What can the "pill against breast
cancer" really do?]
[Article in German]
Junker A, Wiedemann GJ, Possinger K.
Sana Klinikum Remscheld GmbH, Apotheke, Remscheid.
Metastatic cancer of the breast in postmenopausal women can be treated with a
number of "hormone-active" substances. The drugs of first choice are still
anti-estrogens. Today, the three highly selective oral aromatase inhibitors
anastrozole, letrozole and exemestane are additionally available for use in
continuing progression under anti-estrogen treatment. Roughly one woman in three
derives benefit from these new medications as reflected by objective remission
or stabilization of the disease for more than 6 months. Neither chemical
structure (steroidal/non-steroidal), nor the different nature of inhibition of
the active centre of the aromatase, nor whether the inhibition of the enzyme is
reversible or irreversible, has any influence on the parameters: response rate,
response duration and clinical benefit.
PMID: 11883037 [PubMed - indexed for MEDLINE]
26: Toxicol Lett 2002 Mar 24;129(1-2):119-22
Detection of aromatase inhibitors in vitro using rat ovary microsomes.
Odum J, Ashby J.
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire
SK10 4TJ, UK.
Inhibition of aromatase activity in vitro is one of the Tier 1 screening assays
proposed by the Endocrine Disrupter Screening and Testing Advisory Committee
(EDSTAC) for the detection of potential endocrine disrupters. In this report a
rat ovarian aromatase inhibition assay has been evaluated using the reference
aromatase inhibitors anastrozole, fadrozole, letrozole and CGS 18320B. Rat ovary
microsomes were used as the enzyme source, as endocrine disruption studies are
most commonly carried out in this species. Aromatase activity was inhibited in
vitro by anastrozole, fadrozole, letrozole and CGS 18320B with IC(50)s of 25, 7,
7 and 5 nM, respectively. This assay, therefore, appears to have good
sensitivity to aromatase inhibitors and may be useful as a general screening
assay and in mechanistic studies.
PMID: 11879982 [PubMed - indexed for MEDLINE]
27: Trends Endocrinol Metab 2002 Mar;13(2):61-5
Aromatase inhibitors in breast cancer.
Brodie A.
Dept Pharmacology and Experimental Therapeutics, School of Medicine, University
of Maryland, 21201, Baltimore, MD, USA
Several compounds that selectively inhibit estrogen synthesis via aromatase have
been developed. Steroidal substrate analogs, such as formestane and exemestane,
inactivate aromatase by binding irreversibly to it. Non-steroidal inhibitors,
such as the triazole compounds letrozole and anastrozole, are highly potent,
reversible inhibitors with good specificity for aromatase. The intratumoral
aromatase model for postmenopausal breast cancer has been used to investigate
the efficacy of letrozole, anastrozole and exemestane in combination and
sequentially. Combining letrozole or arimidex with tamoxifen or faslodex was not
more effective than the aromatase inhibitors alone, but was more effective than
tamoxifen alone. Letrozole was superior to and longer lasting than the other
agents, suggesting that aromatase inhibitors control tumor growth effectively by
inducing greater tumor response and extending treatment time. In addition,
aromatase inhibitors can be effective in patients relapsing from tamoxifen.
Because two types of aromatase inhibitors are available, steroidal enzyme
inactivators and reversible non-steroidal inhibitors in sequential therapy could
be useful if resistance to one type develops.
PMID: 11854020 [PubMed - in process]
28: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):239-46
17alpha-methyl testosterone is a competitive inhibitor of aromatase activity in
Jar choriocarcinoma cells and macrophage-like THP-1 cells in culture.
Mor G, Eliza M, Song J, Wiita B, Chen S, Naftolin F.
Department of Obstetrics and Gynecology, Center for Research in Reproductive
Biology and Reproductive Neuroscience Unit, Yale University Medical School, 333
Cedar Street, FMB 335, New Haven, CT 06520 8063, USA.
17alpha-methyl testosterone is a synthetic androgen with affinity for the
androgen receptor. 17alpha-methyl testosterone is used widely as a component of
hormone replacement therapy. Previous reports have indicated that contrary to
testosterone, 17alpha-methyl testosterone is not aromatized. However,
17alpha-methyl testosterone still could affect local estrogen formation by
regulating aromatase expression or by inhibiting aromatase action. Both
possibilities have important clinical implications. To evaluate the effect of
17alpha-methyl testosterone on the expression and activity of aromatase, we
tested the choriocarcinoma Jar cell line, a cell line that express high levels
of P450 aromatase, and the macrophage-like THP-1 cells, which express aromatase
only after undergoing differentiation. We found that in both cell lines,
17alpha-methyl testosterone inhibits aromatase activity in a dose-related
manner. The curve of inhibition parallels that of letrozole and gives complete
inhibition at 10(-4) M 17alpha-methyl testosterone, determined by the tritium
release assay. 17alpha-methyl testosterone does not have detectable effects on
aromatase RNA and protein expression by Jar cells. Undifferentiated THP-1 cells
had no aromatase activity and showed no effect of 17alpha-methyl testosterone,
but differentiated THP-1 (macrophage-like) cells had a similar inhibition of
aromatase activity by 17alpha-methyl testosterone to that seen in Jar cells. The
Lineweaver-Burke plot shows 17alpha-methyl testosterone to be a competitive
aromatase inhibitor. Our results show for the first time that 17alpha-methyl
testosterone acts as an aromatase inhibitor. These findings are relevant for
understanding the effects of 17alpha-methyl testosterone as a component of
hormone replacement therapy. 17alpha-methyl testosterone may, as a functional
androgen and orally active steroidal inhibitor of endogenous estrogen
production, also offer special possibilities for the prevention/treatment of
hormone-sensitive cancers.
PMID: 11850230 [PubMed - indexed for MEDLINE]
29: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):227-37
Where do selective estrogen receptor modulators (SERMs) and aromatase inhibitors
(AIs) now fit into breast cancer treatment algorithms?
Howell A, Howell SJ, Clarke R, Anderson E.
CRC Department of Medical Oncology, Christie Hospital NHS Trust, M20 4BX,
Manchester, UK. [email protected]
The agents used for endocrine therapy in patients with breast cancer have
changed markedly over the past decade. Tamoxifen remains the anti-oestrogen of
choice, but could be replaced by the oestrogen receptor down-regulator ICI
182780 or by the fixed ring triphenylethylene arzoxifene (previously SERM III)
soon. Whilst aminoglutethimide and 4-OH androstenedione were the aromatase
inhibitors of choice, they have been replaced by non-steroidal (anastrozole and
letrozole) and steroidal (exemestane) inhibitors of high potency and low side
effect profile. Previously, often used treatments such as progestogens
(megestrol acetate and medroxyprogesterone acetate) and androgens are now rarely
used or confined to fourth or fifth line treatments. The LHRH agonist,
goserelin, remains the treatment of choice for pre-menopausal patients with
advanced breast cancer although recent randomised trials indicate a response,
time to progression and survival advantage for the combination of goserelin and
tamoxifen compared with goserelin alone.The newer treatments have led to
questions concerning the optimum sequence of agents to use in advanced breast
cancer and as neo-adjuvant and adjuvant therapy in relation to surgery. Two
trials of anastrozole compared with tamoxifen and one trial of letrozole
compared with tamoxifen indicate that the new triazole aromatase inhibitors have
a significant advantage over the anti-oestrogen with respect to time to
progression and survival. Similarly, triazole aromatase inhibitors give faster
and more complete responses compared with tamoxifen when used in post-menopausal
women before surgery.Major research questions remain with respect to the
aromatase inhibitors used as adjuvant therapy. Anastrozole is being tested alone
or in combination with tamoxifen compared with tamoxifen in the 'so-called' ATAC
trial. Over 9000 patients have been randomised to this important study: the
results will be available late-2001. A similar study comparing letrozole and
tamoxifen started recently under the auspices of the Breast International Group.
Importantly, this trial is also comparing the sequence of tamoxifen followed by
letrozole (or vice versa). A similar trial of exemestane given after 2-3 years
of tamoxifen compared with 5 years of tamoxifen is recruiting well as is a study
comparing letrozole (or placebo) for 5 years after 5 years of adjuvant
tamoxifen. These studies may show that aromatase inhibitors are superior to
tamoxifen or that a sequence is preferable.ICI 182780 causes complete oestrogen
receptor down-regulation leading to a the lack of agonist activity of the drug.
Two trials of ICI 182780 compared with anastrozole for advanced disease will
report later this year and a comparison with tamoxifen next year. Arzoxifene
(SERM III) is being tested against tamoxifen. These studies are likely to result
in new anti-oestrogens being introduced into the clinic.Most of our endocrine
treatments deprived the tumour cell of oestradiol. In vitro experiments with
MCF-7 cells indicate that tumour cells can adapt and then grow in response to
low oestrogen concentrations in the tissue--culture medium. Importantly, the
cells were shown to apoptose in response to high oestrogen concentrations. A
recent clinical trial has demonstrated a high response rate to stilboestrol
given after a median of four previous oestrogen depriving endocrine therapies.
These data and the newer treatments available indicate a need to re-think our
general approach to endocrine therapy and endocrine prevention.
Publication Types:
Review
Review, Tutorial
PMID: 11850229 [PubMed - indexed for MEDLINE]
30: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):133-41
Adjuvant trials of aromatase inhibitors: determining the future landscape of
adjuvant endocrine therapy.
Ragaz J.
British Columbia Cancer Agency, 600, West 10th Avenue, British Columbia, V5Z
4E6, Vancouver, Canada. [email protected]
This review will discuss the role of aromatase inhibitors (AIs) in the adjuvant
setting, and will summarize major strategies behind individual adjuvant trials
using aromatase inhibitors. Studies with the third generation AIs including
anastrozole, letrozole and exemestane, have shown better outcome and improved
therapeutic ratio over second line hormonal approaches (i.e. progestins or
aminoglutethimide) and, more recently, over tamoxifen also. These promising
results have led recently to testing of AIs in the adjuvant setting for
postmenopausal patients. Most trials now in progress are evaluating the role of
new AIs versus tamoxifen (T) given x 5 years, which in most institutions is
currently the standard hormonal adjuvant therapy for breast cancer. Three
adjuvant approaches are being tested. First is the use of AI+T x 5 years in
combination versus each agent alone, as reflected in the recently completed ATAC
trial. Second is a sequential approach T first x 2-3 years followed by AIs x 2-3
years, or the other way round; and third, T x 5 years followed by AIs for
additional 5 years (i.e. total duration of adjuvant hormones of 10 years). Many
patients in the above trials will survive their first cancer. Hence, the
non-oncological outcomes known to be affected by hormones are of rising
importance. Therefore, the assessment of lipids as surrogates for cardiovascular
morbidity, and of bone mineral status, as a marker for osteoporosis/bone
fractures, is an important component of these trials. Also discussed in this
review are proposals for future studies of AIs with focus on hormone resistance,
such as early alteration of multiple hormonal agents or their intermittent use,
the impact of the new generation of SERMs or 'pure' antiestrogens on activity of
AIs, and the rising importance of AIs interacting with biologicals, cytokines or
hormone modulators.
Publication Types:
Review
Review, Tutorial
PMID: 11850217 [PubMed - indexed for MEDLINE]
31: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):109-14
A summary of second-line randomized studies of aromatase inhibitors.
Buzdar AU.
Department of Breast Medical Oncology, M.D. Anderson Cancer Center, M.D.
University of Texas, Box 424, 1515 Holcombe Blvd, Houston, TX 77030, USA.
[email protected]
The new generation of selective aromatase inhibitors (anastrozole, letrozole and
exemestane) offer a significant efficacy and safety advantage over both older
agents in this class (aminoglutethimide) and the progestins (megestrol acetate
(MA)), as second-line treatment for postmenopausal women with advanced
hormone-dependent breast cancer who have failed on tamoxifen therapy.
Exemestane, a steroidal aromatase inhibitor, has been shown to have activity
after failure with the non-steroidal aromatase inhibitors, anastrozole and
letrozole, and could be used as third-line treatment. Although the newer
aromatase inhibitors belong to the same class and appear, from indirect
comparisons, to have similar efficacy compared with the older therapies, they
have different pharmacokinetic and pharmacodynamic profiles, suggesting the
potential for clinical differences. Compared with exemestane and letrozole,
anastrozole shows greater selectivity for aromatase, as it lacks any evidence of
an effect on adrenal steroidogenesis and has no androgenic effects. Therefore,
it is clear that these agents should not be considered to be similar in all
respects. In summary, the introduction of the aromatase inhibitors represents a
significant step forward in the treatment of advanced breast cancer in
postmenopausal women. Studies in the adjuvant setting will ultimately determine
whether the differences in pharmacokinetics and phamacodynamics will be of
clinical relevance.
Publication Types:
Review
Review, Tutorial
PMID: 11850214 [PubMed - indexed for MEDLINE]
32: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):103-7
Biological and clinical effects of aromatase inhibitors in neoadjuvant therapy.
Miller WR, Dixon JM, Cameron DA, Anderson TJ.
Department of Clinical Oncology, and Breast Unit, Western General Hospital,
University of Edinburgh, Crewe Road South, EH4 2XU, Edinburgh, UK.
[email protected]
Postmenopausal women with large primary oestrogen receptor-rich (>20 fmol/mg
protein or 80 histoscore) breast cancers have been treated neoadjuvantly with
either letrozole (2.5 or 10 mg daily n=12 in each case) or anastrozole (1 or
10mg daily n=12 and 11, respectively). Tumour was available for analysis before
treatment (wedge biopsy) and 3 months later at definitive surgery (wide local
excision or mastectomy). Clinical response to treatment was assessed by
sequential measurements of tumour volume based on caliper assessment, ultrasound
and mammography. Results showed that in these selected groups of patients a
reduction in tumour volume with treatment was observed in 43 of 47 cases (91%).
Pathological responses, i.e. clear decrease in tumour cellularity or increased
fibrosis was evident in 32 cases (68%). Furthermore, there was a decrease with
therapy in immunohistochemical staining for Ki67 in all tumours. Staining for
progesterone receptor (PgR) was reduced in all 21 PgR-positive cancers treated
with letrozole and in 16 of 17 positive cancers treated with anastrozole. These
effects are at least as great as those seen in a non-randomised group of
patients treated with tamoxifen over the same time period (additionally
tamoxifen treatment was often associated with an increase in PgR staining). The
results suggest that potent specific aromatase inhibitors will be valuable in
treating hormone-dependent cancers.
PMID: 11850213 [PubMed - indexed for MEDLINE]
33: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):93-102
Local endocrine effects of aromatase inhibitors within the breast.
Miller WR, Dixon JM.
Breast Unit, Department of Clinical Oncology, Western General Hospital,
University of Edinburgh, Crewe Road South, EH4 2XU, Edinburgh, UK.
[email protected]
To determine the effects of aromatase inhibitors on oestrogen uptake, in situ
aromatase activity and endogenous oestrogens in the breast, postmenopausal women
with large primary ER-rich breast cancers have been treated neoadjuvantly for 3
months with either letrozole (2.5 or 10mg daily) or anastrozole (1 or 10mg
daily) or exemestane (25mg daily). Patients were given an infusion of
3H-androstenedione and 14C-oestrone for 18h before and at the end of the study
period. Blood, tumour and non-malignant breast were taken immediately after each
infusion; oestrogens were extracted and purified. Tumour volume was measured
before and during treatment at monthly intervals so that endocrinological
changes could be related to clinical response. Treatment with each of the
aromatase inhibitors was associated with a profound reduction in peripheral
aromatase (as monitored by the level of plasma 3H-oestrone). There was no
consistent effect on uptake of radioactively labelled oestrogen into breast
tumours but a tendency for levels to increase after treatment in non-malignant
breast. Conversely, therapy was associated with a marked inhibition of in situ
oestrogen synthesis in both tumour and non-malignant breast (in occasional
tissues, inhibitors appeared to be less effective but the effect was not related
to clinical or pathological responses). Similar decreases were apparent in
endogenous levels of oestrone and oestradiol. The absence of in situ aromatase
activity tended to be associated with lack of clinical response to aromatase
inhibition but the relationship was not absolute, limiting the utility of
measurements of tumour aromatase as a predictive indices. Ex vivo studies of
tissue aromatase indicated that such measurements consistently underestimate the
inhibitory potential of reversible non-steroidal agents (and occasionally
paradoxical in vitro increases in aromatase activity were seen with treatment).
However, in situ assays demonstrate that new aromatase inhibitors such as
anastrozole, exemestane and letrozole have profound effects on the local
endocrinology within the postmenopausal breast, these being compatible with the
clinico-pathological changes which occur with treatment.
PMID: 11850212 [PubMed - indexed for MEDLINE]
34: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):85-91
Comparative clinical pharmacology and pharmacokinetic interactions of aromatase
inhibitors.
Boeddinghaus IM, Dowsett M.
The Academic Department of Biochemistry, Royal Marsden Hospital, Fulham Road,
SW3 6JJ, London, UK.
The clinical development of aromatase inhibitors (AIs) has been closely guided
by clinical pharmacological investigations. During the early phases of
development studies were focused on dose-related pharmacological effectiveness
and specificity. More recently attention has been given to the metabolic changes
which AIs elicit, with particular regard to their potential use in early breast
cancer and the prophylactic setting. Pharmacological effectiveness has been
studied with plasma oestrogen assays but primary oestrogens (E1 and E2) are not
helpful in comparing the third generation inhibitors: anastrozole, letrozole,
exemestane. All three of these compounds suppress whole body aromatisation by
>96%. Most recently, we have established that significantly greater inhibition
is achieved by letrozole than anastrozole at their clinically used dosages. This
more complete inhibition is paralleled by significantly greater suppression of
E1S.A broad panel of endocrine investigations has indicated that these compounds
have essentially complete specificity at their clinical dosages. A minor
androgenic effect of exemestane is revealed by a significant suppression of sex
hormone binding globulin (SHBG). Lipid and bone biomarker data are being
collected in many current studies. A pharmacokinetic interaction has been
established between letrozole and tamoxifen, whereby reduced circulating levels
of letrozole are found with combined application. Neither anastrozole nor
letrozole have any effect on plasma concentrations of tamoxifen when given in
combination with it.
Publication Types:
Review
Review, Tutorial
PMID: 11850211 [PubMed - indexed for MEDLINE]
35: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):41-7
Aromatase and COX-2 expression in human breast cancers.
Brodie AM, Lu Q, Long BJ, Fulton A, Chen T, Macpherson N, DeJong PC,
Blankenstein MA, Nortier JW, Slee PH, van de Ven J, van Gorp JM, Elbers JR,
Schipper ME, Blijham GH, Thijssen JH.
Department of Pharmacology, School of Medicine, University of Maryland, Room 580
G, Baltimore, MD 21201, USA. [email protected]
We have investigated aromatase and the inducible cyclooxygenase COX-2 expression
using immunocytochemistry in tumors of a series of patients with advanced breast
cancer treated with aromatase inhibitors. Aromatase was expressed in 58/102
breast cancers. This is similar to the percentage previously reported for
aromatase activity. Interestingly, aromatase was expressed in a variety of cell
types, including tumor, stromal, adipose, and endothelial cells. Since
prostaglandin E2 is known to regulate aromatase gene expression and is the
product of COX-2, an enzyme frequently overexpressed in tumors,
immunocytochemistry was performed on the tissue sections using a polyclonal
antibody to COX-2. Aromatase was strongly correlated (P<0.001) with COX-2
expression. These results suggest that PGE2 produced by COX-2 in the tumor may
be important in stimulating estrogen synthesis in the tumor and surrounding
tissue. No correlation was observed between aromatase or COX-2 expression and
the response of the patients to aromatase inhibitor treatment. However, only 13
patients responded. Nine of these patients were aromatase positive. Although
similar to responses in other studies, this low response rate to second line
treatment suggests that tumors of most patients were no longer sensitive to the
effects of estrogen. Recent clinical studies suggest that greater responses
occur when aromatase inhibitors are used as first line treatment. In the
intratumoral aromatase mouse model, expression of aromatase in tumors is highly
correlated with increased tumor growth. First line treatment with letrozole was
effective in all animals treated and was more effective than tamoxifen in
suppressing tumor growth. Letrozole was also effective in tumors failing to
respond to tamoxifen, consistent with clinical findings. In addition, the
duration of response was significantly longer with the aromatase inhibitor than
with tamoxifen, suggesting that aromatase inhibitors may offer better control of
tumor growth than this antiestrogen.
PMID: 11850206 [PubMed - indexed for MEDLINE]
36: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):27-34
Aromatase overexpression transgenic mice model: cell type specific expression
and use of letrozole to abrogate mammary hyperplasia without affecting normal
physiology.
Mandava U, Kirma N, Tekmal RR.
Department of Gynecology and Obstetrics, Emory University, 4217 Woodruff
Memorial Building, 1639 Pierce Drive, Atlanta, GA 30322-4710, USA.
Our recent studies have shown that overexpression of aromatase results in
increased tissue estrogenic activity and induction of hyperplastic and
dysplastic lesions in female mammary glands and gynecomastia and testicular
cancer in male aromatase transgenic mice. Both aromatase mRNA and protein are
overexpressed in transgenic mammary glands and its expression is not limited to
epithelial cells. However, it is more in epithelial than in stromal cells. Our
results also indicate aromatase overexpression-induced changes in mammary glands
can be abrogated with very low concentrations of the aromatase inhibitor,
letrozole. Low concentration of letrozole had no effect on normal physiology as
indicated by no significant change in the circulating levels of estradiol and
follicle stimulating hormone as well as no change in estrogen responsive genes
such as the progesterone receptor and lactoferrin in the uterine tissue. These
observations indicate that the expression of aromatase in both epithelial and
stromal cells can influence the complex interactions of biochemical pathways
leading to mammary carcinogenesis and that the aromatase inhibitor, letrozole
can be used as chemopreventive agents without affecting normal physiology.
PMID: 11850204 [PubMed - indexed for MEDLINE]
37: Lakartidningen 2002 Jan 17;99(3):165-8
[Growth rate can be manipulated. Estrogen production in pubertal boys can be
blocked by an aromatase inhibitor]
[Article in Swedish]
Hagenas L.
Barnendokrinologiska enheten, Astrid Lindgrens barnklinik, Karolinska sjukhuset,
Stockholm. [email protected]
A review of a twelve month clinical trial [1] using a new, effective aromatase
inhibitor treatment in boys with delayed puberty shows that the pubertal
increase in estrogen levels can be blocked, with concomitant preserved pubertal
growth rate. Circulating testosterone levels are greatly enhanced during
treatment due to increased gonadotrophin secretion. Despite this, bone age
maturation is slow leading to an increased final height prognosis (mean 5.1 cm)
for the boys treated with aromatase inhibitor.
PMID: 11838072 [PubMed - indexed for MEDLINE]
38: J Pediatr Endocrinol Metab 2001;14 Suppl 6:1541-6
Treatment of delayed male puberty: efficacy of aromatase inhibition.
Dunkel L, Wickman S.
University of Helsinki, Hospital for Children and Adolescents, Finland.
[email protected]
We hypothesized that inhibition of estrogen synthesis would delay maturation of
the growth plates and ultimately result in increased adult height in boys with
delayed puberty. We conducted a randomized, double-blind, placebo-controlled
study in which we treated boys with constitutional delay of puberty with
testosterone plus placebo (testosterone-placebo) or with testosterone plus
letrozole (testosterone-letrozole). Letrozole effectively inhibited estrogen
synthesis: 17beta-estradiol concentrations increased in the testosterone-placebo
group, but in the testosterone-letrozole group, no such increase was observed
until letrozole treatment was discontinued. After 1.5 years, bone age had
advanced by 1.7 +/- 0.3 years in the testosterone-placebo group, but by only 0.9
+/- 0.2 years in the testosterone-letrozole group (p = 0.02). Predicted adult
height did not change significantly in the testosterone-placebo group, whereas
in the testosterone-letrozole group the increase was 5.1 +/- 1.2 cm (p = 0.004).
Our findings suggest that, if estrogen action is inhibited in growing
adolescents, adult height will increase. This observation provides a rationale
for studies aimed at delaying bone maturation in several growth disorders.
PMID: 11837512 [PubMed - in process]
39: Ann Oncol 2001 Nov;12(11):1539-43
Formestane, a steroidal aromatase inhibitor after failure of non-steroidal
aromatase inhibitors (anastrozole and letrozole): is a clinical benefit still
achievable?
Carlini P, Frassoldati A, De Marco S, Casali A, Ruggeri EM, Nardi M, Papaldo P,
Fabi A, Paoloni F, Cognetti F.
Department of Medical Oncology, Regina Elena National Cancer Institute, Rome,
Italy. [email protected]
BACKGROUND: There are few clinical data on the sequential use of aromatase
inhibitors (AI). This paper focuses on the relevance of clinical benefit CB (CR
+ PR + SD > or = 6 months) in postmenopausal metastatic breast cancer (MBC)
patients treated with the steroidal aromatase inhibitor (SAI) formestane (FOR).
who had already received non-steroidal aromatase inhibitor (nSAI): letrozole
(LTZ) or anastrozole (ANZ). PATIENTS AND METHODS: Twenty postmenopausal women
with MBC were analysed in this retrospective two-centre study with the sequence
nSAI-FOR. When receiving ANZ, 1 of 11 achieved a complete response and 9 of 11 a
stable disease > or = 6 months, and receiving LTZ 1 of 9 achieved a partial
response and 4 of 9 a stable disease > or = 6 months. The analysis of the entire
population treated with FOR showed an overall CB of 55% (11 of 20) with a median
duration of 15 months and median time to progression (TTP) of 6 months.
CONCLUSIONS: Formestane 250 mg once bi-weekly seems to be an attractive
alternative third-line hormonal therapy for the treatment of patients with MBC,
previously treated with nSAI.
PMID: 11822752 [PubMed - in process]
40: Ann Oncol 2001 Nov;12(11):1527-32
Preoperative treatment of postmenopausal breast cancer patients with letrozole:
A randomized double-blind multicenter study.
Eiermann W, Paepke S, Appfelstaedt J, Llombart-Cussac A, Eremin J, Vinholes J,
Mauriac L, Ellis M, Lassus M, Chaudri-Ross HA, Dugan M, Borgs M; Letrozole
Neo-Adjuvant Breast Cancer Study Group.
Frauenklinik Vom, Roten Kreuz, Munich.
BACKGROUND: A randomized, double-blind, multicenter study was conducted to
compare the anti-tumor activity of letrozole vs. tamoxifen in postmenopausal
women with ER and/or PgR positive primary untreated breast cancer. PATIENTS AND
METHODS: Three hundred thirty-seven postmenopausal women with ER and/or PgR
positive primary untreated breast cancer were randomly assigned once daily
treatment with either letrozole 2.5 mg or tamoxifen 20 mg for four months. At
baseline none of the patients were considered to be candidates for
breast-conserving surgery (BCS) and 14% of the patients were considered
inoperable. The primary endpoint was to compare overall objective response (CR +
PR) determined by clinical palpation. Secondary endpoints included overall
objective response on ultrasound and mammography and the number of patients who
qualified for BCS. RESULTS: Overall objective response rate (clinical palpation)
was statistically significantly superior in the letrozole group, 55% compared to
tamoxifen, 36% (P < 0.001). Secondary endpoints of ultrasound response, 35% vs.
25% (P = 0.042), mammographic response, 34% vs. 16% (P < 0.001), and BCS, 45%
vs. 35% (P = 0.022) between the letrozole and tamoxifen groups, respectively,
showed letrozole to be significantly superior. Both treatments were well
tolerated. CONCLUSIONS: This study shows that letrozole is more effective than
tamoxifen as preoperative therapy in postmenopausal patients with ER and/or PgR
positive primary untreated breast cancer and is at least as well tolerated.
PMID: 11822750 [PubMed - in process]
41: J Clin Oncol 2002 Feb 1;20(3):876-8
Superior efficacy of letrozole versus tamoxifen as first-line therapy.
Buzdar AU.
Publication Types:
Letter
PMID: 11821477 [PubMed - indexed for MEDLINE]
42: J Clin Oncol 2002 Feb 1;20(3):751-7
Influence of letrozole and anastrozole on total body aromatization and plasma
estrogen levels in postmenopausal breast cancer patients evaluated in a
randomized, cross-over study.
Geisler J, Haynes B, Anker G, Dowsett M, Lonning PE.
Department of Oncology, Haukeland University Hospital, Bergen, Norway.
PURPOSE: To compare the effects of the two novel, potent, nonsteroidal aromatase
inhibitors anastrozole and letrozole on total-body aromatization and plasma
estrogen levels. PATIENTS AND METHODS: Twelve postmenopausal women with estrogen
receptor-positive, metastatic breast cancer were treated with anastrozole 1 mg
orally (PO) and letrozole 2.5 mg PO once daily, each given for a time interval
of 6 weeks in a randomized sequence. Total-body aromatization was determined
before treatment and at the end of each treatment period using a dual-label
isotopic technique involving isolation of the metabolites with high-performance
liquid chromatography. Plasma levels of estrone (E(1)), estradiol (E(2)), and
estrone sulfate (E(1)S) were determined in samples obtained before each
injection using highly sensitive radioimmunoassays. RESULTS: Pretreatment
aromatase levels ranged from 1.68% to 4.27%. On-treatment levels of aromatase
were detectable in 11 of 12 patients during treatment with anastrozole (mean
percentage inhibition in the whole group, 97.3%) but in none of the 12 patients
during treatment with letrozole (> 99.1% suppression in all patients; Wilcoxon,
P =.0022, comparing the two drug regimens). Treatment with anastrozole
suppressed plasma levels of E(1), E(2), and E(1)S by a mean of 81.0%, 84.9%, and
93.5%, respectively, whereas treatment with letrozole caused a corresponding
decrease of 84.3%, 87.8% and 98.0%, respectively. The suppression of E(1) and
E(1)S was found to be significantly better during treatment with letrozole
compared with anastrozole (P =.019 and.0037, respectively). CONCLUSION: This
study revealed letrozole (2.5 mg once daily) to be a more potent suppressor of
total-body aromatization and plasma estrogen levels compared with anastrozole (1
mg once daily) in postmenopausal women with metastatic breast cancer.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 11821457 [PubMed - indexed for MEDLINE]
43: Pharmacol Biochem Behav 2002 Jan-Feb;71(1-2):301-5
Reproductive changes in male rats treated perinatally with an aromatase
inhibitor.
Gerardin DC, Pereira OC.
Department of Pharmacology, Institute of Biosciences, Sao Paulo State University
18618-000 Botucatu, Sao Paulo, Brazil.
The effects of maternal exposure to aromatase inhibitor during the perinatal
period of sexual brain differentiation were studied. The fertility was assessed
in adult, male rat offspring of aromatase inhibitor-treated dams. The following
results were obtained: (1) Sexual maturation, body weight, and wet weights of
testis, pituitary, seminal vesicle, ventral prostate, and levatori ani muscle
were unchanged at adult life. (2) Fifty percent of the animals were able to mate
with normal females, which became pregnant but exhibited an increased number of
preimplantation loss. (3) There was a decrease in the number of spermatozoa
found in the testes and in the daily sperm production. (4) Of those, 25% of the
male rats treated with aromatase inhibitor did not present male sexual behavior,
showing female behavior when pretreated with estrogen. These results indicate
that perinatal exposure to aromatase inhibitor during the critical period of
male brain sexual differentiation has a long-term effect on the reproductive
physiology and behavior of male rats.
PMID: 11812536 [PubMed - indexed for MEDLINE]
44: Curr Opin Obstet Gynecol 2002 Feb;14(1):67-73
Current status and future innovations of hormonal agents, chemotherapy and
investigational agents in endometrial cancer.
Elit L, Hirte H.
Division of Gynecologic Oncology, MacMaster University, Hamilton, Ontario,
Canada. [email protected]
The median survival of women with advanced or recurrent endometrial cancer is
less than one year. Only half the women with early stage endometrial cancer and
poor prognostic factors such as high grade or deep myometrial invasion will
survive for 5 years. Over the past decade, incredible strides have been taken in
evaluating systemic therapy for this disease. However, survival rates remain
poor. A literature search was conducted using CANCERLIT, EMBASE, Medline,
Investigational Drug database (Current Drug Ltd.) and R&D Focus (IMSworld
Publications). The references of the articles were also explored. Search terms
included: endometrial cancer, chemotherapy, endocrine/hormonal therapies,
molecular biologics, and specific drug names. Progestin therapy offers a 10-20%
response rate and survival of less than 1 year. Progestins are most effective in
women with well-differentiated tumours and a long disease-free interval. There
is no role for adjuvant progestin therapy in early stage disease. Single-agent
chemotherapy with the most activity includes ifosfamide, cisplatin/carboplatin,
doxorubicin and paclitaxel. Combination chemotherapy provides a response rate of
40-60%; however, median survival is still less than a year. New areas of
research include the identification and evaluation of new active endocrine
therapies (i.e. LY353381.HCl and letrozole), chemotherapeutics (i.e. herceptin),
evaluating chemotherapeutic agents in combination (i.e. paclitaxel, doxorubicin
and platinum), in addition to radiation or instead of radiation. New avenues
under development involve the specific molecules and pathways responsible for
the initiation and growth of endometrial carcinoma, including: tumour suppressor
genes, DNA mismatch repair genes, oncogenes, molecules involved in adhesion and
invasion and angiogenesis. Further significant advances in radiotherapy,
hormonal therapy and chemotherapy are unlikely. Exciting developments in
understanding the molecules involved in tumour development and metastasis will
allow the development of specific and selective inhibitors.
Publication Types:
Review
Review, Tutorial
PMID: 11801879 [PubMed - indexed for MEDLINE]
45: US News World Rep 2001 Dec 24;131(26):52
New breast cancer drug.
Brink S.
Publication Types:
News
PMID: 11793594 [PubMed - indexed for MEDLINE]
46: Breast Cancer 2001;8(4):329-32
Aromatase and aromatase inhibitors.
Toi M, Bando H, Saji S.
Tokyo Metropolitan Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo
113, Japan. [email protected]
Aromatase inhibition provides both paracrine/intracrine and endocrine treatment.
Recent accumulated data clarified that 3rd generation aromatase inhibitors
potently suppress intratumoral estrogen synthesis particularly in postmenopausal
patients. In the 2nd-line treatment for metastatic breast cancer patients,
aromatase inhibitors achieved results antitumor activity at least equal to and
sometimes better than that of tamoxifen. In the first-line treatment for
metastatic breast cancer patients, a recent pivotal study clearly demonstrated
that aromatase inhibitor was superior to tamoxifen. Based upon these results,
various adjuvant trials which compare aromatase inhibitors with tamoxifen and
attempt to determine optimal combination therapies and treatment periods with
aromatase inhibitors are currently being conducted. In addition, preliminary
studies conducted in neoadjuvant setting indicated that aromatase inhibitors
showed an extremely high response rate, which predicts a future paradigm, that
neoadjuvant therapy using aromatase inhibitors singly or in combination may
become standard for hormone-responsive and post-menopausal breast cancer
patients.
Publication Types:
Review
Review, Tutorial
PMID: 11791126 [PubMed - indexed for MEDLINE]
47: Breast Cancer 2001;8(4):305-9
Third-generation aromatase inhibitors in the treatment of advanced breast
cancer.
Nabholtz JM, Reese DM.
Cancer Therapy Development Program and Jonsson Comprehensive Cancer Center,
University of California, Los Angeles, Peter Ueberroth Building 3360B, 10945 Le
Conte Avenue, Los Angeles, CA 90095-7077, USA. [email protected]
Publication Types:
Review
Review, Tutorial
PMID: 11791122 [PubMed - indexed for MEDLINE]
48: Vopr Onkol 2001;47(5):571-4
[Neoadjuvant use of the aromatase inhibitor letrozole in uterine cancer:
endocrine and clinical effects]
[Article in Russian]
Bershtein LM, Maksimov SIa, Gershfel'd ED, Gamaiunova VB, Tsyrlina EV, Meshkova
IE, Kovalenko IG, Larionov AA, Kovalevskii AIu, Vasil'ev DA.
N.N. Petrov Research Institute of Oncology, St. Petersburg, Russia.
Endometrial cancer (EC) is estrogen-dependent tumor in the hormonal treatment of
which mostly progestins are used. During last 5-7 years feasibility of aromatase
inhibitors use in EC is discussed without any special practical move in this
direction. To evaluate possible biological response of tumor and patients to
such treatment, we conducted a short pilot study involving 10 primary
postmenopausal EC patients, mostly stage Ia,b (average age 59) who received
letrozole (Femara, Novartis) 2.5 mg/day during 14 days before operation.
Clinical, sonographical, morphological, cytological and hormonal-metabolic
(blood estradiol, FSH, LH, glucose, lipid fractions by RIA or
enzyme-colorimetric methods; tumor progesterone receptors by LBA and aromatase
activity by 3H-water release assay) studies were included into the protocol
before and after treatment. Tolerability of letrozole was satisfactory in all
patients. 2 patients reported decrease of pain and pathological secretions from
uterine cavity. In 3 patients, decrease in M-sonographical endometrial signal
was registered; average value after treatment was 31.1% lower than before it.
Tendency to the decrease in estrogenicity of vaginal smears was revealed.
Average decrease in blood estradiol was 37.8% and in progesterone receptor level
and aromatase activity 34.4% and 17.5% respectively. Decrease of aromatase
activity in tumor tissue was registered mostly in normal weight patients. A more
detailed and longer randomized study of aromatase inhibitors in EC performed in
neoadjuvant setting deserves consideration.
PMID: 11785098 [PubMed - indexed for MEDLINE]
49: J Bone Miner Res 2002 Jan;17(1):172-8
Role of low levels of endogenous estrogen in regulation of bone resorption in
late postmenopausal women.
Heshmati HM, Khosla S, Robins SP, O'Fallon WM, Melton LJ 3rd, Riggs BL.
Division of Endocrinology and Metabolism, Mayo Clinic and Mayo Foundation,
Rochester, Minnesota 55905, USA.
Although median levels of bone turnover are increased in postmenopausal women,
it is unclear whether the low circulating levels of endogenous estrogen exert a
regulatory role on these levels. This issue was evaluated by assessing the
effect of a blockade of estrogen synthesis on bone turnover markers in 42 normal
women (mean age +/- SD, 69 +/- 5 years) randomly assigned to groups receiving
the potent aromatase inhibitor letrozole or placebo for 6 months. Letrozole
treatment reduced serum estrone (E1) and estradiol (E2) to near undetectable
levels (p < 0.0001). This treatment did not affect bone formation markers but,
as compared with the placebo group, increased bone resorption markers (urine
24-h pyridinoline [PYD] by 13.3% [p < 0.05] and 24-h urine deoxypyridinoline
[DPD] by 14.2% [p < 0.05]) and decreased serum parathyroid hormone (PTH) by 22%
(p = 0.002). These data indicate that in late postmenopausal women even the low
serum estrogen levels present exert a restraining effect on bone turnover and
support the concept that variations in these low levels may contribute to
differences in their rate of bone loss.
PMID: 11771665 [PubMed - in process]
50: Biopharm Drug Dispos 2001 Jul;22(5):191-7
Effect of age and single versus multiple dose pharmacokinetics of letrozole
(Femara) in breast cancer patients.
Pfister CU, Martoni A, Zamagni C, Lelli G, De Braud F, Souppart C, Duval M,
Hornberger U.
Novartis Pharma AG, Basel, Switzerland. [email protected]
Letrozole (trademark Femara) is a new orally active, potent and selective
aromatase inhibitor for the hormonal treatment of advanced breast cancer in
postmenopausal women. The pharmacokinetics of letrozole and the suppression of
peripheral estrogens were studied in 28 breast cancer patients after a single
dose and at steady state. The pharmacokinetics of two distinct age groups (> or
=50, < or =65, N=15 and > or =70 years old, N=9) were compared. There were no
significant differences in area under the curve (AUC) or terminal half-life
between the two age groups neither after a single dose nor at steady state.
However, when comparing steady state to single dose kinetics, half-life and AUC
increased significantly by 42% (90% CI: 1.13, 1.78) and 28% (90% CI: 1.12,
1.47), respectively. This deviation from linearity was probably due to a partial
saturation or auto-inhibition of the dominant metabolic clearance mechanism of
letrozole. At steady state, approximately 70% of the administered dose was
excreted in urine as unchanged letrozole (6.0+/-3.8%) or as the glucuronide of
the major, pharmacologically inactive metabolite CGP44645 (64.2+/-22.7%). A
single dose of letrozole caused suppression of serum estrogen levels close to
the quantification limit of the assay. No difference between single dose
suppression and suppression at steady state could be detected. Copyright 2001
John Wiley & Sons, Ltd.
Publication Types:
Clinical Trial
Clinical Trial, Phase II
Multicenter Study
PMID: 11745921 [PubMed - indexed for MEDLINE]
51: Surgery 2001 Dec;130(6):947-53
High dehydroepiandrosterone-sulfate predicts breast cancer progression during
new aromatase inhibitor therapy and stimulates breast cancer cell growth in
tissue culture: a renewed role for adrenalectomy.
Morris KT, Toth-Fejel S, Schmidt J, Fletcher WS, Pommier RF.
Department of Surgery, Section of Surgical Oncology, Oregon Health Sciences
University, Portland, OR 97201, USA.
BACKGROUND: Stage IV hormone-sensitive breast cancer is often treated with
aromatase inhibitors (anastrozole, letrozole, exemestane), which block the
conversion of dehydroepiandrosterone (DHEA) to estrone and estradiol. This is
intended to obviate the need for steroid replacement and antiquate
adrenalectomy. METHODS: Patients who underwent oophorectomy and were being
treated with new aromatase inhibitor therapy received serial measurements of
serum estrone, estradiol, and DHEA-sulfate (DHEA-S). Steroid values during
responsive and progressive phases of disease were compared. In vitro, human
breast cancer cell lines T-47D (estrogen-receptor and progesterone-receptor
positive) and HCC 1937 (estrogen-receptor and progesterone-receptor negative)
were treated with DHEA-S. Proliferation rates were measured by colorimetric
assay. RESULTS: Disease in 12 of the 19 patients progressed. DHEA-S was less
than 89 microg/dL in patients during the responsive phase and more than or equal
to 89 microg/dL during disease progression, with 1 exception (P < .0005).
Estrone and estradiol remained suppressed. After disease progression, the
condition of 9 patients stabilized with aminoglutethimide therapy (n = 8) or
adrenalectomy (n = 1), and their DHEA-S levels were reduced to less than 89
microg/dL. In vitro, elevated DHEA-S induced cell proliferation in T-47D cells.
CONCLUSIONS: DHEA-S levels more than or equal to 89 microg/dL predicted disease
progression in states of low estrogen. Tissue culture results supported the role
of DHEA-S as an estrogenic agent. Oophorectomies with either aminoglutethimide
therapy or adrenalectomy were effective remedies for breast cancer progression
due to high DHEA-S.
PMID: 11742322 [PubMed - indexed for MEDLINE]
52: J Clin Oncol 2001 Dec 1;19(23):4353
False shortening of time to progression in letrozole 2.5-mg dose?
Cocconi G.
Publication Types:
Letter
PMID: 11731525 [PubMed - indexed for MEDLINE]
53: J Clin Oncol 2001 Dec 1;19(23):4353-5
Letrozole in second-line therapy of advanced breast cancer: more questions than
answers.
Mackey JR, Joy AA.
Publication Types:
Letter
PMID: 11731524 [PubMed - indexed for MEDLINE]
54: Clin Ter 2001 Jul-Aug;152(4):263-5
Huge response to letrozole in inoperable T4 breast cancer: a case report.
Di Cosimo S, Altomare V, Ferretti G, Gravante G, Rabitti C, Rea F, Arullani A,
D'Aprile M.
Breast Cancer Unit, University Campus Bio-Medico, Rome, Italy.
[email protected]
A 73 years-old woman presented with locally advanced breast cancer (cT4b cN1 M0,
stage IIIB) and atrial flutter. Because of the arrhythmia, chemotherapy or
tamoxifen, although malignancy was hormone-sensitive, were discarded. Letrozole
was started. Two months later, the breast nodule and skin ulceration cleared up.
Surgery was performed. Nowadays, 24 months later, patient does fine, continuing
letrozole as adjuvant treatment.
PMID: 11725620 [PubMed - in process]
55: Prescrire Int 2001 Aug;10(54):108-9
Exemestane: new preparation. No tangible advance in metastatic breast cancer
after tamoxifen failure.
(1) The reference second-line hormone treatment for breast cancer in
postmenopausal women, after failure of anti-oestrogen therapy, is an aromatase
inhibitor such as letrozole. (2) The clinical assessment file on exemestane, a
new aromatase inhibitor licensed for this indication, contains no data from
clinical trials versus letrozole or anastrozole, the other oral aromatase
inhibitors. Data from non comparative trials fail to show whether
cross-resistance between aromatase inhibitors exists. (3) In a double-blind
trial involving 769 patients in whom tamoxifen had failed, the antitumour effect
of exemestane appeared to be equivalent to that of the progestagen megestrol.
(4) This trial showed that the adverse effect profile of exemestane was similar
to that of other aromatase inhibitors, with mainly vasomotor flushes, nausea,
fatigue and sweating. (5) In practice, the arrival of exemestane changes nothing
in the hormone therapy of breast cancer in postmenopausal women, which should
consist of tamoxifen (an anti-oestrogen) first; followed by the aromatase
inhibitor letrozole if tamoxifen fails.
PMID: 11718178 [PubMed - indexed for MEDLINE]
56: Cancer Chemother Pharmacol 2001 Oct;48(4):259-65
Role of anti-aromatase agents in postmenopausal advanced breast cancer.
Murray R.
Peter MacCallum Cancer Institute, St Andrew's Place, East Melbourne, Australia.
[email protected]
PURPOSE: Endocrine therapy is a well-recognized approach to the treatment of
postmenopausal patients with advanced breast cancer, particularly those with
estrogen receptor-positive tumors. The availability of anti-aromatase agents,
both reversible (nonsteroidal) and irreversible (steroidal), provides clinicians
with additional hormonal treatment options. METHODS: A MEDLINE search was
conducted to identify studies that evaluated anti-aromatase therapy in the
treatment of postmenopausal women with advanced breast cancer. In selecting
studies, priority was given to randomized, controlled trials. RESULTS: Tamoxifen
is the standard first-line therapy for advanced breast cancer. However, recent
results have demonstrated the efficacy of newer anti-aromatase agents in this
setting. Among patients who have progressed after tamoxifen therapy,
anti-aromatase agents have emerged as first choice therapy based on their better
tolerability and improved efficacy compared with megestrol acetate. Exemestane
and anastrozole (irreversible and reversible anti-aromatase agents,
respectively) have demonstrated survival benefits over megestrol acetate in
second-line therapy. Anti-aromatase agents have also demonstrated efficacy in
patients who have failed multiple hormonal therapies. Based on these data, an
algorithm for the treatment of postmenopausal women with advanced breast cancer
is proposed. CONCLUSIONS: The enhanced tolerability and superior efficacy of
anti-aromatase inhibitors compared with megestrol acetate has resulted in these
agents becoming the endocrine treatment of choice for women with advanced breast
cancer who have progressed after tamoxifen treatment. The increased use of
tamoxifen in the adjuvant setting and the demonstrated activity of aromatase
inhibitors in first-line therapy will further increase the role of these agents.
Publication Types:
Review
Review, Tutorial
PMID: 11710624 [PubMed - indexed for MEDLINE]
57: Vopr Onkol 2001;47(4):425-7
[Interrelationship between response to neoadjuvant hormone therapy and
hormonal-metabolic status in breast cancer patients]
[Article in Russian]
Semiglazov VF, Ivanov VG, Gamaiunova VB, Zhil'tsova EK, Tsyrlina EV, Kovalenko
IG, Bershtein LM.
N.N. Petrov Research Institute of Oncology, Ministry of Health of the RF, St.
Petersburg.
Twenty seven breast cancer patients with receptor-positive tumors stage IIb-IIIa
(TNM) were treated with an aromatase inhibitor--letrozole, 2.5 mg/day, or an
antiestrogen--tamoxifen, 20 mg/day, 4 months before surgery. Complete or partial
response (CP + PR) was recorded in patients older than those with stabilization
or progression of the disease. Moreover, the former group tended to show higher
of suppression of blood-estradiol and progesterone receptors levels in tumor and
lower suppression of serum-FSH concentration after treatment. These,
practically, first findings of the kind suggest that the search for hormonal
markers to predict the efficiency of neoadjuvant hormonal therapy for breast
cancer should be continued.
PMID: 11710283 [PubMed - indexed for MEDLINE]
58: Lancet 2001 Oct 27;358(9291):1459-60
Role of hormones in puberty.
Cianfarani S.
Publication Types:
Letter
PMID: 11705526 [PubMed - indexed for MEDLINE]
59: Ann Ital Med Int 2001 Apr-Jun;16(2):112-7
Flare and tumor lysis syndrome with atypical features after letrozole therapy in
advanced breast cancer. A case report.
Zigrossi P, Brustia M, Bobbio F, Campanini M.
U.O.A. Medicina Generale II, Azienda Ospedaliera Maggiore della Carita di
Novara.
Tumor lysis syndrome, which develops after effective therapy of malignant
conditions and leads to hyperuricemia, hyperkaliemia, hyperphosphatemia,
hypocalcemia and elevated lactate dehydrogenase, is uncommon in solid tumors. In
breast carcinoma it can be associated with tamoxifen flare, i.e. a transient
increase in symptoms, mainly bone pain, observed shortly after the start of
tamoxifen therapy. We report the case of a patient with advanced breast
carcinoma involving the pleural space, unresponsive to combined chemotherapy,
who experienced rapid worsening after the initiation of letrozole. Her symptoms
included shock, bilateral pleural effusion, cardiac tamponade and oliguria.
Laboratory parameters disclosed elevated transaminase, lactate dehydrogenase,
uric acid and D-dimer blood levels. The patient was in critical condition for
nearly 2 weeks. She improved progressively and has remained well and in complete
remission for 20 months. This clinical picture suggests increased damage to the
pleura (and probably the pericardium) and rapid leakage of tumor products,
following the start of endocrine therapy. Letrozole is a non-steroidal aromatase
inhibitor which is used in advanced breast cancer, resistant to first-line
endocrine/chemotherapeutic treatment. Our review of the literature did not
disclose any other descriptions of flare and tumor lysis syndrome after
aromatase inhibitor therapy. Moreover, this case was characterized by atypical
and complex clinical features. The aim of this presentation is to point out the
practical significance, in neoplastic patients, of the differential diagnosis
between symptoms due to tumor progression and those associated with anomalous
reactions to therapy.
PMID: 11688358 [PubMed - in process]
60: BMJ 2001 Oct 20;323(7318):880-1
Aromatase inhibitors and inactivators in breast cancer.
Lonning PE.
Publication Types:
Editorial
PMID: 11668120 [PubMed - indexed for MEDLINE]
61: J Clin Endocrinol Metab 2001 Oct;86(10):4887-94
Inhibition of P450 aromatase enhances gonadotropin secretion in early and
midpubertal boys: evidence for a pituitary site of action of endogenous E.
Wickman S, Dunkel L.
University of Helsinki, Hospital for Children and Adolescents, FIN-00029
Helsinki, Finland. [email protected]
In early pubertal boys, E concentrations are very low. We studied the role and
site of action of endogenous E in the regulation of gonadotropin secretion in
early and midpubertal boys by inhibiting the action of E with a potent and
specific P450 aromatase inhibitor, letrozole. A total of 35 boys who were
referred to us because of suspicion of delayed puberty were included in the
study. The boys were in either early or midpuberty, and they composed 3 groups:
10 boys did not receive any treatment, 12 boys received T alone, and 13 boys
received T and letrozole. In the untreated group during the 5-month follow-up,
no changes were observed in 17beta-E2, T, basal gonadotropin, or inhibin B
concentrations or in the GnRH-induced gonadotropin responses. In the T-treated
group during the 5-month treatment, the T concentration increased by 55% (P <
0.05), and the 17beta-E2 concentration increased by 130% (P < 0.02).
Concurrently, basal gonadotropin concentrations were suppressed, but the
GnRH-induced gonadotropin responses and the inhibin B concentration remained
unchanged. In the T- plus letrozole-treated group during the 5-month treatment,
an increase in T concentration of 606% was observed (P < 0.001), but the
17beta-E2 concentration remained unchanged. The changes in the 17beta-E2
concentration within 5 months in the untreated and the T- plus letrozole-treated
groups were different (P < 0.02), indicating significant inhibition of
endogenous E synthesis during letrozole treatment. During the T plus letrozole
treatment, basal gonadotropin concentration, the GnRH-induced LH response, and
inhibin B concentration increased, and the GnRH-induced FSH response did not
change significantly. Serum nocturnal gonadotropin pulses were determined in 5
boys treated with T and in 5 boys treated with T plus letrozole. In the T- plus
letrozole-treated group, the nocturnal LH pulse amplitude increased, and the LH
pulse frequency and interpulse interval remained unchanged. In conclusion, in
early and midpubertal boys, suppression of the action of E by the P450 aromatase
inhibitor increased LH concentration, LH pulse amplitude, and the GnRH-induced
LH response, which indicates that in boys during early and midpuberty,
endogenous E regulates LH secretion at the site of the pituitary.
PMID: 11600558 [PubMed - indexed for MEDLINE]
62: J Clin Oncol 2001 Oct 1;19(19):3999-4000
Aromatase inhibitors: treatment of advanced breast cancer.
Panasci LC.
Publication Types:
Letter
PMID: 11579125 [PubMed - indexed for MEDLINE]
63: Prostaglandins Other Lipid Mediat 2001 Oct;66(3):155-63
Developmental maturation of primate placental trophoblast: placental cytosolic
and secretory phospholipase A2 expression after estrogen suppression of baboons.
Rosenthal MD, Albrecht ED, Pepe GJ.
Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk
23507, USA.
We have demonstrated that the baboon placenta expressed the mRNAs and proteins
for secretory and cytosolic phospholipase A2 (PLA2) enzymes and that cPLA2
expression increased with advancing gestation in association with the increase
in placental estrogen production. To determine whether estrogen regulates
placental PLA2 expression, as it does other aspects of syncytiotrophoblast
functional differentiation, we compared sPLA2 and cPLA2 mRNA levels in placentas
obtained on day 165 of gestation (term = day 184) from baboons that were
untreated or treated during the second half of gestation with the aromatase
inhibitor CGS 20267 or CGS 20267 and estradiol. Maternal saphenous and uterine
vein estradiol levels were reduced (P < 0.05) by approximately 95% by treatment
with CGS 20267 and restored by concomitant administration of CGS 20267 and
estrogen. However, sPLA2 and cPLA2 mRNA levels expressed as a ratio of
beta-actin were similar in whole villous placenta from baboons that were
untreated or treated with CGS 20267 or CGS 20267 plus estrogen. PLA2 expression
in an enriched fraction of nontrophoblast cells of the baboon placenta was also
not altered by CGS 20267 treatment. Collectively these findings indicate that
placental cPLA2 and sPLA2 expression is not estrogen-dependent. Because estrogen
has been shown to regulate other aspects of placental steroidogenesis, we
suggest that the regulatory role of estrogen on syncytiotrophoblast functional
maturation is specific.
PMID: 11577780 [PubMed - indexed for MEDLINE]
64: J Clin Oncol 2001 Sep 15;19(18):3808-16
Comment in:
J Clin Oncol. 2001 Sep 15;19(18):3795-7.
Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for
ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast
cancer: evidence from a phase III randomized trial.
Ellis MJ, Coop A, Singh B, Mauriac L, Llombert-Cussac A, Janicke F, Miller WR,
Evans DB, Dugan M, Brady C, Quebe-Fehling E, Borgs M.
Duke University Breast Cancer Program, Duke University Comprehensive Cancer
Center, Durham, NC 27710, USA. [email protected]
PURPOSE: Expression of ErbB-1 and ErbB-2 (epidermal growth factor receptor and
HER2/neu) in breast cancer may cause tamoxifen resistance, but not all studies
concur. Additionally, the relationship between ErbB-1 and ErbB-2 expression and
response to selective aromatase inhibitors is unknown. A neoadjuvant study for
primary breast cancer that randomized treatment between letrozole and tamoxifen
provided a context within which these issues could be addressed prospectively.
PATIENTS AND METHODS: Postmenopausal patients with estrogen- and/or progesterone
receptor-positive (ER+ and/or PgR+) primary breast cancer ineligible for
breast-conserving surgery were randomly assigned to 4 months of neoadjuvant
letrozole 2.5 mg daily or tamoxifen 20 mg daily in a double-blinded study.
Immunohistochemistry (IHC) for ER and PgR was conducted on pretreatment biopsies
and assessed by the Allred score. ErbB-1 and ErbB-2 IHC were assessed by
intensity and completeness of membranous staining according to published
criteria. RESULTS: For study biopsy-confirmed ER+ and/or PgR+ cases that
received letrozole, 60% responded and 48% underwent successful breast-conserving
surgery. The response to tamoxifen was inferior (41%, P =.004), and fewer
patients underwent breast conservation (36%, P =.036). Differences in response
rates between letrozole and tamoxifen were most marked for tumors that were
positive for ErbB-1 and/or ErbB-2 and ER (88% v 21%, P =.0004). CONCLUSION: ER+,
ErbB-1+, and/or ErbB-2+ primary breast cancer responded well to letrozole, but
responses to tamoxifen were infrequent. This suggests that ErbB-1 and ErbB-2
signaling through ER is ligand-dependent and that the growth-promoting effects
of these receptor tyrosine kinases on ER+ breast cancer can be inhibited by
potent estrogen deprivation therapy.
Publication Types:
Clinical Trial
Clinical Trial, Phase III
Randomized Controlled Trial
PMID: 11559718 [PubMed - indexed for MEDLINE]
65: J Clin Oncol 2001 Sep 15;19(18):3795-7
Comment on:
J Clin Oncol. 2001 Sep 15;19(18):3808-16.
Use of ErbB-1 and ErbB-2 to select endocrine therapy for breast cancer: will it
play in Peoria?
Pritchard KI.
Publication Types:
Comment
Editorial
PMID: 11559715 [PubMed - indexed for MEDLINE]
66: J Exp Zool 2001 Sep 15;290(5):490-7
Sex reversal and aromatase in the European pond turtle: treatment with letrozole
after the thermosensitive period for sex determination.
Belaid B, Richard-Mercier N, Pieau C, Dorizzi M.
Institut Jacques Monod, C.N.R.S. et Universites Paris 6 et 7, 75251 Paris,
France.
In the European pond turtle (Emys orbicularis), gonadal sex differentiation is
temperature-dependent. The temperature sensitive period (TSP) of gonadogenesis
lies between stages 16 and 22 of embryonic development. Previous studies have
shown that embryos incubated at 30 degrees C, a temperature yielding 100%
phenotypic females, can be sex reversed by treatments with an aromatase
inhibitor administered during TSP or even somewhat after TSP (as of stage 22+).
The goal of the present study was to determine whether the ovary still retains
male potential at later stages of embryonic development and whether the induced
male characters persist after hatching. For this purpose, eggs of E. orbicularis
were treated with letrozole, a nonsteroidal aromatase inhibitor, at or as of
stages 23, 24 or 25, then gonadal aromatase activity in each individual and the
related gonadal structure were studied at hatching (stage 26) and for one year
after hatching. Two kinds of treatments were carried out: 1) repeated
applications of 10 microg of letrozole in ethanolic solution onto the eggshell;
and 2) a single injection of 10 microg of letrozole in olive oil. Similar
results were obtained with either application or injection of the aromatase
inhibitor. In treatments as of or at stage 23, individuals with gonadal
aromatase activity lower than 20 fmoles/hour/gonad had ovotestes, i.e., 22% of
the treated individuals. At hatching, the inner part of these ovotestes
contained testicular cords and also mixed lacunae presenting various degrees of
transdifferentiation of the epithelium into a Sertolian epithelium. The cortex
was maintained, although some germ cells degenerated within it. These processes
continued after hatching. However, at 12 months, gonads were still ovotestes
displaying some follicles with a growing oocyte in the remaining parts of the
cortex. In treatments as of or at stages 24 or 25, only a few individuals were
masculinized. One had ovotestes; in others, the cortex was absent in some parts
and when it was present oocytes were degenerating. These results show that in
the European pond turtle, differentiation of ovotestes from ovaries can be
induced by treatment with an aromatase inhibitor starting at late stages of
embryonic development (between the end of TSP and hatching), although such
differentiation is less frequent as embryonic development proceeds. Sex reversal
persists for at least one year after hatching. J. Exp. Zool. 290:490-497, 2001.
Copyright 2001 Wiley-Liss, Inc.
PMID: 11555856 [PubMed - indexed for MEDLINE]
67: Clin Cancer Res 2001 Sep;7(9):2620-35
Advances in aromatase inhibition: clinical efficacy and tolerability in the
treatment of breast cancer.
Buzdar A, Howell A.
Department of Breast Medical Oncology, M. D., Anderson Cancer Center, University
of Texas, Houston, 77030, USA.
Publication Types:
Review
Review, Tutorial
PMID: 11555572 [PubMed - indexed for MEDLINE]
68: Am J Ther 2001 Sep-Oct;8(5):333-44
Aromatase, aromatase inhibitors, and breast cancer.
Brueggemeier RW.
Medicinal Chemistry and Pharmacognosy, College of Pharmacy, and Hormones and
Cancer Program, Comprehensive Cancer Center, The Ohio State University,
Columbus, OH 43210, USA. [email protected]
Estrogens are involved in numerous physiologic processes and have crucial roles
in particular disease states, such as mammary carcinomas. Estradiol, the most
potent endogenous estrogen, is biosynthesized from androgens by the cytochrome
P-450 enzyme complex called aromatase. Aromatase is found in breast tissue, and
the importance of intratumoral aromatase and local estrogen production is being
unraveled. Inhibition of aromatase is an important approach for reducing growth
stimulatory effects of estrogens in hormone-dependent breast cancer. Effective
aromatase inhibitors have been developed as therapeutic agents for controlling
estrogen-dependent breast cancer. Investigations into the development of
aromatase inhibitors began in the 1970s and have expanded greatly in the past
three decades. Competitive aromatase inhibitors are molecules that compete with
the substrate androstenedione for noncovalent binding to the active site of the
enzyme to decrease the amount of product formed. Steroidal inhibitors that have
been developed to date build on the basic androstenedione nucleus and
incorporate chemical substituents at varying positions on the steroid. The
structure-activity relationships for steroidal inhibitors have become more
refined in the past decade, and only some modifications can be made to the
steroid and still keep its affinity for aromatase. Nonsteroidal aromatase
inhibitors can be divided into three classes: aminoglutethimide-like molecules,
imidazole/triazole derivatives, and flavonoid analogs. Mechanism-based aromatase
inhibitors are inhibitors that mimic the substrate, are converted by the enzyme
to a reactive intermediate, and result in the inactivation of aromatase.
Aromatase inhibitors, both steroidal and nonsteroidal, have shown clinical
efficacy for the treatment of breast cancer. The initial nonselective nature of
nonsteroidal inhibitors such as aminoglutethimide has been greatly reduced in
the later generations of inhibitors, anastrozole and letrozole. Mechanism-based
steroidal inhibitors such as 4-hydroxyandrostenedione and exemestane produce
prolonged aromatase inhibition in patients. The potent and selective
third-generation aromatase inhibitors anastrozole, letrozole, and exemestane are
approved for clinical use as second-line endocrine therapy in postmenopausal
patients failing antiestrogen therapy alone or multiple hormonal therapies.
Publication Types:
Review
Review, Tutorial
PMID: 11550075 [PubMed - indexed for MEDLINE]
69: Oncology (Huntingt) 2001 Aug;15(8):965-72; discussion 972, 977-9
Nonsteroidal and steroidal aromatase inhibitors in breast cancer.
Hamilton A, Volm M.
Kaplan Comprehensive Cancer Center, New York University, School of Medicine, New
York 10016, USA. [email protected]
Anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are
members of the third generation of aromatase inhibitors that has now replaced
aminoglutethimide (Cytadren), the progestins, and tamoxifen (Nolvadex) as the
hormonal therapy of choice in estrogen-receptor-positive, postmenopausal,
metastatic breast cancer. This article will review the role of aromatase in the
pathogenesis of breast cancer and the results of recent studies that have
established the role of its inhibitors in estrogen-receptor-positive breast
cancer. We will also briefly outline the rationale and design of ongoing
studies.
Publication Types:
Review
Review Literature
PMID: 11548977 [PubMed - indexed for MEDLINE]
70: Gynecol Oncol 2001 Aug;82(2):384-8
Endometrial stromal sarcoma: objective response to letrozole.
Maluf FC, Sabbatini P, Schwartz L, Xia J, Aghajanian C.
The Developmental Chemotherapy Service, Department of Medicine, Memorial
Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
BACKGROUND: Low-grade endometrial stromal sarcoma is generally an indolent tumor
rich in estrogen and progesterone receptors. Objective responses to hormonal
therapy, most commonly with megestrol acetate, have been reported. CASE: The
patient is a 51-year-old woman who presented with low-grade endometrial stromal
sarcoma confined to the uterus in 1991 and was treated with total abdominal
hysterectomy and bilateral salpingo-oophorectomy. Approximately 5 years later,
the patient had recurrent pelvic disease treated with radiation therapy,
followed by an attempt at resection. She was treated with megestrol acetate
during the period she received radiation therapy with poor tolerance. Tamoxifen
was then given with no tumor response. Megestrol acetate was restarted with
progression of disease in the pelvis and abdomen. Letrozole was then given at a
daily dose of 2.5 mg with partial response for a duration of 9 months.
CONCLUSION: Letrozole at a daily dose of 2.5 mg may be effective in low-grade
endometrial stromal sarcoma with positive estrogen receptors. Copyright 2001
Academic Press.
PMID: 11531300 [PubMed - indexed for MEDLINE]
71: Breast Cancer Res Treat 2001 Apr;66(3):191-9
Letrozole as primary medical therapy for locally advanced and large operable
breast cancer.
Dixon JM, Love CD, Bellamy CO, Cameron DA, Leonard RC, Smith H, Miller WR.
Edinburgh Breast Unit, Western General Hospital. [email protected]
AIMS: To investigate the efficacy of letrozole 2.5 mg and 10 mg used as primary
neoadjuvant therapy for patients with locally advanced and large operable breast
cancer. PATIENTS AND METHODS: Twenty-four postmenopausal patients with locally
advanced or large operable breast cancer were treated in two consecutive series
with letrozole 2.5 mg (n = 12) or letrozole 10 mg (n = 12). Response at three
months was measured by change in tumor volume according to WHO criteria (partial
response was defined as a reduction in tumor volume > or = 65%). Tumor volumes
were assessed clinically, by ultrasound and mammography, and pathologically.
RESULTS: All 24 patients were estrogen receptor-positive, were considered
'receptor-rich', and mean age was 77.6 years and 71.6 years in the letrozole 2.5
mg and 10 mg treatment groups, respectively. There were five complete clinical
responses and seven partial clinical responses in the patients treated with 2.5
mg letrozole, and nine partial responses and three patients with stable disease
in patients treated with 10 mg letrozole. Assessed by ultrasound and
mammography, the 12 patients treated with 2.5 mg had one complete response, nine
partial responses and two with no change. In the 12 patients treated with 10 mg
letrozole, imaging gave eight partial responses and four with no change. One
patient treated with the 2.5 mg dose had a complete clinical and pathological
response. There was no significant difference between the two doses in effect on
tumor volume, and no recordable side effects associated with either dose.
CONCLUSION: Letrozole used in a neoadjuvant setting is highly effective,
producing clinically beneficial reductions in tumor volume allowing all patients
to have breast conserving surgery, and has an acceptable safety profile.
Publication Types:
Clinical Trial
PMID: 11510690 [PubMed - indexed for MEDLINE]
72: Eur J Cancer 2001 Aug;37(12):1510-3
Effect of letrozole on the lipid profile in postmenopausal women with breast
cancer.
Elisaf MS, Bairaktari ET, Nicolaides C, Kakaidi B, Tzallas CS, Katsaraki A,
Pavlidis NA.
Department of Internal Medicine, Medical School, University of Ioannina, GR 451
10 Ioannina, Greece. [email protected]
Hormonal therapy plays a central role in the overall treatment of breast cancer.
Aromatase inhibitors can inhibit the aromatase enzyme system resulting in a
reduction of oestrogens. Letrozole is a non-steroidal aromatase inhibitor that
effectively blocks aromatase activity without interfering with adrenal steroid
biosynthesis. The drug can significantly reduce the levels of plasma oestrogens,
which remain suppressed throughout the treatment. Data are scarce concerning the
influence of these drugs on serum lipid levels. In the present study, we
evaluated the effects of letrozole on the serum lipid profile in postmenopausal
women with breast cancer. A total of 20 patients with breast cancer were treated
with letrozole, 2.5 mg once daily. After an overnight fast, serum lipid
parameters (total cholesterol, high density lipoprotein (HDL) cholesterol, low
density lipoprotein (LDL) cholesterol, triglycerides, apolipoproteins A1, B and
E and lipoprotein (a)) were measured before treatment and at 8 and 16 weeks
afterwards. A significant increase in total cholesterol (P=0.05), LDL
cholesterol (P<0.01) and apolipoprotein B levels (P=0.05) in the serum, as well
as in the atherogenic risk ratios total cholesterol/HDL cholesterol (P<0.005)
and LDL cholesterol/HDL cholesterol (P<0.005) was noticed after letrozole
treatment. We conclude that letrozole administration in postmenopausal women
with breast cancer has an unfavourable effect on the serum lipid profile.
PMID: 11506958 [PubMed - indexed for MEDLINE]
73: Acta Pharmacol Sin 2000 Aug;21(8):680-4
Gender difference in letrozole pharmacokinetics in rats.
Liu XD, Xie L, Zhong Y, Li CX.
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University,
Nanjing 210009, China. [email protected]
AIM: To study gender difference in letrozole (Letr) pharmacokinetics in rats.
METHODS: Letr concentrations in plasma and tissues were determined after ig
administration of Letr 2 mg/kg. Recoveries of Letr in urine and feces were also
analyzed. RESULTS: Marked gender differences were found 6 h after ig Letr 2
mg/kg, the plasma concentrations of Letr in male rats were significantly (P <
0.01) lower than those in female rats. For example, at 24, 36, 48, and 72 h
after administration, plasma concentrations in female rats were about 3.3, 5.6,
10.5, and 7.4-fold of that of male rats, respectively. AUC value of Letr in male
was only about one-third of that in female rats. Estimated terminal phase
half-lives (T1/2) were 10.5 and 40.4 h, respectively. In female rats, cumulative
excreted fractions of Letr in urine and feces were 5.8% +/- 1.4% and 6.6% +/-
1.1% within 120 h after administration, respectively, but in male rats, the
excreted fractions of Letr in urine and feces were only 1.30% +/- 0.59% and
0.87% +/- 0.31%. Letr concentrations in female rat tissues were significantly (P
< 0.01) higher than those in male rat tissues 24 h after administration.
CONCLUSION: There are marked gender differences in Letr pharmacokinetics in
rats.
PMID: 11501174 [PubMed - indexed for MEDLINE]
74: Gan To Kagaku Ryoho 2001 Jul;28(7):909-16
[Endocrine therapy for advanced or recurrent breast cancer]
[Article in Japanese]
Sonoo H, Kurebayashi J.
Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577
Matsushima, Kurashiki 701-0192, Japan.
Endocrine therapy of advanced or recurrent breast cancer was described. The
presence of ER or PgR in primary breast tumors is the best-established marker
for response to endocrine therapy. However, ER-positive breast tumors
overexpressing EGF-R and/or HER-2 (Erb B2) are resistant to endocrine therapy.
Recently it was suggested that an elevated level of the circulating
extracellular domain of HER-2 could be a predictor for poor response to
endocrine therapy. LH-RH agonist is used as a first-line therapy for
premenopausal patients. And LH-RH agonist plus tamoxifen (TAM) has shown a
higher response rate and more prolonged survival than LH-RH agonist or TAM
alone. As two new aromatase inhibitors, anastrozole (ANA) and letrozole, have
shown an equal or higher response rate and a prolonged time to progression than
TAM as a first-line therapy, these could be used as a first-line therapy instead
of TAM. In a cross-over trial of ANA and TAM, the response rate of ANA after TAM
failure was equal to that of TAM after ANA failure. As these drugs showed an
equal or higher response rate and longer survival than progestin in TAM
resistant cases, these drugs could also used as a second-line therapy. In
addition, the trend of recent studies regarding the mechanisms of hormone
resistance is also described.
Publication Types:
Review
Review, Tutorial
PMID: 11478139 [PubMed - indexed for MEDLINE]
75: Gan To Kagaku Ryoho 2001 Jul;28(7):892-901
[Developments of hormonal agents for breast cancer]
[Article in Japanese]
Tominaga T.
Breast Cancer Center Toyosu Hospital, Showa University School of Medicine,
4-1-18 Toyosu, Koto-ku, Tokyo 135-8577, Japan.
Endocrine therapy for breast cancer, which began with ovariectomy, has a history
of more than 100 years. Tamoxifen has been an epoch-making drug during the late
20th century. Recently LHRH analogues which work as downregulators of estrogen
production and many aromatase inhibitors (AI), both non-steroidal and steroidal
have been developed in Japan. Fadrozole was the only AI until anastrozole was
approved a few months ago. Letrozole was shown to be a better AI than fadrozole
by prospective randomized double blind examination; however, it is not licenced
yet. The reason is that the appropriate dosage is not identical to that of
Western countries. We have reached a time when order-made medicine should take
into consideration such differences as race and individuality.
Publication Types:
Review
Review, Tutorial
PMID: 11478137 [PubMed - indexed for MEDLINE]
76: FDA Consum 2001 May-Jun;35(3):5
Femara approved as first-line breast cancer therapy.
Publication Types:
News
PMID: 11458552 [PubMed - indexed for MEDLINE]
77: J Clin Oncol 2001 Jul 15;19(14):3357-66
Phase III, multicenter, double-blind, randomized study of letrozole, an
aromatase inhibitor, for advanced breast cancer versus megestrol acetate.
Buzdar A, Douma J, Davidson N, Elledge R, Morgan M, Smith R, Porter L, Nabholtz
J, Xiang X, Brady C.
University of Texas M.D. Anderson Cancer Center and Baylor College of Medicine,
Houston, TX, USA. [email protected]
PURPOSE: To compare two doses of letrozole (0.5 mg and 2.5 mg every day) and
megestrol acetate (40 mg qid) as endocrine therapy in postmenopausal women with
advanced breast cancer previously treated with antiestrogens. PATIENTS AND
METHODS: This double-blind, randomized, multicenter, multinational study
enrolled 602 patients, all of whom were included in the primary analysis in the
protocol. Patients had advanced or metastatic breast cancer with evidence of
disease progression while receiving continuous adjuvant antiestrogen therapy,
had experienced relapse within 12 months of stopping adjuvant antiestrogen
therapy given for at least 6 months, or had experienced disease progression
while receiving antiestrogen therapy for advanced disease. Tumors were required
to be estrogen receptor- and/or progesterone receptor-positive or of unknown
status. Confirmed objective response rate was the primary efficacy variable.
Karnofsky Performance Status and European Organization for Research and
Treatment of Cancer quality-of-life assessments were collected for 1 year.
RESULTS: There were no statistically significant differences among the three
treatment groups for overall objective tumor response. Patients treated with
letrozole 0.5 mg had improvements in disease progression (P =.044) and a
decreased risk of treatment failure (P =.018), compared with patients treated
with megestrol acetate. Letrozole 0.5 mg showed a trend (P =.053) for survival
benefit when compared with megestrol acetate. Megestrol acetate was more likely
to produce weight gain, dyspnea, and vaginal bleeding, and the letrozole groups
were more likely to experience headache, hair thinning, and diarrhea.
CONCLUSION: Given a favorable tolerability profile, once-daily dosing, and
evidence of clinically relevant benefit, letrozole is equivalent to megestrol
acetate and should be considered for use as an alternative treatment of advanced
breast cancer in postmenopausal women after treatment failure with
antiestrogens.
Publication Types:
Clinical Trial
Clinical Trial, Phase III
Multicenter Study
Randomized Controlled Trial
PMID: 11454883 [PubMed - indexed for MEDLINE]
78: Lancet 2001 Jun 2;357(9270):1743-8
Comment in:
Lancet. 2001 Jun 2;357(9270):1723-4.
A specific aromatase inhibitor and potential increase in adult height in boys
with delayed puberty: a randomised controlled trial.
Wickman S, Sipila I, Ankarberg-Lindgren C, Norjavaara E, Dunkel L.
Hospital for Children and Adolescents, University of Helsinki, Ph 281,
FIN-00029, Hus, Finland
BACKGROUND: The role of oestrogens in the closure of growth plates in both sexes
is unequivocal. We postulated that inhibition of oestrogen synthesis in boys
with delayed puberty would delay maturation of the growth plates and ultimately
result in increased adult height. METHODS: We did a randomised, double-blind,
placebo-controlled study in which we treated boys with constitutional delay of
puberty with testosterone and placebo, or testosterone and letrozole. Boys who
decided to wait for the spontaneous progression of puberty without medical
intervention composed the untreated group. FINDINGS: Letrozole effectively
inhibited oestrogen synthesis and delayed bone maturation. Progression of bone
maturation was slower in the letrozole group than in the placebo group. In 18
months, bone age had advanced 1.1 (SD 0.8) years in the untreated group and 1.7
(0.9) years in the group treated with testosterone and placebo, but only 0.9
(0.6) years in the letrozole group (p=0.03 between the treatment groups).
Predicted adult height did not change significantly in the untreated group and
in the placebo group, whereas in the group treated with letrozole the increase
was 5.1 (3.7) cm (p=0.004). INTERPRETATIONS: Our findings suggest that if
oestrogen action is inhibited in growing adolescents, adult height will
increase. This finding provides a rationale for studies that aim to delay bone
maturation in several growth disorders.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 11403810 [PubMed - indexed for MEDLINE]
79: Lancet 2001 Jun 2;357(9270):1723-4
Comment on:
Lancet. 2001 Jun 2;357(9270):1743-8.
Use of a specific aromatase inhibitor in delayed puberty.
Stanhope R.
Department of Endocrinology, Great Ormond Street Hospital for Children and
Middlesex Hospital (UCLH), WCIN IEH, London, UK. [email protected]
Publication Types:
Comment
PMID: 11403802 [PubMed - indexed for MEDLINE]
80: Semin Oncol 2001 Jun;28(3):291-304
Endocrine therapy in the treatment of metastatic breast cancer.
Buzdar AU.
Department of Breast Medical Oncology, M.D. Anderson Cancer Center, 1515
Holcombe Blvd., Houston, TX 77037, USA.
The goals of treating patients with metastatic breast cancer are to prolong
survival, slow or halt disease progression, and enhance the patient's quality of
life. In patients with estrogen receptor (ER)-positive cancers that are not
progressing rapidly, endocrine therapy is generally the first treatment option.
If a patient initially responds to an endocrine agent and then progresses,
another endocrine agent may still provide benefit. Tamoxifen has been used as
first-line therapy for metastatic breast cancer for many years. Until recently,
no other endocrine agent has shown superiority to tamoxifen in this setting. The
nonsteroidal aromatase inhibitors, anastrozole and letrozole, have been widely
accepted as second-line therapy after failure of tamoxifen; they have replaced
megestrol acetate in this setting. Recently, anastrozole was shown to have at
least equivalent efficacy and a superior side effect profile compared with
tamoxifen for treating postmenopausal women in the first-line setting. Thus,
this aromatase inhibitor has become a viable option for first-line therapy in
postmenopausal women. Trials of letrozole in this setting are nearing
completion. Exemestane has been shown to be an effective second-line agent and
to have at least some efficacy as a third-line agent even after failure of a
nonsteroidal aromatase inhibitor. Results are anxiously awaited from trials of
new endocrine agents including the first member of a new class of endocrine
agent, the estrogen-receptor downregulator class. Semin Oncol 28:291-304.
Copyright 2001 by W.B. Saunders Company.
Publication Types:
Review
Review, Tutorial
PMID: 11402439 [PubMed - indexed for MEDLINE]
81: Oncology (Huntingt) 2001 May;15(5 Suppl 7):28-34
Aromatase inhibition and antiestrogen therapy in early breast cancer treatment
and chemoprevention.
Ingle JN.
Mayo Clinic, Rochester, Minnesota, USA. [email protected]
The aromatase inhibitors represent an important class of hormonal agents for the
management of breast cancer. The third-generation aromatase inhibitors have
replaced megestrol acetate as second-line hormonal therapy in advanced breast
cancer, and large clinical trials are maturing to establish their efficacy
relative to tamoxifen (Nolvadex) in the first-line metastatic setting. The
increased potency, increased specificity, and established efficacy of aromatase
inhibitors in advanced breast cancer have provided the rationale for a large
number of randomized trials in the adjuvant setting evaluating anastrozole
(Arimidex), exemestane (Aromasin), and letrozole (Femara). These trials are
addressing the value of these agents in sequence with, instead of, and in
combination with tamoxifen. The relationship between estrogen exposure and
breast cancer risk has long been accepted and traditionally related to
estrogen-receptor-mediated events. The emergence of the estrogen genotoxicity
hypothesis as a mechanism for breast cancer carcinogenesis provides additional
rationale for considering aromatase inhibitors in the chemoprevention setting.
Publication Types:
Review
Review, Tutorial
PMID: 11396362 [PubMed - indexed for MEDLINE]
82: J Steroid Biochem Mol Biol 2001 Jan-Mar;76(1-5):199-202
Intracellular aromatase and its relevance to the pharmacological efficacy of
aromatase inhibitors.
Bhatnagar AS, Brodie AM, Long BJ, Evans DB, Miller WR.
Novartis Pharma AG, CH-4002, Basel, Switzerland.
An important feature of the pharmacological profile of aromatase inhibitors is
the ability of the various inhibitors to inhibit intracellular aromatase. It is
now well documented that a large proportion of breast tumors express their own
aromatase. This intratumoral aromatase produces estrogen in situ and therefore
may contribute significantly to the amount of estrogen to which the cell is
exposed. Thus it is not only important that aromatase inhibitors potently
inhibit the peripheral production of estrogen and eliminate the external supply
of estrogen to the tumor cell, but that they in addition potently inhibit
intratumoral aromatase and prevent the tumor cell from making its own estrogen
within the cell. To study the inhibition of intracellular aromatase we have
compared the aromatase-inhibiting potency of the non-steroidal aromatase
inhibitors, letrozole, anastrozole and fadrozole in a variety of model cellular
endocrine and tumor systems which contain aromatase. We have used hamsters
ovarian tissue fragments, adipose tissue fibroblasts from normal human breast,
the MCF-7Ca human breast cancer cell line transfected with the human aromatase
gene and the JEG-3 human choriocarcinoma cell line. Although letrozole and
anastrozole are approximately equipotent in a cell-free aromatase system (human
placental microsomes), letrozole is consistently 10-30 times more potent than
anastrozole in inhibiting intracellular aromatase in intact rodent cells, normal
human adipose fibroblasts and human cancer cell lines. Whether these differences
between letrozole and anastrozole are seen in the clinical setting will have to
await the results of clinical trials which are currently in progress.
PMID: 11384878 [PubMed - indexed for MEDLINE]
83: Vopr Onkol 2001;47(2):195-9
[Modern approaches to hormone therapy of breast cancer as a reflection of
pathogenesis of the disease]
[Article in Russian]
Semiglazov VP.
N.N. Petrov Research Institute of Oncology, Ministry of Health of the RF, St.
Petersburg.
Experimental and epidemiological studies have pointed to a major role of
estrogens in the pathogenesis of human breast cancer. The Oxford meta-analysis
(1998) once again confirmed the efficacy of antiestrogens (tamoxifen) as
adjuvant therapy. We need to know whether the new non-steroid antiestrogens
(idoxifen, droloxifen and TAT-59) and selective estrogen receptor modulator
(raloxifen), whith preclinical characteristics better than those of tamoxifen
will be more efficient clinically. Large-scale trials to compare the new drugs
with tamoxifen are under way. Faslodex, a pure antiestrogen, looks highly
promising, too. Zoladex, a luteinising hormone-releasing hormone agonist, is
looking as a better choice than ovariectomy or irradiation of the pelvis for
ovarian ablation in premenopausal breast cancer. New aromatase inhibitors are
more efficient than progestins and much safer than aminoglutethimide. It has
been shown recently that these inhibitors keep metastatic breast cancer at bay
longer, and with longer survival. The non-steroid inhibitors (anastrozole and
letrozole) and the steroid oral drug exemestane are undergoing clinical trials
as means of adjuvant treatment of breast cancer. The trial of arimidex and
tamoxifen administered alone or in combination (ATAC) is unique since it is
using a combination of tamoxifen and an aromatase inhibitor (anastrozole). New
methods of endocrine therapy have resulted in less toxic and more convenient
procedures. Also, longer therapeutic effects and survival are becoming more
apparent.
PMID: 11383456 [PubMed - indexed for MEDLINE]
84: Clin Endocrinol (Oxf) 2001 May;54(5):563-71
Aromatase regulation and breast cancer.
Reed MJ, Purohit A.
Endocrinology and Metabolic Medicine, Imperial College School of Medicine, St
Mary's Hospital, London, UK. [email protected]
Publication Types:
Review
Review, Academic
PMID: 11380485 [PubMed - indexed for MEDLINE]
85: J Clin Oncol 2001 May 15;19(10):2596-606
Erratum in:
J Clin Oncol 2001 Jul 1;19(13):3302
Superior efficacy of letrozole versus tamoxifen as first-line therapy for
postmenopausal women with advanced breast cancer: results of a phase III study
of the International Letrozole Breast Cancer Group.
Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A,
Apffelstaedt J, Smith R, Sleeboom HP, Janicke F, Pluzanska A, Dank M, Becquart
D, Bapsy PP, Salminen E, Snyder R, Lassus M, Verbeek JA, Staffler B,
Chaudri-Ross HA, Dugan M.
Rigshospitalet, Copenhagen, Denmark.
PURPOSE: To compare the efficacy and tolerability of tamoxifen with that of
letrozole, an oral aromatase inhibitor, with tamoxifen as first-line therapy in
postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: Nine
hundred seven patients were randomly assigned letrozole 2.5 mg once daily (453
patients) or tamoxifen 20 mg once daily (454 patients). Patients had estrogen
receptor- and/or progesterone receptor-positive tumors, or both receptors were
unknown. Recurrence during adjuvant antiestrogen therapy or within the following
12 months or prior endocrine therapy for advanced disease precluded enrollment.
One prior chemotherapy regimen for metastatic disease was allowed. The primary
end point was time to progression (TTP). Secondary end points included overall
objective response rate (ORR), its duration, rate and duration of clinical
benefit, time to treatment failure (TTF), overall survival, and tolerability.
RESULTS: TTP was significantly longer for letrozole than for tamoxifen (median,
41 v 26 weeks). Treatment with letrozole reduced the risk of progression by 30%
(hazards ratio, 0.70; 95% confidence interval, 0.60 to 0.82, P =.0001). TTP was
significantly longer for letrozole irrespective of dominant site of disease,
receptor status, or prior adjuvant antiestrogen therapy. Similarly, TTF was
significantly longer for letrozole (median, 40 v 25 weeks). ORR was higher for
letrozole (30% v 20%; P =.0006), as was the rate of clinical benefit (49% v 38%;
P =.001). Survival data are currently immature and not reported here. Both
treatments were well tolerated. CONCLUSION: Letrozole was significantly superior
to tamoxifen in TTP, TTF, ORR, and clinical benefit rate. Our results support
its use as first-line endocrine therapy in postmenopausal women with advanced
breast cancer.
Publication Types:
Clinical Trial
Clinical Trial, Phase III
Multicenter Study
Randomized Controlled Trial
PMID: 11352951 [PubMed - indexed for MEDLINE]
86: Oncol Nurs Forum 2001 Apr;28(3):507-12; quiz 513-4
Erratum in:
Oncol Nurs Forum 2001 Jun;28(5):794
Metastatic breast cancer: understanding current management options.
McGinn K, Moore J.
Kaiser Permanente, South San Francisco, CA, USA. [email protected]
PURPOSE/OBJECTIVES: To review the standard treatment options for metastatic
breast cancer, present recently approved chemotherapeutic and hormonal
approaches, and describe novel biologic therapies, particularly the use of
monoclonal antibodies. DATA SOURCES: Published articles, abstracts, and
conference proceedings. DATA SYNTHESIS: Standard treatment options available to
women with metastatic breast cancer include surgery, radiation therapy, hormonal
therapy, chemotherapy, and palliative approaches. New chemotherapeutic
approaches for the management of metastatic breast cancer include the recently
approved agents paclitaxel, docetaxel, and capecitabine. New hormonal agents
such as toremifene, letrozole, and exemestane also have been approved. Finally,
an agent from a new class of agents--biologic response modifiers (BRMs)--now. Is
available. Trastuzumab, a monoclonal antibody (one class of BRMs), is a new and
promising approach available to a subpopulation of women with metastatic breast
cancer. CONCLUSION: Although standard treatment options for the management of
metastatic breast cancer may prolong survival for some, they have not resulted
in a cure for the majority of women. Recent advances in the understanding of
cancer cellular biology have led to newer approaches such as monoclonal
antibodies and other BRMs that may offer hope of extended survival and improved
quality of life for certain women. This field is growing quickly, and new
targets for breast cancer therapy are being studied. IMPLICATIONS FOR NURSING
PRACTICE: Nurses who become familiar with newer treatment options available for
the management of metastatic breast cancer, including new chemotherapeutic and
hormonal approaches and monoclonal antibody therapy, are better able to provide
information and support for their patients. Clinicians must understand the
criteria for patient selection for newer agents, particularly trastuzumab. In
addition, recognizing adverse effects and knowing the management strategies for
treatment-related toxicities help to ensure positive patient outcomes.
Publication Types:
Review
Review, Tutorial
PMID: 11338758 [PubMed - indexed for MEDLINE]
87: Placenta 2001 Apr;22(4):276-83
Developmental regulation of morphological differentiation of placental villous
trophoblast in the baboon.
Babischkin JS, Burleigh DW, Mayhew TM, Pepe GJ, Albrecht ED.
Department of Obstetrics, Center for Studies in Reproduction, The University of
Maryland School of Medicine, Baltimore, MD 21201, USA.
The present study determined whether morphological differentiation of placental
villous cytotrophoblasts into syncytiotrophoblast during primate pregnancy was
developmentally regulated and whether oestrogen has a role in this process.
Placental volumetric composition of the cytotrophoblast and syncytiotrophoblast
was determined by the test-point counting method on days 45-54, 60, 100, and 170
of gestation (term=184 days) in untreated baboons, on day 60 after placental
oestrogen production was prematurely elevated by administration of aromatizable
androstenedione or oestradiol, and on day 170 after oestrogen production was
suppressed by administration of aromatase inhibitor CGS 20267.Cytotrophoblast
and syncytiotrophoblast volumes and oestrogen levels increased (P< 0.01) with
advancing gestation. Due to the rise in syncytiotrophoblast volume (12-fold)
exceeded that of the cytotrophoblast (threefold), the mean (sem) ratio of
syncytiotrophoblast and cytotrophoblast volumes increased (P< 0.001) from 3.4
(0.5) ml on day 60 to 12.1 (2.8) ml on day 170. Androstenedione administration
elevated serum oestradiol levels threefold (P< 0.01) and increased the ratio of
syncytiotrophoblast: cytotrophoblast volumes on day 60 by 50 per cent (P< 0.03)
to that normally observed on day 100. However, the ratio of trophoblast volumes
was unaltered in oestradiol-treated and CGS 20267-treated baboons. It is
concluded that there is a developmental increase in morphological
differentiation of the placental villous trophoblast during primate pregnancy
and that androstenedione potentially via its conversion to oestrogen has a role
in this process. Copyright 2001 Harcourt Publishers Ltd.
PMID: 11286563 [PubMed - indexed for MEDLINE]
88: Curr Med Res Opin 2001;16(4):276-84
The Twenty-third Annual San Antonio Breast Cancer Symposium.
Mokbel K.
St George's Hospital, Blackshaw Road, London SW17 0QT, UK.
[email protected]
This paper reviews the recent Twenty-third Annual San Antonio Breast Cancer
Symposium. A total of 580 studies were presented either orally or as posters.
Two phase III multi-centre clinical trials found that fulvestrant (Falsodex),
given as a once-monthly intramuscular injection (250 mg), was well-tolerated and
at least as good as anastrozole (1 mg) in postmenopausal women with advanced
breast cancer that had progressed or recurred on prior endocrine therapy.
Another phase III randomised trial found that letrozole (2.5 mg daily) was
superior to tamoxifen as a neoadjuvant therapy in postmenopausal women with ER-
and/or PgR-positive breast cancer unsuitable for breast-conserving surgery. In a
phase III study, capecitabine (Xeloda) was found to be well-tolerated and able
to improve survival by three months when added to Taxotere. Cutting edge data on
microarray gene profiling in breast cancer were presented. The potential role of
this new technology in predicting outcome and selecting therapy was discussed.
Furthermore, its limitations and the need for validation were highlighted. The
role of new diagnostic tools, such as fibre-optic ductoscopy (FDS) and
microcatheters to obtain ductal cells, was discussed. Finally, the worldwide
overview was presented.
Publication Types:
Congresses
PMID: 11268712 [PubMed - indexed for MEDLINE]
89: JAMA 2001 Mar 7;285(9):1146
From the Food and Drug Administration.
Schwetz BA.
Food and Drug Administration, USA.
PMID: 11231734 [PubMed - indexed for MEDLINE]
90: Bull Cancer 2000 Dec;87 Spec No:31-39
[Aromatase inhibitors: a review of clinical trials]
[Article in French]
Kerbrat P, Lefeuvre C.
Departement d'oncologie medicale, Centre Eugene-Marquis, rue de la
Bataille-Flandres-Dunkerque, CS 44229, 35042 Rennes Cedex, France.
To increase the therapeutic index of second line hormonal treatment of breast
cancer, new aromatase inhibitors have been synthetized; they belong to two
groups: type I (formestane and exemestane) are steroidal irreversible and
specific inhibitors, type II (anastrozole, letrozole and vorozole) are non
steroidal reversible inhibitors, interfering with the aromatase heme. Several
phase II and III trials demonstrated that these drugs are, at least, as active
as aminoglutethimid or progestins in second line treatment, and are less toxic.
Recently, an identical activity have been observed for anastrozole and tamoxifen
in first line. In metastatic and adjuvant settings, large trials are ongoing to
clarify the exact value of these drugs.
Publication Types:
Review
Review Literature
PMID: 11250606 [PubMed - indexed for MEDLINE]
91: Bull Cancer 2000 Dec;87 Spec No:23-29
[Aromatase inhibitors: pharmacological aspects]
[Article in French]
de Cremoux P.
Laboratoire de physiopathologie et de pharmacologie, Institut Curie, 26, rue
d'Ulm, 75248 Paris Cedex 05, France.
Selective new aromatase inhibitors are a new class of agents that are of
considerable interest in the treatment of hormone-dependent breast cancer in
postmenopausal women. Aromatase is an enzymic complex that catalyses the
conversion of the adrenal androgens androstenedione and testosterone to estrone.
In postmenopausal women, the process of peripheral aromatisation accounts for
the majority of circulating estrogens. The selective inhibition of estrogen
production by aromatase inhibitors is an efficient strategy for breast cancer
treatment. These compounds are classified as irreversible inhibitors of
aromatase (type I), and comprise steroidal compounds. Reversible inhibitors of
aromatase, which comprises non-steroidal compounds are type II aromatase
inhibitors. Second and third generation aromatase inhibitors are considerably
more potent and more specific in their ability to inhibit aromatase, as compared
with first generation compounds (aminoglutethimide).
Publication Types:
Review
Review Literature
PMID: 11250605 [PubMed - indexed for MEDLINE]
92: Bull Cancer 2000 Dec;87 Spec No:7-22
[Preclinical evaluation of aromatase inhibitors antitumor activity]
[Article in French]
Auvray P, Bichat F, Genne P.
Oncodesign Biotechnology, Parc technologique de la Toison-d'Or, 28, rue de
Broglie, 21000 Dijon, France.
Aromatase is an enzymatic complex responsible for the conversion of androgens
into estrogens; these hormones are important in development, reproduction, but
also in the growth of estrogen-dependent cancer. This enzyme is present in
60-70% of the breast cancer. The aromatase inhibitors are important drugs in the
breast cancer treatment of postmenopausal women. In order to study their in vivo
activity, animal models have been developed, e.g. rat with tumour induced by
7,12-dimethylbenz[a]anthracene, PMSG-primed immature rat or athymic nude mice
with aromatase transfected MCF-7 xenograft. In this review, we were interested
in preclinical results obtained with both classes: steroidal and nonsteroidal
inhibitors. The former group, as substrate analogs formestane or exemestane, are
irreversible, selective and long-lasting inhibitors of aromatase. The
nonsteroidal molecules, such as letrozole or anastrozole, are reversible
inhibitors with high affinity. Finally, knowledge of the enzyme active site,
with molecular modeling and site-directed mutagenesis, could be useful to
develop new inhibitor families, more specific and potent in vivo.
Publication Types:
Review
Review Literature
PMID: 11250604 [PubMed - indexed for MEDLINE]
93: Fertil Steril 2001 Feb;75(2):305-9
Use of an aromatase inhibitor for induction of ovulation in patients with an
inadequate response to clomiphene citrate.
Mitwally MF, Casper RF.
Division of Reproductive Sciences, Samuel Lunenfeld Research Institute, Mount
Sinai Hospital, Ontario, Toronto, Canada.
OBJECTIVE: To use aromatase inhibition for induction of ovulation in women in
whom clomiphene citrate (CC) treatment was unsuccessful. DESIGN: Prospective
trial in infertility patients treated with CC. SETTING: Two tertiary-referral
infertility clinics associated with the Division of Reproductive Sciences,
University of Toronto. PATIENT(S): Twelve patients with anovulatory polycystic
ovary syndrome (PCOS) and 10 patients with ovulatory infertility, all of whom
had previously received CC with an inadequate outcome (no ovulation and/or
endometrial thickness of < or =0.5 cm). INTERVENTION(S): The aromatase inhibitor
letrozole was given orally in a dose of 2.5 mg on days 3-7 after menses. MAIN
OUTCOME MEASURE(S): Occurrence of ovulation, endometrial thickness, and
pregnancy rates. RESULT(S): With CC treatment in patients with PCOS, ovulation
occurred in 8 of 18 cycles (44.4%), and all ovulatory cycles for the women
included in this study had endometrial thickness of < or =0.5 cm. In 10
ovulatory patients, 15 CC cycles resulted in a mean number of 2.5 mature
follicles, but all cycles had endometrial thickness of < or =0.5 cm on the day
of hCG administration. With letrozole treatment in the same patients with PCOS,
ovulation occurred in 9 of 12 cycles (75%) and pregnancy was achieved in 3
patients (25%). In the 10 patients with ovulatory infertility, letrozole
treatment resulted in a mean number of 2.3 mature follicles and mean endometrial
thickness of 0.8 cm. Pregnancy was achieved in 1 patient (10%). CONCLUSION(S):
Oral administration of the aromatase inhibitor letrozole is effective for
ovulation induction in anovulatory infertility and for increased follicle
recruitment in ovulatory infertility. Letrozole appears to avoid the unfavorable
effects on the endometrium frequently seen with antiestrogen use for ovulation
induction.
Publication Types:
Clinical Trial
PMID: 11172831 [PubMed - indexed for MEDLINE]
94: J Natl Cancer Inst 2001 Feb 7;93(3):175-6
FDA panel recommends two new cancer drugs for approval.
Finkelstein JB.
Publication Types:
News
PMID: 11158184 [PubMed - indexed for MEDLINE]
95: J Clin Oncol 2001 Feb 1;19(3):881-94
Comment in:
J Clin Oncol. 2001 May 15;19(10):2767.
Aromatase inhibitors in the treatment and prevention of breast cancer.
Goss PE, Strasser K.
Division of Hematology/Oncology, Princess Margaret Hospital, Toronto, Ontario,
Canada. [email protected]
PURPOSE: The purpose of this article is to provide an overview of the current
clinical status and possible future applications of aromatase inhibitors in
breast cancer. METHODS: A review of the literature on the third-generation
aromatase inhibitors was conducted. Some data that have been presented but not
published are included. In addition, the designs of ongoing trials with
aromatase inhibitors are outlined and the implications of possible results
discussed. RESULTS: All of the third-generation oral aromatase
inhibitors--letrozole, anastrozole, and vorozole (nonsteroidal, type II) and
exemestane (steroidal, type I)--have now been tested in phase III trials as
second-line treatment of postmenopausal hormone-dependent breast cancer. They
have shown clear superiority compared with the conventional therapies and are
therefore considered established second-line hormonal agents. Currently, they
are being tested as first-line therapy in the metastatic, adjuvant, and
neoadjuvant settings. Preliminary results suggest that the inhibitors might
displace tamoxifen as first-line treatment, but further studies are needed to
determine this. CONCLUSION: The role of aromatase inhibitors in premenopausal
breast cancer and in combination with chemotherapy and other anticancer
treatments are areas of future exploration. The ongoing adjuvant trials will
provide important data on the long-term safety of aromatase inhibitors, which
will help to determine their suitability for use as chemopreventives in healthy
women at risk of developing breast cancer.
Publication Types:
Review
Review Literature
PMID: 11157042 [PubMed - indexed for MEDLINE]
96: Anticancer Drugs 2000 Oct;11(9):701-6
Survival in patients with metastatic breast cancer: analysis of randomized
studies comparing oral aromatase inhibitors versus megestrol.
Messori A, Cattel F, Trippoli S, Vaiani M.
Laboratorio SIFO di Farmacoeconomia, Centro Informazione Farmaci, Azienda
Ospedaliera Careggi, Florence, Italy. [email protected]
In patients with metastatic breast cancer, second-line therapy with aromatase
inhibitors can improve survival in comparison with megestrol. We conducted a
meta-analysis to assess the effectiveness of aromatase inhibitors versus
megestrol. After a Medline search, three trials (evaluating letrozole,
anastrozole or exemestane versus megestrol) were included in the survival
meta-analysis. Our methodology retrieved patient-level information on survival.
In comparison with megestrol, aromatase inhibitors prolonged survival at levels
of statistical significance (relative death risk for oral aromatase
inhibitors=0.79, 95% confidence interval 0.69-0.91; p=0.0011). A lifetime
analysis of the pooled survival curves of aromatase inhibitors versus megestrol
found a mean survival gain of 4.1 months per patient. Aromatase inhibitors
confer a significant survival benefit to patients with metastatic breast cancer
as compared with megestrol. A preliminary calculation of the cost per life year
gained shows that the pharmacoeconomic profile of these drugs is favorable.
Publication Types:
Meta-Analysis
PMID: 11129731 [PubMed - indexed for MEDLINE]
97: Toxicol Pathol 2000 Nov-Dec;28(6):799-801
Aromatase inhibitors prevent spontaneous granular cell tumors in the distal
female reproductive tract of Sprague-Dawley rats.
Markovits JE, Sahota PS.
Novartis Pharmaceuticals, East Hanover, New Jersey 07936, USA.
[email protected]
We recently established diagnostic criteria for granular cell changes in the
distal female reproductive tract of rats. In a review of control animals from 9
carcinogenicity studies, we found that approximately 23% of animals had granular
cell alterations. Because estrogen may play a role in the pathogenesis of
granular cell alterations, we reviewed tissue sections from carcinogenicity
studies with 2 aromatase inhibitors and found compound-related decreases in the
incidence of granular cell changes. Since these aromatase inhibitors selectively
prevent the conversion of androgenic steroids to the corresponding estrogens,
these data further suggest that estrogen may play a role in the pathogenesis of
granular cell tumors of the reproductive tract of rats.
PMID: 11127293 [PubMed - indexed for MEDLINE]
98: Expert Opin Investig Drugs 2000 Dec;9(12):2831-53
Novel strategies for systemic treatment of endometrial cancer.
Elit L, Hirte H.
Division of Gynecologic Oncology, Hamilton Regional Cancer Centre, 699
Concession Street, Hamilton, Ontario, L8V 5C2, Canada. [email protected]
The median survival of women with advanced or recurrent endometrial cancer is
less than one year. Of the women with early stage endometrial cancer and poor
prognostic factors like high grade or deep myometrial invasion, 40% will recur.
Over the last decade, incredible strides have been taken in evaluating systemic
therapy for this disease, however, survival rates remain poor. Progestin therapy
offers a 10 - 20% response rate and survival of less than one year. Progestins
are most effective in women with well-differentiated tumours and long
disease-free interval. There is no role for adjuvant progestin therapy in early
stage disease. Single-agent chemotherapy with most activity include ifosfamide,
cisplatin/carboplatin, doxorubicin and paclitaxel. Combination chemotherapy
provides a response rate of 40 - 60%, however, median survival is still less
than a year. New areas of research include the identification and evaluation of
new active endocrine therapies (i.e., LY-353381.HCl and letrozole),
chemotherapeutics (i.e., paclitaxel), evaluating chemotherapeutic agents in
combination (i.e., paclitaxel, doxorubicin and platinum), in addition to
radiation or instead of radiation. New avenues under development involve the
specific molecules and pathways responsible for the initiation and growth of
endometrial carcinoma (i.e., Herceptintrade mark). Exciting developments in the
understanding of the molecules involved in tumour development and metastasis
will allow the development of specific and selective inhibitors.
Publication Types:
Review
Review, Academic
PMID: 11093356 [PubMed - indexed for MEDLINE]
99: Eur J Cancer 2000 Sep;36 Suppl 4:S82-4
An overview of the use of non-steroidal aromatase inhibitors in the treatment of
breast cancer.
Buzdar A.
Department of Medical Oncology, The University of Texas - MD University Cancer
Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
[email protected]
A number of potent and selective non-steroidal aromatase inhibitors are now
available for the treatment of advanced breast cancer in postmenopausal women.
In particular, anastrozole represents a significant advantage over earlier
agents, such as aminoglutethimide and formestane, in terms of both efficacy and
tolerability. These agents are now established as the second-line therapy of
choice in postmenopausal women with advanced disease progressing on tamoxifen
and, furthermore, data are now available on the efficacy and tolerability of
anastrozole as first-line treatment of advanced breast cancer compared with
tamoxifen. The full potential of the new-generation aromatase inhibitors in the
treatment of breast cancer is currently being investigated in a large programme
of clinical trials, including evaluation as neoadjuvant treatment in
postmenopausal women with newly-diagnosed locally-advanced or large operable
breast cancers, as first-line treatment of advanced breast cancer in
postmenopausal women. Aromatase inhibitors have been available for over 20
years; the ability of these compounds to reduce circulating oestradiol levels
has been shown to produce clinical benefit in postmenopausal women with advanced
breast cancer. Early aromatase inhibitors, however, such as aminoglutethimide
and formestane, were not specific for the aromatase enzyme and resulted in
significant side-effects.
PMID: 11056331 [PubMed - indexed for MEDLINE]
100: Eur J Cancer 2000 Sep;36 Suppl 4:S81-2
Clinico-pharmacological aspects of different hormone treatments.
Lonning PE.
Department of Oncology, Haukeland University Hospital, N-5021, Bergen, Norway.
[email protected]
During the last decade, several new drugs and classes of drugs have become
available for breast cancer treatment. Thus, in addition to tamoxifen we have
got several new selective oestrogen receptor modulators (SERMs) with a partially
different pharmacological profile. The first generation aromatase inhibitor,
aminoglutethimide, has been replaced by more potent and less toxic inhibitors
belonging to the triazole class (anastrozole and letrozole) and, more recently,
the steroidal aromatase inactivator exemestane [1-3]. These drugs have all
revealed a better toxicity profile and, in general, an improved antitumour
activity, compared with conventional therapy. Faslodex, the first representative
of the so-called 'pure' oestrogen antagonists, has shown beneficial effects in
patients resistant to tamoxifen [4].
PMID: 11056330 [PubMed - indexed for MEDLINE]
101: Anticancer Drugs 2000 Aug;11(7):591-601
Cost-utility analysis of second-line hormonal therapy in advanced breast cancer:
a comparison of two aromatase inhibitors to megestrol acetate.
Dranitsaris G, Leung P, Mather J, Oza A.
Department of Pharmacy, Ontario Cancer Institute/Princess Margaret Hospital,
Toronto, Canada. [email protected]
Randomized trials comparing the aromatase inhibitors, anastrozole and letrozole,
to megestrol acetate (MA) in postmenopausal women with advanced breast cancer
demonstrated that both agents are better tolerated than MA with comparable
efficacy. In addition, one trial revealed that tumor response and time to
treatment failure were significantly better with letrozole. Since oncologists
are faced with a choice between three agents with at least comparable efficacy
but different toxicity profiles and cost, a cost-utility analysis was conducted
to quantify these differences and to determine if the new agents are more
cost-effective than MA. In the absence of a randomized three-arm trial, a
decision model was developed to simulate the most common therapeutic outcomes.
The clinical data were obtained from an overview analysis of randomized trials.
Total hospital resource consumption was collected from 87 patients with advanced
disease that had failed second-line hormonal therapy. Utility estimates were
obtained from interviewing a random sample of 25 women from the general public
and 25 female health care professionals using the Time Trade-Off technique. The
model suggested a similar duration of quality-adjusted progression-free survival
between drugs (letrozole 150 days, anastrozole 153 days and MA 146 days).
Letrozole had an overall cost of Can$2949 per patient which was comparable to MA
at Can$2966 per patient. In contrast, anastrozole was slightly more costly than
MA at $Can3149 per patient, respectively. The analysis revealed that letrozole
has comparable overall costs relative to MA while providing at least equivalent
quality-adjusted progression-free survival. These outcomes were largely related
to its higher tumor response rate, which translated to a lower proportion of
patients requiring chemotherapy. Anastrozole was slightly more costly than MA
and did not demonstrate superiority in quality-adjusted progression-free
survival in this palliative setting.
PMID: 11036964 [PubMed - indexed for MEDLINE]
102: Int J Oncol 2000 Nov;17(5):1037-41
New aromatase inhibitors in the treatment of advanced breast cancer.
Crucitta E, Lorusso V, Attolico M, Sambiasi D, Mazzei A, De Lena M.
Operative Unit of Medical Oncology, Oncology Institute of Bari, Bari, Italy.
New aromatase inhibitors are an exciting treatment option for postmenopausal
women with hormone sensitive breast cancer. They have been shown to reduce
tumors in a significant number of patients, and exhibit definite antitumor
activity at a relatively low daily dose, and are highly potent, highly
selective, and well-tolerated. Results from recent clinical phase III studies
have confirmed their efficacy and the key role they have in the therapy for
advanced breast cancer in postmenopausal women. The agents available for
clinical use are: letrozole, anastrozole, and exemestane. These drugs have
demonstrated high activity in women failing tamoxifen in locally advanced or
metastatic disease. This communication reviews the clinical use of aromatase
inhibitors, particularly in second and first line hormonal treatment of advanced
breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 11029510 [PubMed - indexed for MEDLINE]
103: Nippon Rinsho 2000 Apr;58 Suppl:322-7
[Aromatase inhibitors for treatment of advanced breast cancers]
[Article in Japanese]
Sonoo H.
Department of Breast & Thyroid Surgery, Kawasaki Medical School.
Publication Types:
Review
Review, Tutorial
PMID: 11026013 [PubMed - indexed for MEDLINE]
104: Rev Med Suisse Romande 2000 Jun;120(6):495-500
[Aromatase inhibitors in the treatment of breast cancer]
[Article in French]
Perey L.
Centre pluridisciplinaire d'oncologie, Lausanne.
PMID: 11014093 [PubMed - indexed for MEDLINE]
105: J Exp Clin Cancer Res 2000 Mar;19(1):17-9
Letrozole for the treatment of pretreated advanced breast cancer patients:
preliminary report.
Casali A, Sega FM, Casali M, Giuntini T, Cappellini GC, Terzoli E.
Service of Complementary Medical Oncology, Regina Elena Cancer Institute, Rome,
Italy.
Twenty patients (pts) with metastatic breast cancer with disease progression,
previously treated with chemotherapy and tamoxifen, were administered oral
letrozole (2.5 mg/day) therapy. Fifteen of the patients were postmenopausal and
5 were premenopausal. Ten were estrogen receptor (ER)-positive, 7 were unknown
and 3 were ER-negative. All the patients were assessed after 6 months (mo) of
chemotherapy. Nine pts (45%) presented a partial response (PR), five (25%) had a
stable disease (SD) and six (30%) had a progressive disease (PD). In the pts
with PD, six out of 15 (33%) obtained a PR while undergoing tamoxifen therapy.
The treatment caused no significant toxicity.
PMID: 10840931 [PubMed - indexed for MEDLINE]
106: J Clin Oncol 2000 Apr;18(8):1802-3
Comment on:
J Clin Oncol. 1998 Feb;16(2):453-61.
J Clin Oncol. 1999 Dec;17(12):3856-60.
Letrozole: which dose to be used?
Buzdar AU, Chaudri HA, Trunet PF.
Publication Types:
Comment
Letter
PMID: 10764444 [PubMed - indexed for MEDLINE]
107: Crit Rev Oncol Hematol 2000 Feb;33(2):137-42
Steroidal aromatase inhibitors in elderly patients.
Bajetta E, Zilembo N, Bichisao E, Pozzi P, Toffolatti L.
Division of Medical Oncology, Istituto Nazionale per lo Studio e la Cura dei
Tumori, Milan, Italy.
The choice of treatment for elderly breast cancer patients needs particular care
because the presence of physiological functional impairments can modify the drug
bioavailability in an unpredictable manner. Hormonal treatment remains one of
the choices and, although tamoxifen has proved to be effective in any setting,
the use of selective aromatase inhibitors is arousing. Depending on their
chemical structure, aromatase inhibitors are either steroidal (such as
exemestane and formestane) or non-steroidal (such as letrozole, vorozole and
anastrozole). Formestane has been studied in elderly patients with breast cancer
and has been found to induce an overall response rate of 51% (95% CI, 35-67%).
The drug suppresses estradiol (E2) levels, and changes in other hormones (FSH,
LH and SHBG) are observed, but with poor clinical significance, thus confirming
its selectivity and potency. Formestane has also been demonstrated to be as
effective as tamoxifen. Exemestane and non-steroidal aromatase inhibitors appear
to be very promising drugs.
Publication Types:
Review
Review, Tutorial
PMID: 10737375 [PubMed - indexed for MEDLINE]
108: Endocr Relat Cancer 1999 Mar;6(1):75-92
Use of aromatase inhibitors in breast carcinoma.
Santen RJ, Harvey HA.
Department of Medicine, University of Virginia Health Sciences Center,
Charlottesville 22908, USA.
Aromatase, a cytochrome P-450 enzyme that catalyzes the conversion of androgens
to estrogens, is the major mechanism of estrogen synthesis in the
post-menopausal woman. We review some of the recent scientific advances which
shed light on the biologic significance, physiology, expression and regulation
of aromatase in breast tissue. Inhibition of aromatase, the terminal step in
estrogen biosynthesis, provides a way of treating hormone-dependent breast
cancer in older patients. Aminoglutethimide was the first widely used aromatase
inhibitor but had several clinical drawbacks. Newer agents are considerably more
selective, more potent, less toxic and easier to use in the clinical setting.
This article reviews the clinical data supporting the use of the potent, oral
competitive aromatase inhibitors anastrozole, letrozole and vorozole and the
irreversible inhibitors 4-OH androstenedione and exemestane. The more potent
compounds inhibit both peripheral and intra-tumoral aromatase. We discuss the
evidence supporting the notion that aromatase inhibitors lack cross-resistance
with antiestrogens and suggest that the newer, more potent compounds may have a
particular application in breast cancer treatment in a setting of adaptive
hypersensitivity to estrogens. Currently available aromatase inhibitors are safe
and effective in the management of hormone-dependent breast cancer in
post-menopausal women failing antiestrogen therapy and should now be used before
progestational agents. There is abundant evidence to support testing these
compounds as first-line hormonal therapy for metastatic breast cancer as well as
part of adjuvant regimens in older patients and quite possibly in
chemoprevention trials of breast cancer.
Publication Types:
Review
Review, Academic
PMID: 10732791 [PubMed - indexed for MEDLINE]
109: Endocr Relat Cancer 1999 Jun;6(2):307-14
Aromatase overexpression and breast hyperplasia, an in vivo model--continued
overexpression of aromatase is sufficient to maintain hyperplasia without
circulating estrogens, and aromatase inhibitors abrogate these preneoplastic
changes in mammary glands.
Tekmal RR, Kirma N, Gill K, Fowler K.
Department of Gynecology and Obstetrics, Emory University School of Medicine,
Atlanta, Georgia 30322-4710, USA.
To test directly the role of breast-tissue estrogen in initiation of breast
cancer, we have developed the aromatase-transgenic mouse model and demonstrated
for the first time that increased mammary estrogens resulting from the
overexpression of aromatase in mammary glands lead to the induction of various
preneoplastic and neoplastic changes that are similar to early breast cancer.
Continued overexpression of aromatase that leads to increased breast-tissue
estrogen contributes to a number of epigenetic changes in mammary tissue such as
alteration in the regulation of genes involved in apoptosis, activation of genes
involved in cell cycle and cell proliferation, and activation of a number of
growth factors. Our current studies show aromatase overexpression is sufficient
to induce and maintain early preneoplastic and neoplastic changes in female mice
without circulating ovarian estrogen. Preneoplastic and neoplastic changes
induced in mammary glands as a result of aromatase overexpression can be
completely abrogated with the administration of the aromatase inhibitor,
letrozole. Consistent with complete reduction in hyperplasia, we have also seen
downregulation of estrogen receptor and a decrease in cell proliferation
markers, suggesting aromatase-induced hyperplasia can be treated with aromatase
inhibitors. Our studies demonstrate that aromatase overexpression alone, without
circulating estrogen, is responsible for the induction of breast hyperplasia and
these changes can be abrogated using aromatase inhibitors.
PMID: 10731124 [PubMed - indexed for MEDLINE]
110: Endocr Relat Cancer 1999 Jun;6(2):265-9
Combination hormonal therapy involving aromatase inhibitors in the management of
women with breast cancer.
Ingle JN, Suman VJ, Jordan VC, Dowsett M.
Mayo Clinic, Rochester, Minnesota 55905, USA.
Numerous comparative clinical trials have been conducted evaluating combination
hormonal therapy involving the aromatase inhibitor aminoglutethimide, but there
is no evidence for any superiority of this approach over single-agent therapy
alone. The advent of new aromatase inhibitors with greater potency, selectivity,
and better tolerability has prompted a reconsideration of the combined therapy
approach, with attention being focused on pharmacologic and endocrinologic
clinical research. The value of combining newer aromatase inhibitors with other
hormonal agents remains to be established.
Publication Types:
Review
Review, Tutorial
PMID: 10731119 [PubMed - indexed for MEDLINE]
111: Endocr Relat Cancer 1999 Jun;6(2):259-63
Aromatase inhibitors and their use in the sequential setting.
Coombes RC, Harper-Wynne C, Dowsett M.
Cancer Research Campaign, Department of Cancer Medicine, Imperial College School
of Medicine, Charing Cross Hospital, London, UK.
Over the past decade several novel aromatase inhibitors have been introduced
into clinical practice. The discovery of these drugs followed on from the
observation that the main mechanism of action of aminogluthemide was via
inhibition of the enzyme aromatase thereby reducing peripheral levels of
oestradiol in postmenopausal patients. The second-generation drug,
4-hydroxyandrostenedione (formestane), was introduced in 1990 and although its
use was limited by its need to be given parenterally it was found to be a
well-tolerated form of endocrine therapy. Third-generation inhibitors include
vorozole, letrozole, anastrozole and exemestane, the former three being
non-steroidal inhibitors, the latter being a steroidal inhibitor. All are
capable of inhibiting aromatase action by >95% compared with 80% in the case of
4-hydroxyandrostenedione. The sequential use of different generations of
aromatase inhibitors in the same patients is discussed. Studies suggest that an
optimal sequence of these compounds may well result in longer remission in
patients with hormone receptor positive tumours.
Publication Types:
Review
Review, Tutorial
PMID: 10731118 [PubMed - indexed for MEDLINE]
112: Endocr Relat Cancer 1999 Jun;6(2):245-9
Aromatase inhibitors: a dose-response effect?
Smith IE.
Section of Medicine, Royal Marsden Hospital and Institute of Cancer Research,
London, UK.
Publication Types:
Review
Review, Tutorial
PMID: 10731116 [PubMed - indexed for MEDLINE]
113: Endocr Relat Cancer 1999 Jun;6(2):231-4
Use of aromatase inhibitors in the adjuvant treatment of breast cancer.
Baum M.
Institute of Surgical Studies, University College London, UK.
The value of endocrine treatment of early breast cancer has been illustrated by
the antioestrogen, tamoxifen, which has now been available for nearly 30 years.
However, if the recognised side effects and pharmacological properties of
tamoxifen are taken into consideration, it is possible that other endocrine
treatments that are now available can provide equal or superior efficacy, along
with improved tolerability. One such group of agents is the aromatase inhibitors
specifically the new-generation triazole aromatase inhibitors, such as
anastrozole and letrozole, which have both shown tolerability and efficacy
advantages over standard treatments in postmenopausal women with advanced breast
cancer. There are convincing reasons why the new generation of aromatase
inhibitors have advantages over tamoxifen. For instance, from their agonist
properties, the effects on the endometrium and tumour stimulation seen with
tamoxifen would not be expected, nor would the visual disturbances that have
been associated with the triphenylethylene compounds, including tamoxifen. A
number of aromatase inhibitors, for instance, anastrozole, letrozole and
exemestane, are currently being investigated for treatment of early breast
cancer. The results of the trials of aromatase inhibitors and tamoxifen will, in
the next few years, define whether or not the new-generation aromatase
inhibitors have a role to play in the treatment of postmenopausal women with
early breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 10731114 [PubMed - indexed for MEDLINE]
114: Endocr Relat Cancer 1999 Jun;6(2):227-30
Lessons from the use of aromatase inhibitors in the neoadjuvant setting.
Dixon JM, Love CD, Renshaw L, Bellamy C, Cameron DA, Miller WR, Leonard RC.
Edinburgh Breast Unit, Western General Hospital, UK.
Postmenopausal patients with oestrogen receptor-positive locally advanced T4b,
N0-1, M0 and large operable breast cancers T2>3 cm, T3, T4, N0-1 and M0 have
been treated with 2.5 mg letrozole (12 patients), 10 mg letrozole (12 patients),
1 or 10 mg anastrozole (24 patients) and 20 mg tamoxifen (65 patients). There
was no apparent difference in response rate between 2.5 and 10 mg letrozole.
Only 17 patients with anastrozole have so far completed the 3-month treatment
period. Median clinical, mammographic and ultrasound reductions in tumour
volumes for patients treated with letrozole were 81% (95% confidence interval
(CI) 66-88), 77% (95% CI 64-82) and 81% (95% CI 69-86) respectively and for
anastrozole, values were 87% (95% CI 59-97), 73% (95% CI 58-82) and 64% (95% CI
52-76) respectively. This compares with a median reduction in tumour volume for
tamoxifen-treated patients as assessed by ultrasound of 48% (95% CI 27-48).
There were seven complete clinical responses (CR), sixteen patients who achieved
50% or greater reduction in tumour volume (PR) and one no change (NC) for
letrozole and four CRs, twelve PRs and one progressive disease for anastrozole.
Best radiological responses were one CR, twenty PRs and three NCs for letrozole
and one CR, fifteen PRs and one NC for anastrozole. This study has shown that
the new aromatase inhibitors, letrozole and anastrozole, are highly effective
agents in the neoadjuvant setting and they should now be compared with tamoxifen
as first-line treatment in a randomised study.
Publication Types:
Review
Review, Tutorial
PMID: 10731113 [PubMed - indexed for MEDLINE]
115: Endocr Relat Cancer 1999 Jun;6(2):219-25
Role of aromatase inhibitors in advanced breast cancer.
Buzdar AU.
Department of Medical Oncology, The University of Texas, MD Anderson University
Cancer Center, Houston 77030, USA.
A number of potent and selective non-steroidal aromatase inhibitors are now
available for treatment of advanced breast cancer in postmenopausal women, of
which anastrozole and letrozole, in particular, represent a significant
advantage over the earlier agents in terms of both efficacy and tolerability.
These agents are rapidly becoming established as the second-line therapy of
choice in postmenopausal women with advanced disease, progressing on tamoxifen,
and data on their efficacy as first-line treatment compared with tamoxifen will
be available in the near future. Exemestane, a new, steroidal aromatase
inhibitor which potentially lacks cross-resistance with non-steroidal agents is
still in clinical development. The full potential of the new-generation
aromatase inhibitors in the treatment of breast cancer is currently being
investigated in a large program of clinical trials evaluating their use as
adjuvant treatment following surgery in postmenopausal patients with early
disease.
Publication Types:
Review
Review, Tutorial
PMID: 10731112 [PubMed - indexed for MEDLINE]
116: Endocr Relat Cancer 1999 Jun;6(2):205-10
Aromatase inhibitors and their antitumor effects in model systems.
Brodie A, Lu Q, Liu Y, Long B.
Department of Pharmacology and Experimental Therapeutics, and Greenebaum Cancer
Center, School of Medicine, University of Maryland, Baltimore 21201, USA.
The potential of aromatase (estrogen synthetase) within the breast to provide a
significant source of estrogen mediating tumor proliferation is suggested by
studies reporting 4- to 6-fold higher estrogen levels in tumors than in plasma
of postmenopausal patients with breast cancer. Recent studies in our laboratory
have identified aromatase and its mRNA in tumor epithelial cells using
immunocytochemistry and in situ hybridization. In addition, significant
aromatase activity, which was stimulated 7-fold by dexamethasone, was measured
in metastatic cells isolated from a breast cancer patient. Increase in
proliferation, as measured by proliferating cell nuclear antigen immunostaining
in tumor sections and by thymidine incorporation into DNA in response to
testosterone, was observed in histocultures of breast cancer samples. This
latter effect could be inhibited by 4-hydroxyandrostenedione. These results
imply that intratumoral aromatase has functional significance and may be an
important target for successful inhibitor treatment of breast cancer patients.
To investigate treatment strategies with aromatase inhibitors and antiestrogens,
we developed an intratumoral aromatase model to simulate the hormone responsive
postmenopausal breast cancer patient. Tumors of estrogen receptor positive human
breast carcinoma cells (MCF-7) transfected with the human aromatase gene are
grown in ovariectomized nude mice. These cells synthesize sufficient estrogen to
stimulate tumor formation. We have utilized this model to investigate the
effects on tumor growth of the antiestrogens, tamoxifen and ICI 182780, and the
aromatase inhibitors, letrozole and anastrozole (arimidex), alone and in
combination. Both the aromatase inhibitors and the antiestrogens were effective
in suppressing tumor growth. However, letrozole was significantly more effective
than the antiestrogens. When the aromatase inhibitors were combined with the
antiestrogen, tamoxifen, tumor growth was suppressed to about the same extent as
with the aromatase inhibitors alone. Furthermore, the results do not suggest any
benefit from combining tamoxifen with the pure antiestrogen, ICI 182780. Thus
sequential use of these agents is likely to be more advantageous to the patient
in terms of longer duration of effective treatment.
PMID: 10731110 [PubMed - indexed for MEDLINE]
117: Endocr Relat Cancer 1999 Jun;6(2):187-95
Biology of aromatase inhibitors: pharmacology/endocrinology within the breast.
Miller WR.
Breast Research Unit, Western General Hospital, Edinburgh, UK.
Both mammary adipose tissue and breast cancers have the ability to aromatize
androgens into oestrogens. Such potential may maintain the growth of
hormone-dependent tumours. It has therefore been important to determine the
effects of new aromatase inhibitors such as formestane, exemestane, anastrozole
and letrozole on oestrogen biosynthesis and concentrations of endogenous
hormones within the breast. Studies based on in vitro incubations of breast
cancer and cultures of mammary adipose tissue fibroblasts demonstrate that these
drugs are highly effective inhibitors, with IC50 values ranging between 1 and 50
nM (although the relative efficacy varies between tissues and test systems).
Despite this potential, in vitro incubations of breast tissues from patients
treated with type II inhibitors such as aminoglutethimide and letrozole can
display paradoxically high aromatase activity; this appears to be caused by the
reversible nature of the inhibition, coupled with induction/stabilization of the
aromatase enzyme. To assess in situ effects within the breast, postmenopausal
women with large primary breast cancers have been treated neoadjuvantly with
aromatase inhibitors using a protocol that included (i) breast biopsy before
treatment, (ii) definitive surgery after 3 months of treatment and (iii)
infusion of [3H]androstenedione and [14C]oestrone in the 18 h immediately before
biopsy and surgery. With this study design, it has been shown that drugs such as
letrozole profoundly inhibit in situ aromatase activity and reduce endogenous
oestrogens within the breast.
PMID: 10731108 [PubMed - indexed for MEDLINE]
118: Endocr Relat Cancer 1999 Jun;6(2):181-5
Drug and hormone interactions of aromatase inhibitors.
Dowsett M.
Academic Department of Biochemistry, The Royal Marsden NHS Trust, London, UK.
The clinical development of aromatase inhibitors has been largely confined to
postmenopausal breast cancer patients and strongly guided by pharmacological
data. Comparative oestrogen suppression has been helpful in circumstances in
which at least one of the comparitors has caused substantially non-maximal
aromatase inhibition. However, the triazole inhibitors, letrozole and
anastrozole, and the steroidal inhibitor, exemestane, all cause >95% inhibition.
Comparisons between these drugs therefore require more sensitive approaches such
as the direct measurement of enzyme activity by isotopic means. None of these
three agents has significant effects on other endocrine pathways at its
clinically applied doses. Pharmacokinetic analyses of the combination of
tamoxifen and letrozole have revealed that these drugs interact, resulting in
letrozole concentrations approximately 35-40% lower than when letrozole is used
alone.
Publication Types:
Review
Review, Tutorial
PMID: 10731107 [PubMed - indexed for MEDLINE]
119: Steroids 2000 Apr;65(4):171-9
Aromatase inhibitors and their application in breast cancer treatment*.
Brodie AM, Njar VC.
Department of Pharmacology, School of Medicine, University of Maryland, 685 West
Baltimore Street, Baltimore, MD, USA. [email protected]
Estrogens are known to be important in the growth of breast cancers in both pre-
and postmenopausal women. The number of breast cancer patients with
hormone-dependent disease increases with age, as does the incidence of breast
cancer. Although estrogens are no longer made in the ovaries after menopause,
peripheral tissues produce sufficient concentrations to stimulate tumor growth.
Because aromatase catalyzes the rate-limiting step in the biosynthesis of
estrogen, inhibitors of this enzyme have been developed in the last few years as
a logical treatment strategy. Two classes of aromatase inhibitors, steroidal and
nonsteroidal compounds, are now in use. Among the steroid substrate analogs,
formestane and examestane have been shown to be effective in breast cancer
patients with advanced disease. Highly potent and selective nonsteroidal
inhibitors have recently been found to suppress plasma and urinary estrogens by
more than 95% in breast cancer patients. Two of these compounds recently were
approved in the United States and have been shown to be more effective than
other second-line agents in terms of overall response rates and treatment
failure, as well as better tolerated. Although studies of the efficacy of these
agents in earlier stage disease are awaited, it is evident that aromatase
inhibitors can extend the duration of treatment in breast cancer patients.
Publication Types:
Review
Review, Tutorial
PMID: 10713305 [PubMed - indexed for MEDLINE]
120: Am J Obstet Gynecol 2000 Feb;182(2):432-8
The role of estrogen in the maintenance of primate pregnancy.
Albrecht ED, Aberdeen GW, Pepe GJ.
Department of Obstetrics, Gynecology, and Reproductive Sciences, Center for
Studies in Reproduction, the University of Maryland School of Medicine,
Baltimore 21201, USA.
OBJECTIVE: The aim of this study was to determine the role of estrogen in
pregnancy maintenance in baboons by suppressing estrogen synthesis through
administration of a highly specific nonsteroidal aromatase inhibitor, CGS 20267.
STUDY DESIGN: CGS 20267 was administered subcutaneously at maximal dosages of
2.0 mg/d to pregnant baboons (n = 24) daily beginning on either day 30 (n = 8),
day 60 (n = 8), or day 100 (n = 8) of gestation (normal length of gestation is
184 days) until animals miscarried or were delivered abdominally on days 160
through 168 of gestation. CGS 20267 and estradiol (n = 9), each at maximal
dosages of 2 mg/d, were administered at the same intervals of gestation. Twenty
baboons served as untreated control animals. Serum estradiol and progesterone
levels were determined by radioimmunoassay from serum samples obtained at 1- to
3-day intervals from a maternal peripheral vein. RESULTS: Within 1 to 3 days of
the initiation of CGS 20267 administration, maternal serum estradiol
concentration decreased to and remained at a level that was substantially lower
(mean +/- SE, 0. 096 +/- 0.003 ng/mL) than in the untreated control animals
throughout gestation (0.35-4.0 ng/mL; P <.001). Although pregnancy was
maintained in 19 of the 20 untreated control baboons (95%), only 12 of the 24
animals that received CGS 20267 (50%) maintained pregnancy. In contrast, all the
baboons treated concomitantly with estradiol and CGS 20267 (9/9) maintained
pregnancy. Thus estradiol alone prevented the high rate of miscarriage induced
by the antiestrogenic agent CGS 20267. Serum progesterone concentrations were
not significantly different throughout the experimental period between the CGS
20267-treated baboons that maintained pregnancy (12. 9 +/- 1.4 ng/mL) and those
that miscarried (13.6 +/- 1.6 ng/mL) and were not lower in antiestrogen-treated
baboons than in untreated control baboons (10.6 +/- 0.8 ng/mL). CONCLUSION:
Estrogen, acting directly, indirectly, or both through a factor or factors other
than the level of progesterone, plays a critically important physiologic role in
the maintenance of primate pregnancy.
PMID: 10694348 [PubMed - indexed for MEDLINE]
121: Vopr Onkol 1999;45(5):504-10
[Aromatase gene expression and its modifying factors in breast tumor tissue]
[Article in Russian]
Berstein LM, Larionov AA, Pauley RJ, Chernitsa OI, Semiglazov VF, Yue W,
Edamatsu Kh, Ito Kh, Santen R.
N.N. Petrov Research Institute of Oncology, St. Petersburg, Russia.
Aromatase (CYP 19) gene expression was studied in 70 breast tumors. When
RNA-dot-blot or rt-polymerase chain reaction were used expression frequency was
60.4 and 91.7%, respectively. An analysis of individual variants of non-coding
exon of aromatase gene confirmed that, unlike normal mammary tissue, tumor
switched from activation of exon I.4 ("sensitive" to glucocorticoids) to exons
II ("sensitive" to cAMP) or I.3. This difference was relatively somewhat more
pronounced in the Russian material. Direct correlation between aromatase
enzymatic activity and expression of exons II and I.3 in tumor tissue appeared
more significant than that of aromatase gene coding site. An evaluation of the
expression of adenylate cyclase G-protein alpha-subunit genes established an
inverse correlation between expression of Gi2a and exon I.3. Breast tumors with
elevated basal aromatase activity were more sensitive to aromatase inhibitors
(letrozole, 4-OHA) in vitro although no relationship between use of CYP19
(aromatase) 5' exon variant and in vitro inhibition of aromatase was detected. A
correlation was observed between expression of aromatase gene and variants of
its 5' exon, on the one hand, and age, tumor grade, steroid receptor presence
and tumor lymphocytic infiltration, on the other. To summarize, local estrogen
production in breast tumor tissue is regulated by a wide range of factors
expression both aromatase gene influencing and its enzymatic activity, thus
providing leverage on both.
PMID: 10629706 [PubMed - indexed for MEDLINE]
122: Pharmacoeconomics 1999 Oct;16(4):379-97
Cost effectiveness of letrozole in the treatment of advanced breast cancer in
postmenopausal women in the UK.
Nuijten M, Meester L, Waibel F, Wait S.
MEDTAP, Amsterdam, The Netherlands. [email protected]
OBJECTIVE: To simulate the treatment of postmenopausal women with advanced
breast cancer from second-line hormone therapy to death, and to generate
estimates of the cost and effectiveness of letrozole and megestrol in order to
determine the incremental cost effectiveness of letrozole, expressed as cost per
life-years gained. DESIGN: A decision-analytic model, using Markov process
techniques, was designed to evaluate the lifetime clinical and economic
consequences of treatment with letrozole compared with standard care with
megestrol. The model was based on clinical trial results showing a clear
advantage of letrozole in terms of time to progression and duration of response.
SETTING: The setting of the study was that of the UK healthcare system in 1996.
PATIENTS AND PARTICIPANTS: A hypothetical cohort of patients, identical to the
patients recruited for the AR/BC2 clinical trial, who were postmenopausal women
with advanced breast cancer who had previously failed to respond to first-line
or adjuvant anti-estrogen therapy. INTERVENTIONS: The dosages of medications
were 2.5 and 160 mg/day for letrozole and megestrol, respectively. The analysis
covered the period from treatment initiation until death (lifetime model).
Effectiveness was expressed as survival and time without progression, and the
model also included all relevant economic measures. MAIN OUTCOME MEASURES AND
RESULTS: Based on the model, the average survival time of the letrozole group
was 2.1 years (25.3 months) versus 1.9 years (21.5 months) for the megestrol
group, a gain in survival of 2.4 months (10.5%). The average time without
progression, cumulatively calculated over the different treatment options,
amounted to 20.2 months for letrozole and 17.8 months for megestrol, an increase
of 13.7% for the former patients. The total average cost per patient for the
treatment of advanced breast cancer starting from second-line hormone therapy
until death was higher in the letrozole group at 7547 Pounds versus 6820 Pounds
for the megestrol group (discounted at an annual rate of 5%), leading to an
incremental cost-effectiveness ratio of 3588 Pounds per life-year gained (1996
values). CONCLUSIONS: Based on the assumptions used in this model, letrozole
offers a suitable alternative to megestrol in the treatment of second-line
hormone therapy.
PMID: 10623366 [PubMed - indexed for MEDLINE]
123: Breast Cancer Res Treat 1999 Sep;57(2):183-92
The effect of combining aromatase inhibitors with antiestrogens on tumor growth
in a nude mouse model for breast cancer.
Lu Q, Liu Y, Long BJ, Grigoryev D, Gimbel M, Brodie A.
Department of Pharmacology and Experimental Therapeutics, University of
Maryland, School of Medicine, Baltimore 21201, USA.
We have previously established a model for postmenopausal, hormone-dependent
breast cancer in nude mice which is responsive to both antiestrogens and
aromatase inhibitors. In this model, MCF-7 human breast carcinoma cells
transfected with the aromatase gene (MCF-7CA) synthesize sufficient estrogen to
form tumors in ovariectomized nude mice. In the present study we used this
intratumoral aromatase model to investigate the effects on tumor growth of the
new nonsteroidal aromatase inhibitors letrozole (CGS 20,267) and anastrozole (ZD
1033) and the antiestrogens tamoxifen (ICI 47,474) and faslodex (ICI 182,780).
Furthermore, we determined whether the inhibition of estrogen synthesis together
with inhibition of estrogen action would be more effective in controlling breast
tumor growth. The results of our studies indicate that the aromatase inhibitors
anastrozole and letrozole, as well as the new pure antiestrogen faslodex, have
potent antitumor effects in the mouse model. In the treatment of mice with
mammary tumors, letrozole was more effective in suppressing tumor growth than
anastrozole. This was consistent with the Ki values of these inhibitors against
placental aromatase and the IC50 values in cell culture (MCF-7CA), which
indicated the greater potency of letrozole as an aromatase inhibitor. Letrozole
also had greater antitumor effects than tamoxifen and faslodex. The antitumor
effect of letrozole was substantial, making it difficult to detect any
additional effect on the tumors when letrozole was combined with the
antiestrogens. However, the combined treatment of anastrozole + tamoxifen and
anastrozole + faslodex also did not increase efficacy compared to the aromatase
inhibitor alone. In addition, combining the two antiestrogens did not suppress
tumor growth more effectively than faslodex alone. Our results show that
treatment with the combinations of aromatase inhibitors with either tamoxifen or
faslodex are not more effective in blocking estrogen stimulation of tumor growth
than the aromatase inhibitors alone.
PMID: 10598045 [PubMed - indexed for MEDLINE]
124: Drugs Aging 1999 Oct;15(4):271-83
Aromatase inhibitors in the treatment of postmenopausal breast cancer.
Bajetta E, Zilembo N, Bichisao E.
Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
[email protected]
Anastrozole, letrozole and vorozole are new aromatase inhibitors with a
nonsteroidal structure (NSS), and have been demonstrated to be highly effective
and better tolerated than standard endocrine therapy with megestrol (megestrol
acetate) and aminoglutethimide (AG). These agents are very potent and selective:
all of them are capable of suppressing estrone (E1) and estradiol (E2) to the
limit of sensitivity methods, and plasma estrone sulfate (E1S) levels are also
suppressed. However, the fact that this potency has not led to any greater
clinical efficacy, and that there is no relationship between estrogen
suppression and clinical response, suggests that aromatase inhibitors may have
additional mechanisms of action. A number of international, multicentre clinical
trials have compared anastrozole, letrozole and vorozole with megestrol 160
mg/day or AG 500 mg/day plus hydrocortisone in patients with advanced breast
cancer. Letrozole proved to be significantly more effective than megestrol but
anastrozole had a greater effect on survival than either agent. However,
letrozole therapy led to longer survival than that observed in patients treated
with AG. The activity of vorozole was similar to that of megestrol and AG. These
results have raised a number of questions. The first is how should the clinical
results be evaluated, given that 'disease stabilisation lasting > or =6 months'
has been considered a response? The second is how should these drugs be used,
and whether there is a rationale for using them in combination or sequentially
in the treatment of patients with advanced breast cancer? Finally, is the
possible effect of formestane and vorozole on intratumoral aromatase an
alternative or concomitant mechanism of action? Anastrozole, letrozole and
vorozole will be compared with tamoxifen in postmenopausal patients with breast
cancer in adjuvant and primary settings. However, we feel that concomitant
biological and clinical studies should also be carried out in order to clarify
the properties of these drugs and avoid possible risks for patients over time.
Publication Types:
Review
Review, Tutorial
PMID: 10582774 [PubMed - indexed for MEDLINE]
125: J Clin Oncol 1999 Dec;17(12):3856-60
Comment in:
J Clin Oncol. 2000 Apr;18(8):1802-3.
Comment on:
J Clin Oncol. 1998 Feb;16(2):453-61.
Letrozole: updated duration of response.
Chaudri HA, Trunet PF.
Publication Types:
Comment
Letter
PMID: 10577865 [PubMed - indexed for MEDLINE]
126: Bull Cancer 1999 Oct;86(10):821-7
[Aromatase inhibitors]
[Article in French]
Feutrie ML, Bonneterre J.
Hopital civil d'Armentieres, 112, rue Sadi-Carnot, 59285 Armentieres.
Aromatase inhibitors used in breast cancer, are drugs that inhibit the
transformation of androstenedione and testosterone, respectively in estradiol
and estrone. Two classes have been described: steroidal inhibitors which act
competitively and irreversibly and non steroidal inhibitors which block the P
450 cytochrome. The first one is aminoglutethimide which has an adrenal effect
on 11, 18 and 21 hydroxylase. Rogletimide, less powerful and less specific is a
aminoglutethimide analogue. The response rates obtained with formestane is not
different. The clinical development has been stopped due to a lack of
specificity. Letrozole, vorozole, exemestane and anastrozole are more powerful
and more specific. Letrozole and vorozole are at least as efficient and better
tolerated than aminoglutethimide. Anastrozole, letrozole and vorozole are at
least as efficient as megestrol acetate and better tolerated in advanced breast
cancer patients receiving a second line hormone therapy.
Publication Types:
Review
Review, Tutorial
PMID: 10572233 [PubMed - indexed for MEDLINE]
127: Vopr Onkol 1999;45(4):361-8
[Letrozole (Femara), a new aromatase inhibitor for advanced breast cancer]
[Article in Russian]
Gershanovich M, Chaudri Kh, Campos D, Lurie H, Bonaventura A, Jeffrey M, Buzzi
F, Bodrogi I, Ludwig H, Reichard P, O'Higgins NO, Romieu G, Friedrich P, Lassus
M.
N.N. Petrov Research Institute of Oncology, Ministry of Health of the RF, St.
Petersburg, Russia.
The study compares letrozole (Femara and aminoglutethimide (AG), a standard
therapy for postmenopausal women with advanced breast cancer, previously treated
with anti-estrogens. 555 women were randomly assigned letrozole 2.5 mg once
daily (n = 185), letrozole 0.5 mg once daily (n = 192) or aminoglutethimide 250
mg twice daily with corticosteroid support (n = 178) in an open-label,
multicenter trial. The primary end-point was objective response rate (ORR), with
time events as secondary. ORR was analysed nine months after enrollment of the
last patient, while survival was analysed 15 months after the last patients was
enrolled. We report the results of these analyses plus an extended period of
observation (covering a total duration of approximately 45 months) to determine
the duration of response and clinical benefit. Overall objective response rates
(complete + partial) of 19.5%, 16.7% and 12.4% were seen for letrozole 2.5 mg,
0.5 mg and AG respectively. Median duration of response and stable disease was
longest for letrozole 2.5 mg (21 months) compared with letrozole 0.5 mg (18
months) and AG (14 months). Letrozole 2.5 mg was superior to AG in time to
progression, time to treatment failure and overall survival. Treatment-related
adverse events occurred in fewer patients on letrozole (33%) than on AG (46%).
Letrozole 2.5 mg offers longer disease control than aminoglutethimide and
letrozole 0.5 mg in the treatment of postmenopausal women with advanced breast
cancer, previously treated with anti-estrogens.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 10532092 [PubMed - indexed for MEDLINE]
128: J Steroid Biochem Mol Biol 1999 Jul-Aug;70(1-3):89-95
Rainbow trout, Oncorhynchus mykiss, as a model for aromatase inhibition.
Shilling AD, Carlson DB, Williams DE.
Department of Environmental and Molecular Toxicology and Marine/Freshwater
Biomedical Sciences Center, Oregon State University, Corvallis, 97331-6601, USA.
The feasibility of utilizing rainbow trout, Oncorhynchus mykiss, as an
alternative model for studying the inhibition of aromatase (CYP 19) was
investigated. The suppression of estrogen-dependent tumors by aromatase
inhibitors has been important in the treatment of breast cancer. Estrogens,
estrogen precursors and xenoestrogens have been found to promote liver cancer in
the trout model. A steroid, 4-hydroxy-4-androstene-3,17-dione (4-OHA), and
non-steroids, aminoglutethimide (AG) and Letrozole (CGS 20267), all of which are
known aromatase inhibitors in rats and humans, were examined in vitro for
activity in trout ovarian microsomes. Aromatase activity was quantified as the
release of 3H2O from the conversion of [3H]-4-androstene-3,17-dione to
17beta-estradiol and estrone. Trout ovarian microsomes exhibited activity
between 39-60 fmol mg(-1) min(-1) with a calculated Vmax of 71.1 fmol mg(-1)
min(-1) when incubated at 25 degrees C with 200 nM 4-androstene-3,17-dione (K(M)
= 435 nM). Significant inhibition by 4-OHA up to 80% was seen at 1.5 microM. At
2000 microM, AG decreased aromatase activity by up to 82%. Letrozole reduced
aromatase activity a maximum of 90% in a dose-dependent manner, but the Ki (2.3
microM) was 1000-fold higher than reported in human trials. Indole-3-carbinol
and some of its derivatives, two DDE isomers and four flavones (except
alpha-naphthoflavone) at 1000 microM did not significantly inhibit aromatase in
vitro. Letrozole and clotrimazole, fed to juvenile rainbow trout at doses up to
1000 ppm for 2 weeks, were not effective in suppressing dehydroepiandrosterone
(DHEA) induced increases in vitellogenin and 17beta-estradiol levels. These
results document that trout aromatase is sensitive to inhibition in vitro by
known inhibitors of the mammalian enzyme. The mechanism(s) for lack of
inhibition in vivo is currently unknown and must be further investigated in
order to develop a trout model for studying the role of aromatase in
carcinogenesis.
PMID: 10529006 [PubMed - indexed for MEDLINE]
129: Drug Saf 1999 Oct;21(4):297-309
Risks and benefits of aromatase inhibitors in postmenopausal breast cancer.
Michaud LB, Buzdar AU.
Division of Pharmacy, The University of Texas M.D. Anderson Cancer Center,
Houston 77030, USA.
Aromatase inhibitors were first reported in the early 1970s and have been used
to treat breast cancer since that time. Until recently, essentially the only
agent available in this class was aminoglutethimide, a nonspecific inhibitor
with multiple adverse effects and drug interactions. Selective and potent
aromatase inhibitors are now available (formestane, exemestane, fadrozole,
anastrozole and letrozole), and we review the risks and benefits of these agents
in order to assist clinicians in making treatment decisions. Formestane is an
injectable steroidal aromatase inhibitor with significant activity against
metastatic breast cancer. It has been shown to have similar efficacy and
superior tolerability compared with megestrol, and is similar to tamoxifen in
the metastatic setting. Exemestane is an oral steroidal aromatase inhibitor. It
has been shown to be effective third-line therapy after tamoxifen and megestrol
in postmenopausal patients with metastatic breast cancer. All the nonsteroidal
(imidazole/triazole) aromatase inhibitors are orally available. Fadrozole has
similar activity to megestrol and tamoxifen in the setting of metastasis, but
has been shown in phase II trials to inhibit cortisol and aldosterone
production. Anastrozole and letrozole have similar toxicity profiles. Compared
with megestrol, anastrozole improves overall survival and has superior
tolerability. Letrozole is superior to megestrol and aminoglutethimide in terms
of overall survival and time to progression, and is also better tolerated.
Although there is a strong rationale for using these agents in the treatment of
breast cancer, the information presently available is insufficient to recommend
any one agent over another. Direct comparative studies are lacking, and
comparing agents across studies is limited by many biases and may not be valid.
Formestane is only available as an injection and exemestane is not commercially
available in many countries, making these agents more difficult to recommend
over the other 3 agents. Fadrozole is less potent and less selective in
inhibiting aromatase than letrozole. The efficacies of fadrozole, megestrol and
tamoxifen appear to be similar; however, comparative data show no advantage of
fadrozole over letrozole. Anastrozole and letrozole are generally considered to
be similar agents. The clinical future of the selective aromatase inhibitors is
promising, and these agents may change the way postmenopausal breast cancer is
treated at all stages of the disease.
Publication Types:
Review
Review, Tutorial
PMID: 10514021 [PubMed - indexed for MEDLINE]
130: Clin Cancer Res 1999 Sep;5(9):2338-43
Impact of tamoxifen on the pharmacokinetics and endocrine effects of the
aromatase inhibitor letrozole in postmenopausal women with breast cancer.
Dowsett M, Pfister C, Johnston SR, Miles DW, Houston SJ, Verbeek JA, Gundacker
H, Sioufi A, Smith IE.
Department of Biochemistry, Royal Marsden Hospital, London, United Kingdom.
This study examined whether the addition of tamoxifen to the treatment regimen
of patients with advanced breast cancer being treated with the aromatase
inhibitor letrozole led to any pharmacokinetic or pharmacodynamic interaction.
Twelve of 17 patients completed the core period of the trial in which 2.5 mg/day
letrozole was administered alone for 6 weeks and in combination with 20 mg/day
tamoxifen for the subsequent 6 weeks. Patients responding to treatment continued
on the combination until progression of disease or any other reason for
discontinuation. Plasma levels of letrozole were measured at the end of the
6-week periods of treatment with letrozole alone and the combination and once
more between 4 and 8 months on combination therapy. No further measurements were
done thereafter. Hormone levels were measured at 2-week intervals throughout the
core period. Marked suppression of estradiol, estrone, and estrone sulfate
occurred with letrozole treatment, and this was not significantly affected by
the addition of tamoxifen. However, plasma levels of letrozole were reduced by a
mean 37.6% during combination therapy (P<0.0001), and this reduction persisted
after 4-8 months of combination therapy. Letrozole is the first drug to be
described in which this pharmacokinetic interaction occurs with tamoxifen. The
mechanism is likely to be a consequence of an induction of
letrozole-metabolizing enzymes by tamoxifen but was not further addressed in
this study. It is possible that the antitumor efficacy of letrozole may be
affected. Thus, sequential therapy may be preferable with these two drugs. It is
not known whether tamoxifen interacts with other members of this class of drugs
or with other drugs in combination.
Publication Types:
Clinical Trial
Multicenter Study
PMID: 10499602 [PubMed - indexed for MEDLINE]
131: Neth J Med 1999 Aug;55(2):50-8
New aromatase inhibitors for the treatment of advanced breast cancer in
postmenopausal women.
de Jong PC, Blijham GH.
Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The
Netherlands.
Inhibition of the enzyme aromatase, the rate limiting step in estrogen
production, is an effective endocrine treatment of advanced postmenopausal
breast cancer. Recently, several new aromatase inhibitors have been developed to
improve efficacy and reduce toxicity compared to the prototype aromatase
inhibitor aminoglutethimide. Aromatase inhibitors can be divided into two types.
The first are the non-steroidal inhibitors that have a mechanism of action
similar to aminoglutethimide. The second are the steroidal inhibitors that
function as a false substrate for aromatase. Of the non-steroidal aromatase
inhibitors, two drugs, anastrozole and letrozole, have recently been registered
for the second line endocrine treatment of advanced postmenopausal breast cancer
after failure on tamoxifen. The phase III studies of these drugs indicate at
least equal efficacy compared to current second line treatment with
aminoglutethimide or megestrol acetate. Their toxicity profile, however, is much
more favourable. This makes them the drugs of choice for the second line
endocrine treatment of advanced breast cancer in postmenopausal patients, who
failed during adjuvant or first line treatment with tamoxifen. Of the steroidal
aromatase inhibitors, the orally active drug exemestane is still in phase III
clinical study; the registration is expected in 1999.
Publication Types:
Review
Review, Tutorial
PMID: 10474272 [PubMed - indexed for MEDLINE]
132: Drugs 1999 Aug;58(2):233-55
Comprehensive pharmacology and clinical efficacy of aromatase inhibitors.
Njar VC, Brodie AM.
Department of Pharmacology and Experimental Therapeutics, School of Medicine,
University of Maryland, Baltimore 21201, USA.
The goal of hormone therapy is to deprive breast tumours of estrogens, since
estrogens have been implicated in the development or progression of tumours.
This can be accomplished by the use of antiestrogens that block estrogen action
or by inhibiting aromatase, the enzyme that catalyses the final and
rate-limiting step in estrogen biosynthesis. A number of steroidal and
nonsteroidal compounds have been developed as aromatase inhibitors. This review
highlights the valuable role that a few of these aromatase inhibitors have
played, and continue to play, in the treatment of breast cancer. Following
background information regarding the biochemistry of aromatase, the rationale
for its inhibition, and an outline of the test systems for evaluating and
characterising aromatase inhibitors, the discussion focuses on the new
generation of aromatase inhibitors that are in clinical trials or clinically
available. Specifically, it discusses the pharmacology and clinical efficacy of
formestane, exemestane, rogletimide, fadrozole, vorozole, anastrozole and
letrozole. The role of these agents as the optimal second-line agents (after
tamoxifen) for the treatment of advanced breast cancer has been established;
their prospects in other clinical settings and as potential breast cancer
chemopreventives are warranted but are yet to be fully determined.
Publication Types:
Review
Review, Academic
PMID: 10473018 [PubMed - indexed for MEDLINE]
133: Ann Ital Chir 1999 May-Jun;70(3):377-89
[Treatment of metastatic breast carcinoma]
[Article in Italian]
Puglisi F, Sobrero A.
Dipartimento di Ricerche Mediche e Morfologiche, Cattedra di Oncologia Medica,
Universita degli Studi di Udine.
In spite of major advances in early detection and adjuvant therapy, metastatic
breast cancer remains a major clinical problem affecting a significant number of
patients. Metastatic disease is generally considered incurable and conventional
therapy is used mainly with palliative intent. Therefore, the choice of
appropriate therapeutic approach requires a reasoned evaluation of the
likelihood of benefit from therapy balanced with the impact of therapy on the
patient's quality of life. The estimated aggressiveness of the tumour and
indicators of response to therapy (e.g. the status of hormonal receptors) are
useful parameters to take into account before selecting a given treatment.
Endocrine therapy is an important option in the management of stage IV disease,
with tamoxifen the most widely used first-line drug in postmenopausal women. For
progressing patients, the third generation of aromatase inhibitors (letrozole,
anastrazole) are considered good second-line endocrine agents. The LH-RH
agonists represent the initial choice in premenopausal patients candidate to
receive hormonal therapy, with the use of tamoxifen as a valuable alternative.
Combination chemotherapy regimens (e.g. CMF or CAF) are usually used for
first-line treatment of patients with aggressive, steroid receptor-negative
disease. Recently, several relatively new agents have shown significant activity
in metastatic breast cancer. In particular, the taxanes (paclitaxel and
docetaxel) are particularly promising as single agents but also in combination
with other drugs, especially anthracyclines. Finally, another class of agents,
the d mention because they represent an important new treatment modality in the
management of metastatic.
Publication Types:
Review
Review, Tutorial
PMID: 10466241 [PubMed - indexed for MEDLINE]
134: Eur J Cancer 1999 Feb;35(2):208-13
Double-blind, randomised, multicentre endocrine trial comparing two letrozole
doses, in postmenopausal breast cancer patients.
Bajetta E, Zilembo N, Dowsett M, Guillevin L, Di Leo A, Celio L, Martinetti A,
Marchiano A, Pozzi P, Stani S, Bichisao E.
Division of Medical Oncology B, Istituto Nazionale per lo Studio e la Cura dei
Tumori, Milan, Italy.
Letrozole is an orally competitive aromatase inhibitor. This double-blind,
randomised, multicentre trial was carried out to evaluate the endocrine effects
of two doses of letrozole, 0.5 mg versus 2.5 mg orally daily, in postmenopausal
advanced breast cancer patients progressing after tamoxifen. The
pharmacokinetics of letrozole was also assessed. 46 patients entered the trial,
22 on letrozole 0.5 mg and 24 on 2.5 mg. A significant suppression of oestrone
and oestradiol levels was achieved by both letrozole doses. Neither letrozole
dose induced any changes in cortisol and aldosterone production at rest or after
Synacthen stimulation. Androstenedione, testosterone, 17 alpha-OH progesterone,
triiodothyronine (T3) thyroxine, (T4) and thyroid-stimulating hormone (TSH)
plasma levels did not show any significant changes. Sex hormone binding globulin
(SHBG), follicle-stimulating hormone (FSH) and luteinising hormone (LH) levels
increased significantly over time. Plasma letrozole concentrations increased
until reaching steady-state values after 1 month at the dose of 0.5 mg and after
2 months at 2.5 mg. In conclusion, both letrozole doses suppressed oestrogen
levels without affecting adrenal activity.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 10448261 [PubMed - indexed for MEDLINE]
135: Clin Cancer Res 1999 Jul;5(7):1642-9
Evaluation of tamoxifen plus letrozole with assessment of pharmacokinetic
interaction in postmenopausal women with metastatic breast cancer.
Ingle JN, Suman VJ, Johnson PA, Krook JE, Mailliard JA, Wheeler RH, Loprinzi CL,
Perez EA, Jordan VC, Dowsett M.
Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
[email protected]
The goals of this clinical trial involving postmenopausal women with metastatic
breast cancer were to: (a) examine the effects of letrozole on tamoxifen (TAM)
pharmacokinetics; (b) examine estrogen suppression in patients receiving TAM
plus letrozole; and (c) evaluate tolerability, toxicity, objective response, and
time to progression for the combination. Postmenopausal women with measurable or
evaluable metastatic breast cancer received TAM (20 mg daily) for 6 weeks, and
then letrozole (2.5 mg daily) was added. To examine for any effect of letrozole
on the levels of TAM and two metabolites [N-desmethyl-TAM and 4-hydroxy-TAM],
serum samples were obtained at 6, 12, 18, and 24 weeks. To examine for aromatase
inhibition, serum samples were obtained before treatment and at 6, 12, 18, and
24 weeks for estradiol, estrone (E1) E1 sulfate, and sex hormone-binding
globulin. A total of 34 patients were entered on this trial, and 23 patients
were still on study at week 24, 18 of whom had blood samples available at both
week 6 and week 24. The 95% confidence interval for the mean difference between
levels at week 24 and levels at week 6 was -34 to 15 ng/ml for TAM, -35 to 45
ng/ml for N-desmethyl-TAM, and -1 to 2 for 4-hydroxy-TAM. For estradiol, a
significant decrease (median, 88.5%; range, 73.7-95.2%) was identified after 6
weeks of letrozole, which was maintained for an additional 12 weeks. Similar
significant reductions were identified for E1. E1 sulfate levels increased after
6 weeks of TAM alone but then decreased significantly after the addition of
letrozole. Sex hormone-binding globulin levels were significantly elevated after
6 weeks of TAM alone and remained elevated after the addition of letrozole. Six
of the 34 patients (17.6%) achieved an objective response (95% confidence
interval, 6.8-34.5%), with a median time to disease progression of 7.6 months.
There was no indication of a systematic decrease in TAM, N-desmethyl-TAM, or
4-hydroxy-TAM after the additional of letrozole. Estrogen suppression induced by
letrozole was substantial despite the concomitant administration of TAM. The
antitumor effect of TAM plus letrozole was less than expected.
Publication Types:
Clinical Trial
Clinical Trial, Phase II
PMID: 10430063 [PubMed - indexed for MEDLINE]
136: J Steroid Biochem Mol Biol 1999 Apr-Jun;69(1-6):205-10
Aromatase and its inhibitors.
Brodie A, Lu Q, Long B.
Department of Pharmacology and Experimental Therapeutics, School of Medicine,
University of Maryland, Baltimore 21201, USA. [email protected]
Inhibitors of aromatase (estrogen synthetase) have been developed as treatment
for postmenopausal breast cancer. Both steroidal substrate analogs, type I
inhibitors, which inactivate the enzyme and non-steroidal competitive
reversible, type II inhibitors, are now available. 4-hydroxyandrostenedione
(4-OHA), the first selective aromatase inhibitor, has been shown to reduce serum
estrogen concentrations and cause complete and partial responses in
approximately 25% of patients with hormone responsive disease who have relapsed
from previous endocrine treatment. Letrozole (CGS 20, 269) and anastrozole (ZN
1033) have been recently approved for treatment. Both suppress serum estrogen
levels to the limit of assay detection. Letrozole has been shown to be
significantly superior to megace in overall response rates and time to treatment
failure, whereas anastrozole was found to improve survival in comparison to
megace. Both were better tolerated than the latter. The potential of aromatase
within the breast as a significant source of estrogen mediating tumor
proliferation and which might determine the outcome of inhibitor treatment was
explored. Using immunocytochemistry and in situ hybridization, aromatase and
mRNAarom was detected mainly in the epithelial cells of the terminal ductal
lobular units (TDLU) of the normal breast and also in breast tumor epithelial
cells as well as some stromal cells. Increase in proliferation, measured by
increased thymidine incorporation into DNA and by PCNA immunostaining in
response to testosterone was observed in histocultures of breast cancer samples.
This effect could be inhibited by 4-OHA and implies that intratumoral aromatase
has functional significance. An intratumoral aromatase model in the
ovariectomized nude mouse was developed which simulated the hormone responsive
postmenopausal breast cancer patient. This model also allows evaluation of the
efficacy of aromatase inhibitors and antiestrogens in tumors of estrogen
receptor positive, human breast carcinoma cells transfected with the human
aromatase gene. Thus, the cells synthesized estrogen which stimulated tumor
formation. Both aromatase inhibitors and antiestrogens were effective in
suppressing tumor growth in this model. However, letrozole was more effective
than tamoxifen. When the aromatase inhibitors were combined with tamoxifen,
tumor growth was suppressed to about the same extent as with the aromatase
inhibitors alone. Thus, there was no additive or synergistic effects of
combining tamoxifen with aromatase inhibitors. This suggests that sequential
treatment with these agents is likely to be more beneficial to the patient in
terms of longer response to treatment.
Publication Types:
Review
Review, Tutorial
PMID: 10418994 [PubMed - indexed for MEDLINE]
137: Oncologist 1998;3(2):129-130
Molecular Action and Clinical Relevance of Aromatase Inhibitors.
Murphy MJ Jr.
AlphaMed Press, Miamisburg, Ohio, 45342-3758, USA. mjm@alphamed press.com
BREAST CANCER: HIGH PREVALENCE AND RISING INCIDENCE: Breast cancer is the most
common form of cancer among women in Europe, North and South America and
Australasia; approximately 1 in 10 women in Western countries will develop
breast cancer during their lifetime. It is estimated that the disease will
affect five million women worldwide over the next decade, and the incidence of
breast cancer is increasing on average by about 1% per year in industrialized
countries and at a greater rate in developing countries. COMPLEX ETIOLOGY:
Although the specific etiology of breast cancer remains unknown, a number of
factors are recognized which increase a woman's risk of developing the disease.
Genetic predisposition, or family history of breast cancer, is known to be
responsible for 5% of all cases. However, the variation in incidence throughout
populations, and changes relating to population migration and adoption of
altered lifestyles, all point to the critical importance of nongenetic
determinants. Such factors include early menarche, late menopause, late age at
birth of first child or nulliparity, a history of benign breast disease, and
diet. There is also evidence that hormones play a major role in the etiology of
breast cancer, with the risk of developing malignancies related to the
cumulative exposure of the breast to estrogen and progesterone, which stimulate
the growth of tumor cells. TREATMENT FOR EARLY BREAST CANCER: SURGERY -/+
ADJUVANT THERAPY: At the time of diagnosis, approximately 50% of patients will
be diagnosed with early breast cancer. This proportion is increasing as a
consequence of the introduction of early detection programs. Surgery remains the
primary treatment for early breast cancer, and the frequency of radical
mastectomy has been replaced by breast conserving surgery. After surgery, other
therapeutic modalities such as radiation, chemotherapy or endocrine therapy may
be given in the adjuvant setting. Surgical cure rates vary for patients with
early breast cancer; the US figure is approximately 40%, and there are no
definitive means to predict those who will be cured and those who will have
recurrent disease. As a result, following primary surgical treatment, adjuvant
therapy is usually recommended to destroy any remaining cancer cells at the
primary site, to control micrometastases and to prolong disease-free survival,
with the ultimate aim of providing an overall survival benefit. Upon disease
recurrence in the remaining 60% of patients, endocrine therapy and chemotherapy
represent the two general classes of treatment. One of the principle decisions
to be taken in advanced breast cancer is which therapy to select in order to
maximize patient benefit. The choice is largely dependent upon prognostic
factors and whether the patient is pre- or postmenopausal. ENDOCRINE THERAPY OR
CHEMOTHERAPY IN ADVANCED BREAST CANCER: Unlike chemotherapy, endocrine therapy
is not cytotoxic and is therefore better tolerated by the patient. A recent
study comparing therapy for prognostically different groups showed that patients
benefiting most from the use of sequential endocrine agents are those regarded
as low risk. The preferred sequence of treatment has been suggested to be
tamoxifen followed by selective aromatase inhibitor and then a progestin.
ENDOCRINES AND ENZYMES OFFER NEW TREATMENTS FOR ADVANCED BREAST CANCER:
ESTROGEN-DRIVEN BREAST CANCER: Since 1896, when Sir George Beatson demonstrated
that ovariectomy induced regression of mammary tumors in women, the aim of
endocrine breast cancer therapy has been to selectively deprive the body of
estrogen. Ovariectomy accomplished this by removing the gland that is the
predominant source of estrogens in premenopausal women. Since the avoidance of
such surgery is preferable, emphasis is devoted to the pharmacological
inhibitors of estrogen production. ENDOCRINE PATHWAY REVEALS "ACHILLES' HEEL":
Like other steroid hormones, the two circulating estrogens-estrone and
estradiol-are produced from cholesterol. Inhibiting the enzymes that are
involved at earlier steps in the branching pathway of steroidogenesis could have
an undesirable impact on the production of other physiologically important
hormones such as aldosterone and cortisol. Since aromatase catalyzes the last
step in estrogen production, it makes an ideal target for the development of
selective and potent inhibitors (Fig. 1). STRUCTURE OF AROMATASE REVEALS SECRETS
OF SELECTIVE INHIBITION: Aromatase is a cytochrome P450 enzyme, with both an
iron-containing and a steroid-binding site. The substrate, androstenedione, sits
in the enzyme's steroid-binding site, that site which otherwise catalyzes the
formation of estrogen. From this structural relationship, there are, therefore,
two reasonable ways to inhibit aromatase: * by occupying the steroid-binding
site of the enzyme with a compound such as formestane (Lentaron®), or * by
binding the iron with nitrogen-containing compounds such as aminoglutethimide
(Orimeten®), the oldest aromatase inhibitor. AROMATASE INHIBITORS: STEROIDAL
AND NON-STEROIDAL: Formestane (Lentaron®) is the only commercially available
steroidal compound which inhibits aromatase and must be administered
parenterally. Other new aromatase inhibitors such as fadrozole (Afema®) and
letrozole (Femara®) are orally active nitrogen-containing compounds that
bind the heme iron of aromatase. AMINOGLUTETHIMIDE VERSUS LETROZOLE: OLD VERSUS
NEW: Although aminoglutethimide has long been used to treat advanced breast
cancer, its aromatase inhibition is not selective. Consequently,
aminoglutethimide also binds to and thereby inhibits several other cytochrome
P450 enzymes in the steroidogenesis pathway. An ideal aromatase inhibitor would
fit the catalytic site of aromatase optimally and would thus interact only with
aromatase. The affinity of letrozole (Femara®) for the heme group of
aromatase makes it a selective and potent inhibitor (Fig. 2). In fact, studies
show that Femara® has little effect on the other adrenal steroids, and is
the most selective aromatase inhibitor available today.
PMID: 10388095 [PubMed - as supplied by publisher]
138: Ann Oncol 1999 Apr;10(4):377-84
The third-generation non-steroidal aromatase inhibitors: a review of their
clinical benefits in the second-line hormonal treatment of advanced breast
cancer.
Hamilton A, Piccart M.
Institut Jules Bordet, Brussels, Belgium.
Three new aromatase inhibitors have recently completed phase III evaluation as
treatment of metastatic breast cancer in post-menopausal women whose disease has
progressed despite tamoxifen therapy: anastrozole (ARIMIDEX, Zeneca), letrozole
(FEMARA, Novartis) and vorozole (RIVIZOR, Janssen). All belong to the third
generation of non-steroidal aromatase inhibitors, and each is superior to
previous generations in terms of potency and selectivity. The trials that have
been performed compare each agent to megestrol acetate, and letrozole and
vorozole to aminoglutethimide. Although the studies are not directly comparable
due to differing study designs and patient populations, it has been demonstrated
each of these drugs provides single agent, once-daily, oral palliation of
hormone-responsive, post-menopausal metastatic breast cancer. Letrozole is
clearly more effective than megestrol acetate, and anastrozole and vorozole are
possibly so. All three are better tolerated than the progestin, particularly in
terms of weight gain. Both letrozole and vorozole are significantly more
effective, and better tolerated than aminoglutethimide. Overall, this most
recent generation of aromatase inhibitors is a clear improvement on our current
standard second-line therapies. In 1999, tamoxifen remains the first choice in
the hormonal therapy of breast cancer. Following tamoxifen failure, the optimal
second-line hormonal therapy remains undefined, but aminoglutethimide and
megestrol acetate are no longer optimal therapy in this setting. The
third-generation non-steroidal aromatase inhibitors must now be compared to each
other, to the steroidal aromatase inhibitors, to the pure anti-oestrogens, and
to tamoxifen.
Publication Types:
Review
Review, Academic
PMID: 10370778 [PubMed - indexed for MEDLINE]
139: Ross Fiziol Zh Im I M Sechenova 1998 Nov;84(11):1242-6
[Metabolism of the androgenic precursor androstenedione and effects of aromatase
inhibitors in cultured blood lymphocytes]
[Article in Russian]
Bershtein LM, Poroshina TE, Larionov AA, Zimarina TS.
Petrov Research Institute of Oncology, St. Petersburg.
Blood lymphocytes from 26 women were cultivated in RPMI-1640 for 72 hrs with or
without dexamethasone, dbcAMP, and TPA. Androstenedione conversion was most
often activated by the dbcAMP, then by Dex and TPA. Response to dbcAMP was most
obvious in women under 50, whereas response to Dex--in women over 50. Aromatase
inhibitor fadrosol displayed a tendency towards prevention of the activation of
androstenedione conversion in cultivated lymphocytes. A possibility of aromatase
gene induction in cultivated lymphocytes cannot be completely excluded and
demands further investigation with the aid of molecular-genetic methods.
PMID: 10204168 [PubMed - indexed for MEDLINE]
140: J Steroid Biochem Mol Biol 1998 Dec;67(5-6):403-11
Macrophages, estrogen and the microenvironment of breast cancer.
Mor G, Yue W, Santen RJ, Gutierrez L, Eliza M, Berstein LM, Harada N, Wang J,
Lysiak J, Diano S, Naftolin F.
Department of Obstetrics and Gynecology, Center for Research in Reproductive
Biology, Yale University School of Medicine, New Haven, CT 06520, USA.
Estrogen is a major mitogenic stimulus to established breast cancer. Estrogen
sources include ovarian, extraglandular sites and breast tissue. Which source
primarily maintains benign and breast cancer tissue estrogen concentrations
remains unclear. While macrophages may comprise up to 50% of the mass of breast
carcinomas, previous studies neglected to study them as possible sources of
estrogen. We present evidence that breast macrophages constitute an in situ
source of estradiol and that the amount produced is sufficient to mediate
cellular proliferation. We utilized immunohistochemistry and RT-PCR to study
cell-specific aromatase expression in (i) 29 breast biopsies, (ii) human
monocytes/macrophages and (iii) a myeloid cell line (THP-1) capable of
differentiating into macrophages. Use of a breast cancer cell line (MCF-7)
provided biologic confirmation of the role of aromatization in cell
proliferation. We demonstrated considerable amounts of immunoreactive-aromatase
(irARO) in breast tissue macrophages and a positive correlation between the
proportion of irARO present in macrophages and lesion severity. Using in vitro
techniques, we demonstrated that monocytes and THP-1 cells require
differentiation into macrophages to produce aromatase in amounts approaching
placental levels. The amount of estrogen produced by THP-1 cells stimulated
MCF-7 cells to proliferate, an effect blocked by aromatase inhibitors. Estrogen
production by macrophages in breast tissue appears sufficient to stimulate the
proliferation of adjacent epithelial cells and to autoregulate cytokine
production. These findings represent a new dimension of cellular regulation in
breast tissue with major biologic implications, amenable to pharmacological
manipulation.
PMID: 10030689 [PubMed - indexed for MEDLINE]
141: Recent Results Cancer Res 1998;152:277-84
Aromatase inhibitors and their use in the adjuvant setting.
Coombes RC.
Department of Cancer Medicine, Imperial College School of Medicine, Charing
Cross Hospital, London, UK.
Over the past decade several novel aromatase inhibitors have been introduced
into clinical practice. The discovery of these drugs followed on from the
observation that the main mechanism of action of aminoglutethemide was via
inhibition of the enzyme aromatase, thereby reducing peripheral levels of
estradiol in post-menopausal patients. The second-generation drug
4-hydroxyandrostenedione was introduced in 1990, and although its use was
limited by its need to be given parenterally, it was found to be a
well-tolerated form of endocrine therapy. The third-generation inhibitors
include vorozole, letrozole, anastrozole and exemestane, the former three being
non-steroidal inhibitors, the latter being a steroidal inhibitor. All these
compounds are capable of reducing estrogen levels to within 5%-10% of baseline
levels compared with 20%-30% base line levels in the case of
4-hydroxyandrostenedione. Studies are currently in progress to determine the
value of these third-generation aromatase inhibitors in the adjuvant setting.
These studies include head-to-head comparison of aromatase inhibitor with
tamoxifen, sequential aromatase inhibitor after tamoxifen and first-line
aromatase inhibitor followed by adjuvant tamoxifen. Current issues revolve
around the toxicity of these compounds in terms of effects on the cardiovascular
system and bone.
Publication Types:
Review
Review, Tutorial
PMID: 9928565 [PubMed - indexed for MEDLINE]
142: Presse Med 1998 Dec 12;27(39):2049-54
[Breast cancer: new therapeutic strategies]
[Article in French]
Espie M.
Hopital St Louis, Centre des Maladies du Sein, Paris. [email protected]
NEED FOR NEW CHEMOTHERAPY AGENTS: Metastasic breast cancer is an excellent model
for studying anticancer agents: chemotherapy or hormonotherapy or compounds
modifying the organism's response. If no adjuvant treatment is given after
locoregional treatment of breast cancer, metastasis will develop within 10 years
in 30% of the patients free of initial nodal invasion and within 5 years in 50%
of the patients with initial nodal invasion. ADJUVANT TREATMENTS: Hormonotherapy
and chemotherapy reduce mortality due to breast cancer by 10%. New adjuvant
agents have been recently introduced. Taxans (docetaxel, paclitaxel) are the
most active molecules since antracyclines. New aromataase inhibitors include
letrozole and anastrozole. Their efficacy has been demonstrated in phase II and
phase III trials, allowing their experimentation as adjuvant treatments.
Publication Types:
Clinical Trial
Clinical Trial, Phase II
Clinical Trial, Phase III
Randomized Controlled Trial
PMID: 9893697 [PubMed - indexed for MEDLINE]
143: J Steroid Biochem Mol Biol 1998 Nov;67(4):293-304
The steroidal antiestrogen ICI 182,780 is an inhibitor of cellular aromatase
activity.
Long BJ, Tilghman SL, Yue W, Thiantanawat A, Grigoryev DN, Brodie AM.
Department of Pharmacology and Experimental Therapeutics, The University of
Maryland School of Medicine, Baltimore 21201, USA.
Two types of endocrine therapy that have been successfully applied to patients
with hormone-dependent breast cancer are the non-steroidal antiestrogen
tamoxifen, and inhibitors of aromatase, the enzyme that synthesizes estrogens.
The major drawback with tamoxifen is that it acts as a partial estrogen-agonist
and this is believed to mediate, at least in part, acquired tumor resistance to
the drug as well as endometrial hyperplasia and carcinoma in some patients. The
newer and more potent antiestrogen ICI 182,780 is a steroidal molecule that is
devoid of estrogenic activity. We now report that ICI 182,780 is also an
inhibitor of aromatase activity in fibroblasts isolated from the normal human
breast as well as other carcinoma cell lines that express aromatase (MCF-7Ca
breast cancer and JEG-3 choriocarcinoma). ICI 182,780 (1 microM) did not affect
aromatase activity levels in human placental microsomes and only inhibited
aromatase activity in each of the cell lines following a prolonged incubation
period. In the fibroblasts, inhibition of aromatase activity by ICI 182,780 was
shown to be time and dose-dependent. In contrast, tamoxifen and 17beta-estradiol
were shown to have no effect on aromatase activity levels. ICI 182,780 inhibited
aromatase activity levels with IC50 values of 16.80 nM in MCF-7Ca cells, 125.50
nM in JEG-3 cells and 386.1 nM in breast fibroblasts. These values were compared
to those for known aromatase inhibitors, and in each of the cell lines the order
of potency was letrozole>4-OHA>anastrozole>ICI 182,780. The inhibition of
aromatase activity by ICI 182,780 was sustained even after the antiestrogen was
removed from the cells indicating that ICI 182,780 may be remaining bound to the
enzyme. Although ICI 182,780 had no effect on the proliferation of the
fibroblasts, or JEG-3 cells, it significantly inhibited the growth of MCF-7Ca
cells. This growth inhibition appeared to be due to the antiestrogenic activity
of ICI 182,780 and not to its aromatase inhibiting effects. ICI 182,780 did not
inhibit aromatase activity by down-regulating levels of the aromatase
transcript. These results show that in addition to being a potent antiestrogen,
ICI 182,780 is also an inhibitor of cellular aromatase activity, and suggest
that by interfering with the actions of estrogen by two distinct mechanisms, ICI
182,780 may be a suitable drug for treating patients with hormone-dependent
breast cancer.
PMID: 9883986 [PubMed - indexed for MEDLINE]
144: Drugs 1998 Dec;56(6):1125-40
Letrozole. A review of its use in postmenopausal women with advanced breast
cancer.
Lamb HM, Adkins JC.
Adis International Limited, Auckland, New Zealand. [email protected]
Letrozole is an oral reversible nonsteroidal aromatase inhibitor. Clinical
tracer studies show that it inhibits peripheral aromatase by over 98% and
suppresses blood and urinary estrogen levels by over 95% after 2 weeks of
treatment in postmenopausal women. Letrozole also significantly inhibits
intratumoral aromatase in vivo. The action of letrozole appears to be selective
for aromatase; long term administration did not affect basal levels of 17
alpha-hydroxyprogesterone or aldosterone, although slight decreases in cortisol
levels were observed in 2 studies, these did not appear to be clinically
significant. In 2 phase IIb/III trials, letrozole 2.5 mg/day achieved objective
response rates of 19.5 and 23.6% which were sustained for a median duration of
24 and 33 months, respectively. The median duration of response compared
favourably with both comparator agents, aminoglutethimide and megestrol (15 and
18 months, respectively), as did objective response rates (12.4 and 16.4%).
Letrozole 2.5 mg/day was associated with an increase in median survival time of
8 and 3 months compared with aminoglutethimide and megestrol, respectively.
According to analyses of overall function, letrozole 2.5 mg/day was
significantly superior to both comparators with respect to duration of response
and aminoglutethimide with respect to survival. Letrozole has a good short term
tolerability profile. The adverse events reported most commonly in association
with letrozole 2.5 mg/day in the 2 phase IIb/III trials were headache (1.1 and
7%), nausea (6 and 10.3%), fatigue (3.2 and 5%), hot flushes (4.9 and 5%) and
peripheral oedema (6%). Events were usually mild to moderate in severity;
adverse events necessitated discontinuation of treatment in 3% of letrozole 2.5
mg/day recipients. CONCLUSIONS: Letrozole, in common with vorozole and
anastrozole, offers greater selectivity and potency of aromatase inhibition than
the prototype aromatase inhibitor, aminoglutethimide, and can be administered
once daily. Available clinical data suggest that letrozole achieves a
significantly longer duration of response than megestrol and aminoglutethimide
and longer overall survival than aminoglutethimide. However, direct comparisons
are required to distinguish between the newer aromatase inhibitors. For this
reason, letrozole should be recommended as a second-line treatment in
postmenopausal women with advanced breast cancer whose disease has progressed on
or failed to respond to antiestrogen therapy.
Publication Types:
Review
Review, Tutorial
PMID: 9878997 [PubMed - indexed for MEDLINE]
145: Cancer Pract 1998 Nov-Dec;6(6):349-52
Drug update: letrozole: A new aromatase inhibitor for metastatic breast cancer.
Mays-Holland T.
Pharmacy Practice, College of Pharmacy, University of Utah, Salt Lake City.
Publication Types:
Review
Review Literature
PMID: 9824427 [PubMed - indexed for MEDLINE]
146: Clin Cancer Res 1995 Dec;1(12):1511-5
In vivo measurement of aromatase inhibition by letrozole (CGS 20267) in
postmenopausal patients with breast cancer.
Dowsett M, Jones A, Johnston SR, Jacobs S, Trunet P, Smith IE.
Academic Department of Biochemistry and Department of Medicine, Royal Marsden
National Health Service Trust, Fulham Road, London SW3 6JJ, United Kingdom.
Thirteen postmenopausal women with advanced breast cancer were enrolled in an
open randomized Phase I trial of a new p.o. active aromatase inhibitor, CGS
20267 (letrozole). The primary aim of the trial was to assess the impact of two
doses of letrozole (0.5 and 2. 5 mg/day) on the peripheral aromatization of
androstenedione to estrone. An in vivo isotopic technique was used to measure
peripheral aromatization in each patient before treatment. The patients were
then randomly assigned to one of the two doses, and measurements of
aromatization were repeated after 6 weeks. At 0.5 mg and 2.5 mg/day, letrozole
inhibited aromatization by 98.4% (97.3 to >99.1) and >98.9% (98.5 to >99.1;
geometric means and ranges), respectively. Plasma estrogen levels were also
measured before and during treatment. At the dose of 0.5 mg/day estrone and
estradiol levels fell by 82.0% and 84.1% (geometric means), respectively. At the
dose of 2.5 mg/ day, the estrogens fell by 80.8% and 68.1%, respectively. There
were no significant differences between the doses in aromatase inhibition. No
formal statistical analysis was performed on the estrogen data. Letrozole is
therefore a highly effective inhibitor of aromatase, causing near complete
inhibition of the enzyme in peripheral tissues at the doses investigated. The
falls in estrogen levels were greater than those seen with earlier generation
aromatase inhibitors.
Publication Types:
Clinical Trial
Clinical Trial, Phase I
Randomized Controlled Trial
PMID: 9815951 [PubMed - indexed for MEDLINE]
147: Drugs Aging 1998 Oct;13(4):321-32
Anastrozole. A review of its use in the management of postmenopausal women with
advanced breast cancer.
Wiseman LR, Adkins JC.
Adis International Limited, Auckland, New Zealand. [email protected]
Anastrozole is a new oral nonsteroidal aromatase inhibitor indicated for the
second-line endocrine treatment of postmenopausal women with advanced breast
cancer. In postmenopausal women, anastrozole significantly reduces plasma
estrogen levels; maximal suppression is achieved at dosages > or = 1 mg/day and
levels remain suppressed during long term therapy. In two phase III clinical
trials, anastrozole 1 or 10 mg/day showed similar clinical efficacy to that of
oral megestrol (megestrol acetate) 160 mg/day in postmenopausal women with
advanced breast cancer. Primary end-points [including time to disease
progression (120 to 170 days) and overall response rates (complete and partial
response and stable disease lasting > or = 24 weeks: 29 to 37%)] and secondary
end-points [time to treatment failure (115 to 168 days) and duration of response
(257 to 261 days)] did not differ significantly between treatment groups.
However, a significant survival advantage was observed in patients treated with
anastrozole 1 mg/day compared with megestrol in a follow-up combined analysis of
patients enrolled in both studies (median time to death 26.7 vs 22.5 months).
Quality of life parameters were generally improved to a similar extent in all
treatment groups. Anastrozole is generally well tolerated in the majority of
patients, the most common adverse events being gastrointestinal (GI)
disturbances (incidence 29 to 33%). These events are generally mild or moderate
and transient. Other adverse events reported with anastrozole include headache
(< or = 18%), asthenia (< or = 16%), pain (< or = 15%), hot flushes and bone
pain (both < or = 12%), back pain and dyspnoea (both < or = 11%) and peripheral
oedema (< or = 9%). GI disturbance tended to be more common with anastrozole
than megestrol, particularly at the 10 mg/day dosage; however, compared with
megestrol, anastrozole is less frequently associated with weight gain.
CONCLUSIONS: Anastrozole, with its apparent survival advantage versus megestrol
(demonstrated in a combined analysis of phase III studies), convenient once
daily oral administration and acceptable short term tolerability profile, is a
second-line treatment option for postmenopausal patients with
tamoxifenrefractory advanced breast cancer. The results of ongoing comparative
trials with tamoxifen will determine the relative efficacy of anastrozole as
first-line endocrine therapy for advanced breast cancer and as adjuvant therapy
for early disease. In addition, direct comparative studies are required to
determine the efficacy of anastrozole relative to that of other oral aromatase
inhibitors such as letrozole and vorozole.
Publication Types:
Review
Review, Tutorial
PMID: 9805213 [PubMed - indexed for MEDLINE]
148: Breast Cancer Res Treat 1998 Jul;50(1):63-71
The effects of aromatase inhibitors and antiestrogens in the nude mouse model.
Lu Q, Yue W, Wang J, Liu Y, Long B, Brodie A.
Department of Pharmacology & Experimental Therapeutics, and Greenbaum Cancer
Center, School of Medicine, University of Maryland, Baltimore 21201, USA.
The effects of antiestrogens, tamoxifen and ICI 182,780, and aromatase
inhibitors, arimidex (anastrozole ZD1033) and letrozole (CGS 20,267), on the
growth of tumors were studied in nude mice. In this model, estrogen dependent
MCF-7 human breast cancer cells stably transfected with the aromatase gene were
inoculated in four sites per mouse. Sufficient estrogen is produced from
aromatization of androstenedione supplement (0.1 mg/mouse/day) by the cells to
stimulate their proliferation, tumor formation, and maintain the uterus similar
to that of the intact mouse. Once the tumors reached a measurable size, the mice
were injected with antiestrogen or inhibitor for 35-56 days. Tumor volumes were
measured weekly. At autopsy, the tumors were removed, cleaned, and weighed.
Statistical data was determined from tumor weights. Both antiestrogens were
effective in reducing tumor growth in these mice. Tamoxifen appears to be more
effective than ICI 182,780, although the former stimulated the uterine weight
whereas the pure antiestrogen did not. However, both aromatase inhibitors were
more effective than the antiestrogens. Tumor regression was observed with
letrozole. Thus, after-treatment tumor weights were less than those of a group
of mice at the start of treatment. The aromatase inhibitors also reduced the
weight of the uterus, suggesting that these compounds, as well as the pure
antiestrogen, may not cause endometrial proliferation, unlike tamoxifen. These
aromatase inhibitors may not only benefit patients who have relapsed from
tamoxifen, but may be more effective in patients as first line agents for
suppressing the effects of estrogen.
PMID: 9802621 [PubMed - indexed for MEDLINE]
149: Breast Cancer Res Treat 1998;49 Suppl 1:S93-9; discussion S109-19
Demonstration of aromatase activity and its regulation in breast tumor and
benign breast fibroblasts.
Santen RJ, Martel J, Hoagland M, Naftolin F, Roa L, Harada N, Hafer L, Zaino R,
Pauley R, Santner S.
Department of Internal Medicine, University of Virginia School of Medicine,
Charlottesville, USA.
Breast tumors from post-menopausal women contain higher amounts of estradiol
than would be predicted from levels circulating in plasma. This observation
raised the hypothesis that tumors may synthesize estradiol in situ and increase
their tissue estradiol levels via this mechanism. The key enzyme involved in
tissue estrogen synthesis, aromatase, is present in breast tumors but, according
to some investigators, not in sufficient concentration to be biologically
meaningful. We postulated that foci of cells in breast tumors might contain high
amounts of aromatase and this locally produced estrogen might act in a paracrine
or autocrine fashion. To test this hypothesis, we utilized immunohistochemistry
to localize the aromatase enzyme, an histological scoring system to quantitate
it, and culture of isolated breast cells to demonstrate its potential
regulation. In 26 archival breast tumors, 16 (62%) contained aromatase by
radiometric assay. With the immunohistochemical method, we detected areas with
staining in the stroma as well as tumor epithelial cells. Staining ranged from
the intensity approaching that seen in placenta to levels just distinguishable
from background. We adopted an histological scoring system (H-score) from that
used to quantitate progesterone receptor levels in tissue and used it to
quantitate aromatase activity. A higher histologic score was found in stromal
spindle cells (13) than in tumor epithelial cells (4.8). The biochemical
aromatase results correlated with the H-score of stromal but not epithelial
cells. To further study stromal cells from tumors, we isolated stromal cells
from breast tumors and the benign areas of breast distal to the tumor and grew
them in culture. Addition of dexamethasone, phorbol esters, and cyclic AMP
analogues stimulated aromatase enzyme and messenger RNA levels substantially.
Use of aromatase enzyme inhibitors such as letrozole blocked estrogen production
but did not alter aromatase message levels. Epithelial cells, whether
nonmalignant or cancer derived, exhibited no regulation by dexamethasone,
phorbol esters, or cAMP analogues. These data, taken together, suggest that
stromal cells may be more important than epithelial cancer cells for estrogen
production in breast tumors. The ability to stimulate aromatase activity
substantially with various enhancers of aromatase provides further credence for
an important biologic role of estrogen production in tumor tissue.
PMID: 9797023 [PubMed - indexed for MEDLINE]
150: Breast Cancer Res Treat 1998;49 Suppl 1:S67-71; discussion S73-7
Fadrozole and letrozole in advanced breast cancer: clinical and biochemical
effects.
Smith IE, Norton A.
Breast Unit, Section of Medicine, Royal Marsden Hospital, London, UK.
Publication Types:
Review
Review, Tutorial
PMID: 9797020 [PubMed - indexed for MEDLINE]
151: Breast Cancer Res Treat 1998;49 Suppl 1:S39-44; discussion S73-7
Theoretical considerations for the ideal aromatase inhibitor.
Dowsett M.
Royal Marsden Hospital, London, UK. [email protected]
A definition of the theoretical components of an ideal aromatase inhibitor is
developed, one aspect of which is completeness of enzyme inhibition. The three
triazole inhibitors, letrozole, vorozole and anastrozole all inhibit whole body
aromatisation by > 96% at their clinically used doses and vorozole and letrozole
were more effective in Phase III clinical trials than aminoglutethimide (250 mg
bd) which achieves < 90% inhibition. The possibility is considered that the
apparent small differences between the triazoles may be associated with
differences in clinical effectiveness. These new compounds merit consideration
for studies of breast cancer prevention.
Publication Types:
Review
Review, Tutorial
PMID: 9797016 [PubMed - indexed for MEDLINE]
152: Breast Cancer Res Treat 1998;49 Suppl 1:S27-32; discussion S33-7
Clinical importance of intratumoral aromatase.
Miller WR, Mullen P, Telford J, Dixon JM.
Breast Unit, Western General Hospital, Edinburgh, UK.
Evidence to support the contention that estrogen biosynthesis in breast cancers
is of clinical significance has been sought by relating activity to (i) clinical
response to aromatase inhibitors and (ii) tumor concentrations of estrogens.
Significant correlations have been reported between the presence/high levels of
tumor aromatase in vitro and likelihood of response to aminoglutethimide in
patients with advanced breast cancer, but the association is not absolute and it
has been more difficult to demonstrate similar relationships in patients with
earlier stages of cancers treated with other more potent inhibitors. There are
however data to suggest that in vitro measurements of aromatase may not reflect
in situ estrogen synthesis. For example mammary adipose tissue fibroblasts
preincubated with reversible aromatase inhibitors may paradoxically display
elevated in vitro aromatase activity. Similar enhanced in vitro activity may be
observed in breast material taken from patients treated neo-adjuvantly with
aromatase inhibitors such as aminoglutethamide and letrozole. That this is an
artifact of in vitro systems can be demonstrated by performing in situ
assessments of aromatase activity in patients before and after treatment with
aromatase inhibitors. Thus it can be shown that letrozole markedly inhibits in
situ aromatase and reduces tumor levels of estrogens.
Publication Types:
Review
Review, Tutorial
PMID: 9797015 [PubMed - indexed for MEDLINE]
153: Breast Cancer Res Treat 1998;49 Suppl 1:S23-6; discussion S33-7
Intratumoral aromatase model: the effects of letrozole (CGS 20267).
Brodie A, Lu Q, Yue W, Wang J, Liu Y.
Department of Pharmacology and Experimental Therapeutics, Greenebaum Cancer
Center, School of Medicine, University of Maryland, Baltimore 21201, USA.
An intratumoral aromatase model in the ovariectomized nude mouse was developed
which simulated the hormone responsive postmenopausal breast cancer patient.
MCF-7, human breast cancer cells transfected with the aromatase gene, inoculated
into ovariectomized nude mice are able to synthesize sufficient estrogens to
enhance cell proliferation and the development of tumors. These tumors are
responsive to both antiestrogens and aromatase inhibitors. However, letrozole
was found to be more effective than tamoxifen and caused tumor regression, a
result not previously noted in nude mice with endocrine treatments. When the
aromatase inhibitors were combined with tamoxifen, tumor growth was suppressed
to about the same extent as treatment with the aromatase inhibitors alone. Thus,
there was no additive or synergistic effects of combining tamoxifen with
aromatase inhibitors. These results suggest that letrozole has the potential to
be more effective than tamoxifen for achieving greater reduction in estrogenic
effects on tumors and uterus in postmenopausal breast cancer patients. In
addition, sequential treatment with these agents is likely to be more beneficial
to the patient in terms of longer response to treatment.
PMID: 9797014 [PubMed - indexed for MEDLINE]
154: J Clin Pharmacol 1998 Aug;38(8):727-35
Plasma protein binding of letrozole, a new nonsteroidal aromatase enzyme
inhibitor.
Colussi DM, Parisot CY, Lefevre GY.
Department of Drug Metabolism and Pharmacokinetics, Novartis Pharma S.A.,
Rueil-Malmaison, France.
The protein binding characteristics of the nonsteroidal aromatase inhibitor
letrozole were determined using 14C-labeled letrozole. The binding of letrozole
in human serum was 60.1 +/- 2.9% as a mean obtained in six individual sera and
was similar in human plasma. The binding in human serum remained constant at
concentrations of letrozole ranging from 10 to 500 ng/mL. A similar binding
value in human serum was obtained using equilibrium dialysis and ultrafiltration
technique. Albumin (binding 55.1 +/- 1.4%) is the main protein involved in the
drug binding to plasma proteins. Increases in letrozole concentration (10-500
ng/mL) had no effect on binding. Albumin binding appeared to be nonsaturable
with a binding capacity of 2 L/mmol. Binding to alpha1-acid glycoprotein and to
gamma globulins was lower than 10%. The fraction in erythrocytes with a
hematocrit of 0.4 was found to be 35.2 +/- 2.7%. Letrozole binding to serum
proteins of rat, dog, mouse, and rabbit was approximately 10% lower than that in
human serum and approximately 20% lower than that in baboons. Tamoxifen
(100-1,500 ng/mL) had no effect on the in vitro binding of letrozole. Ex vivo
binding in plasma from patients after repeated administration of letrozole alone
(61.4 +/- 2.6%) was the same as after combined administration of letrozole and
tamoxifen (60.0 +/- 3.2%).
PMID: 9725549 [PubMed - indexed for MEDLINE]
155: J Clin Oncol 1998 Aug;16(8):2892-3
Comment on:
J Clin Oncol. 1998 Feb;16(2):453-61.
Letrozole for advanced breast cancer.
Hoctin-Boes G, Yates R, Steinberg M.
Publication Types:
Comment
Letter
PMID: 9704745 [PubMed - indexed for MEDLINE]
156: Ann Oncol 1998 Jun;9(6):639-45
Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg
daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced
breast cancer. Letrozole International Trial Group (AR/BC3).
Gershanovich M, Chaudri HA, Campos D, Lurie H, Bonaventura A, Jeffrey M, Buzzi
F, Bodrogi I, Ludwig H, Reichardt P, O'Higgins N, Romieu G, Friederich P, Lassus
M.
N. N. Petrov Research Institute of Oncology, St. Petersburg, Russia.
BACKGROUND: The study compares letrozole and aminoglutethimide (AG), a standard
therapy for postmenopausal women with advanced breast cancer, previously treated
with antioestrogens. PATIENTS AND METHODS: 555 women were randomly assigned
letrozole 2.5 mg once daily (n = 185), letrozole 0.5 mg once daily (n = 192) or
aminoglutethimide 250 mg twice daily with corticosteroid support (n = 178) in an
open-label, multicentre trial. The primary endpoint was objective response rate
(ORR), with time events as secondary. ORR was analysed nine months after
enrollment of the last patient, while survival was analysed 15 months after the
last patient was enrolled. We report the results of these analyses plus an
extended period of observation (covering a total duration of approximately 45
months) to determine the duration of response and clinical benefit. RESULTS:
Overall objective response rates (complete + partial) of 19.5%, 16.7% and 12.4%
were seen for letrozole 2.5 mg, 0.5 mg and AG respectively. Median duration of
response and stable disease was longest for letrozole 2.5 mg (21 months)
compared with letrozole 0.5 mg (18 months) and AG (14 months). Letrozole 2.5 mg
was superior to AG in time to progression, time to treatment failure and overall
survival. Treatment-related adverse events occurred in fewer patients on
letrozole (33%) than on AG (46%). Transient nausea was the most frequent event
with letrozole (7% on 0.5 mg, 10% on 2.5 mg, 10% on AG), rash with AG (11%, 1%
on 0.5 mg, 3% on 2.5 mg letrozole). CONCLUSIONS: Letrozole 2.5 mg offers longer
disease control than aminoglutethimide and letrozole 0.5 mg in the treatment of
postmenopausal women with advanced breast cancer, previously treated with
anti-oestrogens.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 9681078 [PubMed - indexed for MEDLINE]
157: Schweiz Rundsch Med Prax 1998 Apr 22;87(17):584-8
[Aromatase inhibitors--new possibilities in treatment of breast carcinoma]
[Article in German]
Friedrichs K, Janicke F.
Frauenklinik und Poliklinik, Universitats-Krankenhaus Eppendorf, Hamburg.
Aromatase inhibition is now an acknowledged second line treatment modality for
advanced breast cancer in postmenopausal women. Aminoglutethimide is an
inhibitor of adrenal steroid biosynthesis and blocks the conversion of
cholesterol to pregnenolone, and therefore reduces levels of adrenal androgens,
which are a source of estrogens in both premenopausal and postmenopausal women.
Aminoglutethimide has produced antitumor response rates of 35% in unselected
patients, most of whom have undergone prior therapy with either chemotherapy or
hormonal manipulation. As is true of other hormonal responses, high response
rates of up to 70% are observed in patients who are ER and/or PR positive. The
reason why these drugs are currently used after tamoxifen is mainly due to the
side effects of aminoglutethimide, which impairs the mineralocorticoid and
glucocorticoid synthesis. New, less toxic compounds appear, which block the
conversion of androstenedione to estrone and efficiently suppress plasma
estrogen levels., e.g. formestane, anastrozole and letrozole. Aromatase
inhibitors are now being compared to tamoxifen as first-line endocrine treatment
in relapsing patients. If these trials confirm a similar or better response rate
to new aromatase inhibitors compared to tamoxifen, the time will come to study
them as the first line adjuvant treatment in non-metastatic disease.
Publication Types:
Review
Review, Tutorial
PMID: 9623325 [PubMed - indexed for MEDLINE]
158: Minerva Ginecol 1998 Mar;50(3):51-63
[Current status and prospectives of aromatase inhibitors in the treatment of
advanced breast cancer]
[Article in Italian]
Boccardo F.
Servizio di Oncologia Medica II, Istituto Nazionale per la Ricerca sul Cancro,
Genova.
Endocrine therapy represents one of the most effective instruments for the
palliative and adjuvant treatment of breast cancer, in particular in
postmenopausal patients. While tamoxifen still forms the treatment of choice
during the adjuvant phase and the first-line treatment during the metastatic
phase, aromatase inhibitors undoubtedly represent the treatment of choice for
patients who do not respond to antiestrogen treatment. These drugs represent a
heterogeneous family of compounds able to provide more or less selective
inhibition of aromatases by forming an irreversible bond with the catalytic site
of the enzymatic complex (type I inhibitors) or using a competitive mechanism
(type II inhibitors). Among the type I drugs, 4-hydroxyandrostenedione and
hexamestane are those that probably attract greatest clinical interest. These
drugs can significantly reduce the circulating levels of estrone and estradiol,
and have been shown to be active in 20% of patients pretreated with tamoxifen.
Moreover, hexamestane was also effective in patients pretreated with type II
inhibitors, of which the parent drug is aminoglutethimide. This drug is still
used in the second and third-line treatment of breast cancer but, since it
causes collateral effects in a substantial percentage of patients, above all
when used at higher doses in combination with hydrocortisone, it will soon be
replaced by second and third generation inhibitors, like letrozole, fadrozole,
vorozole and anastrozole. These drugs have been shown to be significantly more
active than aminoglutethimide, both in vitro and in vivo, and above all more
selective. In particular, even at high doses anastrozole has not been found to
interfere with steroidogenesis at a corticoadrenal level. Moreover, anastrozole
has been shown to be very active even at relatively modest doses given in a
single daily dose. Two recent controlled studies, including a total of over 600
patients, recently demonstrated that, if used in second line in patients who no
longer responded to adjuvant or palliative tamoxifen therapy, anastrozole is
just as effective but probably better tolerated than megestrol acetate. Studies
are now in progress or are currently being launched to evaluate the possible
value of anastrozole and other third generation inhibitors both as first-line
treatment and as adjuvant treatment as an alternative or in combination with
tamoxifen.
Publication Types:
Review
Review Literature
PMID: 9595916 [PubMed - indexed for MEDLINE]
159: Med Lett Drugs Ther 1998 Apr 10;40(1024):43-5
Toremifene and letrozole for advanced breast cancer.
PMID: 9580744 [PubMed - indexed for MEDLINE]
160: Clin Cancer Res 1998 Mar;4(3):697-711
Tamoxifen-resistant fibroblast growth factor-transfected MCF-7 cells are
cross-resistant in vivo to the antiestrogen ICI 182,780 and two aromatase
inhibitors.
McLeskey SW, Zhang L, El-Ashry D, Trock BJ, Lopez CA, Kharbanda S, Tobias CA,
Lorant LA, Hannum RS, Dickson RB, Kern FG.
Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC
20007, USA.
Although the antiestrogen tamoxifen has been the mainstay of therapy for
estrogen receptor (ER)-positive breast cancer, successful treatment of
responsive tumors is often followed by the acquisition of tamoxifen resistance.
Subsequently, only 30-40% of patients have a positive response to second
hormonal therapies. This lack of response might be explained by mechanisms for
tamoxifen resistance that sensitize ER pathways to small amounts of estrogenic
activity present in tamoxifen or that bypass ER pathways completely. To
elucidate one possible mechanism of tamoxifen resistance, we treated
ovariectomized tumor-bearing mice injected with fibroblast growth factor
(FGF)-transfected MCF-7 breast carcinoma cells with the steroidal antiestrogen
ICI 182,780 or one of two aromatase inhibitors, 4-OHA or letrozole. These
treatments did not slow estrogen-independent growth or prevent metastasis of
tumors produced by FGF-transfected MCF-7 cells in ovariectomized nude mice.
FGF-transfected cells had diminished responses to ICI 182,780 in vitro,
suggesting that autocrine activity of the transfected FGF may be replacing
estrogen as a mitogenic stimulus for tumor growth. ER levels in FGF
transfectants were not down-regulated, and basal levels of transcripts for
estrogen-induced genes or of ER-mediated transcription of estrogen response
element (ERE) luciferase reporter constructs in the FGF expressing cells were
not higher than parental cells, implying that altered hormonal responses are not
due to down-regulation of ER or to FGF-mediated activation of ER. These studies
indicate that estrogen independence may be achieved through FGF signaling
pathways independent of ER pathways. If so, therapies directed at the operative
mechanism might produce a therapeutic response or allow a response to a second
course of antiestrogen treatment.
PMID: 9533540 [PubMed - indexed for MEDLINE]
161: Anticancer Res 1998 Jan-Feb;18(1A):171-6
Antitumor effects of SEF19, a new nonsteroidal aromatase inhibitor, on
7,12-dimethylbenz[a]anthracene-induced mammary tumors in rats.
Iino Y, Karakida T, Sugamata N, Andoh T, Takei H, Takahashi M, Yaguchi S,
Matsuno T, Takehara M, Sakato M, Kawashima S, Morishita Y.
Department of Emergency and Critical Care Medicine, Gunma University School of
Medicine, Japan.
The antitumor and endocrine effects of a new nonsteroidal aromatase inhibitor,
2-(imidazol-1-yl)-4,6-dimorphorino-l, 3, 5-triazine (SEF19) were examined in
female Sprague-Dawley rats bearing estrogen dependent
7,12-dimethylbenz[a]anthracene(DMBA)-induced mammary tumors, and the effects
were compared with those of CGS20267. The rats bearing DMBA-induced mammary
tumors within 6-15 weeks after the DMBA administration were divided into the
treatment groups once a week every week, and they were treated with SEF19,
CGS20267 and vehicle for 4 weeks. One hundred rats were sacrificed 4 hours after
the last administration, and the remaining 60 rats were sacrificed after a
4-week recovery period. During the treatment and recovery period, the tumor size
was generally smaller in the SEF19 and CGS20267-treated subgroups than in the
control subgroup. Tumor sizes in the subgroups treated with high doses of SEF19
(25 mg/kg/day and 50 mg/kg/2 days) were reduced to the size of the
CGS20267-treated subgroup. The CGS20267-treated rats showed decrease in the
serum estradiol level and an increase in the serum testosterone level. Their
uterine weights were reduced. SEF19 treatment failed to show any effect on the
serum levels of estrone, estradiol, testosterone and androstenedione, but it
suppressed uterine weight in a dose-dependent manner. After the recovery period,
no effect was detected in the serum concentrations of steroid hormones and the
weight of the organs. At every dose used in the present study the aromatase
inhibitory activity of SEF19 was weaker than that of CGS20267, but the
inhibitory effect on mammary tumor growth of SEF19 at high doses was comparable
to that of CGS20267. We conclude that the antitumor effect of SEF19 is not due
to aromatase inhibition but mainly to its direct cytotoxicity.
PMID: 9568073 [PubMed - indexed for MEDLINE]
162: Oncology (Huntingt) 1998 Mar;12(3 Suppl 5):41-4
Pivotal trials of letrozole: a new aromatase inhibitor.
Smith IE.
Breast Unit, Royal Marsden Hospital, London, England.
Letrozole (Femara) is a nonsteroidal aromatase inhibitor that is approximately
10,000 times as potent as aminoglutethimide in vivo. Two pivotal multinational
phase III trials have compared letrozole (0.5 and 2.5 mg/d) against megestrol
acetate and aminoglutethimide, respectively, in patients with locally advanced
or metastatic breast cancer. The letrozole vs megestrol acetate trial showed the
superiority of letrozole (2.5 mg/d) over megestrol acetate with respect to
response rate, response duration, duration of overall clinical benefit (complete
response plus partial response plus stable disease > or = 6 months), time to
progression, and time to treatment failure. The letrozole-treated patients also
showed a nonsignificant trend toward better survival. In the letrozole vs
aminoglutethimide trial, letrozole (2.5 mg/d) was significantly superior in
terms of duration of overall clinical benefit and survival. There were also
strong trends favoring letrozole with regard to objective response rate and
duration of response. Unexpectedly, both trials demonstrated a dose-response
effect for 2.5 mg of letrozole over 0.5 mg in terms of response and overall
survival. This finding raises the possibility that intratumoral aromatase
suppression may be more relevant in breast cancer therapy than are plasma
estrogen levels.
Publication Types:
Review
Review, Tutorial
PMID: 9556791 [PubMed - indexed for MEDLINE]
163: Oncology (Huntingt) 1998 Mar;12(3 Suppl 5):36-40
Preclinical studies using the intratumoral aromatase model for postmenopausal
breast cancer.
Brodie A, Lu Q, Liu Y, Long B, Wang JP, Yue W.
Department of Pharmacology, School of Medicine, University of Maryland,
Baltimore, USA.
To determine the most effective strategies for the treatment of postmenopausal
hormone dependent breast cancer, we recently developed a model system in nude
mice. In this model, estrogen receptor-positive human breast cancer cells
(MCF-7) stably transfected with the aromatase gene are inoculated into
ovariectomized, immunosuppressed (nude) mice. These cells synthesize sufficient
estrogen from androgen substrate to stimulate their proliferation and the
development of tumors. Moreover, estrogen secreted by the tumor cells maintains
uterine weight comparable to that of the intact mouse. In the present study, we
employed this model to investigate the effects of the aromatase inhibitor,
letrozole (CGS 20267 [Femara]) on mammary tumor growth and on the uterus. We
also used this model to predict the effects of combining two aromatase
inhibitors, letrozole and anastrozole (Arimidex), with the antiestrogen
tamoxifen (Nolvadex). Letrozole was found to be a highly potent inhibitor of
tumor proliferation and more effective than tamoxifen. No stimulation of uterine
growth was observed with the aromatase inhibitors. However, the combination of
letrozole or anastrozole and tamoxifen was no more effective than either
aromatase inhibitor alone. The agonistic effect of tamoxifen on the uterus was
observed when it was given alone and when combined with the aromatase
inhibitors. Furthermore, letrozole had the most potent antitumor activity when
compared to other aromatase inhibitors and antiestrogens. No additional benefit
was observed by combining these agents with tamoxifen over treatment with
aromatase inhibitors alone.
PMID: 9556790 [PubMed - indexed for MEDLINE]
164: Oncology (Huntingt) 1998 Mar;12(3 Suppl 5):32-5
Emerging role of aromatase inhibitors in the treatment of breast cancer.
Harvey HA.
Section of Hematology-Oncology, Hershey Medical Center, Penn State Geissinger
Health Systems, Hershey, Pennsylvania, USA.
The new generation of potent steroidal and nonsteroidal inhibitors of the enzyme
aromatase act by decreasing estrogen production throughout the body in
postmenopausal women. The most potent of these agents may also inhibit estrogen
synthesis within metastatic breast cancer tissue. The newly developed, orally
administered, nonsteroidal competitive inhibitors, such as anastrozole
(Arimidex), letrozole (Femara), and vorozole (Rizivor), are a thousand times
more potent inhibitors of aromatase than is aminoglutethimide. Furthermore,
these agents are highly selective. In several large randomized trials, the new
inhibitors produced similar response rates as megestrol acetate (160 mg/d) in
postmenopausal women with hormone-dependent breast cancer, but showed a trend
toward improved response duration and survival. They also produced less weight
gain and fewer cardiovascular and thromboembolic side effects. In addition,
letrozole proved superior to aminoglutethimide in another randomized trial. Both
anastrozole (1.0 mg/d) and letrozole (2.5 mg/d) have now been approved as
second-line treatment for hormone-dependent breast cancer in postmenopausal
women in whom disease has progressed following tamoxifen treatment. Either drug
should replace the routine use of megestrol acetate in this setting. Ongoing
clinical studies are comparing anastrozole and letrozole to antiestrogens as
first-line endocrine therapy for metastatic breast cancer. Other trials will
study the possible roles of these compounds as adjuvant therapy and
chemoprevention for breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 9556789 [PubMed - indexed for MEDLINE]
165: Breast Cancer Res Treat 1998 Mar;48(1):45-51
Effect of CGS 20267 on ovarian aromatase and gonadotropin levels in the rat.
Sinha S, Kaseta J, Santner SJ, Demers LM, Bremmer WJ, Santen RJ.
Department of Medicine, The Pennsylvania State University, The Milton S. Hershey
Medical Center, Hershey 17033, USA.
Aromatase catalyzes the rate limiting step that converts androgens to estrogens.
Postmenopausal women with hormone dependent breast cancer respond to first
generation aromatase inhibitors such as aminoglutethimide with a marked
suppression of circulating estradiol levels. In contrast, premenopausal women
appear to be resistant to first generation aromatase inhibitors. The inability
to block ovarian aromatase results from the low affinity of first generation
inhibitors for the active site of the enzyme. Under these circumstances, the
high substrate levels in the premenopausal ovary compete effectively with these
inhibitors and do not allow binding of inhibitor to the active site of the
enzyme. Second and third generation aromatase inhibitors with higher affinity
for aromatase have now been developed and potentially could block ovarian
aromatase. To test this possibility, we administered CGS 20267 (letrozole), a
highly potent aromatase inhibitor, to cycling female rats. A dose dependent
inhibition of uterine weight occurred with maximum effects produced by the 5
mg/kg/day dosage. During a period of 4 weeks, uterine weight was reduced to
levels induced by ovariectomy. Ovarian tissue estradiol levels were inhibited by
approximately 80%. As a reflection of inhibition of ovarian aromatase activity,
the levels of androstenedione in the ovary increased by an order of magnitude.
Both LH and FSH plasma levels increased but not to those observed after
ovariectomy. The rise in gonadotropin levels induced a statistically significant
but relatively small increase in ovarian weights. These results demonstrate the
ability to persistently block ovarian aromatase activity in cycling rats with a
potent aromatase inhibitor. This study provides a rationale for clinical trials
of potent aromatase inhibitors in pre-menopausal women with breast cancer.
PMID: 9541188 [PubMed - indexed for MEDLINE]
166: Endocrinology 1998 Mar;139(3):1038-45
The regulation of gonadotropin-releasing hormone-induced calcium signals in male
rat gonadotrophs by testosterone is mediated by dihydrotestosterone.
Tobin VA, Canny BJ.
Department of Physiology, Monash University, Clayton, Victoria, Australia.
The biological effects of testosterone (T) may be mediated directly by T or
indirectly by its metabolites, dihydrotestosterone (DHT) and estradiol. The
present study examined whether the metabolism of T is involved in the regulation
of GnRH-induced Ca2+ signaling at the pituitary. In gonadotrophs from castrated
rats, a significantly greater percentage of gonadotrophs demonstrated
oscillatory Ca2+ responses to 100 nM GnRH than cells from intact rats (72% vs.
24%; P < 0.05). This increase was prevented by the administration of T
propionate (0.1 mg/kg x day), DHT benzoate (2 mg/kg x day,), estradiol benzoate
(EB; 5 microg/kg x day), or the combination of the above doses of DHT benzoate
and EB. In all cases the proportion of gonadotrophs from the steroid-treated
rats having oscillatory Ca2+ responses to 100 nM GnRH was between 21-25% (P >
0.05, compared with intact rats). To assess the importance of T metabolism,
intact male rats were treated with the aromatase inhibitor letrozole (1 mg/kg x
day), the 5alpha-reductase inhibitor finasteride (50 mg/kg x day), or their
respective vehicles for 7 days. Letrozole had no effect on GnRH-induced Ca2+
signals, serum LH concentrations, or ventral prostate or testes weight.
Finasteride treatment, however, mimicked the effects of castration, with
significantly more gonadotrophs exhibiting Ca2+ oscillations in response to 100
nM GnRH than gonadotrophs from the vehicle-treated group (71% vs. 20%
respectively; P < 0.05). Finasteride also caused a significant (P < 0.05)
decrease in prostatic weight and DHT concentration, but had no significant
effect on either prostatic T or serum LH concentrations. These findings suggest
that in the intact male rat, the effects of T on GnRH-induced Ca2+ signaling are
preferentially mediated via DHT. The results of this study also show that in the
absence of androgens, estradiol may regulate GnRH-induced Ca2+ signaling in the
male rat pituitary.
PMID: 9492036 [PubMed - indexed for MEDLINE]
167: J Clin Oncol 1998 Feb;16(2):453-61
Comment in:
J Clin Oncol. 1998 Aug;16(8):2892-3.
J Clin Oncol. 1999 Dec;17(12):3856-60.
J Clin Oncol. 2000 Apr;18(8):1802-3.
Letrozole, a new oral aromatase inhibitor for advanced breast cancer:
double-blind randomized trial showing a dose effect and improved efficacy and
tolerability compared with megestrol acetate.
Dombernowsky P, Smith I, Falkson G, Leonard R, Panasci L, Bellmunt J, Bezwoda W,
Gardin G, Gudgeon A, Morgan M, Fornasiero A, Hoffmann W, Michel J, Hatschek T,
Tjabbes T, Chaudri HA, Hornberger U, Trunet PF.
PURPOSE: To compare two doses of letrozole and megestrol acetate (MA) as
second-line therapy in postmenopausal women with advanced breast cancer
previously treated with antiestrogens. PATIENTS AND METHODS: Five hundred
fifty-one patients with locally advanced, locoregionally recurrent or metastatic
breast cancer were randomly assigned to receive letrozole 2.5 mg (n = 174),
letrozole 0.5 mg (n = 188), or MA 160 mg (n = 189) once daily in a double-blind,
multicenter trial. Data were analyzed for tumor response and safety variables up
to 33 months of follow-up evaluation and for survival up to 45 months. RESULTS:
Letrozole 2.5 mg produced a significantly higher overall objective response rate
(24%) compared with MA (16%; logistic regression, P = .04) or letrozole 0.5 mg
(13%; P = .004). Duration of objective response was significantly longer for
letrozole 2.5 mg compared with MA (Cox regression, P = .02). Letrozole 2.5 mg
was significantly superior to MA and letrozole 0.5 mg in time to treatment
failure (P = .04 and P = .002, respectively). For time to progression, letrozole
2.5 mg was superior to letrozole 0.5 mg (P = .02), but not to MA (P = .07).
There was a significant dose effect in overall survival in favor of letrozole
2.5 mg (P = .03) compared with letrozole 0.5 mg. Letrozole was significantly
better tolerated than MA with respect to serious adverse experiences,
discontinuation due to poor tolerability, cardiovascular side effects, and
weight gain. CONCLUSION: The data show letrozole 2.5 mg once daily to be more
effective and better tolerated than MA in the treatment of postmenopausal women
with advanced breast cancer previously treated with antiestrogens.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 9469328 [PubMed - indexed for MEDLINE]
168: J Steroid Biochem Mol Biol 1997 Nov-Dec;63(4-6):261-7
The aromatase inhibitor letrozole in advanced breast cancer: effects on serum
insulin-like growth factor (IGF)-I and IGF-binding protein-3 levels.
Bajetta E, Ferrari L, Celio L, Mariani L, Miceli R, Di Leo A, Zilembo N, Buzzoni
R, Spagnoli I, Martinetti A, Bichisao E, Seregni E.
Medical Oncology B Division, Istituto Nazionale per lo Studio e la Cura dei
Tumori, Milan, Italy.
Serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 levels were
measured in two groups of postmenopausal women with advanced breast cancer, who
received the aromatase inhibitor letrozole 0.5 or 2.5 mg p.o. once daily. Blood
samples were obtained from 15 patients in each dose group at baseline, and one
and three months after starting therapy. Circulating IGF-I and IGFBP-3
concentrations were determined by means of radioimmunoassay. In both dosage
groups a statistically significant increase in the IGF-I levels was observed
during three months of letrozole treatment (P=0.003). In addition, the multiple
testing procedure yielded in the whole patient population a significant result
in the comparison between mean IGF-I values after three months of therapy and
those observed at baseline (P=0.004), the estimated average increase being of
24%. No significant result was obtained in the analysis for the dose effect
(P=0.077) and for the time x dose interaction (P=0.208). Circulating IGFBP-3
levels did not appear to be affected by letrozole treatment in either of the
dose groups. This is the first report concerning the short-term effects of
letrozole on components of the IGF system in breast cancer patients; further
investigations are warranted in order to confirm these preliminary data.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 9459192 [PubMed - indexed for MEDLINE]
169: Cancer Epidemiol Biomarkers Prev 1998 Jan;7(1):65-78
Aromatase inhibitors as potential cancer chemopreventives.
Kelloff GJ, Lubet RA, Lieberman R, Eisenhauer K, Steele VE, Crowell JA, Hawk ET,
Boone CW, Sigman CC.
Chemoprevention Branch, Division of Cancer Prevention and Control, National
Cancer Institute, Bethesda, Maryland 20852, USA.
Epidemiological and experimental evidence strongly supports a role for estrogens
in the development and growth of breast tumors. A role for estrogen in prostate
neoplasia has also been postulated. Therefore, one chemopreventive strategy for
breast and prostate cancers is to decrease estrogen production. This can be
accomplished by inhibiting aromatase, the enzyme that catalyzes the final,
rate-limiting step in estrogen biosynthesis. The use of aromatase inhibitors is
of clinical interest for cancer therapy, and selective, potent aromatase
inhibitors have been developed. Several of these agents have demonstrated
chemopreventive efficacy in animal models. The rationale for the use of
aromatase inhibitors as chemopreventives and identification of inhibitors to
serve as potential chemopreventive agents are the subjects of this review. After
background information regarding aromatase is presented, the data for each
inhibitor are summarized separately. The discussion focuses on those inhibitors
that are clinically available or in clinical trials, including:
aminoglutethimide (Cytadren), rogletimide, fadrozole hydrochloride, liarozole
hydrochloride, anastrozole (Arimidex), letrozole, vorozole, formestane,
exemestane, and atamestane. On the basis of results from preclinical studies,
aromatase inhibitors may be promising agents for clinical trials in populations
at high risk for developing estrogen-dependent cancers. Total suppression of
aromatase may have adverse effects, as is evident in postmenopausal women
(increased osteoporosis, cardiovascular disease, and urogenital atrophy).
However, on the basis of preclinical studies of chemopreventive efficacy and
chemotherapeutic applications of aromatase inhibitors showing dose-response
efficacy, it may be possible to obtain chemopreventive effects without total
suppression of aromatase and circulating estrogen levels. Suppressing local
estrogen production may be an alternative strategy, as suggested by the
discovery of a unique transcriptional promoter of aromatase gene expression,
I.4, in breast adipose tissue. The development of drugs that target this
promoter region may be possible.
Publication Types:
Review
Review, Tutorial
PMID: 9456245 [PubMed - indexed for MEDLINE]
170: Biopharm Drug Dispos 1997 Dec;18(9):779-89
Absolute bioavailability of letrozole in healthy postmenopausal women.
Sioufi A, Gauducheau N, Pineau V, Marfil F, Jaouen A, Cardot JM, Godbillon J,
Czendlik C, Howald H, Pfister C, Vreeland F.
Laboratoires Ciba-Geigy, Bioanalytics and Pharmacokinetics, Rueil-Malmaison,
France.
Letrozole is a new non-steroidal inhibitor of the aromatase enzyme system. It is
currently under development for the treatment of postmenopausal women with
advanced breast cancer. Absolute bioavailability of letrozole when given orally
as one 2.5 mg film-coated tablet in comparison to the same dose given
intravenously as a bolus injection was studied in 12 healthy postmenopausal
women. Letrozole absolute systemic bioavailability after p.o. administration was
99.9 +/- 16.3%. Elimination of letrozole was slow. Total-body clearance of
letrozole from plasma after i.v. administration was low (2.21 L h-1). The
calculated distribution volume at steady state (1.87 L kg-1) suggests a rather
high tissue distribution. Biotransformation of letrozole is the main elimination
mechanism with the glucuronide conjugate of the secondary alcohol metabolite
being the predominant species found in urine. The two study treatments were
tolerated equally well.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 9429742 [PubMed - indexed for MEDLINE]
171: Oncology 1997;54 Suppl 2:11-4
Anastrozole--a new generation in aromatase inhibition: clinical pharmacology.
Dowsett M, Lonning PE.
Department of Academic Biochemistry, Royal Marsden Hospital, London, UK.
Use of the aromatase inhibitor aminoglutethimide is limited by its lack of
selectivity for aromatase and its toxicity. Newer agents are more selective, but
do not always offer improved inhibition of aromatase. Indirect comparison of
their activity in inhibiting aromatase and suppressing plasma oestrogens
indicates that aminoglutethimide, rogletimide, formestane, and fadrozole
inhibited aromatase activity by 74-91%, with reported falls in oestradiol level
of 58-76%. In contrast, the new-generation oral once-daily aromatase inhibitors
anastrozole (Arimidex) and letrozole were of a similar activity, inhibiting
aromatase activity by over 96%, with a concomitant fall in oestradiol and
oestrone levels of at least 80%. Anastrozole at the recommended clinical dose of
1 mg daily also suppressed oestrone sulphate levels by 93.5%; activity with
anastrozole 10 mg daily was not statistically significantly different. The new
generation of aromatase inhibitors, as typified by anastrozole, thus offers
effective and convenient aromatase inhibition which correlates well with
decreases in the levels of plasma oestrogens.
Publication Types:
Review
Review, Tutorial
PMID: 9394854 [PubMed - indexed for MEDLINE]
172: J Surg Oncol 1997 Nov;66(3):215-20
Use of aromatase inhibitors in postmenopausal women with advanced breast cancer.
Roseman BJ, Buzdar AU, Singletary SE.
Department of Surgical Oncology, University of Texas M.D. Anderson Cancer
Center, Houston 77030, USA.
Surgeons have been involved in the management of metastatic breast cancer since
the technique of ovarian ablation was introduced in 1896. However, as newer
hormonal and chemotherapeutic regimens were developed, drug therapy gradually
replaced surgery as the preferred treatment for metastatic breast cancer. Thus,
management of metastatic breast cancer has largely shifted from surgeons to
medical oncologists. Advances in hormonal pharmacology have placed hormonal
therapy alongside surgery and radiation therapy as a standard treatment option
for women with advanced breast cancer. The purpose of this article is to update
surgeons on the current use of hormonal agents for treatment of advanced breast
cancer in postmenopausal women, and to review the aromatase inhibitors, a new
line of hormonal agents for the treatment of advanced breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 9369969 [PubMed - indexed for MEDLINE]
173: J Steroid Biochem Mol Biol 1997 Apr;61(3-6):315-22
Sex differences in the regulation of embryonic brain aromatase.
Hutchison JB, Beyer C, Hutchison RE, Wozniak A.
MRC Neuroendocrine Development and Behaviour Group, The Babraham Institute,
Cambridge, U.K.
Oestrogen formed from androgen by aromatization plays a critical role in the
sexual differentiation of the male brain and behaviour. A question which has
still to be answered is what regulates the gender-specific changes in aromatase
activity forming oestrogen during sensitive periods of brain growth. Using a
primary cell culture technique and sexed embryos, we have shown that in the
fetal mouse brain, oestrogen formation in the male is neuronal rather than glial
and aromatase activity is regionally localized, being higher in the hypothalamus
than in the cortex. The aromatase activity measured from cells in culture has
the same enzyme binding affinity (apparent Km approximately 40 nM) as intact
brain samples. Neurones developing in the embryonic male brain (embryonic day
(ED) 15) contain higher aromatase activity (Vmax, 895 fmol/h/mg protein) than
the female (Vmax, 604). Although a sex difference exists at early stages of
embryonic development (ED 13), the embryonic aromatase system is regulated by
steroids later in fetal development. The developing aromatase-containing
neuroblasts probably form processes which connect to other aromatase neurones.
Immunoreactive staining with an aromatase polyclonal antibody identifies an
increase in numbers of aromatase-immunoreactive hypothalamic neuronal cell
bodies following testosterone treatment. Testosterone treatment also causes both
stimulation of neurite growth and branching as well as functional maturation of
aromatase neurones. In particular, there is an increase in aromatase activity
per neurone as well as a dramatic increase in the number of neurones expressing
the enzyme. Both the functional and morphological changes depend on androgen
receptor stimulation for several days in vitro. This conclusion is supported by
colocalization studies which reveal a high number of fetal hypothalamic
aromatase neurones co-expressing androgen receptor. We conclude that
testosterone influences the growth of male hypothalamic neurones containing
aromatase at a sensitive period of brain development. Endogenous steroid
inhibitors of aromatase, probably formed within the neuroglia, also play a role
in the control of oestrogen production. An endogenous 5alpha-reduced metabolite
of testosterone, 5alpha-androstanedione, is almost as potent in inhibiting
neuronal hypothalamic aromatase activity (Ki = 23 nM) as the synthetic
non-steroidal inhibitors such as the imidazole, fadrozole, and the triazoles,
arimidex and letrozole. It is clear that the oestrogen-forming capacity of the
male hypothalamus has the special characteristics and plasticity of regulation
which could affect brain differentiation at specific steroid-sensitive stages in
ontogeny.
Publication Types:
Review
Review, Tutorial
PMID: 9365207 [PubMed - indexed for MEDLINE]
174: J Steroid Biochem Mol Biol 1997 Apr;61(3-6):241-5
Clinical use of aromatase inhibitors in the treatment of advanced breast cancer.
Trunet PF, Vreeland F, Royce C, Chaudri HA, Cooper J, Bhatnagar AS.
Department of Research and Medicine, Ciba-Geigy Ltd, Rueil-Malmaison, France.
The aim of endocrine therapy is to reduce the estrogenic stimulus for tumour
growth. After failure of tamoxifen--the standard "first-line" hormonotherapy for
advanced breast cancer (ABC)--the most frequently prescribed endocrine therapies
are progestins and aromatase inhibitors (AIs) ("second-line" hormonotherapy).
Estrogen deprivation through AIs provides effective treatment of
hormone-dependent ABC in postmenopausal (PMP) women. Over the past few years,
the goals of our research programme were to develop more potent, more selective
and better tolerated AIs than our first AI, aminoglutethimide (AG). Lentaron
(4-hydroxyandrostenedione, formestane), a highly selective steroidal compound
was the first of the new AIs to be used in clinical trials. It is a substrate
analogue, administered as an i.m. injection every 2 weeks. It is effective in
the treatment of ABC with an objective response rate (ORR) similar to tamoxifen
and megestrol acetate (MA) and is generally well tolerated; rare instances of
injection site reactions have been reported. Afema (fadrozole HCl), a
non-steroidal AI is active orally, and effectively suppresses estrogen levels in
PMP women, but it is not completely selective for aromatase when administered at
higher than therapeutic doses. At the therapeutic dose of 1 mg twice a day it
has an anti-tumour efficacy similar to MA, a good tolerability and no clinically
relevant effects on other hormones of the endocrine system. Letrozole is the
fourth of our AIs in clinical development. It is a non-steroidal, achiral,
orally active, potent and highly selective competitive AI. Clinical endocrine
studies have shown that the dose of 0.5 mg a day is the lowest dose achieving
maximum estrogen suppression. Over a wide dose range, a lack of clinically
relevant effects on other hormones of the endocrine system has confirmed its
high selectivity. In four phase Ib/IIa studies in PMP patients with ABC who
failed previous therapy, letrozole produced ORRs of 9, 31, 33 and 36%. One phase
IIb/III study has been completed and two others are ongoing, comparing two doses
of letrozole with MA or AG to confirm the anti-tumour efficacy of letrozole in
the treatment of ABC in PMP women after treatment with anti-estrogens.
Preliminary results from the completed trial show that letrozole 2.5 mg is
superior to 0.5 mg in terms of ORR, time to progression and time to treatment
failure, and is superior to the standard dose of MA in terms of ORR and
tolerability. Therefore letrozole 2.5 mg can be recommended as a first choice
for the treatment of PMP patients with hormone receptor-positive or unknown ABC
after anti-estrogen therapy.
Publication Types:
Review
Review, Tutorial
PMID: 9365196 [PubMed - indexed for MEDLINE]
175: J Steroid Biochem Mol Biol 1997 Apr;61(3-6):193-202
Regulation of aromatase activity within the breast.
Miller WR, Mullen P, Sourdaine P, Watson C, Dixon JM, Telford J.
University Dept. of Clinical Oncology, Western General Hospital, Edinburgh, U.K.
Local oestrogen biosynthesis within the breast can be highly variable, in vitro
aromatase activity both in breast cancers and mammary adipose tissue displaying
over a 40-fold range between the highest and lowest levels. Evidence is
presented to show that: (i) transcriptional activity may influence oestrogen
biosynthesis within breast cancers in that both aromatase mRNA and STAT nuclear
binding are correlated positively to in vitro aromatase activity; (ii) the local
presence of cancer may enhance aromatase activity in particulate fractions and
primary fibroblast cultures from mammary adipose tissue; (iii) tumour extracts
and breast cyst fluids may induce aromatase in cultured fibroblasts, the active
principles responsible for these effects being incompletely defined (although
the combination of interleukin (IL)-6 and its soluble receptor dramatically
enhances aromatase activity, it is unclear whether this particular cytokine
system can account for the stimulatory effects of breast extracts and fluids);
(iv) the aromatase activities in both breast cancer and adipose tissues are
susceptible to classical aromatase inhibitors such as aminoglutethimide and
4-hydroxyandrostenedione (and to newer inhibitors such as CGS16949 and CGS20267
at low nanomolar concentrations) but reduced sensitivity to
4-hydroxyandrostenedione may be observed in certain breast cancers. These
findings may have important implications for the development and progression of
hormone-dependent cancers within the breast.
PMID: 9365190 [PubMed - indexed for MEDLINE]
176: J Steroid Biochem Mol Biol 1997 Apr;61(3-6):157-66
Effect of estrogen deprivation on the reproductive physiology of male and female
primates.
Shetty G, Krishnamurthy H, Krishnamurthy HN, Bhatnagar S, Moudgal RN.
Center for Reproductive Biology and Molecular Endocrinology, Indian Institute of
Science, Bangalore.
The availability of CGS 16949A, CGS 20267 and CGP 47645, a series of aromatase
inhibitors (AIs) having high specific activity and specificity, made possible
this study wherein the need for estrogen (E) for regulating (a) follicular
maturation/ovulation, luteal function and pregnancy establishment, and (b)
testicular function of the bonnet monkey (Macaca radiata) has been examined.
Generally these compounds, used in the range of 500 microg to 2.5 mg/day did not
inhibit follicular maturation although they did reduce E levels. Although low
doses had no effect on ovulation it appears that relatively high doses of CGS
20267 and CGP 47645 could be inhibiting it. Three oral doses of letrozole (CGS
20267, each dose of 2 mg) during the follicular phase resulted in the formation
of multiple follicles in cycling females, and these could be ovulated by
exogenous hCG (1000 IU) treatment. Although administration of AI during the
early luteal phase had no effect on progesterone (P) production, it prevented
pregnancy establishment. Whereas AI administration in the female had no
significant effect on luteinizing hormone (LH) and follicle stimulating hormone
(FSH) levels (except at high drug dosages), it significantly increased serum
testosterone (T) levels in the male. Sustained high levels of T (30-50 ng/ml)
could be maintained for 100 days by administering 2.5 mg of CGP 47465 orally
once in 5 days. Blockade of E synthesis in the male led to the disruption of
testicular germ cell transformation, which in turn resulted in a significant
reduction in sperm production. These studies with aromatase inhibitors in the
monkey suggest that these compounds have a potential for use as fertility
regulating agents in both the male and female primate.
PMID: 9365186 [PubMed - indexed for MEDLINE]
177: Cancer 1997 Oct 15;80(8 Suppl):1646-51
Issues concerning the role of chemotherapy and hormonal therapy of bone
metastases from breast carcinoma.
Harvey HA.
Division of Hematology-Oncology, The Milton S. Hershey Medical Center,
Pennsylvania 17033, USA.
A significant percentage (50-70%) of patients with metastatic breast carcinoma
(MBC) will have disease involving the bony skeleton. Clonal selection mediated
by parathyroid hormone-related protein and other factors may explain the high
incidence of osseous metastases in MBC. The presence of specific growth factors
and cytokines in the microenvironment of bone may contribute to the successful
establishment and growth of metastatic lesions and also might determine response
or resistance of these lesions to chemotherapy or hormonal therapy. Osteolytic
bone lesions in MBC frequently give rise to serious clinical problems including
bone pain, pathologic fracture, hypercalcemia, and neurologic complications. MBC
often is treated with systemic chemotherapy or hormonal therapy. The purpose of
this article was to review the recent published literature describing the impact
of systemic chemotherapy and hormonal therapy of MBC on the response of bone
lesions and their clinical course and complications. Evaluating the response of
bone lesions can be problematic and may be complicated by the phenomenon of
"tumor flare" that may be observed with either chemotherapy or hormonal therapy.
Use of the International Union Against Cancer criteria for the response of bone
lesions is recommended. Several studies report objective responses (20-60%) of
lytic bone metastases to standard combination chemotherapy regimens such as
cyclophosphamide, methotrexate, and 5-fluorouracil and cyclophosphamide,
doxorubicin, and 5-fluorouracil, mitoxantrone and 5-FU, newer combinations, and
single agents including paclitaxel and docitaxel but responses to vinorelbine
may be less frequent. Complete responses of bone lesions to chemotherapy are
rare but partial responses and disease stabilization can lead to long term
patient benefit. A series from the M. D. Anderson Cancer Center of patients with
bone metastases treated with 5-FU, doxorubicin, and cyclophosphamide
chemotherapy reported a median duration of response of 14 months. In a recent
multicenter study of 195 patients with lytic lesions from MBC treated with
chemotherapy, the objective response rate (complete response + partial response)
in bone was 18% and 65% of the patients developed at least 1 morbid skeletal
event with a median onset of 7.0 months from the start of chemotherapy.
Hormone-dependent breast carcinoma has a proclivity to metastasize to bone. In
earlier studies comparing aminoglutethimide or medroxyprogesterone acetate with
tamoxifen, a higher response rate of bone metastases was observed for the first
two agents. However, in more recent studies comparing newer aromatase
inhibitors, such as anastrozole, fadrozole, and letrozole, with megestrol
acetate, there were no significant differences in rates of response in bone.
Patients with MBC with bony lesions respond to both chemotherapy and hormonal
therapy and can have a prolonged survival. Therefore such patients are in a more
favorable position to benefit from adjunctive supportive therapy such as
bisphosphonates intended to reduce skeletal morbidity.
Publication Types:
Review
Review, Tutorial
PMID: 9362431 [PubMed - indexed for MEDLINE]
178: Gan To Kagaku Ryoho 1997 Oct;24(13):1910-6
[New drugs in metastatic breast cancer--1997]
[Article in Japanese]
Enomoto K.
Dept. of Surgery, Keio University, Tokyo, Japan.
The introduction of new drugs may offer significant hope for improvement in the
treatment of breast cancer. They include new cytotoxic agents such as Taxanes,
Topoisomerase inhibitor, MDR modulator, new hormone such as 3rd generation
nonsteroidal aromatase inhibitor, pure antiestrogen for patients with refractory
metastatic breast cancer and new bisphosphonates for those who have metastases
to bone. Therefore, some reports evaluating such new drugs were reviewed.
Japanese studies revealed response rate of Taxanes in the treatment of
metastatic breast cancer as follows; Six out of 22 (27%) with 1 CR for 24 hours
infusion, 21 out of 52 (34%) with 2 CR for 3 hours infusion of paclitaxel
respectively, 21 out of 31 (41%) with 2 CR for 1 hour infusion, and 32 out of 72
(44%) with 5 CR for 1 hour infusion of Docetaxel, In addition, the MTD of the
combination was reached at dose level with 60 mg/sqm of Docetaxel and 400 mg/sqm
of cyclophosphamide. As regards hormone therapy, thirty four out of 176 (19%)
with 5 CR were observed in phase II study of Fadrozol but results from the phase
II study of 3rd generation aromatase inhibitor is not yet accomplished in Japan.
However, any european reports did not show a difference in response rate in
patients with tamoxifen refractory breast cancer between newer aromatase
inhibitor and megasterol, and a good choice of hormones in the treatment of
metastatic breast cancer appears to be difficult.
Publication Types:
Review
Review, Tutorial
PMID: 9350235 [PubMed - indexed for MEDLINE]
179: Drugs Aging 1997 Sep;11(3):245-50; discussion 251-2
Vorozole.
Wiseman LR, Spencer CM.
Adis International Limited, Auckland, New Zealand. [email protected]
Vorozole is a triazole derivative which binds to the cytochrome P450 moiety of
aromatase, thus causing reversible inhibition of the enzyme. Plasma estradiol
levels are reduced by about 90% in postmenopausal women treated with vorozole.
Phase II clinical studies found vorozole to be an effective agent for the
treatment of postmenopausal women with advanced breast cancer, achieving
objective responses in up to 35% of patients. In 2 large phase III studies,
vorozole 2.5 mg/day demonstrated favourable clinical efficacy compared with
aminoglutethimide and megestrol. Vorozole improved patients' quality of life to
a greater extent than aminoglutethimide. Clinical trials to date indicate that
the tolerability of vorozole is better than that of aminoglutethimide. Vorozole
also appears to be at least as well tolerated as megestrol (although
inappropriate bodyweight gain is more common in megestrol recipients). The most
common adverse events with vorozole are hot flushes, and nausea, which are
generally mild in severity.
Publication Types:
Review
Review, Tutorial
PMID: 9303282 [PubMed - indexed for MEDLINE]
180: Ann Oncol 1997 Jul;8(7):631-2
Aromatase inhibitors come of age.
Dowsett M.
Publication Types:
Editorial
PMID: 9296213 [PubMed - indexed for MEDLINE]
181: Biopharm Drug Dispos 1997 Aug;18(6):489-97
Comparative bioavailability of letrozole under fed and fasting conditions in 12
healthy subjects after a 2.5 mg single oral administration.
Sioufi A, Sandrenan N, Godbillon J, Trunet P, Czendlik C, Howald H, Pfister C,
Ezzet F.
Laboratoires Ciba-Geigy, Bioanalytics and Pharmacokinetics, Medical Department,
Rueil-Malmaison, France.
Letrozole is a new non-steroidal inhibitor of the aromatase enzyme system. It is
currently under development for the treatment of postmenopausal women with
advanced breast cancer. To investigate the influence of food on the
bioavailability of letrozole, 12 healthy male volunteers were treated under fed
and fasted conditions with single oral doses of 2.5 mg letrozole in film-coated
tablets. Plasma concentration profiles were determined. No significant
difference in the extent of absorption (AUC or AUC0-8 h) was observed between
the two treatments but the rate of letrozole absorption decreased slightly under
fed conditions. However, in view of the half-life of about 2 d this small change
in the absorption rate is not considered to be of clinical relevance for
treatment with repeated administrations.
Publication Types:
Clinical Trial
Controlled Clinical Trial
PMID: 9267682 [PubMed - indexed for MEDLINE]
182: Cancer 1997 Jul 15;80(2):218-24
A randomized phase II trial of two dosage levels of letrozole as third-line
hormonal therapy for women with metastatic breast carcinoma.
Ingle JN, Johnson PA, Suman VJ, Gerstner JB, Mailliard JA, Camoriano JK, Gesme
DH Jr, Loprinzi CL, Hatfield AK, Hartmann LC.
Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
BACKGROUND: It is common practice to utilize a series of different hormonal
agents in the treatment of postmenopausal women who, despite disease
progression, continue to be candidates for hormonal therapy on a clinical basis.
Letrozole is a new highly selective and potent aromatase inhibitor. There are
limited data on third-line hormonal therapy in general, and this study was
undertaken to evaluate letrozole in this context. METHODS: A randomized trial
involving two independent Phase II trials of two letrozole dosage levels, 0.5 mg
and 2.5 mg per day, was performed. Eligibility requirements included failure on
two prior hormonal therapies and measurable or evaluable disease. RESULTS:
Ninety-one patients, 46 receiving 0.5 mg and 45 receiving 2.5 mg of letrozole
per day, were assessable for response. At the lower dose, 9 patients (20%)
achieved an objective response; 6 patients (13%) had this documented on 2
occasions separated by 3 months. At the higher dose, 10 patients (22%) achieved
a response; 8 patients (18%) had this documented on 2 occasions separated by 3
months. The median times to progression were 97 days for the lower dose and 154
days for the higher dose. Toxicity was considered acceptable. CONCLUSIONS:
Letrozole has definite antitumor activity as third-line hormonal therapy for
women with metastatic breast carcinoma at doses of 0.5 and 2.5 mg per day. It is
an effective and generally well-tolerated hormonal agent.
Publication Types:
Clinical Trial
Clinical Trial, Phase II
Randomized Controlled Trial
PMID: 9217033 [PubMed - indexed for MEDLINE]
183: Drug Ther Bull 1997 Jul;35(7):55-6
New aromatase inhibitors for breast cancer.
Anastrozole (Arimidex-Zeneca) and letrozole (Femara-Novartis) are the first
selective, oral, non-steroidal aromatase inhibitors. They are licensed for the
treatment of advanced breast cancer in postmenopausal women where tamoxifen or
other anti-oestrogen therapy has failed. The manufacturers of both drugs claim
that their products are more effective, less toxic and better tolerated than the
progestogen megestrol acetate, the standard therapy in this clinical situation.
We assess these claims.
Publication Types:
Review
Review, Tutorial
PMID: 9282426 [PubMed - indexed for MEDLINE]
184: Tumori 1996 Sep-Oct;82(5):417-22
Novel non-steroidal aromatase inhibitors: are there new perspectives in the
treatment of breast cancer?
Bajetta E, Celio L, Buzzoni R, Bichisao E.
Division of Medical Oncology B, Istituto Nazionale per lo Studio e la Cura dei
Tumori, Milan, Italy.
Breast cancer is the most common malignant neoplasm affecting women in Western
countries, and most new cases are manifested during the postmenopausal period.
The clinical results obtained with aminoglutethimide, and later with formestane,
have established aromatase inhibition as one of the major therapeutic options in
hormone-dependent advanced disease. Nevertheless, the lack of specificity of
aminoglutethimide and the less than optimal oral activity of formestane soon led
to further efforts to find a potent, highly selective, orally active,
side-effect-free aromatase inhibitor for use in postmenopausal women with
advanced breast cancer. Here we review the available data on three new,
competitive non-steroidal aromatase inhibitors--letrozole, vorozole and
anastrozole--which are approaching the point of detailed pharmacologic and
clinical evaluation. Preliminary data have confirmed the high potency and
selectivity of these endocrine agents, but their antitumor activity still
remains to be completely defined. Challenges given by these novel aromatase
inhibitors are discussed taking into account the biologic implications related
to their mechanism of action and their future use in the management of breast
cancer.
Publication Types:
Review
Review, Tutorial
PMID: 9063515 [PubMed - indexed for MEDLINE]
185: J Endocrinol 1996 Sep;150 Suppl:S59-63
Oestrogen formation in breast: clinical and biological importance.
Dowsett M, Detre S, Rowlands M, Grimshaw R.
Royal Marsden Hospital, London, UK.
It has been known for many years that many breast carcinomas can synthesize
oestrogens from androgens via the action of the enzyme aromatase. There has been
widespread speculation on the possibility that this acts as an important
intracrine source of growth stimulation. For example, there are data which
indicate that clinical response to aromatase inhibitors is far more common in
tumours which possess measurable amounts of aromatase. In addition, aromatase
activity in the quadrant of the normal breast surrounding breast carcinomas is
generally higher than in the other quadrants. However, these data are only
suggestive and the case for a significant role for intratumoural aromatase in
breast cancer growth remains unproven. We have recently explored this
possibility by the transfection of human breast cancer cells with aromatase. By
a series of experiments in athymic mice we have demonstrated that growth is
supported by this intracrine source in the absence of endocrine oestrogen
stimulation.
PMID: 8943788 [PubMed - indexed for MEDLINE]
186: J Chromatogr B Biomed Appl 1996 Aug 30;683(2):251-8
High-performance liquid chromatography of the aromatase inhibitor, letrozole,
and its metabolite in biological fluids with automated liquid-solid extraction
and fluorescence detection.
Marfil F, Pineau V, Sioufi A, Godbillon SJ.
Laboratory Ciba-Geigy, Rueil-Malmaison, France.
An analytical method for the determination of letrozole (CGS 20,267) in plasma
and of letrozole and its metabolite, CGP 44,645, in urine is described.
Automated liquid-solid extraction of compounds from plasma and urine was
performed on disposable 100-mg C8 columns using the ASPEC system. The separation
was achieved on an ODS Hypersil C18 column using acetonitrile-phosphate buffer,
pH 7, as the mobile phase at a flow-rate of 1.5 ml/min. A fluorescence detector
was used for the quantitation. The excitation and emission wavelengths were 230
and 295 nm, respectively. The limits of quantitation (LOQ) of letrozole in
plasma and in urine were 1.40 nmol/l (0.4 ng/ml) and 2.80 nmol/l, respectively.
The respective mean recoveries and coefficient of variation (C.V.) were 96.5%
(9.8%) in plasma and 104% (7.7%) in urine. The LOQ of CGP 44645 in urine was
8.54 nmol/l (2 ng/ml). The mean recovery was 108% (6.3%). The compounds were
well separated from co-extracted endogenous components and no interferences were
observed at the retention times of compounds. The sensitivity of this method for
letrozole in plasma should be sufficient for kinetic studies in humans with
single doses of 0.5 mg and possibly less.
PMID: 8891923 [PubMed - indexed for MEDLINE]
187: J Steroid Biochem Mol Biol 1996 Jul;58(4):411-5
Paradoxical effect of an aromatase inhibitor, CGS 20267, on aromatase activity
in guinea pig brain.
Choate JV, Resko JA.
Department of Physiology and Pharmacology, Oregon Health Sciences University,
Portland 97201, U.S.A.
To determine the effect of in vivo treatment of guinea pigs with a non-steroidal
aromatase inhibitor (CGS 20267; letrozole), we treated subjects with
subcutaneous Silastic implants containing crystalline letrozole. We studied four
treatment groups: intact, intact letrozole-treated, castrate and castrate
letrozole-treated. After treatment for 1 week, brain tissues (preoptic area,
septum, medial basal hypothalamus, amygdala and parietal cortex) were removed,
and microsomal aromatase activity (AA) was determined by an in vitro 3H2O assay
using 1beta-3H-androstenedione as substrate. Kinetic experiments were performed
to determine the competitive nature of letrozole and an approximate Ki was
calculated. Letrozole appears to be a reversible, competitive inhibitor of
aromatase activity with an apparent Ki of 1.2 nM. Aromatase activity in intact
letrozole-treated animals was elevated compared to untreated controls in all
brain areas tested (P< 0.05). Letrozole also stimulated AA in the brains of
letrozole-treated castrated guinea pigs compared to untreated castrated animals
(P< 0.05). These data indicate that letrozole administered in vivo causes an
increase in AA. Possible mechanisms include an autoregulatory mechanism which is
interrupted by enzyme inhibition, or an effect of the inhibitor on turnover
rates of P450 aromatase.
PMID: 8903425 [PubMed - indexed for MEDLINE]
188: Differentiation 1996 Jul;60(4):193-201
The ovary retains male potential after the thermosensitive period for sex
determination in the turtle Emys orbicularis.
Dorizzi M, Richard-Mercier N, Pieau C.
Institut Jacques Monod, CNRS, Paris, France.
Emys orbicularis is a turtle with temperature-dependent sex determination. The
thermosensitive period (TSP) lies between embryonic stages 16 and 22. Gonadal
differentiation begins during this period involving oestrogens. Treatment with
oestrogens during TSP results in the differentiation of ovaries at a
male-producing temperature (25 degrees C), whereas treatment with an
antioestrogen (tamoxifen) or with nonsteroidal aromatase inhibitors results in
gonadal masculinization at a female-producing temperature (30 degrees C). The
present study examines the effects on the ovary of inhibiting aromatase activity
after TSP. Eggs of E. orbicularis incubated at 30 degrees C were given five or
seven applications of 10 micrograms aromatase inhibitor Letrozole (CGS 20267) in
ethanol, between stages 22+ and 24-25 when ovarian aromatase activity strongly
increases. Individuals which received five applications were sacrificed at
stages 24(+)-25. Those which received seven applications were sacrificed either
at stage 25+ (close to hatching), or 34-36 days after hatching. Gonadal
aromatase activity and related gonadal structure were studied in each
individual. In the three series, the gonadal aromatase activity in individuals
treated with Letrozole varied from similar or close to that in controls to much
lower, and the gonadal structure varied from ovary-like to ovotestis. Ovotestes
had the lowest levels of aromatase activity, under 4 fmoles/h/gonad, close to
testis levels. They were found in 7 out of 26 individuals given Letrozole.
Besides ovotestes, gonads presenting various degrees of masculinization, with
enlarged epithelial cords and lacunae in the medulla, were found. Therefore, by
inhibiting aromatase activity and thus estrogen synthesis, we were able to
obtain the differentiation of testis-like cords or tubes in ovaries of E.
orbicularis, after the period of temperature sensitivity. These results show
that the ovary retains male potential after this period. Thus, besides their
implication during the critical embryonic period for gonadal sex
differentiation, oestrogens play a role in maintaining the ovarian structure
after this period. A decrease in oestrogen levels could explain some other cases
of ovarian masculinization known in vertebrates.
PMID: 8765049 [PubMed - indexed for MEDLINE]
189: Acta Oncol 1996;35 Suppl 5:38-43
Aromatase inhibition for breast cancer treatment.
Lonning PE.
Department of Oncology, Haukeland University Hospital, Bergen, Norway.
While the first generation aromatase inhibitor aminoglutethimide and second- and
third generation inhibitors like formestane and fadrozole all have been found to
inhibit in vivo aromatization by 85-93%, the novel aromatase inhibitors
letrozole and arimidex inhibit in vivo aromatization by 97-99%. However, we do
not know whether these drugs cause a higher response rate or a longer duration
of remission compared with less potent aromatase inhibitors. Lack of
cross-resistance to steroidal and non-steroidal aromatase inhibitors suggests
that these drugs may have partially different mechanisms of action, probably by
influencing the intratumour aromatase enzyme. Recent studies have shown that
breast cancer cells may adapt to alterations in oestrogen concentration in vitro
by increasing their sensitivity. The observation that patients suffering relapse
following castration, hypophysectomy or adrenalectomy may respond to treatment
with aromatase inhibitors suggests that similar mechanisms could be responsible
for acquired resistance to oestrogen deprivation.
Publication Types:
Review
Review, Tutorial
PMID: 9142963 [PubMed - indexed for MEDLINE]
190: Acta Oncol 1996;35 Suppl 5:15-8
Letrozole (CGS 20267), a new oral aromatase inhibitor for the treatment of
advanced breast cancer in postmenopausal patients.
Trunet PF, Bhatnagar AS, Chaudri HA, Hornberger U.
Department of Research, Pharmaceuticals Division, Ciba-Geigy Limited, Basel,
Switzerland.
Letrozole is a new orally, active, potent, and highly specific non-steroidal
aromatase inhibitor. Letrozole is about 200 and 10000 times as potent as
aminoglutethimide (AG) in vitro and in vivo, respectively. Letrozole was tested
in healthy men and postmenopausal women and in postmenopausal patients with
advanced breast cancer (ABC). Levels of circulating estrogens decreased by more
than 75 to 95% from pre-treatment levels have been observed in patients treated
with daily doses of 0.1 to 5 mg letrozole. No clinically relevant changes in
other hormones of the endocrine system were found. In four phase Ib/IIa trials,
letrozole has shown anti-tumor activity in postmenopausal patients with ABC
previously treated with hormonotherapy and/or chemotherapy. Letrozole was well
tolerated. Phase IIb/III studies are on going to compare two doses of letrozole
with megestrol acetate or AG in order to confirm the anti-tumor efficacy of
letrozole in the treatment of ABC in postmenopausal patients who
progressed/relapsed following treatment with anti-estrogens.
Publication Types:
Review
Review, Tutorial
PMID: 9142959 [PubMed - indexed for MEDLINE]
191: Ann Oncol 1996 Jan;7(1):99-102
Letrozole, a new oral non-steroidal aromastase inhibitor in treating
postmenopausal patients with advanced breast cancer. A pilot study.
Bisagni G, Cocconi G, Scaglione F, Fraschini F, Pfister C, Trunet PF.
Medical Oncology Division, University Hospital, Parma.
PURPOSE: To evaluate the endocrine effects as well as the pharmacokinetic
parameters, efficacy and safety of letrozole, a new fourth-generation
non-steroidal aromatase inhibitor. PATIENTS AND METHODS: Fourteen postmenopausal
women with progressive metastatic breast cancer, previously treated with
endocrine therapy and/or chemotherapy for advanced disease, were treated with
0.5 mg daily doses of letrozole, orally. Endocrine and pharmacokinetic
measurements were made before treatment and on days 14, 28, 56, and 84 of
therapy. RESULTS: Letrozole induced a >86% decrease in plasma estrone and a
approximately 67% reduction in circulating estradiol from day 14 on. There was a
statistically significant decrease in plasma cortisol, which appeared clinically
irrelevant since all values remained within the normal range. No significant
changes in aldosterone concentration were noted. One patient achieved a complete
response (CR) and 4 patients a partial response (PR), with an objective response
rate of 36% (95% CI 13% to 65%). Median duration of response was 24 months,
ranging from 4 to 44 months. No toxic effects attributable to letrozole were
noted in any patient. CONCLUSION: Letrozole appears to be a very promising new
antiaromatase drug. The characteristics of the patients more likely to respond,
taking into account prior systemic treatment, should be defined by future
studies. Further phase II and phase III studies comparing letrozole to other
available second or even first-line endocrine-therapy agents, are warranted.
Publication Types:
Clinical Trial
PMID: 9081401 [PubMed - indexed for MEDLINE]
192: J Steroid Biochem Mol Biol 1996 Jan;56(1-6 Spec No):145-50
The control and biological importance of intratumoural aromatase in breast
cancer.
Dowsett M, Lee K, Macaulay VM, Detre S, Rowlands M, Grimshaw R.
Royal Marsden Hospital, London, U.K.
The existence of aromatase activity in human breast carcinomas has been
established for about 20 years but the clinical and biological importance of
this remains unclear. A number of studies in clinical material suggest that
aromatase activity may be a prerequisite of response to aromatase inhibitors and
that aromatase activity may be enhanced in those tumours relapsing during
treatment with one such inhibitor, aminoglutethimide. These results would carry
more significance, however, if it was demonstrable that the growth of breast
carcinomas is affected by the conversion of androgens to oestrogens by
intratumoural aromatase. We have tried to address this by establishing model
systems with aromatase-transfected MCF7 breast cancer cells. We have
demonstrated that these cells can be stimulated mitogenically with androgen and
that this proliferation is suppressible with aromatase inhibitors. Similarly the
growth of aromatase transfected cells but not wild type cells as xenografts is
supported by androstenedione and inhibitable by both the steroidal aromatase
inhibitor, 4-hydroxyandrostenedione and non-steroidal inhibitor, CGS 20267. Work
with the former of these, which is a suicide inhibitor allowed us to demonstrate
that growth can proceed with aromatase activity approximating to the highest
level seen in breast carcinomas indicating that at least at this extreme level
the intratumoural conversion of androgens to oestrogens may indeed be able to
support tumour growth. Further work with this mode system should allow us to
define the minimal amount of intratumoural activity which can support tumour
growth.
Publication Types:
Review
Review, Tutorial
PMID: 8603035 [PubMed - indexed for MEDLINE]
193: Gen Comp Endocrinol 1995 Dec;100(3):314-26
Endocrine sex reversal of gonads by the aromatase inhibitor Letrozole (CGS
20267) in Emys orbicularis, a turtle with temperature-dependent sex
determination.
Richard-Mercier N, Dorizzi M, Desvages G, Girondot M, Pieau C.
Institut Jacques Monod, CNRS et Universite Paris, France.
In embryos of Emys orbicularis, the sexual differentiation of gonads is
influenced by the incubation temperature of eggs. Estrogens administered during
the thermosensitive period result in the feminization of gonads at 25 degrees
(male-producing temperature), whereas an antiestrogen or aromatase inhibitors
masculinize the gonads at 30 degrees (female-producing temperature). The
nonsteroidal aromatase inhibitor Letrozole induces gonads with different degrees
of masculinization, from ovary-like to testis-like. The present study examines
the endocrine function of such masculinized gonads, at the end of embryonic
life. Aromatase activity (which is involved in estrogen synthesis in ovary) and
the status of Mullerian ducts (the regression of which reflects the secretion of
a putative anti-Mullerian hormone by the Sertoli cells) were examined. One month
after treatment with Letrozole, the gonads of embryos presented various levels
of aromatase activity. There was a strong correlation among aromatase activity,
gonadal structure, and Mullerian duct status; high levels of aromatase (similar
or close to those in control females) were found in ovary-like gonads;
intermediate levels were found in gonads (masculinized ovaries or ovotestes?)
exhibiting a cortex and a composite medulla containing a mixture of ovarian
lacunae and testicular cord-like structures; low levels (similar or close to
those in control males) were found in strongly masculinized gonads (testis-like
or ovotestes). Mullerian ducts were regressing in the majority of embryos with
gonads containing low levels of aromatase activity. In these individuals, gonads
functioned as embryonic testes. These results confirm the implication of
estrogens in gonadal differentiation. The origin of these hormones is
controversial, so that the aromatase activity was compared in gonads, in the
undissociated adrenal-mesonephric complex (AM), and in different parts of this
complex during the thermosensitive period. At the female-producing temperature,
the aromatase activity per unit of tissue increased in differentiating ovaries
but it was low in AM and similar to that found in AM at male-producing
temperature. In embryos whose gonads had been masculinized by early treatment
with Letrozole, aromatase activity was unchanged in AM. These results suggest
that the main source of estrogens involved in ovarian differentiation is the
gonad itself.
PMID: 8775058 [PubMed - indexed for MEDLINE]
194: Curr Opin Oncol 1995 Nov;7(6):523-6
Metastatic breast cancer.
Rubens RD.
Imperial Cancer Research Fund, Clinical Oncology Unit, Guy's Hospital, London,
UK.
Tamoxifen as adjuvant systemic treatment after first isolated locoregional
recurrence of breast cancer has been shown to decrease the subsequent
locoregional relapse rate, but it affects neither distant metastases nor
survival. In metastatic disease, tamoxifen has not improved response when added
to ablation of ovarian function. The cyclical sequential use of tamoxifen with
megestrol acetate has not increased the response over tamoxifen alone. Aromatase
inhibitors are an expanding field; formestane and vorozole are effective agents,
and letrozole shows promise. In chemotherapy, major interest has focused on the
use of taxoids, with high activity being reported for both paclitaxel and
docetaxel, the latter being particularly effective as a second-line treatment.
Reports continue to reaffirm the effectiveness of vinorelbine. The in vitro
ability of quinidine to reverse resistance to anthracyclines has not been
repeatable in a clinical setting. The evaluation of high-dose chemotherapy with
bone marrow support continues to be explored, but this approach has thus far not
been demonstrated to improve clinical outcome in advanced disease. The
intra-arterial administration of chemotherapy appears to have a useful
palliative role in selected patients with locoregional disease.
Publication Types:
Clinical Trial
Review
Review, Tutorial
PMID: 8547400 [PubMed - indexed for MEDLINE]
195: Gen Comp Endocrinol 1995 Sep;99(3):316-22
Making males from females: the effects of aromatase inhibitors on a
parthenogenetic species of whiptail lizard.
Wennstrom KL, Crews D.
Department of Zoology, University of Texas at Austin 78712, USA.
The parthenogenetic whiptail lizard Cnemidophorus uniparens provides a good
model for the study of sex determination and sexual differentiation because
genetic variation is minimal and all unmanipulated embryos will develop as
females. Thus any deviation from the established course of development can be
identified as a treatment effect. Previous work has shown that early prenatal
treatment with CGS16949A, a nonsteroidal aromatase inhibitor, causes hatchlings
to develop as males. The present study explores more fully the effects of dosage
and timing of application of CGS16949A and examines the sex-reversing potential
of CGS20267, a new and reputedly more potent aromatase inhibitor. Eggs were
treated with a range of dosages of the aromatase inhibitors. Hatchlings that
received 1 microgram or more of either inhibitor were all male, while those that
received 0.1 microgram or less were all female. No difference in potency between
the two compounds was detected. Animals treated with 100 micrograms of CGS16949A
on Day 20 of incubation or later were all female, while those treated on Day 5
were all male. Seven sex-reversed male parthenogens have been raised to sexual
maturity. The animals appear similar morphologically and behaviorally to males
of the sexually reproducing whiptail species. Spermatogenesis and spermiogenesis
have been confirmed by histological examination of the testes and by
postcopulatory cloacal swabs. Application of aromatase inhibitors has been shown
to sex-reverse both avian and reptilian species. In mammals, the
male-determining gene of the Y chromosome (SRY) may code for an intrinsic
aromatase inhibitor. Studies show the gene's product has a binding domain which
recognizes regulatory elements in the promoter of the aromatase gene.(ABSTRACT
TRUNCATED AT 250 WORDS)
PMID: 8536943 [PubMed - indexed for MEDLINE]
196: J Clin Endocrinol Metab 1995 Sep;80(9):2658-60
Use of ultrasensitive recombinant cell bioassay to measure estrogen levels in
women with breast cancer receiving the aromatase inhibitor, letrozole.
Klein KO, Demers LM, Santner SJ, Baron J, Cutler GB Jr, Santen RJ.
Children's Hospital of Orange County, California 92668, USA.
The development of well tolerated, potent, specific, and nontoxic aromatase
inhibitors for the treatment of postmenopausal women with estrogen-dependent
breast cancer has been a major goal of recent studies. The third generation
inhibitors now under investigation are nearly 10,000-fold more potent than first
generation compounds. Currently available RIAs for plasma estradiol lack
sufficient sensitivity to measure levels during aromatase inhibition and, thus,
to assess drug potency precisely. The availability of an ultrasensitive bioassay
for estradiol provided the opportunity to accurately assess the potency of a new
third generation triazole aromatase inhibitor, letrozole (CGS 20267). We used
this assay to measure estradiol levels in 14 women with metastatic breast cancer
given letrozole at doses of 100 micrograms to 5.0 mg/day over a 12-week period.
The lack of differences between doses and sampling times allowed pooling of
data. Basal estradiol levels of 7.2 +/- 1.9 pmol/L (mean +/- SEM, 1.95 +/- 0.52
pg/mL) fell to 0.26 +/- 0.11 pmol/L (0.07 +/- 0.03 pg/mL) during the first 6
weeks of therapy and to 0.48 +/- 0.18 pmol/L (0.13 +/- 0.05 pg/mL) during the
second 6 weeks of therapy. Although plasma estradiol levels measured by RIA were
significantly correlated with levels measured by bioassay (r = 0.79; P < 0.01),
the degree of suppression assessed by the bioassay (95 +/- 2% after 6 weeks) was
greater than that determined by the RIA (81 +/- 4%), presumably due to improved
ability to measure very low estradiol levels. We conclude that plasma estradiol
is suppressed by letrozole to lower levels than previously observed, with
equivalent suppression at all doses studied. A slight, although not
statistically significant, rebound in estradiol levels occurs during the second
6 weeks of therapy compared to the first 6 weeks. Maximum inhibition of
aromatase is achieved at letrozole doses as low as 100 micrograms.
Publication Types:
Clinical Trial
PMID: 7673408 [PubMed - indexed for MEDLINE]
197: Int J Cancer 1995 Jul 28;62(3):297-302
An in vivo model of intratumoural aromatase using aromatase-transfected MCF7
human breast cancer cells.
Lee K, Macaulay VM, Nicholls JE, Detre S, Ashworth A, Dowsett M.
Academic Department of Biochemistry, Royal Marsden Hospital, London, UK.
About two-thirds of human breast carcinomas contain detectable levels of
aromatase, the enzyme which converts androgens to oestrogens. Assessment of the
importance of this enzyme to breast cancer growth has been hampered by the
absence of an adequate model system. We have previously reported that MCF7 human
hormone-dependent breast cancer cells transfected with human aromatase cDNA
(Arom1 cells) showed a growth response in vitro to exogenous androgens and this
effect was blocked by aromatase inhibitors. We report here our use of these
cells to develop a xenograft model in athymic nude mice. Neither MCF7 cells nor
Arom1 cells formed tumours in oophorectomised (ovx) nude mice unless provided
with oestradiol (E2) support. Once established, Arom1, but not MCF7, tumours
could be grown in ovx females supplemented with androstenedione (delta 4A). The
mean plasma level of delta 4A was 14 nmol/L in supplemented animals and < 0.5
nmol/L in unsupplemented animals. Similarly, unsupplemented male nude mice were
able to support the growth of Arom1 tumours but not MCF7 tumours. The potent and
highly specific aromatase inhibitor CGS20267 (letrozole) significantly decreased
tumour growth at 2 mg/kg/day and completely inhibited growth at 20 mg/kg/day in
delta 4A-supplemented but not E2-supplemented animals. Our results indicate that
delta 4A-dependent growth of Arom1 tumours in vivo is mediated through the
action of intratumoural aromatase. This model should allow an assessment of the
critical levels of aromatase required for tumour growth support.
PMID: 7628871 [PubMed - indexed for MEDLINE]
198: Cancer Res 1995 Jul 15;55(14):3073-7
Effect of aromatase inhibitors on growth of mammary tumors in a nude mouse
model.
Yue W, Wang J, Savinov A, Brodie A.
Department of Pharmacology and Experimental Therapeutics, School of Medicine,
University of Maryland, Baltimore 21201, USA.
The effects of aromatase inhibitors 4-hydroxyandrostenedione (4-OHA), CGS
16949A, and CGS 20267, and of the antiestrogen tamoxifen (TAM), were studied on
the growth of human breast carcinoma in a nude mouse model. To simulate the
postmenopausal breast cancer patient, tumors were formed from inoculates of
MCF-7 cells transfected with the human aromatase gene to provide a source of
non-ovarian estrogen in ovariectomized mice. Tumor growth was significantly
inhibited by all treatments (P < 0.05). Greater reduction in growth occurred in
mice treated with TAM combined with aromatase inhibitors than with TAM alone.
Tumor progesterone receptor concentrations were unaltered by TAM treatment but
were reduced by aromatase inhibitors. Progesterone receptor concentrations
correlated with tumor growth. The greatest reduction occurred in tumors of CGS
20267-treated mice in which no progesterone receptors were detected. In the
ovariectomized mice used in these studies, uterine weight was maintained by
estrogen produced from the tumor. Uterine weight was reduced by aromatase
inhibitors but not by TAM treatment. However, there was a significant increase
in uterine weight in mice treated with the combination of TAM and 4-OHA. Thus,
the agonist effect of TAM was evident when estrogen synthesis was inhibited. The
results indicate that aromatase inhibitors have potent effects on mammary tumor
growth but lack the estrogenic effects on the uterus observed with TAM. There
appeared to be no significant benefit in combining TAM with 4-OHA over 4-OHA
treatment alone.
PMID: 7606729 [PubMed - indexed for MEDLINE]
199: Cancer 1995 Apr 15;75(8):2132-8
Letrozole (CGS 20267). A phase I study of a new potent oral aromatase inhibitor
of breast cancer.
Lipton A, Demers LM, Harvey HA, Kambic KB, Grossberg H, Brady C, Adlercruetz H,
Trunet PF, Santen RJ.
Department of Medicine, M. S. Hershey Medical Center, Pennsylvania State
University, Hershey 17033, USA.
BACKGROUND. Letrozole (CGS 20267), a triazole derivative, is a new, once-daily,
oral nonsteroidal inhibitor of aromatase activity. METHODS. In this Phase I
trial, 23 heavily pretreated postmenopausal patients with metastatic breast
cancer received letrozole at doses ranging from 0.1 to 5.0 mg once daily.
RESULTS. No hematologic, biochemical, or significant clinical toxicity was
encountered. Serial steroid measurements were determined in 19 of these
patients. Letrozole at all doses tested produced a marked suppression of plasma
estrone, estradiol, estrone sulfate, and urine estrone and estradiol. This was
observed within 24 hours of the initial dose of letrozole and resulted in a
greater than 90% suppression of plasma and urinary estrogen levels within 2
weeks. Letrozole appears to be highly selective in its action and does not
compromise glucocorticoid or mineralocorticoid production or thyroid function.
Of the 21 evaluable patients, there were 2 with partial responses and 7 with
stable disease. CONCLUSIONS. Letrozole is a well tolerated, potent, and specific
inhibitor of estrogen biosynthesis in postmenopausal patients with metastatic
breast cancer.
Publication Types:
Clinical Trial
Clinical Trial, Phase I
PMID: 7697604 [PubMed - indexed for MEDLINE]
200: J Endocrinol 1994 Nov;143(2):279-89
Role of reductase and aromatase in sex determination in the red-eared slider
(Trachemys scripta), a turtle with temperature-dependent sex determination.
Crews D, Bergeron JM.
Department of Zoology, University of Texas at Austin 78712.
In many turtles the temperature during the middle of incubation determines the
gonadal sex of the hatchling. In the red-eared slider turtle (Trachemys
scripta), an incubation temperature of 26 degrees C results in all male
offspring, whereas an incubation temperature of 31 degrees C results in all
female offspring; at temperatures intermediate to these (e.g. 29, 29.2, 29.4
degrees C) a mixed sex ratio is obtained. Administration of exogenous oestrogens
will overcome the effects of an all-male producing incubation temperature to
cause female sex determination, whereas administration of exogenous
dihydrotestosterone (DHT) or testosterone to eggs incubating at an all-female
temperature will have no discernible effect. Administration of DHT will cause
male sex determination only if administered at intermediate incubation
temperatures whereas administration of testosterone to eggs incubating at all
male-producing and male-biased intermediate temperatures results in a
significant number of female offspring, an effect presumably due to
aromatization of testosterone to oestradiol (OE2). Since testosterone serves as
the precursor to both DHT and OE2, being metabolized by reductase and aromatase
respectively, three experiments were conducted to determine whether various
putative reductase and aromatase inhibitors would overcome the effect of
incubation temperature. First, while administration of testosterone to eggs
incubating at all male-producing and male-biased intermediate temperatures
produced females in a dose- and temperature-dependent manner, significant
numbers of intersex individuals resulted from high dosage testosterone treatment
to eggs incubating at a female-biased intermediate temperature. The reductase
inhibitors 4MA and MK906 were capable of producing female offspring if
administered at intermediate temperatures, but not in a dose-dependent fashion.
Administration of the aromatase inhibitors CGS16949A and CGS20267 resulted in
male offspring at both female-biased intermediate and at all female-producing
temperatures in a dose-dependent fashion. Second, similar findings were obtained
with combined doses of testosterone and reductase or aromatase inhibitors.
Combined treatment of eggs at male-biased intermediate incubation temperatures
with testosterone and reductase inhibitor resulted in female hatchlings, whereas
combined treatment of testosterone and aromatase inhibitor at both female-biased
intermediate and at all female-producing temperatures resulted in male
hatchlings.(ABSTRACT TRUNCATED AT 400 WORDS)
PMID: 7829992 [PubMed - indexed for MEDLINE]
201: Exp Toxicol Pathol 1994 Aug;46(3):211-3
Changes induced by treatment with aromatase inhibitors in testicular Leydig
cells of rats and dogs.
Junker Walker U, Nogues V.
Preclinical Safety, Pathology, Pharma Division, Ciba-Geigy AG, Basel,
Switzerland.
Treatment of male rats and dogs with CGP 32,349 (formestane), a steroidal
aromatase inhibitor, and CGS 20,267 (letrozole), a non-steroidal aromatase
inhibitor, induced different alterations in testicular interstitial Leydig cells
in the two species. Whereas in dogs Leydig cells were hypertrophic and
hyperplastic, in rats either no effect (CGS 20,267) or atrophy of Leydig cells
(CGP 32,349) was reported. The different response of the two species can be
explained by different regulating mechanisms of gonadotropin secretion by the
anterior pituitary.
PMID: 8000241 [PubMed - indexed for MEDLINE]
202: J Steroid Biochem Mol Biol 1994 Jun;49(4-6):281-7
Aromatase inhibitors in the treatment of breast cancer.
Brodie AM.
Department of Pharmacology & Experimental Therapeutics, School of Medicine,
University of Maryland, Baltimore 21201.
A number of inhibitors of estrogen synthesis are now becoming available which
could be of value in the treatment of breast cancer. 4-Hydroxyandrostenedione
(4-OHA), the first of these compounds to enter the clinic has been found to be
effective in postmenopausal patients who have relapsed from tamoxifen. Thus, in
studies of 240 patients, 26% patients experienced partial or complete response
to treatment. An additional 25% patients had disease stabilization. 4-OHA is a
potent selective, steroidal inhibitor which causes inactivation of aromatase in
vitro. It is effective in reducing concentrations of ovarian estrogens in rats
and of ovarian and peripheral estrogens in non-human primate species. The
compound has been shown to lower serum estrogen levels in postmenopausal breast
cancer patients. However, not all of these patients experienced disease
remission, suggesting that their tumors were hormone insensitive rather than
that the dose of 4-OHA was suboptimal. In trials of patients who had not
received prior tamoxifen treatment, 4-OHA (250 mg i.m. every 2 weeks) was found
to induce complete or partial tumor regression in 33% of patients. The response
of patients was not significantly different from that observed in patients
treated with tamoxifen (30 mg o.d) of 37%. No significant difference between
treatments was observed for disease stabilization, the duration of response or
median survival. Several other steroidal aromatase inhibitors have been studied,
such as 7 alpha-substituted androstenedione derivatives. MDL 18962
[10-(2-propynyl)estr-4-ene-3,17-dione] and FCE 24304
(6-methylen-androsta-1,4-diene-3,17-dione) are currently in clinical trials.
Non-steroidal inhibitors of cytochrome P-450 enzymes, such as imidazole and
triazole derivatives have been developed which are highly selective for
aromatase. Three triazoles which are very potent and selective inhibitors are
vorazole (6-[(4-chlorophenyl)(1H-1,2,4-triazol-1-yl)-methyl]1-methyl-1H-
benzotriazole R 76713, arimidex 2,2'[5-(1H-1,2,4-triazol-1-yl
methyl)-1,3-phenylene]bis(2-methylpropiononitrile) (ZD1033) and letrozole
4-[1-(cyanophenyl)-1-(1,2,4-triazolyl)methyl]benzonitril (CGS 20267). These
compounds reduce serum estradiol concentration to undetectable levels in breast
cancer patients. These highly potent inhibitors provide the opportunity to
determine whether a further degree of estrogen suppression will be important in
producing greater clinical response.(ABSTRACT TRUNCATED AT 400 WORDS)
Publication Types:
Review
Review, Tutorial
PMID: 8043490 [PubMed - indexed for MEDLINE]
203: J Pharm Sci 1994 Apr;83(4):520-4
Development, application and comparison of an enzyme immunoassay and a
high-performance liquid chromatography method for the determination of the
aromatase inhibitor CGS 20,267 in biological fluids.
Pfister CU, Duval M, Godbillon J, Gosset G, Gygax D, Marfil F, Sioufi A, Winkler
B.
Ciba-Geigy Ltd., Pharma Research and Development, Basle, Switzerland.
CGS 20,267 is a new potent and selective, nonsteroidal, oral aromatase
inhibitor. For its determination in human plasma and urine, an enzyme
immunoassay (EIA) and an HPLC method were developed. The EIA showed good
precision and accuracy (intra- and interassay variation between 3.0 and 17.7%,
recoveries between 81 and 106%) and a quantitation limit of 0.7 nmol/L. A strong
cross reactivity of the antibodies with the hydroxy metabolite of CGS 20,267
(CGP 44,645) was observed. The HPLC method showed a quantitation limit in plasma
of 28 and 34 nmol/L for CGS 20,267 and CGP 44,645, respectively. For urine,
concentrations down to 180 nmol/L (CGS 20,267) and 210 nmol/L (CGP 44,645) could
be measured. A cross check between EIA and HPLC on plasma samples from healthy
male volunteers or breast cancer patients treated orally with CGS 20,267
revealed an excellent correlation (slope = 0.934, intercept = 26, r = 0.991).
However, the EIA measurements of urine samples yielded 3-25 times higher
concentrations than those obtained by HPLC. Further, HPLC analysis revealed the
presence of CGS 20,267 and cross-reacting metabolites in urine but not in
plasma. Therefore, the EIA can only be used for the determination of CGS 20,267
in plasma samples.
PMID: 8046607 [PubMed - indexed for MEDLINE]
204: Breast Cancer Res Treat 1994;30(1):95-102
Effects of Fadrozole (CGS 16949A) and Letrozole (CGS 20267) on the inhibition of
aromatase activity in breast cancer patients.
Demers LM.
Department of Pathology and Medicine, M.S. Hershey Medical Center, Pennsylvania
State University, Hershey 17033.
Fadrozole Hydrochloride (CGS 16949A) and Letrozole (CGS 20267), are two of the
newest non-steroidal, orally active aromatase inhibitors currently being
evaluated as second line treatment of patients with hormone dependent forms of
metastatic breast cancer. In a phase I clinical efficacy study, we examined the
ability of these two imidazole derivatives to suppress the synthesis of estrogen
in a cohort of postmenopausal patients with metastatic breast cancer. Both
medications at relatively low doses were potent and rapid inhibitors of
aromatase activity as evidenced by their ability to suppress the level of blood
and urine estradiol and estrone as well as blood estrone sulfate in these
patients. Letrozole appeared to be the more potent of the two, with over 95%
suppression of both plasma and urinary estrogens observed within 2 weeks of
therapy. Letrozole appeared to be more selective than Fadrozole in inhibiting
aromatase activity in that no compromise in cortisol and aldosterone output was
evident with Letrozole therapy at all of the doses tested, a compromise clearly
seen with Fadrozole. The inhibition of aromatase activity by these imidazole
derivatives as second line therapy for patients with hormone dependent breast
cancer appears to be a favorable alternative form of hormone ablative therapy
and holds considerable promise for the treatment of this malignancy.
Publication Types:
Clinical Trial
Clinical Trial, Phase I
Controlled Clinical Trial
PMID: 7949208 [PubMed - indexed for MEDLINE]
205: J Steroid Biochem Mol Biol 1993 Dec;47(1-6):161-6
The role of estrogen in the feedback regulation of follicle-stimulating hormone
secretion in the female rat.
Bhatnagar AS, Batzl C, Hausler A, Nogues V.
Research Department, Pharmaceuticals Division, CIBA-GEIGY Limited, Basel,
Switzerland.
Letrozole (CGS 20267) is a non-steroidal aromatase inhibitor which, at its
maximally effective dose of 1 mg/kg p.o., elicits endocrine effects equivalent
to those seen after ovariectomy. Adult, female cyclic rats were administered
letrozole (1 mg/kg p.o.) once daily for 14 days. A control group of animals was
ovariectomized on day 1 of treatment and a third group of animals served as
untreated controls. During the experiment, vaginal smears were taken daily and
at the end of 14 days all animals were sacrificed, trunk blood was taken for
serum estradiol, LH and FSH measurements and the uterus and ovaries were removed
and weighed. The ovaries were then fixed and prepared for histological
examination. Serum hormone measurements showed that after treatment with
letrozole, serum estradiol levels were reduced by 76% of untreated controls and
serum LH was elevated to 378% of control values. These compared favorably with
those seen after ovariectomy, serum estradiol was reduced by 78% and serum LH
was elevated to 485% of untreated controls. However, FSH was unchanged after
letrozole treatment (125% of control), whereas after ovariectomy FSH rose to
398% of control. Uterine weight was suppressed in the letrozole-treated animals
as well as the ovariectomized animals by 60 and 70%, respectively. The histology
of the ovaries of animals treated with letrozole were consistent with the serum
hormone findings. Except for the effects on serum FSH, these results confirm
previous findings that treatment with letrozole elicits endocrine effects
similar to those seen after ovariectomy. Furthermore, these results demonstrate
that FSH secretion is not under the control of estradiol whereas LH secretion is
under feedback control of ovarian estrogen.
PMID: 8274431 [PubMed - indexed for MEDLINE]
206: J Clin Endocrinol Metab 1993 Aug;77(2):324-31
Comment in:
J Clin Endocrinol Metab. 1993 Aug;77(2):316-7
Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in healthy
postmenopausal women.
Iveson TJ, Smith IE, Ahern J, Smithers DA, Trunet PF, Dowsett M.
Breast Unit, Royal Marsden Hospital, London, United Kingdom.
We have performed a phase I study of the effect of a single dose of CGS 20267,
an oral nonsteroidal aromatase inhibitor, in 12 healthy volunteer postmenopausal
women. Each subject received 2 single doses of CGS 20267 (0.1, 0.5, or 2.5 mg)
or placebo separated by a washout period of at least 6 weeks. There was
statistically significant suppression of serum estrone and estradiol at all
three doses of CGS 20267 tested. Serum estrone and estradiol concentrations were
maximally suppressed by 76% and 79% from baseline levels, respectively. Urinary
excretion of estrone and estradiol was also suppressed, although this did not
reach statistical significance. Serum concentrations of aldosterone, cortisol,
17 alpha-hydroxyprogesterone, androstenedione, testosterone, FSH, LH, and TSH
were unaffected by CGS 20267. The drug was well tolerated, with no significant
side-effects. This study has shown CGS 20267 to be a potent and specific
aromatase inhibitor, and further studies are now needed to assess its clinical
efficacy.
Publication Types:
Clinical Trial
Clinical Trial, Phase I
Randomized Controlled Trial
PMID: 8345035 [PubMed - indexed for MEDLINE]
207: J Clin Endocrinol Metab 1993 Aug;77(2):319-23
Comment in:
J Clin Endocrinol Metab. 1993 Aug;77(2):316-7
Open dose-finding study of a new potent and selective nonsteroidal aromatase
inhibitor, CGS 20 267, in healthy male subjects.
Trunet PF, Mueller P, Bhatnagar AS, Dickes I, Monnet G, White G.
Research and Development Department, CIBA-GEIGY Limited, Basel, Switzerland.
The aim of this open, dose-finding study was to evaluate the effects of single
dose CGS 20 267, a new oral nonsteroidal aromatase inhibitor, on the inhibition
of estrogen production and also on the production of adrenal and testicular
steroids in healthy male subjects. Nine dose levels ranging from 0.02-30 mg and
placebo were tested, each dose being given to 3 subjects only. A total of 18
subjects were included; 12 of them received 2 single administration, the
remaining 6 were exposed only once to one of the 2 highest dose levels. A
reduction in serum estrogen levels when compared to baseline was already
observed after 2 h, reaching maximum suppression between 10 and 48 h after
administration. After 24 h, a suppression of estrone levels by 60-85% from
baseline was achieved with all tested doses. A reduction in estradiol levels by
about 30% from baseline was observed at the lowest dose (0.02 mg). This
reduction was further enhanced dose dependently to a maximum of about 90% from
baseline at 24 h after administration of the highest dose (30 mg). With the
higher doses (10 and 30 mg), estrogen suppression was maintained up to 3 days. A
dose-dependent increase of testosterone, LH, and FSH was observed and was most
pronounced in the 10- and 30-mg dose groups, which can be considered as a
consequence of the long-lasting aromatase inhibition achieved with these high
doses. No effect on serum cortisol and aldosterone levels was observed up to the
highest dose. No clinically relevant changes were observed in blood chemistry
and hematology tests. The systemic and subjective tolerability of CGS 20 267 was
good at all doses. This study has shown that CGS 20 267 is a well tolerated,
potent, selective, and long-acting inhibitor of the aromatase enzyme after
single administration.
Publication Types:
Clinical Trial
Controlled Clinical Trial
PMID: 8345034 [PubMed - indexed for MEDLINE]
208: J Clin Endocrinol Metab 1993 Aug;77(2):316-8
Comment on:
J Clin Endocrinol Metab. 1993 Aug;77(2):319-23
J Clin Endocrinol Metab. 1993 Aug;77(2):324-31
Estrogen synthesis inhibitors: from "off the rack" to haute couture.
Santen RJ.
Publication Types:
Comment
Editorial
PMID: 8345033 [PubMed - indexed for MEDLINE]
209: J Steroid Biochem Mol Biol 1993 Mar;44(4-6):687-91
The efficacy of CGS 20267 in suppressing estrogen biosynthesis in patients with
advanced stage breast cancer.
Demers LM, Lipton A, Harvey HA, Kambic KB, Grossberg H, Brady C, Santen RJ.
Department of Medicine, Pennsylvania State University, Milton S. Hershey Medical
Center, Hershey 17033.
The pharmacologic inhibition of aromatase activity has been the focus of
clinical trials in patients with advanced stage breast cancer. Recent
developments with imidazole compounds that inhibit aromatase activity suggest
their clinical use as potent inhibitors of estrogen biosynthesis in
postmenopausal breast cancer patients. In this Phase I, open-label, dose-range
finding study, we examined the inhibitory potency of CGS 20267 on blood and
urine levels of estradiol, estrone and estrone sulfate in 8 patients with
metastatic breast cancer. Studies included evaluation of adrenal and thyroid
function to look for evidence of general hydroxylase inhibition at dose levels
effective for aromatase blockade. Patients were administered CGS 20267 at doses
of 0.1 and 0.25 mg, once a day in ascending doses over a 12-week period.
Preliminary data reveal that CGS 20267 elicits a striking suppression in plasma
estradiol, estrone and estrone sulphate which was observed in some patients as
quickly as within 24 h of the first dose. Estrogen suppression of over 90% was
achieved within 2 weeks of therapy. No alterations in either baseline or ACTH
(cortrosyn) stimulated cortisol and aldosterone levels were observed through the
12 weeks of therapy. In addition, 24 h urine sodium and potassium values were
not appreciably altered during therapy. We conclude that CGS 20267 is a potent,
specific inhibitor of estrogen biosynthesis in postmenopausal patients with
metastatic breast cancer and effectively reduces blood and urine estrogens to
undetectable levels.
Publication Types:
Clinical Trial
Clinical Trial, Phase I
PMID: 8476785 [PubMed - indexed for MEDLINE]
210: J Steroid Biochem Mol Biol 1993 Mar;44(4-6):633-6
Anti-tumor and endocrine effects of non-steroidal aromatase inhibitors on
estrogen-dependent rat mammary tumors.
Schieweck K, Bhatnagar AS, Batzl C, Lang M.
Research Department, CIBA-GEIGY Limited, Basel, Switzerland.
The non-steroidal aromatase inhibitor CGS 20,267, at maximally effective doses
in non-tumor bearing adult female rats, elicits endocrine effects mimicking
those seen after surgical ovariectomy and thus induces a "medical" ovariectomy.
We now report on studies characterizing the anti-tumor and endocrine effects of
three orally active non-steroidal aromatase inhibitors, CGS 20,267, CGP 45,688
and CGP 47,645, in adult female rats bearing estrogen-dependent DMBA-induced
mammary tumors. Doses ranging from 3 to 3000 micrograms/kg were given by gavage
once daily for 6 weeks. After 6 weeks of treatment, the ED50 for suppression of
tumor volume was 10-30, 100 and 3-10 micrograms/kg for CGS 20,267, CGP 45,688
and CGP 47,645, respectively. The maximally effective dose for anti-tumor
efficacy was 300, 1000 and 100 micrograms/kg for each of the three inhibitors,
respectively. The observed potent anti-tumor efficacy was accompanied by potent
endocrine effects. Thus, disruption of ovarian cyclicity (at maximal doses rats
remained in constant diestrus) was observed in all animals from the 2nd or 3rd
week of treatment to the end of the 6-week treatment period. Uterine weight, at
the maximally effective doses for each of the three inhibitors, was suppressed
to between 42 and 28% of pre-treatment levels. This suppression was similar to
the suppression of uterine weight (27% of pre-treatment) seen after ovariectomy.
Serum estradiol concentrations in rats treated with 300 micrograms/kg CGS 20,267
were significantly suppressed to 12% of pre-treatment levels and serum
luteinizing hormone (LH) concentrations were elevated 3 to 4-fold over
pre-treatment levels. Thus the potent anti-tumor efficacy seen with each of the
three non-steroidal aromatase inhibitors was accompanied in each case by a
variety of endocrine effects corresponding to those seen after ovariectomy.
PMID: 8476774 [PubMed - indexed for MEDLINE]
211: J Steroid Biochem Mol Biol 1993 Mar;44(4-6):421-8
Structure-activity relationships and binding model of novel aromatase
inhibitors.
Lang M, Batzl C, Furet P, Bowman R, Hausler A, Bhatnagar AS.
Pharmaceutical Research Department, CIBA-GEIGY Limited, Basel, Switzerland.
The use of aromatase inhibitors is an established therapy for
oestrogen-dependent breast cancer in postmenopausal women. However, the sole
commercially available aromatase inhibitor, aminoglutethimide, is not very
selective. We have therefore developed fadrozole hydrochloride and CGS 20,267,
which are both currently under clinical evaluation. This report will present an
analysis of structure-activity relationships in the azole series of inhibitors
and give an account of the further optimization of our development compounds,
starting from CGS 20,267 over CGP 45,688 and leading to CGP 47,645, the most
potent aromatase inhibitor in vivo reported to date. In addition, on the basis
of comparisons of these azole-type inhibitors with the most potent steroidal
inhibitors published in the literature, we propose a CAMM-generated model
describing the relative binding modes of these two classes of compounds at the
active site of the enzyme.
PMID: 8476755 [PubMed - indexed for MEDLINE]
212: Cancer Res 1993 Jan 15;53(2):266-70
Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in
postmenopausal patients with advanced breast cancer.
Iveson TJ, Smith IE, Ahern J, Smithers DA, Trunet PF, Dowsett M.
Breast Unit, Royal Marsden Hospital, London, England.
A phase I study was performed of CGS 20267, an oral nonsteroidal, highly potent,
and selective aromatase inhibitor, in 21 postmenopausal patients with advanced
breast cancer. The patients were recruited in 3 successive groups of 7,
receiving 0.1, 0.5, and 2.5 mg p.o./day, respectively. All patients had received
at least one prior endocrine treatment (range, 1-4), and six patients had
received prior chemotherapy. The treatment was very well tolerated, and no
toxicity was seen at any of the three doses. There was a statistically
significant suppression of estradiol (E2) and estrone (E1) levels by 74% and 79%
from baseline levels, respectively (P < 0.0001). Suppression occurred in all
three patient groups, with many patients having serum concentrations of
estradiol and estrone, which were below the limit of detection of the assays (3
and 10 pM, respectively), which corresponds to a maximum measurable estrogen
suppression of 86%. CGS 20267 had no significant effect on serum levels of
follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating hormone,
cortisol, 17 alpha-hydroxyprogesterone, androstenedione, and aldosterone. Seven
(33%, 95% confidence interval, 15-57%) of the 21 patients have responded to
treatment (one complete remission, 6 partial remissions according to criteria of
the Union Internationale contre le Cancer), and 6 are still responding to CGS
20267 (duration of response; 4+, 6+, 6+, 9+, 9, 12+, and 12+ months). Five have
had stable disease for more than 3 months, and 9 had progressive disease. These
results suggest that CGS 20267 is a very potent and specific aromatase
inhibitor, and phase II studies are now required to confirm its clinical
efficacy.
Publication Types:
Clinical Trial
Clinical Trial, Phase I
PMID: 8417819 [PubMed - indexed for MEDLINE]
213: J Cell Biochem Suppl 1993;17G:242-6
Clinical use of aromatase inhibitors in the treatment of breast cancers.
Manni A.
Milton S. Hershey Medical Center, Department of Medicine, Pennsylvania State
University, Hershey 17033.
Estrogens are the major hormones supporting the growth of human breast cancer.
Aromatization of androgen precursors in peripheral tissues, including the breast
cancer itself, is the major source of estrogens in postmenopausal women.
Therefore, inhibition of the aromatase enzyme offers an effective means of
inducing regression of hormone-responsive breast cancer. Aminoglutethimide, the
first and most widely tested aromatase inhibitor, suppresses estrogen production
to the level of adrenalectomy and exerts an anti-tumor action comparable to
other standard endocrine therapies such as tamoxifen. However, conventional
doses of the drug (1000 mg daily) cause moderate toxicity and inhibit other
critical cytochrome P-450 steroidogenic enzymes, thus requiring concomitant
glucocorticoid administration. New non-steroidal, competitive aromatase
inhibitors with greater selectivity and less toxicity are being developed. The
second generation compound, fadrazole (CGS 16949), lowers estrogen production to
a degree similar to aminoglutethimide (50-80%), but at much lower doses
(approximately 2 mg daily) and is associated with minimal toxicity. Although not
totally specific, this drug is sufficiently selective not to require
simultaneous cortisol replacement. CGS 16949 has been shown to possess
significant anti-tumor action in pilot studies and is currently being tested in
Phase III trials. Recently, a third generation inhibitor, CGS 20267, has been
found to have virtually complete selectivity for the aromatase enzyme.
Furthermore, this drug suppresses estrogen biosynthesis to a greater extent
(approximately 90%) than previously observed with other aromatase inhibitors.
Such enhanced activity may lead to a superior anti-tumor action, and may extend
the use of this drug to a variety of other conditions where optimal suppression
of estrogen biosynthesis is desired.
Publication Types:
Review
Review, Tutorial
PMID: 8007705 [PubMed - indexed for MEDLINE]
214: J Int Med Res 1992 Aug;20(4):303-12
Aromatase inhibitors: clinical pharmacology and therapeutic implications in
breast cancer.
Perez N, Borja J.
Medical Department, Ciba-Geigy SA, Barcelona, Spain.
Aminoglutethimide was the first aromatase inhibitor to be used in breast cancer
therapy but, since it interacts with the synthetic glucocorticoids,
hydrocortisone must also be given as a replacement. The most important
side-effects of aminoglutethimide are at the level of the central nervous
system. Other aromatase inhibitors with greater potency and selectivity are
being developed. Pyridoglutethimide, a compound resulting from modifications to
the structure of aminoglutethimide, seems to be devoid of sedative properties
according to preliminary tests on the central nervous system.
4-Hydroxyandrostenedione is significantly more potent and better tolerated than
aminoglutethimide. Fadrozole (CGS 16,949 A) is 200-400 times more potent than
aminoglutethimide and is now in phase II of its clinical development. CGS 20,267
has no effect on adrenal steroidogenesis and is currently in phase I of its
clinical development. Availability of newer aromatase inhibitors could make a
worthwhile contribution to endocrine therapy in breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 1387368 [PubMed - indexed for MEDLINE]
215: J Steroid Biochem Mol Biol 1992 Mar;41(3-8):437-43
Inhibition of estrogen biosynthesis and its consequences on gonadotrophin
secretion in the male.
Bhatnagar AS, Muller P, Schenkel L, Trunet PF, Beh I, Schieweck K.
Department of Research and Development, Pharmaceuticals Division CIBA-GEIGY
Limited, Basel, Switzerland.
Of the gonadal steroids in the male, testosterone is the most important
regulator of gonadotrophin secretion. However, whether testosterone affects
gonadotrophin secretion directly or whether it must first be aromatized to
estrogens is controversial. We have reported extensively on the endocrine and
anti-tumor effects of the non-steroidal aromatase inhibitors CGS 16949A and CGS
20267 in adult female rats. In these animals, both inhibitors potently and
selectively inhibit estrogen biosynthesis. Thus these agents can be effectively
used in studying estrogen-dependent processes. CGS 16949A was administered for
14 days to adult male rats, over a dose range which in females suppresses
estradiol and elevates LH. In male rats a suppression of estradiol was seen,
however, there was no significant effect on either serum LH or on the weights of
androgen-dependent organs. CGS 16949A, when administered to healthy men at a
dose of 1 mg b.i.d. for 10 days, causes a significant fall in plasma estradiol
and significant elevations of plasma FSH and testosterone. Dose-dependent
suppression of serum estradiol and an increase in serum testosterone and LH are
seen after administration of single oral doses of CGS 20267. These results
indicate that in the male rat, inhibition of aromatization of testosterone to
estrogens does not influence gonadotrophin secretion whereas in men the negative
feedback exerted by testosterone on gonadotrophin secretion is dependent on the
aromatization of testosterone to estrogens.
PMID: 1532903 [PubMed - indexed for MEDLINE]
216: J Steroid Biochem Mol Biol 1990 Dec 20;37(6):1021-7
Highly selective inhibition of estrogen biosynthesis by CGS 20267, a new
non-steroidal aromatase inhibitor.
Bhatnagar AS, Hausler A, Schieweck K, Lang M, Bowman R.
Research Department, Ciba-Geigy Limited, CH-4002 Basel, Switzerland.
CGS 20267 is a new non-steroidal compound which potently inhibits aromatase in
vitro (IC50 of 11.5 nM) and in vivo (ED50 of 1-3 micrograms/kg p.o.), CGS 20267
maximally inhibits estradiol production in vitro in LH-stimulated hamster
ovarian tissue at 0.1 microM with an IC50 of 0.02 microM and does not
significantly affect progesterone production up to 350 microM. In
ACTH-stimulated rat adrenal tissue in vitro, aldosterone production was
inhibited with an IC50 of 210 microM (10,000 times higher than the IC50 for
estradiol production); no significant effect on corticosterone production was
seen at 350 microM. In vivo, in ACTH-treated rats, CGS 20267 does not affect
plasma levels of corticosterone or aldosterone at a dose of 4 mg/kg p.o. (1000
times higher than the ED50 for aromatase inhibition in vivo). In adult female
rats, a 14-day treatment with 1 mg/kg p.o. daily, completely interrupts ovarian
cyclicity and suppresses uterine weight to that seen 14 days after ovariectomy.
In adult female rats bearing estrogen-dependent DMBA-induced mammary tumors, 0.1
mg/kg p.o. given daily for 42 days caused almost complete regression of tumors
present at the start of treatment. Thus compared to each other, CGS 16949A and
CGS 20267 are both highly potent in inhibiting estrogen biosynthesis in vitro
and in vivo. The striking difference between them is that unlike CGS 16949A, CGS
20267 does not affect adrenal steroidogenesis in vitro or in vivo, at
concentrations and doses several orders of magnitude higher than those required
to inhibit estrogen biosynthesis.
Publication Types:
Review
Review, Tutorial
PMID: 2149502 [PubMed - indexed for MEDLINE]
1: Gan To Kagaku Ryoho 2002 May;29(5):741-9
[CGS20267 (Letrozole), a new aromatase inhibitor: late phase II study in
postmenopausal women with advanced or recurrent breast cancer (no.
2)--evaluation of efficacy and safety at the recommended clinical dose CGS20267
Study Group]
[Article in Japanese]
Kimijima I, Tominaga T, Nomizu T, Nomura Y, Takashima S, Koyama H, Sano M, Tohge
T, Ueo H, Ikeda S, Ohashi Y; CGS20267 Study Group.
Dept. of Surgery II, Fukushima Medical College.
In the first part of this late phase II study, we determined the recommended
clinical dose of CGS20267 to be 1.0 mg once daily for the treatment of
postmenopausal women with advanced or recurrent breast cancer. To further
evaluate the efficacy and safety of CGS20267 at the derived or recommended
clinical dose, 30 more patients were enrolled in the second part of the study,
and were added to the patients treated at 1.0 mg in the first part. As a result
of putting the first and second parts together, the objective response rate at
1.0 mg was found to be 38.3%, which was almost equal to that of the early phase
II study (40.7%). Drug-related adverse events occurred in 35.4% of the patients
at 1.0 mg, and all of the events were of grade 2 or lower. These results
demonstrated that CGS20267 1.0 mg once daily is effective and well tolerated in
the treatment of postmenopausal women with advanced or recurrent breast cancer.
PMID: 12040678 [PubMed - in process]
2: Gan To Kagaku Ryoho 2002 May;29(5):729-40
[CGS20267 (Letrozole), a new aromatase inhibitor: late phase II study for
postmenopausal women with advanced or recurrent breast cancer (no.
1)--investigation of recommended clinical dose CGS20267 Study Group]
[Article in Japanese]
Abe R, Tominaga T, Nomizu T, Nomura Y, Takashima S, Koyama H, Sano M, Tohge T,
Ueo H, Ikeda S, Ohashi Y; CGS20267 Study Group.
Dept. of Surgery II, Fukushima Medical College.
To determine the recommended clinical dose of CGS20267 (Letrozole), we conducted
a randomized comparative study as a late phase II study (first part) in
postmenopausal women with advanced or recurrent breast cancer. Forty-one
patients were randomly assigned to receive 0.5 mg or 1.0 mg once daily. There
were no statistically significant differences in background between the two
groups. Although there was no significant difference in the objective response
rates between the two groups, the rate was higher at 1.0 mg (44.4%) than at 0.5
mg (38.1%). We also combined these data with the results of an early phase II
study. The objective response rates (CR + PR) were 31.4% at 0.5 mg and 42.2% at
1.0 mg, and response rates consisting of CR, PR, and NC for longer than 6 months
were significantly higher at a dose of 1.0 mg (68.9%) than 0.5 mg (41.2%). Side
effects included drug-related adverse events in 36.8% at 0.5 mg and in 31.6% at
1.0 mg. All of the events were grade 2 or lower, indicating a favorable
tolerability of CGS20267. These results demonstrated that CGS20267 1.0 mg once
daily is more effective than 0.5 mg, and has comparable safety, in the treatment
of postmenopausal women with advanced or recurrent breast cancer. We conclude
the recommended clinical dose of CGS20267 should be 1.0 mg once daily.
PMID: 12040677 [PubMed - in process]
3: Clin Breast Cancer 2002 Apr;3(1):33-42
Antiaromatase agents: evolving role in adjuvant therapy.
Jones SE.
Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX
75246, USA. [email protected]
The goal of adjuvant hormonal therapy is to prevent breast cancer recurrence.
Standard therapy with tamoxifen has shown great value in the adjuvant setting;
however, its tolerability profile can render it unsuitable for some patients.
The aromatase inactivator, exemestane, and the 2 aromatase inhibitors, letrozole
and anastrozole, have been shown to be equivalent or superior to tamoxifen with
respect to multiple endpoints in patients with metastatic breast cancer. With
tolerability profiles that are similar to, and in many cases, more acceptable
than that of tamoxifen, and efficacy potentially superior to tamoxifen, studies
using the antiaromatase agents as adjuvant therapy are currently ongoing. These
trials will answer some important questions, such as the order in which adjuvant
hormonal therapies are selected to maximize efficacy, whether the antiaromatase
agents show improved tolerability, and whether combination therapy is more
effective than monotherapy.
Publication Types:
Review
Review, Tutorial
PMID: 12020394 [PubMed - indexed for MEDLINE]
4: Curr Med Res Opin 2002;18(1):26-9
Recent advances in breast cancer (the Twenty-fourth San Antonio Breast Cancer
Symposium, December, 2001).
Mokbel K, Kirkpatrick KL.
The Breast Unit, St. George's Hospital and Medical School, London, UK.
This paper reviews the Twenty-fourth Annual San Antonio Breast Cancer Symposium.
The preliminary results of the ATAC study have shown that Arimidex is superior
to tamoxifen in postmenopausal women with ER-positive early breast cancer in
terms of DFS, adverse effects and prevention of contralateral breast cancer.
However, longer follow up is required to assess the drug safety regarding bone
mineral density and cognitive function. Letrozole seems to be superior to
tamoxifen as a first-line therapy in ER-positive advanced breast cancer in
postmenopausal women. Although the incidence of acute myeloid leukaemia is
significantly increased (cumulative incidence at 5 years = 1.1%) in breast
cancer patients receiving cyclophosphamide and anthracyclines, the risk of this
complication is easily outweighed by the benefits of chemotherapy. Adjuvant
clodronate was found to be associated with a significant reduction in the
incidence of bone metastases during the treatment period. A randomised trial
comparing axillary dissection and axillary radiotherapy (RT) for early breast
cancer reported no significant difference in survival at 15 years. However,
axillary recurrence was significantly increased in the RT group. hTERT protein
expression by IHC was found to correlate significantly with breast
cancer-specific survival. There is no evidence to support the use of IHC of the
sentinel node in routine clinical practice. LCIS is currently considered as a
non-obligate precursor to breast cancer rather than just a risk factor.
PMID: 11999142 [PubMed - in process]
5: Expert Opin Pharmacother 2002 May;3(5):607-17
Letrozole in the treatment of breast cancer.
Shaw HS, Ellis MJ.
Multidisciplinary Breast Program, Duke University Medical Center, Box 3381,
Durham, NC 27710, USA. [email protected]
Over the last 30 years the role of tamoxifen in breast cancer treatment has been
progressively expanded by clinical investigation to encompass the entire
spectrum of disease from cancer chemoprevention to palliation of advanced
disease. The primacy of tamoxifen for these indications in postmenopausal women
is now under challenge by the selective aromatase inhibitors, a class of
endocrine agent that induces oestrogen deprivation rather than oestrogen
receptor blockade. This review considers the biochemical, pharmacological and
clinical properties of the nonsteroidal aromatase inhibitor letrozole. This
agent is superior to tamoxifen for the treatment of metastatic breast cancer, a
finding that suggests that letrozole may ultimately eclipse tamoxifen for other
indications, including chemoprevention. Further clinical investigation will be
necessary to establish the risks and benefits of letrozole versus tamoxifen for
each new indication, with adjuvant therapy being the next in line. The object of
this review is to provide a reference source on the biochemical, pharmacological
and clinical properties of letrozole for clinicians to consider both established
and future indications.
PMID: 11996638 [PubMed - in process]
6: J Steroid Biochem Mol Biol 2002 Apr;80(4-5):411-8
Short-term effects of anastrozole treatment on insulin-like growth factor system
in postmenopausal advanced breast cancer patients.
Ferrari L, Martinetti A, Zilembo N, Pozzi P, Buzzoni R, La Torre I, Gattinoni L,
Catena L, Vitali M, Celio L, Seregni E, Bombardieri E, Bajetta E.
Nuclear Medicine, Istituto Nazionale per lo Studio e la Cura dei Tumori of
Milan, Via G. Venezian, 1, 20133, Milan, Italy
Insulin-like growth factors (IGFs) play a fundamental role in cancer development
by acting in both an endocrinal and paracrinal manner, and hormone breast cancer
treatments affect the IGF system by modifying circulating growth factor levels.
We evaluated total IGF-1, IGF-2, IGF binding protein (IGFBP)-1 and IGFBP-3 in
the blood of 34 postmenopausal advanced breast cancer patients (median age 63
years, range 41-85) treated with anastrozole, a non-steroidal structure
aromatase inhibitor (NSS-AI). The plasma samples were obtained at baseline, and
after 2, 4, 8 and 12 weeks of treatment. The IGFs were quantitated by means of
sensitive radioimmunoassays (RIAs). IGF-1 significantly increased during
anastrozole treatment (baseline versus 12 weeks, P=0.031), IGF-2 showed a trend
towards an increase, and IGFBP-1 constantly but not significantly decreased;
IGFBP-3 did not seem to be affected at all. The anastrozole-induced changes in
IGFs and IGFBP-1 appeared to be different in the patients receiving a clinical
benefit from those observed in non-responders. We have previously shown that
letrozole (a different type of NSS-AI) modifies blood IGF-1 levels, and the
results of this study of the biological effects of anastrozole on the components
of the IGF system confirm our previous observations.
PMID: 11983488 [PubMed - in process]
7: Gan To Kagaku Ryoho 2002 Apr;29(4):551-62
[CGS 20267 (Letrozole), a new aromatase inhibitor: early phase II study for
postmenopausal women with advanced breast cancer]
[Article in Japanese]
Nomura Y, Tominaga T, Enomoto K, Aoyama H, Nakamura Y, Abe R, Sano M, Nomizu T,
Tohge T, Takashima S, Ohashi Y.
Dept. of Breast Surgery, National Kyushu Cancer Center.
A multicenter, open labeled, randomized early Phase II study for CGS 20267 was
conducted at the doses 0.5 mg once daily and 1.0 mg once daily in postmenopausal
women with advanced breast cancer. Sixty-four patients were randomly assigned to
the doses of either 0.5 mg once daily (n = 33) or 1.0 mg once daily (n = 31).
Thirty-one patients were eligible for 0.5 mg group, and 29 for 1.0 mg group. A
total of 57 patients (30 in the 0.5 mg group and 27 in the 1.0 mg group) were
eligible for the evaluation of efficacy. There were 3 CR, 5 PR, 5 stable disease
(SD: NC lasting over 24 weeks), 7 NC and 10 PD in the 0.5 mg group. The
objective response rate (ORR) was 26.7%. There were 4 CR, 7 PR, 8 SD, 3 NC and 5
PD in the 1.0 mg group. The ORR was 40.7%. A total of 57 patients (29 in the 0.5
mg group and 28 in the 1.0 mg group) were eligible for safety evaluation.
Adverse clinical events related to CGS 20267 in the 0.5 mg group were headache,
nausea, cold sweat, sleepiness and muscle ache in the lower extremities (2
patients, incidence rate 6.9%) whereas those in the 1.0 mg group were
generalized itching and generalized hot feeling (2 patients, incidence rate
7.1%). All of the adverse events were grade 1 except the generalized itching
which was grade 2. CGS 20267-related abnormalities in the laboratory tests for
the 0.5 mg group were a decrease in WBC, and increases in GOT, GPT, LDH and
gamma-GTP (5 patients, 14.3%) whereas those in the 1.0 mg group were increases
in GPT, gamma-GTP, alkaline phosphatase, and total bilirubin (1 patient, 3.6%).
The increases in GOT and GPT were grade 2, but others were grade 1. The data
show both CGS 20267 0.5 mg once daily and 1.0 mg once daily to be effective and
tolerable in the treatment of postmenopausal women with advanced breast cancer.
Publication Types:
Clinical Trial
Clinical Trial, Phase II
Multicenter Study
Randomized Controlled Trial
PMID: 11977539 [PubMed - indexed for MEDLINE]
8: Clin Breast Cancer 2000 Sep;1 Suppl 1:S68-73
Comparison of in vitro exemestane activity versus other antiaromatase agents.
Soudon J.
Pharmacell, Paris, France; [email protected]
Anastrozole, letrozole, and exemestane are the most selective and potent oral
antiaromatase agents currently available. However, in vitro and in vivo studies
comparing these agents are lacking. Anastrozole and letrozole are reversible,
competitive nonsteroidal type II inhibitors, whereas exemestane is an
irreversible steroidal type I inactivator. The study was conducted to determine
the impact of this characteristic on in vitro residual aromatase activity and
protein levels after incubation of JEG-3 cells with aminoglutethimide (a type II
inhibitor), anastrozole, exemestane, or letrozole. Aromatase activity was
measured after various incubation times with each antiaromatase agent at a
concentration 10 times higher than IC50 (concentration giving 50% inhibition).
Only exemestane induced a residual inhibition of aromatase activity after its
removal, without any change in the aromatase protein level. Aromatase activity
increased after preincubation of JEG-3 cells with either aminoglutethimide or
anastrozole without any change in the aromatase protein level. The aromatase
protein level increased rapidly when cells were incubated with letrozole and
aromatase activity inhibition disappeared immediately after removal of the drug.
The breakthrough effects in aromatase activity or protein levels observed after
treatment with reversible inhibitors may be a factor in therapeutic failure with
these agents. These results suggest a possible advantage for exemestane because
it is the only clinically available oral irreversible aromatase inactivator.
PMID: 11970753 [PubMed - in process]
9: Cancer Control 2002 Mar-Apr;9(2 Suppl):9-15
Endocrine and clinical endpoints of exemestane as neoadjuvant therapy.
Miller WR, Dixon JM.
Breast Research Unit, University of Edinburgh, Western General Hospital,
Edinburgh EH4 2XU, Scotland, UK. [email protected]
A series of in vitro and in vivo studies have been performed to establish the
endocrine and clinical endpoints of the type I anti-aromatase agent exemestane
in neoadjuvant therapy. In vitro studies demonstrated a dose-related inhibition
of aromatase activity with exemestane, even when activity was measured in a
system in which the aromatase enzyme was induced in fibroblasts preincubated
with exemestane but assayed in the absence of the drug. In contrast, type II
anti-aromatase agents (eg, aminoglutethimide, anastrozole, and letrozole) often
caused a paradoxical increase in aromatase activity when measured under similar
conditions. In vivo and in situ studies were performed in 12 postmenopausal
women with untreated large or locally advanced estrogen receptor-rich tumors.
The effect of exemestane 25 mg daily for 3 months on aromatization peripherally
and in breast cancer and surrounding normal tissue was determined. Immediately
before starting therapy, patients received an 18-hour infusion of radioactively
labeled androgen and estrogen, followed by a wedge biopsy. This procedure was
repeated after 3 months of treatment with exemestane, and the data were used to
calculate peripheral and local aromatization. Changes in tumor volume were based
on clinical examination, ultrasound, and mammography. Exemestane treatment was
associated with a marked reduction in aromatization peripherally and in
nonmalignant breast tissue in every patient and in breast tumor in all but one
patient. Median reduction in tumor volume was 85.5% for clinical examination,
82.5% for ultrasound, and 84% for mammography. Eight of 10 patients who would
have required mastectomy before treatment were able to undergo breast-conserving
surgery after treatment. Clinical benefits were accompanied by a marked
reduction in cellular proliferation and progesterone receptor expression. These
data support the use of exemestane in neoadjuvant therapy of breast cancer in
postmenopausal women.
PMID: 11965226 [PubMed - in process]
10: Cancer Control 2002 Mar-Apr;9(2 Suppl):2-8
Anti-aromatase Agents in the Treatment and Prevention of Breast Cancer.
Goss P.
Breast Cancer Prevention Program at the Princess Margaret Hospital, Toronto, ON
M5G 2M9, Canada. [email protected]
Anti-aromatase agents now have a central role in the management of breast cancer
in postmenopausal women; they are superior to megestrol acetate as second-line
therapy and to tamoxifen for initial therapy of metastatic disease. They also
are highly active as neoadjuvant therapy. Two classes of anti-aromatase agents
are available: steroidal (eg, exemestane) and nonsteroidal (eg, anastrozole,
letrozole). Although both types of agents act on the aromatase enzyme, they do
so by different mechanisms and have different effects on cellular aromatase
activity. Nonsteroidal agents are associated with increased aromatase enzyme
content and steroidal agents are associated with decreased content. The increase
in aromatase content seen with the nonsteroidal agents may in part explain the
development of resistance with these agents and the ability of the steroidal
agent exemestane to induce a response when nonsteroidal agents fail. Because the
anti-aromatase agents almost completely eliminate endogenous estrogen
production, they not only affect breast cancer tissues, but also may alter the
function of other estrogen-responsive tissues. However, preclinical data show
that the steroidal agent exemestane may actually improve bone and lipid
metabolism. In addition, no increase in clinical fracture rate has been noted in
women treated with exemestane in metastatic trials; the fracture risk has not
yet been studied following prolonged exposure in healthy women. Exemestane
associated beneficial effects on these end organs may be due to the steroidal
nature of both the parent compound and its principal metabolite,
17-hydroexemestane. Similar benefits have not been reported with nonsteroidal
antiaromatase agents. Based on their excellent activity in the metastatic
setting, anti-aromatase agents are now being evaluated in the adjuvant setting
and in pilot studies for chemoprevention. These studies will provide long-term
data in healthy women and will help to differentiate anti-aromatase agents, in
terms of their efficacy in the treatment of breast cancer and their effects on
end organs.
PMID: 11965225 [PubMed - in process]
11: Harv Womens Health Watch 2002 Apr;9(8):7
New breast cancer drugs expand treatment options.
Publication Types:
News
PMID: 11959538 [PubMed - indexed for MEDLINE]
12: Strahlenther Onkol 2002 Feb;178(2):111-3
[Superiority of letrozole compared with tamoxifen as first line therapy of
postmenopausal women with advanced breast cancer: results of a phase III study
of the International Letrozole Breast Cancer Group]
[Article in German]
Illiger HJ.
Publication Types:
Clinical Trial
Clinical Trial, Phase III
Multicenter Study
Randomized Controlled Trial
PMID: 11942036 [PubMed - indexed for MEDLINE]
13: Fertil Steril 2002 Apr;77(4):776-80
Aromatase inhibition improves ovarian response to follicle-stimulating hormone
in poor responders(1).
Mitwally MF, Casper RF.
Division of Reproductive Sciences, Department of Obstetrics and Gynecology,
Samuel Lunenfeld Research Institute and Mount Sinai Hospital, University of
Toronto, Toronto, Ontario, Canada
Objective: To examine the use of the aromatase inhibitor letrozole with FSH for
ovarian stimulation in poor responders undergoing ovarian superovulation and
IUI.Design: Observational cohort study as a prospective clinical trial in
patients with unexplained infertility and a low response to ovarian stimulation
with FSH.Setting: Two tertiary referral infertility clinics associated with the
Reproductive Sciences Division, University of Toronto.Patient(s): Twelve
patients with unexplained infertility undergoing IUI who received FSH alone in
25 prior cycles with poor response (less than three dominant
follicles).Intervention(s): Patients were offered letrozole, 2.5 mg/day from day
3-7 of the menstrual cycle with FSH (50-225 IU/day) starting on day 5-7. hCG
(10,000 IU) was given when two leading follicles were >/=2 cm followed by
IUI.Main Outcome Measure(s): Number of mature follicles (>1.8 cm), FSH dose,
endometrial thickness, and pregnancy rate.Result(s): Improved response to FSH
stimulation with letrozole co-treatment was evidenced by the significantly lower
FSH dose associated with significantly higher number of mature follicles. During
letrozole plus FSH stimulation cycles, clinical pregnancy was achieved in three
cycles (21%).Conclusion(s): In this preliminary report, we demonstrate a
potential benefit of aromatase inhibition for improving ovarian response to FSH
in poor responders.
PMID: 11937133 [PubMed - in process]
14: Drugs 2002;62(6):957-66
Tamoxifen resistant and refractory breast cancer: the value of aromatase
inhibitors.
Goss PE, Strasser K.
Breast Cancer Prevention Program, Princess Margaret Hospital, University Health
Network, Toronto, Ontario, Canada. [email protected]
Tamoxifen has dominated endocrine treatment of breast cancer for over two
decades. It is useful in metastatic breast cancer, adjuvant therapy,
preoperative treatment, ductal carcinoma-in-situ and chemoprevention. However,
breast cancer may be refractory to tamoxifen or develop resistance to it with
ongoing treatment. This resistance involves several mechanisms including
receptor mutation causing 'estrogen hypersensitivity' and an increasing agonist
effect of tamoxifen. Megestrol (megestrol acetate), in North America, and
aminoglutethimide, in Europe, have been the traditional second line therapies
after tamoxifen in advanced breast cancer. Aromatase (estrogen synthetase)
inhibitors are a logical alternative to tamoxifen to antagonise the effects of
estrogen on breast cancer. The third-generation non-steroidal aromatase
inhibitors anastrozole, letrozole and vorozole, and the steroidal inhibitor
exemestane, have been studied after tamoxifen versus either megestrol or
aminoglutethimide. They showed enhanced efficacy and significantly superior
toxicity profiles. Compliance with the inhibitors was also significantly better
than with the traditional treatments. Aromatase inhibitors have most recently
been shown to be superior to tamoxifen as initial therapy and are being
extensively tested in the adjuvant setting after, or instead of, tamoxifen.
Pilot studies of chemoprevention are also being undertaken. The aromatase
inhibitors are an important new addition to the armamentarium of breast cancer
therapy.
Publication Types:
Review
Review, Tutorial
PMID: 11929341 [PubMed - indexed for MEDLINE]
15: Clin Cancer Res 2001 Dec;7(12 Suppl):4402s-4410s; discussion 4411s-4412s
Future use of selective estrogen receptor modulators and aromatase inhibitors.
Howell A.
CRC Department of Medical Oncology, University of Manchester, Christie Hospital,
United Kingdom.
Selective estrogen receptor modulators (SERMs) may act as estrogens or
antiestrogens depending on the cell and tissue targets. The triphenylethylene
SERMs are represented by tamoxifen and toremifene and a new agent with a novel
carboxylic acid side chain (GW5638). Because of isomerization in the
triphenylethylene molecule, "fixed ring" SERMs were introduced. The major one in
development is the benzothiophene arzoxiphene (LY353381), which is now in Phase
III clinical trial versus tamoxifen. A fourth group of SERMs is based on the
estrogen molecule and comprises the so-called "pure" antiestrogen ICI 182,780
(fulvestrant, Faslodex) and a new oral analogue just entering trials, SR16234.
The steroidal aromatase inhibitors [AIs (40H androstenedione 'and exemestane)]
inactivate aromatase, whereas the triazole AIs (anastrozole and letrozole)
inhibit the enzyme via the heme prosthetic group. Thus, there are two groups of
AIs that show relative non-cross-resistance in advanced breast cancer and four
groups of SERMs that also show a high degree of non-cross-resistance. With six
different treatments and six or more clinical situations (prevention,
neoadjuvant, adjuvant, and first- and second-line treatments for advanced
disease) in which they may be used, the possible combinations of treatment are
enormous. At present, we have few clinical pointers to optimal sequence of
treatments. Now that most of the appropriate comparative trials have been
performed, it may be the time to initiate novel approaches. These include
alternating and sequential treatments, preferably with treatments changed before
overt progression occurs.
PMID: 11916232 [PubMed - in process]
16: Clin Cancer Res 2001 Dec;7(12 Suppl):4397s-4401s; discussion 4411s-4412s
Preliminary data from ongoing adjuvant aromatase inhibitor trials.
Goss P E.
Princess Margaret Hospital, Toronto, Ontario, Canada. [email protected]
With recent results showing letrozole and anastrozole to be superior to
tamoxifen as initial therapy for advanced disease, the aromatase inhibitors are
poised to establish their place in the adjuvant therapy of postmenopausal
receptor-positive breast cancer. A review of the rationale, design, and
preliminary results of the ongoing adjuvant trials that include aromatase
inhibitors will be presented, along with the ongoing or planned substudies. Two
strategies employing aromatase inhibitors after tamoxifen are being evaluated.
The MA.17 international intergroup trial is randomizing postmenopausal patients
who are disease-free after 5 years of adjuvant tamoxifen to an additional 5
years of letrozole or placebo. In a similar design, the National Surgical
Adjuvant Breast and Bowel Project (NSABP) B33 trial is randomizing this patient
population to 2 years of exemestane or placebo after the standard 5 years of
adjuvant tamoxifen. The second approach under study is the use of both aromatase
inhibitor and tamoxifen in sequence within the first 5 postoperative years. The
International Cancer Collaboration Group (ICCG) trial is comparing 2 years of
exemestane after 3 years of tamoxifen to a standard 5-year course of tamoxifen.
Similarly, the ARNO trial is comparing 5 years of tamoxifen versus 2 years of
tamoxifen followed by 3 years of anastrozole. In a four-arm study Breast
International Group/Femara-Tamoxifen (BIG/FEMTA) conducted by the BIG, one arm
contains letrozole given for 3 years after 2 years of tamoxifen. Several trials
are investigating the role of anastrozole, letrozole, or exemestane as a 5-year
adjuvant therapy to replace the standard 5 years of tamoxifen. Only the Arimidex
and Tamoxifen, Alone or in Combination (ATAC) trial is testing a 5-year
combination of tamoxifen plus an aromatase inhibitor in this setting. Companion
studies of effects on end-organs other than the breast are ongoing in a number
of these trials. Aromatase inhibitors are poised to alter the treatment paradigm
of breast cancer and hopefully improve outcome for a substantial number of
patients.
PMID: 11916231 [PubMed - in process]
17: Clin Cancer Res 2001 Dec;7(12 Suppl):4388s-4391s; discussion 4411s-4412s
Neoadjuvant endocrine therapy for breast cancer: medical perspectives.
Ellis M J.
Duke University Breast Cancer Program, Duke University Medical Center, Durham,
North Carolina 27710, USA. [email protected]
The indolent nature of estrogen-dependent breast cancer is the most important
obstacle for development of new adjuvant endocrine treatments. Clinical trials
require thousands of study participants and at least a decade of clinical
investigation. How can we be sure that a new endocrine agent warrants this
extraordinary level of investment? Traditionally, we have relied on advanced
breast cancer trials to determine which drugs are suitable for adjuvant studies.
However, with endocrine agents the high incidence of resistance in metastatic
breast cancer may mask important advances in efficacy. Recent clinical results
with the aromatase inhibitor letrozole suggest that neoadjuvant endocrine
therapy is a highly informative additional approach to consider when planning
adjuvant studies. In this report, new neoadjuvant endocrine therapy study
designs are discussed that address the following issues: (a) the scientific
opportunities afforded by gene microarray studies and other genetic technologies
to investigate the molecular basis of estrogen-dependent breast cancer; (b)
studies that address critical drug development questions as a prelude to
adjuvant studies; and (c) the conduct of randomized trials that compare
neoadjuvant chemotherapy with neoadjuvant aromatase inhibitor therapy to
establish a place for neoadjuvant endocrine therapy in routine clinical
practice.
PMID: 11916229 [PubMed - in process]
18: Clin Cancer Res 2001 Dec;7(12 Suppl):4360s-4368s; discussion 4411s-4412s
Are differences in the available aromatase inhibitors and inactivators
significant?
Johnson P E, Buzdar A.
Department of Breast Medical Oncology, The University of Texas M. D. Anderson
Cancer Center, Houston 77030, USA.
Aromatase inhibitors are endocrine agents with a different mode of action than
tamoxifen against breast tumors. In postmenopausal women, estrogen
concentrations are maintained primarily via aromatase, a cytochrome P-450 enzyme
that acts at the final step in the estrogen synthesis pathway. The first
clinically available aromatase inhibitor, aminoglutethimide, was introduced for
the second-line treatment of advanced breast cancer in the late 1970s. Despite
proven efficacy in this setting, its widespread use was limited by its overall
toxicity and its lack of selectivity for the aromatase enzyme. This led to the
search for novel, more effective, and less toxic aromatase inhibitors. As a
result, several aromatase inhibitors with a high degree of selectivity for
aromatase and improved tolerability have become clinically available for the
treatment of postmenopausal women with advanced breast cancer: (a) anastrozole;
(b) letrozole; (c) fadrozole; (d) formestane; and (e) exemestane. Of these,
formestane and exemestane are steroidal nonreversible aromatase inhibitors, also
known as aromatase inactivators, whereas fadrozole, anastrozole, and letrozole
are nonsteroidal reversible aromatase inhibitors. These agents differ in
pharmacokinetics, selectivity, and potency, although all are more selective than
aminoglutethimide. Some differences in adverse effect profile are also
noticeable between and within these two classes of agents. The clinical
significance of these differences is not yet evident but may well prove to be
relevant in the long-term adjunctive setting.
PMID: 11916226 [PubMed - in process]
19: Clin Cancer Res 2001 Dec;7(12 Suppl):4356s-4359s; discussion 4411s-4412s
The role of tamoxifen and aromatase inhibitors/inactivators in postmenopausal
patients.
Pritchard K I.
Toronto-Sunnybrook Regional Cancer Centre, University of Toronto, Ontario,
Canada. [email protected]
The traditional hormonal cascade of the 1970s and 1980s used tamoxifen followed
by megestrol acetate and subsequently by aminoglutethimide. In the 1990s,
however, three trials of third-generation aromatase inhibitors (AIs) compared
with megestrol acetate and two trials of third-generation AIs compared with
aminoglutethimide showed improved efficacy and decreased toxicity for the newer
AIs. Thus, the hormonal cascade changed in the late 1990s, to one in which
tamoxifen, followed by a third-generation AI, followed by megestrol acetate,
seemed more suitable. Now, however, several trials comparing anastrozole,
letrozole, and exemestane to tamoxifen as first-line hormonal agents for
metastatic breast cancer have shown that these drugs are at least equivalent and
perhaps superior to tamoxifen in that setting in terms of response rate and time
to progression. Results from 1021 patients randomized to receive anastrozole
versus tamoxifen showed a slightly improved overall response rate (RR; 29%
versus 26%), slightly improved clinical benefit (CB; 57% versus 52%), and a
significantly improved time to progression (TTP; 8.5 months versus 7.0 months)
in favor of anastrozole. In 907 women randomized to treatment with letrozole
versus tamoxifen, significantly improved RR (30% versus 20%), CB (49% versus
38%), and TTP (9.4 months versus 6 months) have all been shown for those treated
with letrozole. In addition, a randomized Phase II trial of 121 patients has
shown nonsignificant benefits in favor of exemestane (RR 41% versus 14%; CB 56%
versus 42%; TTP not available). To date, none of these trials has demonstrated
any overall survival benefit. Additional follow-up in regard to survival in the
trial of tamoxifen versus letrozole and an expanded Phase III trial of tamoxifen
versus exemestane are ongoing.
PMID: 11916225 [PubMed - in process]
20: Lancet Oncol 2000 Nov;1:132
Breast cancer studies challenge tamoxifen therapy.
Timms B.
Publication Types:
News
PMID: 11905647 [PubMed - indexed for MEDLINE]
21: Curr Med Res Opin 2001;17(3):217-22
Aromatase inhibitors.
Cunnick G H, Mokbel K.
St George's Breast Cancer Centre, St George's Hospital, London, UK.
The new non-steroidal and steroidal aromatase inhibitors are at least as
effective as megestrol acetate (MA) as second-line hormonal agents in
postmenopausal women with breast cancer. However, they are superior to MA in
terms of tolerability and adverse effects. Letrozole and exemestane have been
shown to be superior to MA in terms of efficacy. Furthermore, exemestane and
anastrozole demonstrated a survival advantage over MA. These drugs are therefore
considered established second-line hormonal agents. There is a growing body of
evidence supporting the role of third-generation aromatase inhibitors as
first-line therapy for ER-and/or PgR-positive advanced breast cancer in
postmenopausal women, and as a neoadjuvant therapy in postmenopausal women with
hormone receptor positive tumours unsuitable for breast conserving surgery.
Studies comparing these drugs head-to-head and with adjuvant tamoxifen are
currently in progress. The potential role of these drugs in breast cancer
prevention is worth investigating.
PMID: 11900315 [PubMed - in process]
22: J Clin Oncol 2002 Mar 15;20(6):1467-72
Elevated serum Her-2/neu level predicts decreased response to hormone therapy in
metastatic breast cancer.
Lipton A, Ali SM, Leitzel K, Demers L, Chinchilli V, Engle L, Harvey HA, Brady
C, Nalin CM, Dugan M, Carney W, Allard J.
Department of Hematology and Oncology, Penn State Milton S. Hershey Medical
Center, Hershey, Pennsylvania 17033, USA. [email protected]
PURPOSE: To determine the effect of elevation of serum HER-2/neu on response to
hormone therapy. PATIENTS AND METHODS: Seven hundred nineteen metastatic
patients with estrogen receptor-positive (ER(+)), progesterone
receptor-positive, or both or ER status unknown breast cancer were randomized in
three independent clinical trials to receive second-line hormone therapy with
either megestrol acetate or an aromatase inhibitor (fadrozole or letrozole). An
automated enzyme-linked immunosorbent assay specific for the extracellular
domain of the HER-2/neu (c-erbB-2) oncoprotein product was used to detect serum
levels. RESULTS: Two hundred nineteen patients (30%) had elevated serum
HER-2/neu protein levels, using the mean + 2 SD (15 ng/mL) from the serum of
healthy women as an upper limit. Response to treatment was available for 711
patients. The response rate (complete responses plus partial responses plus
stable disease) to endocrine therapy was 45% in 494 patients with non-elevated
and 23% in 217 patients with elevated serum HER-2/neu levels (P <.0001). Median
duration of treatment response (using the time to progression [TTP] variable for
patients who responded) was shorter in the group with elevated serum HER-2/neu
levels (11.7 months) compared with the patient group with non-elevated levels
(17.4 months). TTP, time to treatment failure, and median survival (17.2 months
v 29.6 months) were also significantly shorter in the patients with elevated
serum HER-2/neu levels (P <.0001). CONCLUSION: Patients with ER(+) and serum
HER-2/neu-positive metastatic breast cancer are less likely to respond to
hormone treatment and have a shorter duration of response than ER(+) and serum
HER-2/neu-negative patients. Their survival duration is also shorter.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 11896093 [PubMed - indexed for MEDLINE]
23: Clin Cancer Res 2002 Mar;8(3):665-9
Approval summary: letrozole in the treatment of postmenopausal women with
advanced breast cancer.
Cohen MH, Johnson JR, Li N, Chen G, Pazdur R.
Division of Oncology Drug Products (HFD-150), Center for Drug Evaluation and
Research, Food and Drug Administration, Rockville, Maryland 20857.
Letrozole (Femara; Novartis Pharmaceuticals Corp., East Hanover, NJ) is a
nonsteroidal inhibitor of aromatase enzyme complex. It inhibits the peripheral
conversion of circulating androgens to estrogens. In postmenopausal women,
letrozole decreases plasma concentrations of estradiol, estrone, and estrone
sulfate by 75-95% from baseline with maximal suppression achieved within 2-3
days of treatment initiation. Suppression is dose related, with doses of >/=0.5
mg giving estrone and estrone sulfate values that were often below assay
detection limits. At clinically used dosage, letrozole does not impair adrenal
synthesis of glucocorticoids or aldosterone. In 1998, letrozole was approved by
the United States Food and Drug Administration (FDA) for the treatment of
advanced breast cancer in postmenopausal women, with hormone receptor positive
or unknown breast cancer, who had failed one prior antiestrogen treatment (i.e.,
for "second-line" treatment). Approval was based on two randomized trials
comparing tumor RRs of patients receiving 0.5 mg of letrozole, 2.5 mg of
letrozole, and either megestrol acetate (MA) or aminoglutethimide. In the
megestrol trial, 2.5 mg/day letrozole was superior to 0.5 mg of letrozole and MA
(RRs 24, 13, and 16%, respectively), whereas in the aminoglutethimide trial,
there was no significant difference in 2.5 mg of letrozole and 0.5 mg of
letrozole RRs (20 and 17%). There was a trend toward RR superiority of 2.5 mg of
letrozole over aminoglutethimide (P = 0.06). Letrozole (2.5 mg) was the dose
chosen for comparison with tamoxifen in the first-line setting. In July 2000, a
marketing application for first-line letrozole treatment of postmenopausal women
with hormone receptor positive or hormone receptor unknown locally advanced or
metastatic breast cancer was submitted to the FDA. A single double-blind, double
dummy, randomized, and multicenter trial compared 2.5 mg of letrozole to 20 mg
of tamoxifen (456 patients/arm). Letrozole was superior to tamoxifen with regard
to time to progression (TTP) and objective response rate (RR). The median TTP
for letrozole treatment was 9.9 months [95% confidence interval (CI) 9.1-12.2]
versus 6.2 months (95% CI 5.8-8.5) for tamoxifen, P = 0.0001, hazard ratio
0.713, (95% CI 0.61-0.84). RR was 32% for letrozole versus 21% for tamoxifen
(odds ratio 1.74, 95% CI 1.29-2.34, P = 0.0003). Preliminary survival data
(survival data are still blinded) indicate that letrozole is unlikely to be
worse than tamoxifen. Both treatments were similarly tolerated. On the basis of
these results, the United States FDA approved letrozole tablets, 2.5 mg/day, for
first-line treatment of postmenopausal women with hormone receptor-positive or
hormone receptor-unknown locally advanced or metastatic breast cancer. The
manufacturer made a commitment to provide updated information on survival.
PMID: 11895893 [PubMed - in process]
24: Eur J Endocrinol 2002 Mar;146(3):339-46
The role of sex steroids in the regulation of insulin sensitivity and serum
lipid concentrations during male puberty: a prospective study with a
P450-aromatase inhibitor.
Wickman S, Saukkonen T, Dunkel L.
Hospital for Children and Adolescents, University of Helsinki, PL281, FIN-00029
HUS, Helsinki, Finland. [email protected]
OBJECTIVE: Our purpose was to study the sex steroid-mediated changes in serum
insulin and lipid concentrations in boys during puberty. DESIGN AND METHODS: We
treated boys with constitutional delay of puberty either with testosterone plus
placebo or with testosterone plus an aromatase inhibitor, letrozole, which
inhibits the conversion of androgens to oestrogens. We demonstrated previously
that during treatment with testosterone plus letrozole the increase in
testosterone concentration was more than 5-fold higher than during treatment
with testosterone plus placebo. The concentrations of 17beta-oestradiol, IGF-I
and IGF-binding protein-3 increased during testosterone-plus-placebo treatment,
but during testosterone-plus-letrozole treatment the concentrations remained
unchanged. These divergent changes in the two groups enabled us to study the
effects of sex steroids and GH on insulin sensitivity and lipid concentrations.
RESULTS: The insulin concentration in the testosterone-plus-placebo-treated
group did not change. In contrast, in the testosterone-plus-letrozole-treated
group, the concentration decreased during letrozole treatment, indicating
improved insulin sensitivity. Changes in insulin and IGF-I concentrations within
12 and 18 months were correlated. In the testosterone-plus-placebo-treated
group, the high-density lipoprotein cholesterol concentration did not change but
in the testosterone-plus-letrozole-treated group the concentration decreased.
The concentrations of low-density lipoprotein cholesterol (LDL-cholesterol) and
triglycerides did not change in either of the groups. CONCLUSIONS: The findings
indicate that androgens do not directly alter insulin sensitivity in boys during
puberty. In contrast, the observations suggest tight regulation of
glucose--insulin homeostasis by GH in boys at this stage. Furthermore, our
findings indicate that sex steroids do not significantly participate in the
regulation of serum concentrations of LDL-cholesterol or triglycerides in boys
during early and mid-puberty.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 11888840 [PubMed - indexed for MEDLINE]
25: MMW Fortschr Med 2002 Jan 31;144(5):46-8
[Aromatase inhibitors of the 3rd generation. What can the "pill against breast
cancer" really do?]
[Article in German]
Junker A, Wiedemann GJ, Possinger K.
Sana Klinikum Remscheld GmbH, Apotheke, Remscheid.
Metastatic cancer of the breast in postmenopausal women can be treated with a
number of "hormone-active" substances. The drugs of first choice are still
anti-estrogens. Today, the three highly selective oral aromatase inhibitors
anastrozole, letrozole and exemestane are additionally available for use in
continuing progression under anti-estrogen treatment. Roughly one woman in three
derives benefit from these new medications as reflected by objective remission
or stabilization of the disease for more than 6 months. Neither chemical
structure (steroidal/non-steroidal), nor the different nature of inhibition of
the active centre of the aromatase, nor whether the inhibition of the enzyme is
reversible or irreversible, has any influence on the parameters: response rate,
response duration and clinical benefit.
PMID: 11883037 [PubMed - indexed for MEDLINE]
26: Toxicol Lett 2002 Mar 24;129(1-2):119-22
Detection of aromatase inhibitors in vitro using rat ovary microsomes.
Odum J, Ashby J.
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire
SK10 4TJ, UK.
Inhibition of aromatase activity in vitro is one of the Tier 1 screening assays
proposed by the Endocrine Disrupter Screening and Testing Advisory Committee
(EDSTAC) for the detection of potential endocrine disrupters. In this report a
rat ovarian aromatase inhibition assay has been evaluated using the reference
aromatase inhibitors anastrozole, fadrozole, letrozole and CGS 18320B. Rat ovary
microsomes were used as the enzyme source, as endocrine disruption studies are
most commonly carried out in this species. Aromatase activity was inhibited in
vitro by anastrozole, fadrozole, letrozole and CGS 18320B with IC(50)s of 25, 7,
7 and 5 nM, respectively. This assay, therefore, appears to have good
sensitivity to aromatase inhibitors and may be useful as a general screening
assay and in mechanistic studies.
PMID: 11879982 [PubMed - indexed for MEDLINE]
27: Trends Endocrinol Metab 2002 Mar;13(2):61-5
Aromatase inhibitors in breast cancer.
Brodie A.
Dept Pharmacology and Experimental Therapeutics, School of Medicine, University
of Maryland, 21201, Baltimore, MD, USA
Several compounds that selectively inhibit estrogen synthesis via aromatase have
been developed. Steroidal substrate analogs, such as formestane and exemestane,
inactivate aromatase by binding irreversibly to it. Non-steroidal inhibitors,
such as the triazole compounds letrozole and anastrozole, are highly potent,
reversible inhibitors with good specificity for aromatase. The intratumoral
aromatase model for postmenopausal breast cancer has been used to investigate
the efficacy of letrozole, anastrozole and exemestane in combination and
sequentially. Combining letrozole or arimidex with tamoxifen or faslodex was not
more effective than the aromatase inhibitors alone, but was more effective than
tamoxifen alone. Letrozole was superior to and longer lasting than the other
agents, suggesting that aromatase inhibitors control tumor growth effectively by
inducing greater tumor response and extending treatment time. In addition,
aromatase inhibitors can be effective in patients relapsing from tamoxifen.
Because two types of aromatase inhibitors are available, steroidal enzyme
inactivators and reversible non-steroidal inhibitors in sequential therapy could
be useful if resistance to one type develops.
PMID: 11854020 [PubMed - in process]
28: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):239-46
17alpha-methyl testosterone is a competitive inhibitor of aromatase activity in
Jar choriocarcinoma cells and macrophage-like THP-1 cells in culture.
Mor G, Eliza M, Song J, Wiita B, Chen S, Naftolin F.
Department of Obstetrics and Gynecology, Center for Research in Reproductive
Biology and Reproductive Neuroscience Unit, Yale University Medical School, 333
Cedar Street, FMB 335, New Haven, CT 06520 8063, USA.
17alpha-methyl testosterone is a synthetic androgen with affinity for the
androgen receptor. 17alpha-methyl testosterone is used widely as a component of
hormone replacement therapy. Previous reports have indicated that contrary to
testosterone, 17alpha-methyl testosterone is not aromatized. However,
17alpha-methyl testosterone still could affect local estrogen formation by
regulating aromatase expression or by inhibiting aromatase action. Both
possibilities have important clinical implications. To evaluate the effect of
17alpha-methyl testosterone on the expression and activity of aromatase, we
tested the choriocarcinoma Jar cell line, a cell line that express high levels
of P450 aromatase, and the macrophage-like THP-1 cells, which express aromatase
only after undergoing differentiation. We found that in both cell lines,
17alpha-methyl testosterone inhibits aromatase activity in a dose-related
manner. The curve of inhibition parallels that of letrozole and gives complete
inhibition at 10(-4) M 17alpha-methyl testosterone, determined by the tritium
release assay. 17alpha-methyl testosterone does not have detectable effects on
aromatase RNA and protein expression by Jar cells. Undifferentiated THP-1 cells
had no aromatase activity and showed no effect of 17alpha-methyl testosterone,
but differentiated THP-1 (macrophage-like) cells had a similar inhibition of
aromatase activity by 17alpha-methyl testosterone to that seen in Jar cells. The
Lineweaver-Burke plot shows 17alpha-methyl testosterone to be a competitive
aromatase inhibitor. Our results show for the first time that 17alpha-methyl
testosterone acts as an aromatase inhibitor. These findings are relevant for
understanding the effects of 17alpha-methyl testosterone as a component of
hormone replacement therapy. 17alpha-methyl testosterone may, as a functional
androgen and orally active steroidal inhibitor of endogenous estrogen
production, also offer special possibilities for the prevention/treatment of
hormone-sensitive cancers.
PMID: 11850230 [PubMed - indexed for MEDLINE]
29: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):227-37
Where do selective estrogen receptor modulators (SERMs) and aromatase inhibitors
(AIs) now fit into breast cancer treatment algorithms?
Howell A, Howell SJ, Clarke R, Anderson E.
CRC Department of Medical Oncology, Christie Hospital NHS Trust, M20 4BX,
Manchester, UK. [email protected]
The agents used for endocrine therapy in patients with breast cancer have
changed markedly over the past decade. Tamoxifen remains the anti-oestrogen of
choice, but could be replaced by the oestrogen receptor down-regulator ICI
182780 or by the fixed ring triphenylethylene arzoxifene (previously SERM III)
soon. Whilst aminoglutethimide and 4-OH androstenedione were the aromatase
inhibitors of choice, they have been replaced by non-steroidal (anastrozole and
letrozole) and steroidal (exemestane) inhibitors of high potency and low side
effect profile. Previously, often used treatments such as progestogens
(megestrol acetate and medroxyprogesterone acetate) and androgens are now rarely
used or confined to fourth or fifth line treatments. The LHRH agonist,
goserelin, remains the treatment of choice for pre-menopausal patients with
advanced breast cancer although recent randomised trials indicate a response,
time to progression and survival advantage for the combination of goserelin and
tamoxifen compared with goserelin alone.The newer treatments have led to
questions concerning the optimum sequence of agents to use in advanced breast
cancer and as neo-adjuvant and adjuvant therapy in relation to surgery. Two
trials of anastrozole compared with tamoxifen and one trial of letrozole
compared with tamoxifen indicate that the new triazole aromatase inhibitors have
a significant advantage over the anti-oestrogen with respect to time to
progression and survival. Similarly, triazole aromatase inhibitors give faster
and more complete responses compared with tamoxifen when used in post-menopausal
women before surgery.Major research questions remain with respect to the
aromatase inhibitors used as adjuvant therapy. Anastrozole is being tested alone
or in combination with tamoxifen compared with tamoxifen in the 'so-called' ATAC
trial. Over 9000 patients have been randomised to this important study: the
results will be available late-2001. A similar study comparing letrozole and
tamoxifen started recently under the auspices of the Breast International Group.
Importantly, this trial is also comparing the sequence of tamoxifen followed by
letrozole (or vice versa). A similar trial of exemestane given after 2-3 years
of tamoxifen compared with 5 years of tamoxifen is recruiting well as is a study
comparing letrozole (or placebo) for 5 years after 5 years of adjuvant
tamoxifen. These studies may show that aromatase inhibitors are superior to
tamoxifen or that a sequence is preferable.ICI 182780 causes complete oestrogen
receptor down-regulation leading to a the lack of agonist activity of the drug.
Two trials of ICI 182780 compared with anastrozole for advanced disease will
report later this year and a comparison with tamoxifen next year. Arzoxifene
(SERM III) is being tested against tamoxifen. These studies are likely to result
in new anti-oestrogens being introduced into the clinic.Most of our endocrine
treatments deprived the tumour cell of oestradiol. In vitro experiments with
MCF-7 cells indicate that tumour cells can adapt and then grow in response to
low oestrogen concentrations in the tissue--culture medium. Importantly, the
cells were shown to apoptose in response to high oestrogen concentrations. A
recent clinical trial has demonstrated a high response rate to stilboestrol
given after a median of four previous oestrogen depriving endocrine therapies.
These data and the newer treatments available indicate a need to re-think our
general approach to endocrine therapy and endocrine prevention.
Publication Types:
Review
Review, Tutorial
PMID: 11850229 [PubMed - indexed for MEDLINE]
30: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):133-41
Adjuvant trials of aromatase inhibitors: determining the future landscape of
adjuvant endocrine therapy.
Ragaz J.
British Columbia Cancer Agency, 600, West 10th Avenue, British Columbia, V5Z
4E6, Vancouver, Canada. [email protected]
This review will discuss the role of aromatase inhibitors (AIs) in the adjuvant
setting, and will summarize major strategies behind individual adjuvant trials
using aromatase inhibitors. Studies with the third generation AIs including
anastrozole, letrozole and exemestane, have shown better outcome and improved
therapeutic ratio over second line hormonal approaches (i.e. progestins or
aminoglutethimide) and, more recently, over tamoxifen also. These promising
results have led recently to testing of AIs in the adjuvant setting for
postmenopausal patients. Most trials now in progress are evaluating the role of
new AIs versus tamoxifen (T) given x 5 years, which in most institutions is
currently the standard hormonal adjuvant therapy for breast cancer. Three
adjuvant approaches are being tested. First is the use of AI+T x 5 years in
combination versus each agent alone, as reflected in the recently completed ATAC
trial. Second is a sequential approach T first x 2-3 years followed by AIs x 2-3
years, or the other way round; and third, T x 5 years followed by AIs for
additional 5 years (i.e. total duration of adjuvant hormones of 10 years). Many
patients in the above trials will survive their first cancer. Hence, the
non-oncological outcomes known to be affected by hormones are of rising
importance. Therefore, the assessment of lipids as surrogates for cardiovascular
morbidity, and of bone mineral status, as a marker for osteoporosis/bone
fractures, is an important component of these trials. Also discussed in this
review are proposals for future studies of AIs with focus on hormone resistance,
such as early alteration of multiple hormonal agents or their intermittent use,
the impact of the new generation of SERMs or 'pure' antiestrogens on activity of
AIs, and the rising importance of AIs interacting with biologicals, cytokines or
hormone modulators.
Publication Types:
Review
Review, Tutorial
PMID: 11850217 [PubMed - indexed for MEDLINE]
31: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):109-14
A summary of second-line randomized studies of aromatase inhibitors.
Buzdar AU.
Department of Breast Medical Oncology, M.D. Anderson Cancer Center, M.D.
University of Texas, Box 424, 1515 Holcombe Blvd, Houston, TX 77030, USA.
[email protected]
The new generation of selective aromatase inhibitors (anastrozole, letrozole and
exemestane) offer a significant efficacy and safety advantage over both older
agents in this class (aminoglutethimide) and the progestins (megestrol acetate
(MA)), as second-line treatment for postmenopausal women with advanced
hormone-dependent breast cancer who have failed on tamoxifen therapy.
Exemestane, a steroidal aromatase inhibitor, has been shown to have activity
after failure with the non-steroidal aromatase inhibitors, anastrozole and
letrozole, and could be used as third-line treatment. Although the newer
aromatase inhibitors belong to the same class and appear, from indirect
comparisons, to have similar efficacy compared with the older therapies, they
have different pharmacokinetic and pharmacodynamic profiles, suggesting the
potential for clinical differences. Compared with exemestane and letrozole,
anastrozole shows greater selectivity for aromatase, as it lacks any evidence of
an effect on adrenal steroidogenesis and has no androgenic effects. Therefore,
it is clear that these agents should not be considered to be similar in all
respects. In summary, the introduction of the aromatase inhibitors represents a
significant step forward in the treatment of advanced breast cancer in
postmenopausal women. Studies in the adjuvant setting will ultimately determine
whether the differences in pharmacokinetics and phamacodynamics will be of
clinical relevance.
Publication Types:
Review
Review, Tutorial
PMID: 11850214 [PubMed - indexed for MEDLINE]
32: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):103-7
Biological and clinical effects of aromatase inhibitors in neoadjuvant therapy.
Miller WR, Dixon JM, Cameron DA, Anderson TJ.
Department of Clinical Oncology, and Breast Unit, Western General Hospital,
University of Edinburgh, Crewe Road South, EH4 2XU, Edinburgh, UK.
[email protected]
Postmenopausal women with large primary oestrogen receptor-rich (>20 fmol/mg
protein or 80 histoscore) breast cancers have been treated neoadjuvantly with
either letrozole (2.5 or 10 mg daily n=12 in each case) or anastrozole (1 or
10mg daily n=12 and 11, respectively). Tumour was available for analysis before
treatment (wedge biopsy) and 3 months later at definitive surgery (wide local
excision or mastectomy). Clinical response to treatment was assessed by
sequential measurements of tumour volume based on caliper assessment, ultrasound
and mammography. Results showed that in these selected groups of patients a
reduction in tumour volume with treatment was observed in 43 of 47 cases (91%).
Pathological responses, i.e. clear decrease in tumour cellularity or increased
fibrosis was evident in 32 cases (68%). Furthermore, there was a decrease with
therapy in immunohistochemical staining for Ki67 in all tumours. Staining for
progesterone receptor (PgR) was reduced in all 21 PgR-positive cancers treated
with letrozole and in 16 of 17 positive cancers treated with anastrozole. These
effects are at least as great as those seen in a non-randomised group of
patients treated with tamoxifen over the same time period (additionally
tamoxifen treatment was often associated with an increase in PgR staining). The
results suggest that potent specific aromatase inhibitors will be valuable in
treating hormone-dependent cancers.
PMID: 11850213 [PubMed - indexed for MEDLINE]
33: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):93-102
Local endocrine effects of aromatase inhibitors within the breast.
Miller WR, Dixon JM.
Breast Unit, Department of Clinical Oncology, Western General Hospital,
University of Edinburgh, Crewe Road South, EH4 2XU, Edinburgh, UK.
[email protected]
To determine the effects of aromatase inhibitors on oestrogen uptake, in situ
aromatase activity and endogenous oestrogens in the breast, postmenopausal women
with large primary ER-rich breast cancers have been treated neoadjuvantly for 3
months with either letrozole (2.5 or 10mg daily) or anastrozole (1 or 10mg
daily) or exemestane (25mg daily). Patients were given an infusion of
3H-androstenedione and 14C-oestrone for 18h before and at the end of the study
period. Blood, tumour and non-malignant breast were taken immediately after each
infusion; oestrogens were extracted and purified. Tumour volume was measured
before and during treatment at monthly intervals so that endocrinological
changes could be related to clinical response. Treatment with each of the
aromatase inhibitors was associated with a profound reduction in peripheral
aromatase (as monitored by the level of plasma 3H-oestrone). There was no
consistent effect on uptake of radioactively labelled oestrogen into breast
tumours but a tendency for levels to increase after treatment in non-malignant
breast. Conversely, therapy was associated with a marked inhibition of in situ
oestrogen synthesis in both tumour and non-malignant breast (in occasional
tissues, inhibitors appeared to be less effective but the effect was not related
to clinical or pathological responses). Similar decreases were apparent in
endogenous levels of oestrone and oestradiol. The absence of in situ aromatase
activity tended to be associated with lack of clinical response to aromatase
inhibition but the relationship was not absolute, limiting the utility of
measurements of tumour aromatase as a predictive indices. Ex vivo studies of
tissue aromatase indicated that such measurements consistently underestimate the
inhibitory potential of reversible non-steroidal agents (and occasionally
paradoxical in vitro increases in aromatase activity were seen with treatment).
However, in situ assays demonstrate that new aromatase inhibitors such as
anastrozole, exemestane and letrozole have profound effects on the local
endocrinology within the postmenopausal breast, these being compatible with the
clinico-pathological changes which occur with treatment.
PMID: 11850212 [PubMed - indexed for MEDLINE]
34: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):85-91
Comparative clinical pharmacology and pharmacokinetic interactions of aromatase
inhibitors.
Boeddinghaus IM, Dowsett M.
The Academic Department of Biochemistry, Royal Marsden Hospital, Fulham Road,
SW3 6JJ, London, UK.
The clinical development of aromatase inhibitors (AIs) has been closely guided
by clinical pharmacological investigations. During the early phases of
development studies were focused on dose-related pharmacological effectiveness
and specificity. More recently attention has been given to the metabolic changes
which AIs elicit, with particular regard to their potential use in early breast
cancer and the prophylactic setting. Pharmacological effectiveness has been
studied with plasma oestrogen assays but primary oestrogens (E1 and E2) are not
helpful in comparing the third generation inhibitors: anastrozole, letrozole,
exemestane. All three of these compounds suppress whole body aromatisation by
>96%. Most recently, we have established that significantly greater inhibition
is achieved by letrozole than anastrozole at their clinically used dosages. This
more complete inhibition is paralleled by significantly greater suppression of
E1S.A broad panel of endocrine investigations has indicated that these compounds
have essentially complete specificity at their clinical dosages. A minor
androgenic effect of exemestane is revealed by a significant suppression of sex
hormone binding globulin (SHBG). Lipid and bone biomarker data are being
collected in many current studies. A pharmacokinetic interaction has been
established between letrozole and tamoxifen, whereby reduced circulating levels
of letrozole are found with combined application. Neither anastrozole nor
letrozole have any effect on plasma concentrations of tamoxifen when given in
combination with it.
Publication Types:
Review
Review, Tutorial
PMID: 11850211 [PubMed - indexed for MEDLINE]
35: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):41-7
Aromatase and COX-2 expression in human breast cancers.
Brodie AM, Lu Q, Long BJ, Fulton A, Chen T, Macpherson N, DeJong PC,
Blankenstein MA, Nortier JW, Slee PH, van de Ven J, van Gorp JM, Elbers JR,
Schipper ME, Blijham GH, Thijssen JH.
Department of Pharmacology, School of Medicine, University of Maryland, Room 580
G, Baltimore, MD 21201, USA. [email protected]
We have investigated aromatase and the inducible cyclooxygenase COX-2 expression
using immunocytochemistry in tumors of a series of patients with advanced breast
cancer treated with aromatase inhibitors. Aromatase was expressed in 58/102
breast cancers. This is similar to the percentage previously reported for
aromatase activity. Interestingly, aromatase was expressed in a variety of cell
types, including tumor, stromal, adipose, and endothelial cells. Since
prostaglandin E2 is known to regulate aromatase gene expression and is the
product of COX-2, an enzyme frequently overexpressed in tumors,
immunocytochemistry was performed on the tissue sections using a polyclonal
antibody to COX-2. Aromatase was strongly correlated (P<0.001) with COX-2
expression. These results suggest that PGE2 produced by COX-2 in the tumor may
be important in stimulating estrogen synthesis in the tumor and surrounding
tissue. No correlation was observed between aromatase or COX-2 expression and
the response of the patients to aromatase inhibitor treatment. However, only 13
patients responded. Nine of these patients were aromatase positive. Although
similar to responses in other studies, this low response rate to second line
treatment suggests that tumors of most patients were no longer sensitive to the
effects of estrogen. Recent clinical studies suggest that greater responses
occur when aromatase inhibitors are used as first line treatment. In the
intratumoral aromatase mouse model, expression of aromatase in tumors is highly
correlated with increased tumor growth. First line treatment with letrozole was
effective in all animals treated and was more effective than tamoxifen in
suppressing tumor growth. Letrozole was also effective in tumors failing to
respond to tamoxifen, consistent with clinical findings. In addition, the
duration of response was significantly longer with the aromatase inhibitor than
with tamoxifen, suggesting that aromatase inhibitors may offer better control of
tumor growth than this antiestrogen.
PMID: 11850206 [PubMed - indexed for MEDLINE]
36: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):27-34
Aromatase overexpression transgenic mice model: cell type specific expression
and use of letrozole to abrogate mammary hyperplasia without affecting normal
physiology.
Mandava U, Kirma N, Tekmal RR.
Department of Gynecology and Obstetrics, Emory University, 4217 Woodruff
Memorial Building, 1639 Pierce Drive, Atlanta, GA 30322-4710, USA.
Our recent studies have shown that overexpression of aromatase results in
increased tissue estrogenic activity and induction of hyperplastic and
dysplastic lesions in female mammary glands and gynecomastia and testicular
cancer in male aromatase transgenic mice. Both aromatase mRNA and protein are
overexpressed in transgenic mammary glands and its expression is not limited to
epithelial cells. However, it is more in epithelial than in stromal cells. Our
results also indicate aromatase overexpression-induced changes in mammary glands
can be abrogated with very low concentrations of the aromatase inhibitor,
letrozole. Low concentration of letrozole had no effect on normal physiology as
indicated by no significant change in the circulating levels of estradiol and
follicle stimulating hormone as well as no change in estrogen responsive genes
such as the progesterone receptor and lactoferrin in the uterine tissue. These
observations indicate that the expression of aromatase in both epithelial and
stromal cells can influence the complex interactions of biochemical pathways
leading to mammary carcinogenesis and that the aromatase inhibitor, letrozole
can be used as chemopreventive agents without affecting normal physiology.
PMID: 11850204 [PubMed - indexed for MEDLINE]
37: Lakartidningen 2002 Jan 17;99(3):165-8
[Growth rate can be manipulated. Estrogen production in pubertal boys can be
blocked by an aromatase inhibitor]
[Article in Swedish]
Hagenas L.
Barnendokrinologiska enheten, Astrid Lindgrens barnklinik, Karolinska sjukhuset,
Stockholm. [email protected]
A review of a twelve month clinical trial [1] using a new, effective aromatase
inhibitor treatment in boys with delayed puberty shows that the pubertal
increase in estrogen levels can be blocked, with concomitant preserved pubertal
growth rate. Circulating testosterone levels are greatly enhanced during
treatment due to increased gonadotrophin secretion. Despite this, bone age
maturation is slow leading to an increased final height prognosis (mean 5.1 cm)
for the boys treated with aromatase inhibitor.
PMID: 11838072 [PubMed - indexed for MEDLINE]
38: J Pediatr Endocrinol Metab 2001;14 Suppl 6:1541-6
Treatment of delayed male puberty: efficacy of aromatase inhibition.
Dunkel L, Wickman S.
University of Helsinki, Hospital for Children and Adolescents, Finland.
[email protected]
We hypothesized that inhibition of estrogen synthesis would delay maturation of
the growth plates and ultimately result in increased adult height in boys with
delayed puberty. We conducted a randomized, double-blind, placebo-controlled
study in which we treated boys with constitutional delay of puberty with
testosterone plus placebo (testosterone-placebo) or with testosterone plus
letrozole (testosterone-letrozole). Letrozole effectively inhibited estrogen
synthesis: 17beta-estradiol concentrations increased in the testosterone-placebo
group, but in the testosterone-letrozole group, no such increase was observed
until letrozole treatment was discontinued. After 1.5 years, bone age had
advanced by 1.7 +/- 0.3 years in the testosterone-placebo group, but by only 0.9
+/- 0.2 years in the testosterone-letrozole group (p = 0.02). Predicted adult
height did not change significantly in the testosterone-placebo group, whereas
in the testosterone-letrozole group the increase was 5.1 +/- 1.2 cm (p = 0.004).
Our findings suggest that, if estrogen action is inhibited in growing
adolescents, adult height will increase. This observation provides a rationale
for studies aimed at delaying bone maturation in several growth disorders.
PMID: 11837512 [PubMed - in process]
39: Ann Oncol 2001 Nov;12(11):1539-43
Formestane, a steroidal aromatase inhibitor after failure of non-steroidal
aromatase inhibitors (anastrozole and letrozole): is a clinical benefit still
achievable?
Carlini P, Frassoldati A, De Marco S, Casali A, Ruggeri EM, Nardi M, Papaldo P,
Fabi A, Paoloni F, Cognetti F.
Department of Medical Oncology, Regina Elena National Cancer Institute, Rome,
Italy. [email protected]
BACKGROUND: There are few clinical data on the sequential use of aromatase
inhibitors (AI). This paper focuses on the relevance of clinical benefit CB (CR
+ PR + SD > or = 6 months) in postmenopausal metastatic breast cancer (MBC)
patients treated with the steroidal aromatase inhibitor (SAI) formestane (FOR).
who had already received non-steroidal aromatase inhibitor (nSAI): letrozole
(LTZ) or anastrozole (ANZ). PATIENTS AND METHODS: Twenty postmenopausal women
with MBC were analysed in this retrospective two-centre study with the sequence
nSAI-FOR. When receiving ANZ, 1 of 11 achieved a complete response and 9 of 11 a
stable disease > or = 6 months, and receiving LTZ 1 of 9 achieved a partial
response and 4 of 9 a stable disease > or = 6 months. The analysis of the entire
population treated with FOR showed an overall CB of 55% (11 of 20) with a median
duration of 15 months and median time to progression (TTP) of 6 months.
CONCLUSIONS: Formestane 250 mg once bi-weekly seems to be an attractive
alternative third-line hormonal therapy for the treatment of patients with MBC,
previously treated with nSAI.
PMID: 11822752 [PubMed - in process]
40: Ann Oncol 2001 Nov;12(11):1527-32
Preoperative treatment of postmenopausal breast cancer patients with letrozole:
A randomized double-blind multicenter study.
Eiermann W, Paepke S, Appfelstaedt J, Llombart-Cussac A, Eremin J, Vinholes J,
Mauriac L, Ellis M, Lassus M, Chaudri-Ross HA, Dugan M, Borgs M; Letrozole
Neo-Adjuvant Breast Cancer Study Group.
Frauenklinik Vom, Roten Kreuz, Munich.
BACKGROUND: A randomized, double-blind, multicenter study was conducted to
compare the anti-tumor activity of letrozole vs. tamoxifen in postmenopausal
women with ER and/or PgR positive primary untreated breast cancer. PATIENTS AND
METHODS: Three hundred thirty-seven postmenopausal women with ER and/or PgR
positive primary untreated breast cancer were randomly assigned once daily
treatment with either letrozole 2.5 mg or tamoxifen 20 mg for four months. At
baseline none of the patients were considered to be candidates for
breast-conserving surgery (BCS) and 14% of the patients were considered
inoperable. The primary endpoint was to compare overall objective response (CR +
PR) determined by clinical palpation. Secondary endpoints included overall
objective response on ultrasound and mammography and the number of patients who
qualified for BCS. RESULTS: Overall objective response rate (clinical palpation)
was statistically significantly superior in the letrozole group, 55% compared to
tamoxifen, 36% (P < 0.001). Secondary endpoints of ultrasound response, 35% vs.
25% (P = 0.042), mammographic response, 34% vs. 16% (P < 0.001), and BCS, 45%
vs. 35% (P = 0.022) between the letrozole and tamoxifen groups, respectively,
showed letrozole to be significantly superior. Both treatments were well
tolerated. CONCLUSIONS: This study shows that letrozole is more effective than
tamoxifen as preoperative therapy in postmenopausal patients with ER and/or PgR
positive primary untreated breast cancer and is at least as well tolerated.
PMID: 11822750 [PubMed - in process]
41: J Clin Oncol 2002 Feb 1;20(3):876-8
Superior efficacy of letrozole versus tamoxifen as first-line therapy.
Buzdar AU.
Publication Types:
Letter
PMID: 11821477 [PubMed - indexed for MEDLINE]
42: J Clin Oncol 2002 Feb 1;20(3):751-7
Influence of letrozole and anastrozole on total body aromatization and plasma
estrogen levels in postmenopausal breast cancer patients evaluated in a
randomized, cross-over study.
Geisler J, Haynes B, Anker G, Dowsett M, Lonning PE.
Department of Oncology, Haukeland University Hospital, Bergen, Norway.
PURPOSE: To compare the effects of the two novel, potent, nonsteroidal aromatase
inhibitors anastrozole and letrozole on total-body aromatization and plasma
estrogen levels. PATIENTS AND METHODS: Twelve postmenopausal women with estrogen
receptor-positive, metastatic breast cancer were treated with anastrozole 1 mg
orally (PO) and letrozole 2.5 mg PO once daily, each given for a time interval
of 6 weeks in a randomized sequence. Total-body aromatization was determined
before treatment and at the end of each treatment period using a dual-label
isotopic technique involving isolation of the metabolites with high-performance
liquid chromatography. Plasma levels of estrone (E(1)), estradiol (E(2)), and
estrone sulfate (E(1)S) were determined in samples obtained before each
injection using highly sensitive radioimmunoassays. RESULTS: Pretreatment
aromatase levels ranged from 1.68% to 4.27%. On-treatment levels of aromatase
were detectable in 11 of 12 patients during treatment with anastrozole (mean
percentage inhibition in the whole group, 97.3%) but in none of the 12 patients
during treatment with letrozole (> 99.1% suppression in all patients; Wilcoxon,
P =.0022, comparing the two drug regimens). Treatment with anastrozole
suppressed plasma levels of E(1), E(2), and E(1)S by a mean of 81.0%, 84.9%, and
93.5%, respectively, whereas treatment with letrozole caused a corresponding
decrease of 84.3%, 87.8% and 98.0%, respectively. The suppression of E(1) and
E(1)S was found to be significantly better during treatment with letrozole
compared with anastrozole (P =.019 and.0037, respectively). CONCLUSION: This
study revealed letrozole (2.5 mg once daily) to be a more potent suppressor of
total-body aromatization and plasma estrogen levels compared with anastrozole (1
mg once daily) in postmenopausal women with metastatic breast cancer.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 11821457 [PubMed - indexed for MEDLINE]
43: Pharmacol Biochem Behav 2002 Jan-Feb;71(1-2):301-5
Reproductive changes in male rats treated perinatally with an aromatase
inhibitor.
Gerardin DC, Pereira OC.
Department of Pharmacology, Institute of Biosciences, Sao Paulo State University
18618-000 Botucatu, Sao Paulo, Brazil.
The effects of maternal exposure to aromatase inhibitor during the perinatal
period of sexual brain differentiation were studied. The fertility was assessed
in adult, male rat offspring of aromatase inhibitor-treated dams. The following
results were obtained: (1) Sexual maturation, body weight, and wet weights of
testis, pituitary, seminal vesicle, ventral prostate, and levatori ani muscle
were unchanged at adult life. (2) Fifty percent of the animals were able to mate
with normal females, which became pregnant but exhibited an increased number of
preimplantation loss. (3) There was a decrease in the number of spermatozoa
found in the testes and in the daily sperm production. (4) Of those, 25% of the
male rats treated with aromatase inhibitor did not present male sexual behavior,
showing female behavior when pretreated with estrogen. These results indicate
that perinatal exposure to aromatase inhibitor during the critical period of
male brain sexual differentiation has a long-term effect on the reproductive
physiology and behavior of male rats.
PMID: 11812536 [PubMed - indexed for MEDLINE]
44: Curr Opin Obstet Gynecol 2002 Feb;14(1):67-73
Current status and future innovations of hormonal agents, chemotherapy and
investigational agents in endometrial cancer.
Elit L, Hirte H.
Division of Gynecologic Oncology, MacMaster University, Hamilton, Ontario,
Canada. [email protected]
The median survival of women with advanced or recurrent endometrial cancer is
less than one year. Only half the women with early stage endometrial cancer and
poor prognostic factors such as high grade or deep myometrial invasion will
survive for 5 years. Over the past decade, incredible strides have been taken in
evaluating systemic therapy for this disease. However, survival rates remain
poor. A literature search was conducted using CANCERLIT, EMBASE, Medline,
Investigational Drug database (Current Drug Ltd.) and R&D Focus (IMSworld
Publications). The references of the articles were also explored. Search terms
included: endometrial cancer, chemotherapy, endocrine/hormonal therapies,
molecular biologics, and specific drug names. Progestin therapy offers a 10-20%
response rate and survival of less than 1 year. Progestins are most effective in
women with well-differentiated tumours and a long disease-free interval. There
is no role for adjuvant progestin therapy in early stage disease. Single-agent
chemotherapy with the most activity includes ifosfamide, cisplatin/carboplatin,
doxorubicin and paclitaxel. Combination chemotherapy provides a response rate of
40-60%; however, median survival is still less than a year. New areas of
research include the identification and evaluation of new active endocrine
therapies (i.e. LY353381.HCl and letrozole), chemotherapeutics (i.e. herceptin),
evaluating chemotherapeutic agents in combination (i.e. paclitaxel, doxorubicin
and platinum), in addition to radiation or instead of radiation. New avenues
under development involve the specific molecules and pathways responsible for
the initiation and growth of endometrial carcinoma, including: tumour suppressor
genes, DNA mismatch repair genes, oncogenes, molecules involved in adhesion and
invasion and angiogenesis. Further significant advances in radiotherapy,
hormonal therapy and chemotherapy are unlikely. Exciting developments in
understanding the molecules involved in tumour development and metastasis will
allow the development of specific and selective inhibitors.
Publication Types:
Review
Review, Tutorial
PMID: 11801879 [PubMed - indexed for MEDLINE]
45: US News World Rep 2001 Dec 24;131(26):52
New breast cancer drug.
Brink S.
Publication Types:
News
PMID: 11793594 [PubMed - indexed for MEDLINE]
46: Breast Cancer 2001;8(4):329-32
Aromatase and aromatase inhibitors.
Toi M, Bando H, Saji S.
Tokyo Metropolitan Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo
113, Japan. [email protected]
Aromatase inhibition provides both paracrine/intracrine and endocrine treatment.
Recent accumulated data clarified that 3rd generation aromatase inhibitors
potently suppress intratumoral estrogen synthesis particularly in postmenopausal
patients. In the 2nd-line treatment for metastatic breast cancer patients,
aromatase inhibitors achieved results antitumor activity at least equal to and
sometimes better than that of tamoxifen. In the first-line treatment for
metastatic breast cancer patients, a recent pivotal study clearly demonstrated
that aromatase inhibitor was superior to tamoxifen. Based upon these results,
various adjuvant trials which compare aromatase inhibitors with tamoxifen and
attempt to determine optimal combination therapies and treatment periods with
aromatase inhibitors are currently being conducted. In addition, preliminary
studies conducted in neoadjuvant setting indicated that aromatase inhibitors
showed an extremely high response rate, which predicts a future paradigm, that
neoadjuvant therapy using aromatase inhibitors singly or in combination may
become standard for hormone-responsive and post-menopausal breast cancer
patients.
Publication Types:
Review
Review, Tutorial
PMID: 11791126 [PubMed - indexed for MEDLINE]
47: Breast Cancer 2001;8(4):305-9
Third-generation aromatase inhibitors in the treatment of advanced breast
cancer.
Nabholtz JM, Reese DM.
Cancer Therapy Development Program and Jonsson Comprehensive Cancer Center,
University of California, Los Angeles, Peter Ueberroth Building 3360B, 10945 Le
Conte Avenue, Los Angeles, CA 90095-7077, USA. [email protected]
Publication Types:
Review
Review, Tutorial
PMID: 11791122 [PubMed - indexed for MEDLINE]
48: Vopr Onkol 2001;47(5):571-4
[Neoadjuvant use of the aromatase inhibitor letrozole in uterine cancer:
endocrine and clinical effects]
[Article in Russian]
Bershtein LM, Maksimov SIa, Gershfel'd ED, Gamaiunova VB, Tsyrlina EV, Meshkova
IE, Kovalenko IG, Larionov AA, Kovalevskii AIu, Vasil'ev DA.
N.N. Petrov Research Institute of Oncology, St. Petersburg, Russia.
Endometrial cancer (EC) is estrogen-dependent tumor in the hormonal treatment of
which mostly progestins are used. During last 5-7 years feasibility of aromatase
inhibitors use in EC is discussed without any special practical move in this
direction. To evaluate possible biological response of tumor and patients to
such treatment, we conducted a short pilot study involving 10 primary
postmenopausal EC patients, mostly stage Ia,b (average age 59) who received
letrozole (Femara, Novartis) 2.5 mg/day during 14 days before operation.
Clinical, sonographical, morphological, cytological and hormonal-metabolic
(blood estradiol, FSH, LH, glucose, lipid fractions by RIA or
enzyme-colorimetric methods; tumor progesterone receptors by LBA and aromatase
activity by 3H-water release assay) studies were included into the protocol
before and after treatment. Tolerability of letrozole was satisfactory in all
patients. 2 patients reported decrease of pain and pathological secretions from
uterine cavity. In 3 patients, decrease in M-sonographical endometrial signal
was registered; average value after treatment was 31.1% lower than before it.
Tendency to the decrease in estrogenicity of vaginal smears was revealed.
Average decrease in blood estradiol was 37.8% and in progesterone receptor level
and aromatase activity 34.4% and 17.5% respectively. Decrease of aromatase
activity in tumor tissue was registered mostly in normal weight patients. A more
detailed and longer randomized study of aromatase inhibitors in EC performed in
neoadjuvant setting deserves consideration.
PMID: 11785098 [PubMed - indexed for MEDLINE]
49: J Bone Miner Res 2002 Jan;17(1):172-8
Role of low levels of endogenous estrogen in regulation of bone resorption in
late postmenopausal women.
Heshmati HM, Khosla S, Robins SP, O'Fallon WM, Melton LJ 3rd, Riggs BL.
Division of Endocrinology and Metabolism, Mayo Clinic and Mayo Foundation,
Rochester, Minnesota 55905, USA.
Although median levels of bone turnover are increased in postmenopausal women,
it is unclear whether the low circulating levels of endogenous estrogen exert a
regulatory role on these levels. This issue was evaluated by assessing the
effect of a blockade of estrogen synthesis on bone turnover markers in 42 normal
women (mean age +/- SD, 69 +/- 5 years) randomly assigned to groups receiving
the potent aromatase inhibitor letrozole or placebo for 6 months. Letrozole
treatment reduced serum estrone (E1) and estradiol (E2) to near undetectable
levels (p < 0.0001). This treatment did not affect bone formation markers but,
as compared with the placebo group, increased bone resorption markers (urine
24-h pyridinoline [PYD] by 13.3% [p < 0.05] and 24-h urine deoxypyridinoline
[DPD] by 14.2% [p < 0.05]) and decreased serum parathyroid hormone (PTH) by 22%
(p = 0.002). These data indicate that in late postmenopausal women even the low
serum estrogen levels present exert a restraining effect on bone turnover and
support the concept that variations in these low levels may contribute to
differences in their rate of bone loss.
PMID: 11771665 [PubMed - in process]
50: Biopharm Drug Dispos 2001 Jul;22(5):191-7
Effect of age and single versus multiple dose pharmacokinetics of letrozole
(Femara) in breast cancer patients.
Pfister CU, Martoni A, Zamagni C, Lelli G, De Braud F, Souppart C, Duval M,
Hornberger U.
Novartis Pharma AG, Basel, Switzerland. [email protected]
Letrozole (trademark Femara) is a new orally active, potent and selective
aromatase inhibitor for the hormonal treatment of advanced breast cancer in
postmenopausal women. The pharmacokinetics of letrozole and the suppression of
peripheral estrogens were studied in 28 breast cancer patients after a single
dose and at steady state. The pharmacokinetics of two distinct age groups (> or
=50, < or =65, N=15 and > or =70 years old, N=9) were compared. There were no
significant differences in area under the curve (AUC) or terminal half-life
between the two age groups neither after a single dose nor at steady state.
However, when comparing steady state to single dose kinetics, half-life and AUC
increased significantly by 42% (90% CI: 1.13, 1.78) and 28% (90% CI: 1.12,
1.47), respectively. This deviation from linearity was probably due to a partial
saturation or auto-inhibition of the dominant metabolic clearance mechanism of
letrozole. At steady state, approximately 70% of the administered dose was
excreted in urine as unchanged letrozole (6.0+/-3.8%) or as the glucuronide of
the major, pharmacologically inactive metabolite CGP44645 (64.2+/-22.7%). A
single dose of letrozole caused suppression of serum estrogen levels close to
the quantification limit of the assay. No difference between single dose
suppression and suppression at steady state could be detected. Copyright 2001
John Wiley & Sons, Ltd.
Publication Types:
Clinical Trial
Clinical Trial, Phase II
Multicenter Study
PMID: 11745921 [PubMed - indexed for MEDLINE]
51: Surgery 2001 Dec;130(6):947-53
High dehydroepiandrosterone-sulfate predicts breast cancer progression during
new aromatase inhibitor therapy and stimulates breast cancer cell growth in
tissue culture: a renewed role for adrenalectomy.
Morris KT, Toth-Fejel S, Schmidt J, Fletcher WS, Pommier RF.
Department of Surgery, Section of Surgical Oncology, Oregon Health Sciences
University, Portland, OR 97201, USA.
BACKGROUND: Stage IV hormone-sensitive breast cancer is often treated with
aromatase inhibitors (anastrozole, letrozole, exemestane), which block the
conversion of dehydroepiandrosterone (DHEA) to estrone and estradiol. This is
intended to obviate the need for steroid replacement and antiquate
adrenalectomy. METHODS: Patients who underwent oophorectomy and were being
treated with new aromatase inhibitor therapy received serial measurements of
serum estrone, estradiol, and DHEA-sulfate (DHEA-S). Steroid values during
responsive and progressive phases of disease were compared. In vitro, human
breast cancer cell lines T-47D (estrogen-receptor and progesterone-receptor
positive) and HCC 1937 (estrogen-receptor and progesterone-receptor negative)
were treated with DHEA-S. Proliferation rates were measured by colorimetric
assay. RESULTS: Disease in 12 of the 19 patients progressed. DHEA-S was less
than 89 microg/dL in patients during the responsive phase and more than or equal
to 89 microg/dL during disease progression, with 1 exception (P < .0005).
Estrone and estradiol remained suppressed. After disease progression, the
condition of 9 patients stabilized with aminoglutethimide therapy (n = 8) or
adrenalectomy (n = 1), and their DHEA-S levels were reduced to less than 89
microg/dL. In vitro, elevated DHEA-S induced cell proliferation in T-47D cells.
CONCLUSIONS: DHEA-S levels more than or equal to 89 microg/dL predicted disease
progression in states of low estrogen. Tissue culture results supported the role
of DHEA-S as an estrogenic agent. Oophorectomies with either aminoglutethimide
therapy or adrenalectomy were effective remedies for breast cancer progression
due to high DHEA-S.
PMID: 11742322 [PubMed - indexed for MEDLINE]
52: J Clin Oncol 2001 Dec 1;19(23):4353
False shortening of time to progression in letrozole 2.5-mg dose?
Cocconi G.
Publication Types:
Letter
PMID: 11731525 [PubMed - indexed for MEDLINE]
53: J Clin Oncol 2001 Dec 1;19(23):4353-5
Letrozole in second-line therapy of advanced breast cancer: more questions than
answers.
Mackey JR, Joy AA.
Publication Types:
Letter
PMID: 11731524 [PubMed - indexed for MEDLINE]
54: Clin Ter 2001 Jul-Aug;152(4):263-5
Huge response to letrozole in inoperable T4 breast cancer: a case report.
Di Cosimo S, Altomare V, Ferretti G, Gravante G, Rabitti C, Rea F, Arullani A,
D'Aprile M.
Breast Cancer Unit, University Campus Bio-Medico, Rome, Italy.
[email protected]
A 73 years-old woman presented with locally advanced breast cancer (cT4b cN1 M0,
stage IIIB) and atrial flutter. Because of the arrhythmia, chemotherapy or
tamoxifen, although malignancy was hormone-sensitive, were discarded. Letrozole
was started. Two months later, the breast nodule and skin ulceration cleared up.
Surgery was performed. Nowadays, 24 months later, patient does fine, continuing
letrozole as adjuvant treatment.
PMID: 11725620 [PubMed - in process]
55: Prescrire Int 2001 Aug;10(54):108-9
Exemestane: new preparation. No tangible advance in metastatic breast cancer
after tamoxifen failure.
(1) The reference second-line hormone treatment for breast cancer in
postmenopausal women, after failure of anti-oestrogen therapy, is an aromatase
inhibitor such as letrozole. (2) The clinical assessment file on exemestane, a
new aromatase inhibitor licensed for this indication, contains no data from
clinical trials versus letrozole or anastrozole, the other oral aromatase
inhibitors. Data from non comparative trials fail to show whether
cross-resistance between aromatase inhibitors exists. (3) In a double-blind
trial involving 769 patients in whom tamoxifen had failed, the antitumour effect
of exemestane appeared to be equivalent to that of the progestagen megestrol.
(4) This trial showed that the adverse effect profile of exemestane was similar
to that of other aromatase inhibitors, with mainly vasomotor flushes, nausea,
fatigue and sweating. (5) In practice, the arrival of exemestane changes nothing
in the hormone therapy of breast cancer in postmenopausal women, which should
consist of tamoxifen (an anti-oestrogen) first; followed by the aromatase
inhibitor letrozole if tamoxifen fails.
PMID: 11718178 [PubMed - indexed for MEDLINE]
56: Cancer Chemother Pharmacol 2001 Oct;48(4):259-65
Role of anti-aromatase agents in postmenopausal advanced breast cancer.
Murray R.
Peter MacCallum Cancer Institute, St Andrew's Place, East Melbourne, Australia.
[email protected]
PURPOSE: Endocrine therapy is a well-recognized approach to the treatment of
postmenopausal patients with advanced breast cancer, particularly those with
estrogen receptor-positive tumors. The availability of anti-aromatase agents,
both reversible (nonsteroidal) and irreversible (steroidal), provides clinicians
with additional hormonal treatment options. METHODS: A MEDLINE search was
conducted to identify studies that evaluated anti-aromatase therapy in the
treatment of postmenopausal women with advanced breast cancer. In selecting
studies, priority was given to randomized, controlled trials. RESULTS: Tamoxifen
is the standard first-line therapy for advanced breast cancer. However, recent
results have demonstrated the efficacy of newer anti-aromatase agents in this
setting. Among patients who have progressed after tamoxifen therapy,
anti-aromatase agents have emerged as first choice therapy based on their better
tolerability and improved efficacy compared with megestrol acetate. Exemestane
and anastrozole (irreversible and reversible anti-aromatase agents,
respectively) have demonstrated survival benefits over megestrol acetate in
second-line therapy. Anti-aromatase agents have also demonstrated efficacy in
patients who have failed multiple hormonal therapies. Based on these data, an
algorithm for the treatment of postmenopausal women with advanced breast cancer
is proposed. CONCLUSIONS: The enhanced tolerability and superior efficacy of
anti-aromatase inhibitors compared with megestrol acetate has resulted in these
agents becoming the endocrine treatment of choice for women with advanced breast
cancer who have progressed after tamoxifen treatment. The increased use of
tamoxifen in the adjuvant setting and the demonstrated activity of aromatase
inhibitors in first-line therapy will further increase the role of these agents.
Publication Types:
Review
Review, Tutorial
PMID: 11710624 [PubMed - indexed for MEDLINE]
57: Vopr Onkol 2001;47(4):425-7
[Interrelationship between response to neoadjuvant hormone therapy and
hormonal-metabolic status in breast cancer patients]
[Article in Russian]
Semiglazov VF, Ivanov VG, Gamaiunova VB, Zhil'tsova EK, Tsyrlina EV, Kovalenko
IG, Bershtein LM.
N.N. Petrov Research Institute of Oncology, Ministry of Health of the RF, St.
Petersburg.
Twenty seven breast cancer patients with receptor-positive tumors stage IIb-IIIa
(TNM) were treated with an aromatase inhibitor--letrozole, 2.5 mg/day, or an
antiestrogen--tamoxifen, 20 mg/day, 4 months before surgery. Complete or partial
response (CP + PR) was recorded in patients older than those with stabilization
or progression of the disease. Moreover, the former group tended to show higher
of suppression of blood-estradiol and progesterone receptors levels in tumor and
lower suppression of serum-FSH concentration after treatment. These,
practically, first findings of the kind suggest that the search for hormonal
markers to predict the efficiency of neoadjuvant hormonal therapy for breast
cancer should be continued.
PMID: 11710283 [PubMed - indexed for MEDLINE]
58: Lancet 2001 Oct 27;358(9291):1459-60
Role of hormones in puberty.
Cianfarani S.
Publication Types:
Letter
PMID: 11705526 [PubMed - indexed for MEDLINE]
59: Ann Ital Med Int 2001 Apr-Jun;16(2):112-7
Flare and tumor lysis syndrome with atypical features after letrozole therapy in
advanced breast cancer. A case report.
Zigrossi P, Brustia M, Bobbio F, Campanini M.
U.O.A. Medicina Generale II, Azienda Ospedaliera Maggiore della Carita di
Novara.
Tumor lysis syndrome, which develops after effective therapy of malignant
conditions and leads to hyperuricemia, hyperkaliemia, hyperphosphatemia,
hypocalcemia and elevated lactate dehydrogenase, is uncommon in solid tumors. In
breast carcinoma it can be associated with tamoxifen flare, i.e. a transient
increase in symptoms, mainly bone pain, observed shortly after the start of
tamoxifen therapy. We report the case of a patient with advanced breast
carcinoma involving the pleural space, unresponsive to combined chemotherapy,
who experienced rapid worsening after the initiation of letrozole. Her symptoms
included shock, bilateral pleural effusion, cardiac tamponade and oliguria.
Laboratory parameters disclosed elevated transaminase, lactate dehydrogenase,
uric acid and D-dimer blood levels. The patient was in critical condition for
nearly 2 weeks. She improved progressively and has remained well and in complete
remission for 20 months. This clinical picture suggests increased damage to the
pleura (and probably the pericardium) and rapid leakage of tumor products,
following the start of endocrine therapy. Letrozole is a non-steroidal aromatase
inhibitor which is used in advanced breast cancer, resistant to first-line
endocrine/chemotherapeutic treatment. Our review of the literature did not
disclose any other descriptions of flare and tumor lysis syndrome after
aromatase inhibitor therapy. Moreover, this case was characterized by atypical
and complex clinical features. The aim of this presentation is to point out the
practical significance, in neoplastic patients, of the differential diagnosis
between symptoms due to tumor progression and those associated with anomalous
reactions to therapy.
PMID: 11688358 [PubMed - in process]
60: BMJ 2001 Oct 20;323(7318):880-1
Aromatase inhibitors and inactivators in breast cancer.
Lonning PE.
Publication Types:
Editorial
PMID: 11668120 [PubMed - indexed for MEDLINE]
61: J Clin Endocrinol Metab 2001 Oct;86(10):4887-94
Inhibition of P450 aromatase enhances gonadotropin secretion in early and
midpubertal boys: evidence for a pituitary site of action of endogenous E.
Wickman S, Dunkel L.
University of Helsinki, Hospital for Children and Adolescents, FIN-00029
Helsinki, Finland. [email protected]
In early pubertal boys, E concentrations are very low. We studied the role and
site of action of endogenous E in the regulation of gonadotropin secretion in
early and midpubertal boys by inhibiting the action of E with a potent and
specific P450 aromatase inhibitor, letrozole. A total of 35 boys who were
referred to us because of suspicion of delayed puberty were included in the
study. The boys were in either early or midpuberty, and they composed 3 groups:
10 boys did not receive any treatment, 12 boys received T alone, and 13 boys
received T and letrozole. In the untreated group during the 5-month follow-up,
no changes were observed in 17beta-E2, T, basal gonadotropin, or inhibin B
concentrations or in the GnRH-induced gonadotropin responses. In the T-treated
group during the 5-month treatment, the T concentration increased by 55% (P <
0.05), and the 17beta-E2 concentration increased by 130% (P < 0.02).
Concurrently, basal gonadotropin concentrations were suppressed, but the
GnRH-induced gonadotropin responses and the inhibin B concentration remained
unchanged. In the T- plus letrozole-treated group during the 5-month treatment,
an increase in T concentration of 606% was observed (P < 0.001), but the
17beta-E2 concentration remained unchanged. The changes in the 17beta-E2
concentration within 5 months in the untreated and the T- plus letrozole-treated
groups were different (P < 0.02), indicating significant inhibition of
endogenous E synthesis during letrozole treatment. During the T plus letrozole
treatment, basal gonadotropin concentration, the GnRH-induced LH response, and
inhibin B concentration increased, and the GnRH-induced FSH response did not
change significantly. Serum nocturnal gonadotropin pulses were determined in 5
boys treated with T and in 5 boys treated with T plus letrozole. In the T- plus
letrozole-treated group, the nocturnal LH pulse amplitude increased, and the LH
pulse frequency and interpulse interval remained unchanged. In conclusion, in
early and midpubertal boys, suppression of the action of E by the P450 aromatase
inhibitor increased LH concentration, LH pulse amplitude, and the GnRH-induced
LH response, which indicates that in boys during early and midpuberty,
endogenous E regulates LH secretion at the site of the pituitary.
PMID: 11600558 [PubMed - indexed for MEDLINE]
62: J Clin Oncol 2001 Oct 1;19(19):3999-4000
Aromatase inhibitors: treatment of advanced breast cancer.
Panasci LC.
Publication Types:
Letter
PMID: 11579125 [PubMed - indexed for MEDLINE]
63: Prostaglandins Other Lipid Mediat 2001 Oct;66(3):155-63
Developmental maturation of primate placental trophoblast: placental cytosolic
and secretory phospholipase A2 expression after estrogen suppression of baboons.
Rosenthal MD, Albrecht ED, Pepe GJ.
Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk
23507, USA.
We have demonstrated that the baboon placenta expressed the mRNAs and proteins
for secretory and cytosolic phospholipase A2 (PLA2) enzymes and that cPLA2
expression increased with advancing gestation in association with the increase
in placental estrogen production. To determine whether estrogen regulates
placental PLA2 expression, as it does other aspects of syncytiotrophoblast
functional differentiation, we compared sPLA2 and cPLA2 mRNA levels in placentas
obtained on day 165 of gestation (term = day 184) from baboons that were
untreated or treated during the second half of gestation with the aromatase
inhibitor CGS 20267 or CGS 20267 and estradiol. Maternal saphenous and uterine
vein estradiol levels were reduced (P < 0.05) by approximately 95% by treatment
with CGS 20267 and restored by concomitant administration of CGS 20267 and
estrogen. However, sPLA2 and cPLA2 mRNA levels expressed as a ratio of
beta-actin were similar in whole villous placenta from baboons that were
untreated or treated with CGS 20267 or CGS 20267 plus estrogen. PLA2 expression
in an enriched fraction of nontrophoblast cells of the baboon placenta was also
not altered by CGS 20267 treatment. Collectively these findings indicate that
placental cPLA2 and sPLA2 expression is not estrogen-dependent. Because estrogen
has been shown to regulate other aspects of placental steroidogenesis, we
suggest that the regulatory role of estrogen on syncytiotrophoblast functional
maturation is specific.
PMID: 11577780 [PubMed - indexed for MEDLINE]
64: J Clin Oncol 2001 Sep 15;19(18):3808-16
Comment in:
J Clin Oncol. 2001 Sep 15;19(18):3795-7.
Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for
ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast
cancer: evidence from a phase III randomized trial.
Ellis MJ, Coop A, Singh B, Mauriac L, Llombert-Cussac A, Janicke F, Miller WR,
Evans DB, Dugan M, Brady C, Quebe-Fehling E, Borgs M.
Duke University Breast Cancer Program, Duke University Comprehensive Cancer
Center, Durham, NC 27710, USA. [email protected]
PURPOSE: Expression of ErbB-1 and ErbB-2 (epidermal growth factor receptor and
HER2/neu) in breast cancer may cause tamoxifen resistance, but not all studies
concur. Additionally, the relationship between ErbB-1 and ErbB-2 expression and
response to selective aromatase inhibitors is unknown. A neoadjuvant study for
primary breast cancer that randomized treatment between letrozole and tamoxifen
provided a context within which these issues could be addressed prospectively.
PATIENTS AND METHODS: Postmenopausal patients with estrogen- and/or progesterone
receptor-positive (ER+ and/or PgR+) primary breast cancer ineligible for
breast-conserving surgery were randomly assigned to 4 months of neoadjuvant
letrozole 2.5 mg daily or tamoxifen 20 mg daily in a double-blinded study.
Immunohistochemistry (IHC) for ER and PgR was conducted on pretreatment biopsies
and assessed by the Allred score. ErbB-1 and ErbB-2 IHC were assessed by
intensity and completeness of membranous staining according to published
criteria. RESULTS: For study biopsy-confirmed ER+ and/or PgR+ cases that
received letrozole, 60% responded and 48% underwent successful breast-conserving
surgery. The response to tamoxifen was inferior (41%, P =.004), and fewer
patients underwent breast conservation (36%, P =.036). Differences in response
rates between letrozole and tamoxifen were most marked for tumors that were
positive for ErbB-1 and/or ErbB-2 and ER (88% v 21%, P =.0004). CONCLUSION: ER+,
ErbB-1+, and/or ErbB-2+ primary breast cancer responded well to letrozole, but
responses to tamoxifen were infrequent. This suggests that ErbB-1 and ErbB-2
signaling through ER is ligand-dependent and that the growth-promoting effects
of these receptor tyrosine kinases on ER+ breast cancer can be inhibited by
potent estrogen deprivation therapy.
Publication Types:
Clinical Trial
Clinical Trial, Phase III
Randomized Controlled Trial
PMID: 11559718 [PubMed - indexed for MEDLINE]
65: J Clin Oncol 2001 Sep 15;19(18):3795-7
Comment on:
J Clin Oncol. 2001 Sep 15;19(18):3808-16.
Use of ErbB-1 and ErbB-2 to select endocrine therapy for breast cancer: will it
play in Peoria?
Pritchard KI.
Publication Types:
Comment
Editorial
PMID: 11559715 [PubMed - indexed for MEDLINE]
66: J Exp Zool 2001 Sep 15;290(5):490-7
Sex reversal and aromatase in the European pond turtle: treatment with letrozole
after the thermosensitive period for sex determination.
Belaid B, Richard-Mercier N, Pieau C, Dorizzi M.
Institut Jacques Monod, C.N.R.S. et Universites Paris 6 et 7, 75251 Paris,
France.
In the European pond turtle (Emys orbicularis), gonadal sex differentiation is
temperature-dependent. The temperature sensitive period (TSP) of gonadogenesis
lies between stages 16 and 22 of embryonic development. Previous studies have
shown that embryos incubated at 30 degrees C, a temperature yielding 100%
phenotypic females, can be sex reversed by treatments with an aromatase
inhibitor administered during TSP or even somewhat after TSP (as of stage 22+).
The goal of the present study was to determine whether the ovary still retains
male potential at later stages of embryonic development and whether the induced
male characters persist after hatching. For this purpose, eggs of E. orbicularis
were treated with letrozole, a nonsteroidal aromatase inhibitor, at or as of
stages 23, 24 or 25, then gonadal aromatase activity in each individual and the
related gonadal structure were studied at hatching (stage 26) and for one year
after hatching. Two kinds of treatments were carried out: 1) repeated
applications of 10 microg of letrozole in ethanolic solution onto the eggshell;
and 2) a single injection of 10 microg of letrozole in olive oil. Similar
results were obtained with either application or injection of the aromatase
inhibitor. In treatments as of or at stage 23, individuals with gonadal
aromatase activity lower than 20 fmoles/hour/gonad had ovotestes, i.e., 22% of
the treated individuals. At hatching, the inner part of these ovotestes
contained testicular cords and also mixed lacunae presenting various degrees of
transdifferentiation of the epithelium into a Sertolian epithelium. The cortex
was maintained, although some germ cells degenerated within it. These processes
continued after hatching. However, at 12 months, gonads were still ovotestes
displaying some follicles with a growing oocyte in the remaining parts of the
cortex. In treatments as of or at stages 24 or 25, only a few individuals were
masculinized. One had ovotestes; in others, the cortex was absent in some parts
and when it was present oocytes were degenerating. These results show that in
the European pond turtle, differentiation of ovotestes from ovaries can be
induced by treatment with an aromatase inhibitor starting at late stages of
embryonic development (between the end of TSP and hatching), although such
differentiation is less frequent as embryonic development proceeds. Sex reversal
persists for at least one year after hatching. J. Exp. Zool. 290:490-497, 2001.
Copyright 2001 Wiley-Liss, Inc.
PMID: 11555856 [PubMed - indexed for MEDLINE]
67: Clin Cancer Res 2001 Sep;7(9):2620-35
Advances in aromatase inhibition: clinical efficacy and tolerability in the
treatment of breast cancer.
Buzdar A, Howell A.
Department of Breast Medical Oncology, M. D., Anderson Cancer Center, University
of Texas, Houston, 77030, USA.
Publication Types:
Review
Review, Tutorial
PMID: 11555572 [PubMed - indexed for MEDLINE]
68: Am J Ther 2001 Sep-Oct;8(5):333-44
Aromatase, aromatase inhibitors, and breast cancer.
Brueggemeier RW.
Medicinal Chemistry and Pharmacognosy, College of Pharmacy, and Hormones and
Cancer Program, Comprehensive Cancer Center, The Ohio State University,
Columbus, OH 43210, USA. [email protected]
Estrogens are involved in numerous physiologic processes and have crucial roles
in particular disease states, such as mammary carcinomas. Estradiol, the most
potent endogenous estrogen, is biosynthesized from androgens by the cytochrome
P-450 enzyme complex called aromatase. Aromatase is found in breast tissue, and
the importance of intratumoral aromatase and local estrogen production is being
unraveled. Inhibition of aromatase is an important approach for reducing growth
stimulatory effects of estrogens in hormone-dependent breast cancer. Effective
aromatase inhibitors have been developed as therapeutic agents for controlling
estrogen-dependent breast cancer. Investigations into the development of
aromatase inhibitors began in the 1970s and have expanded greatly in the past
three decades. Competitive aromatase inhibitors are molecules that compete with
the substrate androstenedione for noncovalent binding to the active site of the
enzyme to decrease the amount of product formed. Steroidal inhibitors that have
been developed to date build on the basic androstenedione nucleus and
incorporate chemical substituents at varying positions on the steroid. The
structure-activity relationships for steroidal inhibitors have become more
refined in the past decade, and only some modifications can be made to the
steroid and still keep its affinity for aromatase. Nonsteroidal aromatase
inhibitors can be divided into three classes: aminoglutethimide-like molecules,
imidazole/triazole derivatives, and flavonoid analogs. Mechanism-based aromatase
inhibitors are inhibitors that mimic the substrate, are converted by the enzyme
to a reactive intermediate, and result in the inactivation of aromatase.
Aromatase inhibitors, both steroidal and nonsteroidal, have shown clinical
efficacy for the treatment of breast cancer. The initial nonselective nature of
nonsteroidal inhibitors such as aminoglutethimide has been greatly reduced in
the later generations of inhibitors, anastrozole and letrozole. Mechanism-based
steroidal inhibitors such as 4-hydroxyandrostenedione and exemestane produce
prolonged aromatase inhibition in patients. The potent and selective
third-generation aromatase inhibitors anastrozole, letrozole, and exemestane are
approved for clinical use as second-line endocrine therapy in postmenopausal
patients failing antiestrogen therapy alone or multiple hormonal therapies.
Publication Types:
Review
Review, Tutorial
PMID: 11550075 [PubMed - indexed for MEDLINE]
69: Oncology (Huntingt) 2001 Aug;15(8):965-72; discussion 972, 977-9
Nonsteroidal and steroidal aromatase inhibitors in breast cancer.
Hamilton A, Volm M.
Kaplan Comprehensive Cancer Center, New York University, School of Medicine, New
York 10016, USA. [email protected]
Anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are
members of the third generation of aromatase inhibitors that has now replaced
aminoglutethimide (Cytadren), the progestins, and tamoxifen (Nolvadex) as the
hormonal therapy of choice in estrogen-receptor-positive, postmenopausal,
metastatic breast cancer. This article will review the role of aromatase in the
pathogenesis of breast cancer and the results of recent studies that have
established the role of its inhibitors in estrogen-receptor-positive breast
cancer. We will also briefly outline the rationale and design of ongoing
studies.
Publication Types:
Review
Review Literature
PMID: 11548977 [PubMed - indexed for MEDLINE]
70: Gynecol Oncol 2001 Aug;82(2):384-8
Endometrial stromal sarcoma: objective response to letrozole.
Maluf FC, Sabbatini P, Schwartz L, Xia J, Aghajanian C.
The Developmental Chemotherapy Service, Department of Medicine, Memorial
Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
BACKGROUND: Low-grade endometrial stromal sarcoma is generally an indolent tumor
rich in estrogen and progesterone receptors. Objective responses to hormonal
therapy, most commonly with megestrol acetate, have been reported. CASE: The
patient is a 51-year-old woman who presented with low-grade endometrial stromal
sarcoma confined to the uterus in 1991 and was treated with total abdominal
hysterectomy and bilateral salpingo-oophorectomy. Approximately 5 years later,
the patient had recurrent pelvic disease treated with radiation therapy,
followed by an attempt at resection. She was treated with megestrol acetate
during the period she received radiation therapy with poor tolerance. Tamoxifen
was then given with no tumor response. Megestrol acetate was restarted with
progression of disease in the pelvis and abdomen. Letrozole was then given at a
daily dose of 2.5 mg with partial response for a duration of 9 months.
CONCLUSION: Letrozole at a daily dose of 2.5 mg may be effective in low-grade
endometrial stromal sarcoma with positive estrogen receptors. Copyright 2001
Academic Press.
PMID: 11531300 [PubMed - indexed for MEDLINE]
71: Breast Cancer Res Treat 2001 Apr;66(3):191-9
Letrozole as primary medical therapy for locally advanced and large operable
breast cancer.
Dixon JM, Love CD, Bellamy CO, Cameron DA, Leonard RC, Smith H, Miller WR.
Edinburgh Breast Unit, Western General Hospital. [email protected]
AIMS: To investigate the efficacy of letrozole 2.5 mg and 10 mg used as primary
neoadjuvant therapy for patients with locally advanced and large operable breast
cancer. PATIENTS AND METHODS: Twenty-four postmenopausal patients with locally
advanced or large operable breast cancer were treated in two consecutive series
with letrozole 2.5 mg (n = 12) or letrozole 10 mg (n = 12). Response at three
months was measured by change in tumor volume according to WHO criteria (partial
response was defined as a reduction in tumor volume > or = 65%). Tumor volumes
were assessed clinically, by ultrasound and mammography, and pathologically.
RESULTS: All 24 patients were estrogen receptor-positive, were considered
'receptor-rich', and mean age was 77.6 years and 71.6 years in the letrozole 2.5
mg and 10 mg treatment groups, respectively. There were five complete clinical
responses and seven partial clinical responses in the patients treated with 2.5
mg letrozole, and nine partial responses and three patients with stable disease
in patients treated with 10 mg letrozole. Assessed by ultrasound and
mammography, the 12 patients treated with 2.5 mg had one complete response, nine
partial responses and two with no change. In the 12 patients treated with 10 mg
letrozole, imaging gave eight partial responses and four with no change. One
patient treated with the 2.5 mg dose had a complete clinical and pathological
response. There was no significant difference between the two doses in effect on
tumor volume, and no recordable side effects associated with either dose.
CONCLUSION: Letrozole used in a neoadjuvant setting is highly effective,
producing clinically beneficial reductions in tumor volume allowing all patients
to have breast conserving surgery, and has an acceptable safety profile.
Publication Types:
Clinical Trial
PMID: 11510690 [PubMed - indexed for MEDLINE]
72: Eur J Cancer 2001 Aug;37(12):1510-3
Effect of letrozole on the lipid profile in postmenopausal women with breast
cancer.
Elisaf MS, Bairaktari ET, Nicolaides C, Kakaidi B, Tzallas CS, Katsaraki A,
Pavlidis NA.
Department of Internal Medicine, Medical School, University of Ioannina, GR 451
10 Ioannina, Greece. [email protected]
Hormonal therapy plays a central role in the overall treatment of breast cancer.
Aromatase inhibitors can inhibit the aromatase enzyme system resulting in a
reduction of oestrogens. Letrozole is a non-steroidal aromatase inhibitor that
effectively blocks aromatase activity without interfering with adrenal steroid
biosynthesis. The drug can significantly reduce the levels of plasma oestrogens,
which remain suppressed throughout the treatment. Data are scarce concerning the
influence of these drugs on serum lipid levels. In the present study, we
evaluated the effects of letrozole on the serum lipid profile in postmenopausal
women with breast cancer. A total of 20 patients with breast cancer were treated
with letrozole, 2.5 mg once daily. After an overnight fast, serum lipid
parameters (total cholesterol, high density lipoprotein (HDL) cholesterol, low
density lipoprotein (LDL) cholesterol, triglycerides, apolipoproteins A1, B and
E and lipoprotein (a)) were measured before treatment and at 8 and 16 weeks
afterwards. A significant increase in total cholesterol (P=0.05), LDL
cholesterol (P<0.01) and apolipoprotein B levels (P=0.05) in the serum, as well
as in the atherogenic risk ratios total cholesterol/HDL cholesterol (P<0.005)
and LDL cholesterol/HDL cholesterol (P<0.005) was noticed after letrozole
treatment. We conclude that letrozole administration in postmenopausal women
with breast cancer has an unfavourable effect on the serum lipid profile.
PMID: 11506958 [PubMed - indexed for MEDLINE]
73: Acta Pharmacol Sin 2000 Aug;21(8):680-4
Gender difference in letrozole pharmacokinetics in rats.
Liu XD, Xie L, Zhong Y, Li CX.
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University,
Nanjing 210009, China. [email protected]
AIM: To study gender difference in letrozole (Letr) pharmacokinetics in rats.
METHODS: Letr concentrations in plasma and tissues were determined after ig
administration of Letr 2 mg/kg. Recoveries of Letr in urine and feces were also
analyzed. RESULTS: Marked gender differences were found 6 h after ig Letr 2
mg/kg, the plasma concentrations of Letr in male rats were significantly (P <
0.01) lower than those in female rats. For example, at 24, 36, 48, and 72 h
after administration, plasma concentrations in female rats were about 3.3, 5.6,
10.5, and 7.4-fold of that of male rats, respectively. AUC value of Letr in male
was only about one-third of that in female rats. Estimated terminal phase
half-lives (T1/2) were 10.5 and 40.4 h, respectively. In female rats, cumulative
excreted fractions of Letr in urine and feces were 5.8% +/- 1.4% and 6.6% +/-
1.1% within 120 h after administration, respectively, but in male rats, the
excreted fractions of Letr in urine and feces were only 1.30% +/- 0.59% and
0.87% +/- 0.31%. Letr concentrations in female rat tissues were significantly (P
< 0.01) higher than those in male rat tissues 24 h after administration.
CONCLUSION: There are marked gender differences in Letr pharmacokinetics in
rats.
PMID: 11501174 [PubMed - indexed for MEDLINE]
74: Gan To Kagaku Ryoho 2001 Jul;28(7):909-16
[Endocrine therapy for advanced or recurrent breast cancer]
[Article in Japanese]
Sonoo H, Kurebayashi J.
Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577
Matsushima, Kurashiki 701-0192, Japan.
Endocrine therapy of advanced or recurrent breast cancer was described. The
presence of ER or PgR in primary breast tumors is the best-established marker
for response to endocrine therapy. However, ER-positive breast tumors
overexpressing EGF-R and/or HER-2 (Erb B2) are resistant to endocrine therapy.
Recently it was suggested that an elevated level of the circulating
extracellular domain of HER-2 could be a predictor for poor response to
endocrine therapy. LH-RH agonist is used as a first-line therapy for
premenopausal patients. And LH-RH agonist plus tamoxifen (TAM) has shown a
higher response rate and more prolonged survival than LH-RH agonist or TAM
alone. As two new aromatase inhibitors, anastrozole (ANA) and letrozole, have
shown an equal or higher response rate and a prolonged time to progression than
TAM as a first-line therapy, these could be used as a first-line therapy instead
of TAM. In a cross-over trial of ANA and TAM, the response rate of ANA after TAM
failure was equal to that of TAM after ANA failure. As these drugs showed an
equal or higher response rate and longer survival than progestin in TAM
resistant cases, these drugs could also used as a second-line therapy. In
addition, the trend of recent studies regarding the mechanisms of hormone
resistance is also described.
Publication Types:
Review
Review, Tutorial
PMID: 11478139 [PubMed - indexed for MEDLINE]
75: Gan To Kagaku Ryoho 2001 Jul;28(7):892-901
[Developments of hormonal agents for breast cancer]
[Article in Japanese]
Tominaga T.
Breast Cancer Center Toyosu Hospital, Showa University School of Medicine,
4-1-18 Toyosu, Koto-ku, Tokyo 135-8577, Japan.
Endocrine therapy for breast cancer, which began with ovariectomy, has a history
of more than 100 years. Tamoxifen has been an epoch-making drug during the late
20th century. Recently LHRH analogues which work as downregulators of estrogen
production and many aromatase inhibitors (AI), both non-steroidal and steroidal
have been developed in Japan. Fadrozole was the only AI until anastrozole was
approved a few months ago. Letrozole was shown to be a better AI than fadrozole
by prospective randomized double blind examination; however, it is not licenced
yet. The reason is that the appropriate dosage is not identical to that of
Western countries. We have reached a time when order-made medicine should take
into consideration such differences as race and individuality.
Publication Types:
Review
Review, Tutorial
PMID: 11478137 [PubMed - indexed for MEDLINE]
76: FDA Consum 2001 May-Jun;35(3):5
Femara approved as first-line breast cancer therapy.
Publication Types:
News
PMID: 11458552 [PubMed - indexed for MEDLINE]
77: J Clin Oncol 2001 Jul 15;19(14):3357-66
Phase III, multicenter, double-blind, randomized study of letrozole, an
aromatase inhibitor, for advanced breast cancer versus megestrol acetate.
Buzdar A, Douma J, Davidson N, Elledge R, Morgan M, Smith R, Porter L, Nabholtz
J, Xiang X, Brady C.
University of Texas M.D. Anderson Cancer Center and Baylor College of Medicine,
Houston, TX, USA. [email protected]
PURPOSE: To compare two doses of letrozole (0.5 mg and 2.5 mg every day) and
megestrol acetate (40 mg qid) as endocrine therapy in postmenopausal women with
advanced breast cancer previously treated with antiestrogens. PATIENTS AND
METHODS: This double-blind, randomized, multicenter, multinational study
enrolled 602 patients, all of whom were included in the primary analysis in the
protocol. Patients had advanced or metastatic breast cancer with evidence of
disease progression while receiving continuous adjuvant antiestrogen therapy,
had experienced relapse within 12 months of stopping adjuvant antiestrogen
therapy given for at least 6 months, or had experienced disease progression
while receiving antiestrogen therapy for advanced disease. Tumors were required
to be estrogen receptor- and/or progesterone receptor-positive or of unknown
status. Confirmed objective response rate was the primary efficacy variable.
Karnofsky Performance Status and European Organization for Research and
Treatment of Cancer quality-of-life assessments were collected for 1 year.
RESULTS: There were no statistically significant differences among the three
treatment groups for overall objective tumor response. Patients treated with
letrozole 0.5 mg had improvements in disease progression (P =.044) and a
decreased risk of treatment failure (P =.018), compared with patients treated
with megestrol acetate. Letrozole 0.5 mg showed a trend (P =.053) for survival
benefit when compared with megestrol acetate. Megestrol acetate was more likely
to produce weight gain, dyspnea, and vaginal bleeding, and the letrozole groups
were more likely to experience headache, hair thinning, and diarrhea.
CONCLUSION: Given a favorable tolerability profile, once-daily dosing, and
evidence of clinically relevant benefit, letrozole is equivalent to megestrol
acetate and should be considered for use as an alternative treatment of advanced
breast cancer in postmenopausal women after treatment failure with
antiestrogens.
Publication Types:
Clinical Trial
Clinical Trial, Phase III
Multicenter Study
Randomized Controlled Trial
PMID: 11454883 [PubMed - indexed for MEDLINE]
78: Lancet 2001 Jun 2;357(9270):1743-8
Comment in:
Lancet. 2001 Jun 2;357(9270):1723-4.
A specific aromatase inhibitor and potential increase in adult height in boys
with delayed puberty: a randomised controlled trial.
Wickman S, Sipila I, Ankarberg-Lindgren C, Norjavaara E, Dunkel L.
Hospital for Children and Adolescents, University of Helsinki, Ph 281,
FIN-00029, Hus, Finland
BACKGROUND: The role of oestrogens in the closure of growth plates in both sexes
is unequivocal. We postulated that inhibition of oestrogen synthesis in boys
with delayed puberty would delay maturation of the growth plates and ultimately
result in increased adult height. METHODS: We did a randomised, double-blind,
placebo-controlled study in which we treated boys with constitutional delay of
puberty with testosterone and placebo, or testosterone and letrozole. Boys who
decided to wait for the spontaneous progression of puberty without medical
intervention composed the untreated group. FINDINGS: Letrozole effectively
inhibited oestrogen synthesis and delayed bone maturation. Progression of bone
maturation was slower in the letrozole group than in the placebo group. In 18
months, bone age had advanced 1.1 (SD 0.8) years in the untreated group and 1.7
(0.9) years in the group treated with testosterone and placebo, but only 0.9
(0.6) years in the letrozole group (p=0.03 between the treatment groups).
Predicted adult height did not change significantly in the untreated group and
in the placebo group, whereas in the group treated with letrozole the increase
was 5.1 (3.7) cm (p=0.004). INTERPRETATIONS: Our findings suggest that if
oestrogen action is inhibited in growing adolescents, adult height will
increase. This finding provides a rationale for studies that aim to delay bone
maturation in several growth disorders.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 11403810 [PubMed - indexed for MEDLINE]
79: Lancet 2001 Jun 2;357(9270):1723-4
Comment on:
Lancet. 2001 Jun 2;357(9270):1743-8.
Use of a specific aromatase inhibitor in delayed puberty.
Stanhope R.
Department of Endocrinology, Great Ormond Street Hospital for Children and
Middlesex Hospital (UCLH), WCIN IEH, London, UK. [email protected]
Publication Types:
Comment
PMID: 11403802 [PubMed - indexed for MEDLINE]
80: Semin Oncol 2001 Jun;28(3):291-304
Endocrine therapy in the treatment of metastatic breast cancer.
Buzdar AU.
Department of Breast Medical Oncology, M.D. Anderson Cancer Center, 1515
Holcombe Blvd., Houston, TX 77037, USA.
The goals of treating patients with metastatic breast cancer are to prolong
survival, slow or halt disease progression, and enhance the patient's quality of
life. In patients with estrogen receptor (ER)-positive cancers that are not
progressing rapidly, endocrine therapy is generally the first treatment option.
If a patient initially responds to an endocrine agent and then progresses,
another endocrine agent may still provide benefit. Tamoxifen has been used as
first-line therapy for metastatic breast cancer for many years. Until recently,
no other endocrine agent has shown superiority to tamoxifen in this setting. The
nonsteroidal aromatase inhibitors, anastrozole and letrozole, have been widely
accepted as second-line therapy after failure of tamoxifen; they have replaced
megestrol acetate in this setting. Recently, anastrozole was shown to have at
least equivalent efficacy and a superior side effect profile compared with
tamoxifen for treating postmenopausal women in the first-line setting. Thus,
this aromatase inhibitor has become a viable option for first-line therapy in
postmenopausal women. Trials of letrozole in this setting are nearing
completion. Exemestane has been shown to be an effective second-line agent and
to have at least some efficacy as a third-line agent even after failure of a
nonsteroidal aromatase inhibitor. Results are anxiously awaited from trials of
new endocrine agents including the first member of a new class of endocrine
agent, the estrogen-receptor downregulator class. Semin Oncol 28:291-304.
Copyright 2001 by W.B. Saunders Company.
Publication Types:
Review
Review, Tutorial
PMID: 11402439 [PubMed - indexed for MEDLINE]
81: Oncology (Huntingt) 2001 May;15(5 Suppl 7):28-34
Aromatase inhibition and antiestrogen therapy in early breast cancer treatment
and chemoprevention.
Ingle JN.
Mayo Clinic, Rochester, Minnesota, USA. [email protected]
The aromatase inhibitors represent an important class of hormonal agents for the
management of breast cancer. The third-generation aromatase inhibitors have
replaced megestrol acetate as second-line hormonal therapy in advanced breast
cancer, and large clinical trials are maturing to establish their efficacy
relative to tamoxifen (Nolvadex) in the first-line metastatic setting. The
increased potency, increased specificity, and established efficacy of aromatase
inhibitors in advanced breast cancer have provided the rationale for a large
number of randomized trials in the adjuvant setting evaluating anastrozole
(Arimidex), exemestane (Aromasin), and letrozole (Femara). These trials are
addressing the value of these agents in sequence with, instead of, and in
combination with tamoxifen. The relationship between estrogen exposure and
breast cancer risk has long been accepted and traditionally related to
estrogen-receptor-mediated events. The emergence of the estrogen genotoxicity
hypothesis as a mechanism for breast cancer carcinogenesis provides additional
rationale for considering aromatase inhibitors in the chemoprevention setting.
Publication Types:
Review
Review, Tutorial
PMID: 11396362 [PubMed - indexed for MEDLINE]
82: J Steroid Biochem Mol Biol 2001 Jan-Mar;76(1-5):199-202
Intracellular aromatase and its relevance to the pharmacological efficacy of
aromatase inhibitors.
Bhatnagar AS, Brodie AM, Long BJ, Evans DB, Miller WR.
Novartis Pharma AG, CH-4002, Basel, Switzerland.
An important feature of the pharmacological profile of aromatase inhibitors is
the ability of the various inhibitors to inhibit intracellular aromatase. It is
now well documented that a large proportion of breast tumors express their own
aromatase. This intratumoral aromatase produces estrogen in situ and therefore
may contribute significantly to the amount of estrogen to which the cell is
exposed. Thus it is not only important that aromatase inhibitors potently
inhibit the peripheral production of estrogen and eliminate the external supply
of estrogen to the tumor cell, but that they in addition potently inhibit
intratumoral aromatase and prevent the tumor cell from making its own estrogen
within the cell. To study the inhibition of intracellular aromatase we have
compared the aromatase-inhibiting potency of the non-steroidal aromatase
inhibitors, letrozole, anastrozole and fadrozole in a variety of model cellular
endocrine and tumor systems which contain aromatase. We have used hamsters
ovarian tissue fragments, adipose tissue fibroblasts from normal human breast,
the MCF-7Ca human breast cancer cell line transfected with the human aromatase
gene and the JEG-3 human choriocarcinoma cell line. Although letrozole and
anastrozole are approximately equipotent in a cell-free aromatase system (human
placental microsomes), letrozole is consistently 10-30 times more potent than
anastrozole in inhibiting intracellular aromatase in intact rodent cells, normal
human adipose fibroblasts and human cancer cell lines. Whether these differences
between letrozole and anastrozole are seen in the clinical setting will have to
await the results of clinical trials which are currently in progress.
PMID: 11384878 [PubMed - indexed for MEDLINE]
83: Vopr Onkol 2001;47(2):195-9
[Modern approaches to hormone therapy of breast cancer as a reflection of
pathogenesis of the disease]
[Article in Russian]
Semiglazov VP.
N.N. Petrov Research Institute of Oncology, Ministry of Health of the RF, St.
Petersburg.
Experimental and epidemiological studies have pointed to a major role of
estrogens in the pathogenesis of human breast cancer. The Oxford meta-analysis
(1998) once again confirmed the efficacy of antiestrogens (tamoxifen) as
adjuvant therapy. We need to know whether the new non-steroid antiestrogens
(idoxifen, droloxifen and TAT-59) and selective estrogen receptor modulator
(raloxifen), whith preclinical characteristics better than those of tamoxifen
will be more efficient clinically. Large-scale trials to compare the new drugs
with tamoxifen are under way. Faslodex, a pure antiestrogen, looks highly
promising, too. Zoladex, a luteinising hormone-releasing hormone agonist, is
looking as a better choice than ovariectomy or irradiation of the pelvis for
ovarian ablation in premenopausal breast cancer. New aromatase inhibitors are
more efficient than progestins and much safer than aminoglutethimide. It has
been shown recently that these inhibitors keep metastatic breast cancer at bay
longer, and with longer survival. The non-steroid inhibitors (anastrozole and
letrozole) and the steroid oral drug exemestane are undergoing clinical trials
as means of adjuvant treatment of breast cancer. The trial of arimidex and
tamoxifen administered alone or in combination (ATAC) is unique since it is
using a combination of tamoxifen and an aromatase inhibitor (anastrozole). New
methods of endocrine therapy have resulted in less toxic and more convenient
procedures. Also, longer therapeutic effects and survival are becoming more
apparent.
PMID: 11383456 [PubMed - indexed for MEDLINE]
84: Clin Endocrinol (Oxf) 2001 May;54(5):563-71
Aromatase regulation and breast cancer.
Reed MJ, Purohit A.
Endocrinology and Metabolic Medicine, Imperial College School of Medicine, St
Mary's Hospital, London, UK. [email protected]
Publication Types:
Review
Review, Academic
PMID: 11380485 [PubMed - indexed for MEDLINE]
85: J Clin Oncol 2001 May 15;19(10):2596-606
Erratum in:
J Clin Oncol 2001 Jul 1;19(13):3302
Superior efficacy of letrozole versus tamoxifen as first-line therapy for
postmenopausal women with advanced breast cancer: results of a phase III study
of the International Letrozole Breast Cancer Group.
Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A,
Apffelstaedt J, Smith R, Sleeboom HP, Janicke F, Pluzanska A, Dank M, Becquart
D, Bapsy PP, Salminen E, Snyder R, Lassus M, Verbeek JA, Staffler B,
Chaudri-Ross HA, Dugan M.
Rigshospitalet, Copenhagen, Denmark.
PURPOSE: To compare the efficacy and tolerability of tamoxifen with that of
letrozole, an oral aromatase inhibitor, with tamoxifen as first-line therapy in
postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: Nine
hundred seven patients were randomly assigned letrozole 2.5 mg once daily (453
patients) or tamoxifen 20 mg once daily (454 patients). Patients had estrogen
receptor- and/or progesterone receptor-positive tumors, or both receptors were
unknown. Recurrence during adjuvant antiestrogen therapy or within the following
12 months or prior endocrine therapy for advanced disease precluded enrollment.
One prior chemotherapy regimen for metastatic disease was allowed. The primary
end point was time to progression (TTP). Secondary end points included overall
objective response rate (ORR), its duration, rate and duration of clinical
benefit, time to treatment failure (TTF), overall survival, and tolerability.
RESULTS: TTP was significantly longer for letrozole than for tamoxifen (median,
41 v 26 weeks). Treatment with letrozole reduced the risk of progression by 30%
(hazards ratio, 0.70; 95% confidence interval, 0.60 to 0.82, P =.0001). TTP was
significantly longer for letrozole irrespective of dominant site of disease,
receptor status, or prior adjuvant antiestrogen therapy. Similarly, TTF was
significantly longer for letrozole (median, 40 v 25 weeks). ORR was higher for
letrozole (30% v 20%; P =.0006), as was the rate of clinical benefit (49% v 38%;
P =.001). Survival data are currently immature and not reported here. Both
treatments were well tolerated. CONCLUSION: Letrozole was significantly superior
to tamoxifen in TTP, TTF, ORR, and clinical benefit rate. Our results support
its use as first-line endocrine therapy in postmenopausal women with advanced
breast cancer.
Publication Types:
Clinical Trial
Clinical Trial, Phase III
Multicenter Study
Randomized Controlled Trial
PMID: 11352951 [PubMed - indexed for MEDLINE]
86: Oncol Nurs Forum 2001 Apr;28(3):507-12; quiz 513-4
Erratum in:
Oncol Nurs Forum 2001 Jun;28(5):794
Metastatic breast cancer: understanding current management options.
McGinn K, Moore J.
Kaiser Permanente, South San Francisco, CA, USA. [email protected]
PURPOSE/OBJECTIVES: To review the standard treatment options for metastatic
breast cancer, present recently approved chemotherapeutic and hormonal
approaches, and describe novel biologic therapies, particularly the use of
monoclonal antibodies. DATA SOURCES: Published articles, abstracts, and
conference proceedings. DATA SYNTHESIS: Standard treatment options available to
women with metastatic breast cancer include surgery, radiation therapy, hormonal
therapy, chemotherapy, and palliative approaches. New chemotherapeutic
approaches for the management of metastatic breast cancer include the recently
approved agents paclitaxel, docetaxel, and capecitabine. New hormonal agents
such as toremifene, letrozole, and exemestane also have been approved. Finally,
an agent from a new class of agents--biologic response modifiers (BRMs)--now. Is
available. Trastuzumab, a monoclonal antibody (one class of BRMs), is a new and
promising approach available to a subpopulation of women with metastatic breast
cancer. CONCLUSION: Although standard treatment options for the management of
metastatic breast cancer may prolong survival for some, they have not resulted
in a cure for the majority of women. Recent advances in the understanding of
cancer cellular biology have led to newer approaches such as monoclonal
antibodies and other BRMs that may offer hope of extended survival and improved
quality of life for certain women. This field is growing quickly, and new
targets for breast cancer therapy are being studied. IMPLICATIONS FOR NURSING
PRACTICE: Nurses who become familiar with newer treatment options available for
the management of metastatic breast cancer, including new chemotherapeutic and
hormonal approaches and monoclonal antibody therapy, are better able to provide
information and support for their patients. Clinicians must understand the
criteria for patient selection for newer agents, particularly trastuzumab. In
addition, recognizing adverse effects and knowing the management strategies for
treatment-related toxicities help to ensure positive patient outcomes.
Publication Types:
Review
Review, Tutorial
PMID: 11338758 [PubMed - indexed for MEDLINE]
87: Placenta 2001 Apr;22(4):276-83
Developmental regulation of morphological differentiation of placental villous
trophoblast in the baboon.
Babischkin JS, Burleigh DW, Mayhew TM, Pepe GJ, Albrecht ED.
Department of Obstetrics, Center for Studies in Reproduction, The University of
Maryland School of Medicine, Baltimore, MD 21201, USA.
The present study determined whether morphological differentiation of placental
villous cytotrophoblasts into syncytiotrophoblast during primate pregnancy was
developmentally regulated and whether oestrogen has a role in this process.
Placental volumetric composition of the cytotrophoblast and syncytiotrophoblast
was determined by the test-point counting method on days 45-54, 60, 100, and 170
of gestation (term=184 days) in untreated baboons, on day 60 after placental
oestrogen production was prematurely elevated by administration of aromatizable
androstenedione or oestradiol, and on day 170 after oestrogen production was
suppressed by administration of aromatase inhibitor CGS 20267.Cytotrophoblast
and syncytiotrophoblast volumes and oestrogen levels increased (P< 0.01) with
advancing gestation. Due to the rise in syncytiotrophoblast volume (12-fold)
exceeded that of the cytotrophoblast (threefold), the mean (sem) ratio of
syncytiotrophoblast and cytotrophoblast volumes increased (P< 0.001) from 3.4
(0.5) ml on day 60 to 12.1 (2.8) ml on day 170. Androstenedione administration
elevated serum oestradiol levels threefold (P< 0.01) and increased the ratio of
syncytiotrophoblast: cytotrophoblast volumes on day 60 by 50 per cent (P< 0.03)
to that normally observed on day 100. However, the ratio of trophoblast volumes
was unaltered in oestradiol-treated and CGS 20267-treated baboons. It is
concluded that there is a developmental increase in morphological
differentiation of the placental villous trophoblast during primate pregnancy
and that androstenedione potentially via its conversion to oestrogen has a role
in this process. Copyright 2001 Harcourt Publishers Ltd.
PMID: 11286563 [PubMed - indexed for MEDLINE]
88: Curr Med Res Opin 2001;16(4):276-84
The Twenty-third Annual San Antonio Breast Cancer Symposium.
Mokbel K.
St George's Hospital, Blackshaw Road, London SW17 0QT, UK.
[email protected]
This paper reviews the recent Twenty-third Annual San Antonio Breast Cancer
Symposium. A total of 580 studies were presented either orally or as posters.
Two phase III multi-centre clinical trials found that fulvestrant (Falsodex),
given as a once-monthly intramuscular injection (250 mg), was well-tolerated and
at least as good as anastrozole (1 mg) in postmenopausal women with advanced
breast cancer that had progressed or recurred on prior endocrine therapy.
Another phase III randomised trial found that letrozole (2.5 mg daily) was
superior to tamoxifen as a neoadjuvant therapy in postmenopausal women with ER-
and/or PgR-positive breast cancer unsuitable for breast-conserving surgery. In a
phase III study, capecitabine (Xeloda) was found to be well-tolerated and able
to improve survival by three months when added to Taxotere. Cutting edge data on
microarray gene profiling in breast cancer were presented. The potential role of
this new technology in predicting outcome and selecting therapy was discussed.
Furthermore, its limitations and the need for validation were highlighted. The
role of new diagnostic tools, such as fibre-optic ductoscopy (FDS) and
microcatheters to obtain ductal cells, was discussed. Finally, the worldwide
overview was presented.
Publication Types:
Congresses
PMID: 11268712 [PubMed - indexed for MEDLINE]
89: JAMA 2001 Mar 7;285(9):1146
From the Food and Drug Administration.
Schwetz BA.
Food and Drug Administration, USA.
PMID: 11231734 [PubMed - indexed for MEDLINE]
90: Bull Cancer 2000 Dec;87 Spec No:31-39
[Aromatase inhibitors: a review of clinical trials]
[Article in French]
Kerbrat P, Lefeuvre C.
Departement d'oncologie medicale, Centre Eugene-Marquis, rue de la
Bataille-Flandres-Dunkerque, CS 44229, 35042 Rennes Cedex, France.
To increase the therapeutic index of second line hormonal treatment of breast
cancer, new aromatase inhibitors have been synthetized; they belong to two
groups: type I (formestane and exemestane) are steroidal irreversible and
specific inhibitors, type II (anastrozole, letrozole and vorozole) are non
steroidal reversible inhibitors, interfering with the aromatase heme. Several
phase II and III trials demonstrated that these drugs are, at least, as active
as aminoglutethimid or progestins in second line treatment, and are less toxic.
Recently, an identical activity have been observed for anastrozole and tamoxifen
in first line. In metastatic and adjuvant settings, large trials are ongoing to
clarify the exact value of these drugs.
Publication Types:
Review
Review Literature
PMID: 11250606 [PubMed - indexed for MEDLINE]
91: Bull Cancer 2000 Dec;87 Spec No:23-29
[Aromatase inhibitors: pharmacological aspects]
[Article in French]
de Cremoux P.
Laboratoire de physiopathologie et de pharmacologie, Institut Curie, 26, rue
d'Ulm, 75248 Paris Cedex 05, France.
Selective new aromatase inhibitors are a new class of agents that are of
considerable interest in the treatment of hormone-dependent breast cancer in
postmenopausal women. Aromatase is an enzymic complex that catalyses the
conversion of the adrenal androgens androstenedione and testosterone to estrone.
In postmenopausal women, the process of peripheral aromatisation accounts for
the majority of circulating estrogens. The selective inhibition of estrogen
production by aromatase inhibitors is an efficient strategy for breast cancer
treatment. These compounds are classified as irreversible inhibitors of
aromatase (type I), and comprise steroidal compounds. Reversible inhibitors of
aromatase, which comprises non-steroidal compounds are type II aromatase
inhibitors. Second and third generation aromatase inhibitors are considerably
more potent and more specific in their ability to inhibit aromatase, as compared
with first generation compounds (aminoglutethimide).
Publication Types:
Review
Review Literature
PMID: 11250605 [PubMed - indexed for MEDLINE]
92: Bull Cancer 2000 Dec;87 Spec No:7-22
[Preclinical evaluation of aromatase inhibitors antitumor activity]
[Article in French]
Auvray P, Bichat F, Genne P.
Oncodesign Biotechnology, Parc technologique de la Toison-d'Or, 28, rue de
Broglie, 21000 Dijon, France.
Aromatase is an enzymatic complex responsible for the conversion of androgens
into estrogens; these hormones are important in development, reproduction, but
also in the growth of estrogen-dependent cancer. This enzyme is present in
60-70% of the breast cancer. The aromatase inhibitors are important drugs in the
breast cancer treatment of postmenopausal women. In order to study their in vivo
activity, animal models have been developed, e.g. rat with tumour induced by
7,12-dimethylbenz[a]anthracene, PMSG-primed immature rat or athymic nude mice
with aromatase transfected MCF-7 xenograft. In this review, we were interested
in preclinical results obtained with both classes: steroidal and nonsteroidal
inhibitors. The former group, as substrate analogs formestane or exemestane, are
irreversible, selective and long-lasting inhibitors of aromatase. The
nonsteroidal molecules, such as letrozole or anastrozole, are reversible
inhibitors with high affinity. Finally, knowledge of the enzyme active site,
with molecular modeling and site-directed mutagenesis, could be useful to
develop new inhibitor families, more specific and potent in vivo.
Publication Types:
Review
Review Literature
PMID: 11250604 [PubMed - indexed for MEDLINE]
93: Fertil Steril 2001 Feb;75(2):305-9
Use of an aromatase inhibitor for induction of ovulation in patients with an
inadequate response to clomiphene citrate.
Mitwally MF, Casper RF.
Division of Reproductive Sciences, Samuel Lunenfeld Research Institute, Mount
Sinai Hospital, Ontario, Toronto, Canada.
OBJECTIVE: To use aromatase inhibition for induction of ovulation in women in
whom clomiphene citrate (CC) treatment was unsuccessful. DESIGN: Prospective
trial in infertility patients treated with CC. SETTING: Two tertiary-referral
infertility clinics associated with the Division of Reproductive Sciences,
University of Toronto. PATIENT(S): Twelve patients with anovulatory polycystic
ovary syndrome (PCOS) and 10 patients with ovulatory infertility, all of whom
had previously received CC with an inadequate outcome (no ovulation and/or
endometrial thickness of < or =0.5 cm). INTERVENTION(S): The aromatase inhibitor
letrozole was given orally in a dose of 2.5 mg on days 3-7 after menses. MAIN
OUTCOME MEASURE(S): Occurrence of ovulation, endometrial thickness, and
pregnancy rates. RESULT(S): With CC treatment in patients with PCOS, ovulation
occurred in 8 of 18 cycles (44.4%), and all ovulatory cycles for the women
included in this study had endometrial thickness of < or =0.5 cm. In 10
ovulatory patients, 15 CC cycles resulted in a mean number of 2.5 mature
follicles, but all cycles had endometrial thickness of < or =0.5 cm on the day
of hCG administration. With letrozole treatment in the same patients with PCOS,
ovulation occurred in 9 of 12 cycles (75%) and pregnancy was achieved in 3
patients (25%). In the 10 patients with ovulatory infertility, letrozole
treatment resulted in a mean number of 2.3 mature follicles and mean endometrial
thickness of 0.8 cm. Pregnancy was achieved in 1 patient (10%). CONCLUSION(S):
Oral administration of the aromatase inhibitor letrozole is effective for
ovulation induction in anovulatory infertility and for increased follicle
recruitment in ovulatory infertility. Letrozole appears to avoid the unfavorable
effects on the endometrium frequently seen with antiestrogen use for ovulation
induction.
Publication Types:
Clinical Trial
PMID: 11172831 [PubMed - indexed for MEDLINE]
94: J Natl Cancer Inst 2001 Feb 7;93(3):175-6
FDA panel recommends two new cancer drugs for approval.
Finkelstein JB.
Publication Types:
News
PMID: 11158184 [PubMed - indexed for MEDLINE]
95: J Clin Oncol 2001 Feb 1;19(3):881-94
Comment in:
J Clin Oncol. 2001 May 15;19(10):2767.
Aromatase inhibitors in the treatment and prevention of breast cancer.
Goss PE, Strasser K.
Division of Hematology/Oncology, Princess Margaret Hospital, Toronto, Ontario,
Canada. [email protected]
PURPOSE: The purpose of this article is to provide an overview of the current
clinical status and possible future applications of aromatase inhibitors in
breast cancer. METHODS: A review of the literature on the third-generation
aromatase inhibitors was conducted. Some data that have been presented but not
published are included. In addition, the designs of ongoing trials with
aromatase inhibitors are outlined and the implications of possible results
discussed. RESULTS: All of the third-generation oral aromatase
inhibitors--letrozole, anastrozole, and vorozole (nonsteroidal, type II) and
exemestane (steroidal, type I)--have now been tested in phase III trials as
second-line treatment of postmenopausal hormone-dependent breast cancer. They
have shown clear superiority compared with the conventional therapies and are
therefore considered established second-line hormonal agents. Currently, they
are being tested as first-line therapy in the metastatic, adjuvant, and
neoadjuvant settings. Preliminary results suggest that the inhibitors might
displace tamoxifen as first-line treatment, but further studies are needed to
determine this. CONCLUSION: The role of aromatase inhibitors in premenopausal
breast cancer and in combination with chemotherapy and other anticancer
treatments are areas of future exploration. The ongoing adjuvant trials will
provide important data on the long-term safety of aromatase inhibitors, which
will help to determine their suitability for use as chemopreventives in healthy
women at risk of developing breast cancer.
Publication Types:
Review
Review Literature
PMID: 11157042 [PubMed - indexed for MEDLINE]
96: Anticancer Drugs 2000 Oct;11(9):701-6
Survival in patients with metastatic breast cancer: analysis of randomized
studies comparing oral aromatase inhibitors versus megestrol.
Messori A, Cattel F, Trippoli S, Vaiani M.
Laboratorio SIFO di Farmacoeconomia, Centro Informazione Farmaci, Azienda
Ospedaliera Careggi, Florence, Italy. [email protected]
In patients with metastatic breast cancer, second-line therapy with aromatase
inhibitors can improve survival in comparison with megestrol. We conducted a
meta-analysis to assess the effectiveness of aromatase inhibitors versus
megestrol. After a Medline search, three trials (evaluating letrozole,
anastrozole or exemestane versus megestrol) were included in the survival
meta-analysis. Our methodology retrieved patient-level information on survival.
In comparison with megestrol, aromatase inhibitors prolonged survival at levels
of statistical significance (relative death risk for oral aromatase
inhibitors=0.79, 95% confidence interval 0.69-0.91; p=0.0011). A lifetime
analysis of the pooled survival curves of aromatase inhibitors versus megestrol
found a mean survival gain of 4.1 months per patient. Aromatase inhibitors
confer a significant survival benefit to patients with metastatic breast cancer
as compared with megestrol. A preliminary calculation of the cost per life year
gained shows that the pharmacoeconomic profile of these drugs is favorable.
Publication Types:
Meta-Analysis
PMID: 11129731 [PubMed - indexed for MEDLINE]
97: Toxicol Pathol 2000 Nov-Dec;28(6):799-801
Aromatase inhibitors prevent spontaneous granular cell tumors in the distal
female reproductive tract of Sprague-Dawley rats.
Markovits JE, Sahota PS.
Novartis Pharmaceuticals, East Hanover, New Jersey 07936, USA.
[email protected]
We recently established diagnostic criteria for granular cell changes in the
distal female reproductive tract of rats. In a review of control animals from 9
carcinogenicity studies, we found that approximately 23% of animals had granular
cell alterations. Because estrogen may play a role in the pathogenesis of
granular cell alterations, we reviewed tissue sections from carcinogenicity
studies with 2 aromatase inhibitors and found compound-related decreases in the
incidence of granular cell changes. Since these aromatase inhibitors selectively
prevent the conversion of androgenic steroids to the corresponding estrogens,
these data further suggest that estrogen may play a role in the pathogenesis of
granular cell tumors of the reproductive tract of rats.
PMID: 11127293 [PubMed - indexed for MEDLINE]
98: Expert Opin Investig Drugs 2000 Dec;9(12):2831-53
Novel strategies for systemic treatment of endometrial cancer.
Elit L, Hirte H.
Division of Gynecologic Oncology, Hamilton Regional Cancer Centre, 699
Concession Street, Hamilton, Ontario, L8V 5C2, Canada. [email protected]
The median survival of women with advanced or recurrent endometrial cancer is
less than one year. Of the women with early stage endometrial cancer and poor
prognostic factors like high grade or deep myometrial invasion, 40% will recur.
Over the last decade, incredible strides have been taken in evaluating systemic
therapy for this disease, however, survival rates remain poor. Progestin therapy
offers a 10 - 20% response rate and survival of less than one year. Progestins
are most effective in women with well-differentiated tumours and long
disease-free interval. There is no role for adjuvant progestin therapy in early
stage disease. Single-agent chemotherapy with most activity include ifosfamide,
cisplatin/carboplatin, doxorubicin and paclitaxel. Combination chemotherapy
provides a response rate of 40 - 60%, however, median survival is still less
than a year. New areas of research include the identification and evaluation of
new active endocrine therapies (i.e., LY-353381.HCl and letrozole),
chemotherapeutics (i.e., paclitaxel), evaluating chemotherapeutic agents in
combination (i.e., paclitaxel, doxorubicin and platinum), in addition to
radiation or instead of radiation. New avenues under development involve the
specific molecules and pathways responsible for the initiation and growth of
endometrial carcinoma (i.e., Herceptintrade mark). Exciting developments in the
understanding of the molecules involved in tumour development and metastasis
will allow the development of specific and selective inhibitors.
Publication Types:
Review
Review, Academic
PMID: 11093356 [PubMed - indexed for MEDLINE]
99: Eur J Cancer 2000 Sep;36 Suppl 4:S82-4
An overview of the use of non-steroidal aromatase inhibitors in the treatment of
breast cancer.
Buzdar A.
Department of Medical Oncology, The University of Texas - MD University Cancer
Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
[email protected]
A number of potent and selective non-steroidal aromatase inhibitors are now
available for the treatment of advanced breast cancer in postmenopausal women.
In particular, anastrozole represents a significant advantage over earlier
agents, such as aminoglutethimide and formestane, in terms of both efficacy and
tolerability. These agents are now established as the second-line therapy of
choice in postmenopausal women with advanced disease progressing on tamoxifen
and, furthermore, data are now available on the efficacy and tolerability of
anastrozole as first-line treatment of advanced breast cancer compared with
tamoxifen. The full potential of the new-generation aromatase inhibitors in the
treatment of breast cancer is currently being investigated in a large programme
of clinical trials, including evaluation as neoadjuvant treatment in
postmenopausal women with newly-diagnosed locally-advanced or large operable
breast cancers, as first-line treatment of advanced breast cancer in
postmenopausal women. Aromatase inhibitors have been available for over 20
years; the ability of these compounds to reduce circulating oestradiol levels
has been shown to produce clinical benefit in postmenopausal women with advanced
breast cancer. Early aromatase inhibitors, however, such as aminoglutethimide
and formestane, were not specific for the aromatase enzyme and resulted in
significant side-effects.
PMID: 11056331 [PubMed - indexed for MEDLINE]
100: Eur J Cancer 2000 Sep;36 Suppl 4:S81-2
Clinico-pharmacological aspects of different hormone treatments.
Lonning PE.
Department of Oncology, Haukeland University Hospital, N-5021, Bergen, Norway.
[email protected]
During the last decade, several new drugs and classes of drugs have become
available for breast cancer treatment. Thus, in addition to tamoxifen we have
got several new selective oestrogen receptor modulators (SERMs) with a partially
different pharmacological profile. The first generation aromatase inhibitor,
aminoglutethimide, has been replaced by more potent and less toxic inhibitors
belonging to the triazole class (anastrozole and letrozole) and, more recently,
the steroidal aromatase inactivator exemestane [1-3]. These drugs have all
revealed a better toxicity profile and, in general, an improved antitumour
activity, compared with conventional therapy. Faslodex, the first representative
of the so-called 'pure' oestrogen antagonists, has shown beneficial effects in
patients resistant to tamoxifen [4].
PMID: 11056330 [PubMed - indexed for MEDLINE]
101: Anticancer Drugs 2000 Aug;11(7):591-601
Cost-utility analysis of second-line hormonal therapy in advanced breast cancer:
a comparison of two aromatase inhibitors to megestrol acetate.
Dranitsaris G, Leung P, Mather J, Oza A.
Department of Pharmacy, Ontario Cancer Institute/Princess Margaret Hospital,
Toronto, Canada. [email protected]
Randomized trials comparing the aromatase inhibitors, anastrozole and letrozole,
to megestrol acetate (MA) in postmenopausal women with advanced breast cancer
demonstrated that both agents are better tolerated than MA with comparable
efficacy. In addition, one trial revealed that tumor response and time to
treatment failure were significantly better with letrozole. Since oncologists
are faced with a choice between three agents with at least comparable efficacy
but different toxicity profiles and cost, a cost-utility analysis was conducted
to quantify these differences and to determine if the new agents are more
cost-effective than MA. In the absence of a randomized three-arm trial, a
decision model was developed to simulate the most common therapeutic outcomes.
The clinical data were obtained from an overview analysis of randomized trials.
Total hospital resource consumption was collected from 87 patients with advanced
disease that had failed second-line hormonal therapy. Utility estimates were
obtained from interviewing a random sample of 25 women from the general public
and 25 female health care professionals using the Time Trade-Off technique. The
model suggested a similar duration of quality-adjusted progression-free survival
between drugs (letrozole 150 days, anastrozole 153 days and MA 146 days).
Letrozole had an overall cost of Can$2949 per patient which was comparable to MA
at Can$2966 per patient. In contrast, anastrozole was slightly more costly than
MA at $Can3149 per patient, respectively. The analysis revealed that letrozole
has comparable overall costs relative to MA while providing at least equivalent
quality-adjusted progression-free survival. These outcomes were largely related
to its higher tumor response rate, which translated to a lower proportion of
patients requiring chemotherapy. Anastrozole was slightly more costly than MA
and did not demonstrate superiority in quality-adjusted progression-free
survival in this palliative setting.
PMID: 11036964 [PubMed - indexed for MEDLINE]
102: Int J Oncol 2000 Nov;17(5):1037-41
New aromatase inhibitors in the treatment of advanced breast cancer.
Crucitta E, Lorusso V, Attolico M, Sambiasi D, Mazzei A, De Lena M.
Operative Unit of Medical Oncology, Oncology Institute of Bari, Bari, Italy.
New aromatase inhibitors are an exciting treatment option for postmenopausal
women with hormone sensitive breast cancer. They have been shown to reduce
tumors in a significant number of patients, and exhibit definite antitumor
activity at a relatively low daily dose, and are highly potent, highly
selective, and well-tolerated. Results from recent clinical phase III studies
have confirmed their efficacy and the key role they have in the therapy for
advanced breast cancer in postmenopausal women. The agents available for
clinical use are: letrozole, anastrozole, and exemestane. These drugs have
demonstrated high activity in women failing tamoxifen in locally advanced or
metastatic disease. This communication reviews the clinical use of aromatase
inhibitors, particularly in second and first line hormonal treatment of advanced
breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 11029510 [PubMed - indexed for MEDLINE]
103: Nippon Rinsho 2000 Apr;58 Suppl:322-7
[Aromatase inhibitors for treatment of advanced breast cancers]
[Article in Japanese]
Sonoo H.
Department of Breast & Thyroid Surgery, Kawasaki Medical School.
Publication Types:
Review
Review, Tutorial
PMID: 11026013 [PubMed - indexed for MEDLINE]
104: Rev Med Suisse Romande 2000 Jun;120(6):495-500
[Aromatase inhibitors in the treatment of breast cancer]
[Article in French]
Perey L.
Centre pluridisciplinaire d'oncologie, Lausanne.
PMID: 11014093 [PubMed - indexed for MEDLINE]
105: J Exp Clin Cancer Res 2000 Mar;19(1):17-9
Letrozole for the treatment of pretreated advanced breast cancer patients:
preliminary report.
Casali A, Sega FM, Casali M, Giuntini T, Cappellini GC, Terzoli E.
Service of Complementary Medical Oncology, Regina Elena Cancer Institute, Rome,
Italy.
Twenty patients (pts) with metastatic breast cancer with disease progression,
previously treated with chemotherapy and tamoxifen, were administered oral
letrozole (2.5 mg/day) therapy. Fifteen of the patients were postmenopausal and
5 were premenopausal. Ten were estrogen receptor (ER)-positive, 7 were unknown
and 3 were ER-negative. All the patients were assessed after 6 months (mo) of
chemotherapy. Nine pts (45%) presented a partial response (PR), five (25%) had a
stable disease (SD) and six (30%) had a progressive disease (PD). In the pts
with PD, six out of 15 (33%) obtained a PR while undergoing tamoxifen therapy.
The treatment caused no significant toxicity.
PMID: 10840931 [PubMed - indexed for MEDLINE]
106: J Clin Oncol 2000 Apr;18(8):1802-3
Comment on:
J Clin Oncol. 1998 Feb;16(2):453-61.
J Clin Oncol. 1999 Dec;17(12):3856-60.
Letrozole: which dose to be used?
Buzdar AU, Chaudri HA, Trunet PF.
Publication Types:
Comment
Letter
PMID: 10764444 [PubMed - indexed for MEDLINE]
107: Crit Rev Oncol Hematol 2000 Feb;33(2):137-42
Steroidal aromatase inhibitors in elderly patients.
Bajetta E, Zilembo N, Bichisao E, Pozzi P, Toffolatti L.
Division of Medical Oncology, Istituto Nazionale per lo Studio e la Cura dei
Tumori, Milan, Italy.
The choice of treatment for elderly breast cancer patients needs particular care
because the presence of physiological functional impairments can modify the drug
bioavailability in an unpredictable manner. Hormonal treatment remains one of
the choices and, although tamoxifen has proved to be effective in any setting,
the use of selective aromatase inhibitors is arousing. Depending on their
chemical structure, aromatase inhibitors are either steroidal (such as
exemestane and formestane) or non-steroidal (such as letrozole, vorozole and
anastrozole). Formestane has been studied in elderly patients with breast cancer
and has been found to induce an overall response rate of 51% (95% CI, 35-67%).
The drug suppresses estradiol (E2) levels, and changes in other hormones (FSH,
LH and SHBG) are observed, but with poor clinical significance, thus confirming
its selectivity and potency. Formestane has also been demonstrated to be as
effective as tamoxifen. Exemestane and non-steroidal aromatase inhibitors appear
to be very promising drugs.
Publication Types:
Review
Review, Tutorial
PMID: 10737375 [PubMed - indexed for MEDLINE]
108: Endocr Relat Cancer 1999 Mar;6(1):75-92
Use of aromatase inhibitors in breast carcinoma.
Santen RJ, Harvey HA.
Department of Medicine, University of Virginia Health Sciences Center,
Charlottesville 22908, USA.
Aromatase, a cytochrome P-450 enzyme that catalyzes the conversion of androgens
to estrogens, is the major mechanism of estrogen synthesis in the
post-menopausal woman. We review some of the recent scientific advances which
shed light on the biologic significance, physiology, expression and regulation
of aromatase in breast tissue. Inhibition of aromatase, the terminal step in
estrogen biosynthesis, provides a way of treating hormone-dependent breast
cancer in older patients. Aminoglutethimide was the first widely used aromatase
inhibitor but had several clinical drawbacks. Newer agents are considerably more
selective, more potent, less toxic and easier to use in the clinical setting.
This article reviews the clinical data supporting the use of the potent, oral
competitive aromatase inhibitors anastrozole, letrozole and vorozole and the
irreversible inhibitors 4-OH androstenedione and exemestane. The more potent
compounds inhibit both peripheral and intra-tumoral aromatase. We discuss the
evidence supporting the notion that aromatase inhibitors lack cross-resistance
with antiestrogens and suggest that the newer, more potent compounds may have a
particular application in breast cancer treatment in a setting of adaptive
hypersensitivity to estrogens. Currently available aromatase inhibitors are safe
and effective in the management of hormone-dependent breast cancer in
post-menopausal women failing antiestrogen therapy and should now be used before
progestational agents. There is abundant evidence to support testing these
compounds as first-line hormonal therapy for metastatic breast cancer as well as
part of adjuvant regimens in older patients and quite possibly in
chemoprevention trials of breast cancer.
Publication Types:
Review
Review, Academic
PMID: 10732791 [PubMed - indexed for MEDLINE]
109: Endocr Relat Cancer 1999 Jun;6(2):307-14
Aromatase overexpression and breast hyperplasia, an in vivo model--continued
overexpression of aromatase is sufficient to maintain hyperplasia without
circulating estrogens, and aromatase inhibitors abrogate these preneoplastic
changes in mammary glands.
Tekmal RR, Kirma N, Gill K, Fowler K.
Department of Gynecology and Obstetrics, Emory University School of Medicine,
Atlanta, Georgia 30322-4710, USA.
To test directly the role of breast-tissue estrogen in initiation of breast
cancer, we have developed the aromatase-transgenic mouse model and demonstrated
for the first time that increased mammary estrogens resulting from the
overexpression of aromatase in mammary glands lead to the induction of various
preneoplastic and neoplastic changes that are similar to early breast cancer.
Continued overexpression of aromatase that leads to increased breast-tissue
estrogen contributes to a number of epigenetic changes in mammary tissue such as
alteration in the regulation of genes involved in apoptosis, activation of genes
involved in cell cycle and cell proliferation, and activation of a number of
growth factors. Our current studies show aromatase overexpression is sufficient
to induce and maintain early preneoplastic and neoplastic changes in female mice
without circulating ovarian estrogen. Preneoplastic and neoplastic changes
induced in mammary glands as a result of aromatase overexpression can be
completely abrogated with the administration of the aromatase inhibitor,
letrozole. Consistent with complete reduction in hyperplasia, we have also seen
downregulation of estrogen receptor and a decrease in cell proliferation
markers, suggesting aromatase-induced hyperplasia can be treated with aromatase
inhibitors. Our studies demonstrate that aromatase overexpression alone, without
circulating estrogen, is responsible for the induction of breast hyperplasia and
these changes can be abrogated using aromatase inhibitors.
PMID: 10731124 [PubMed - indexed for MEDLINE]
110: Endocr Relat Cancer 1999 Jun;6(2):265-9
Combination hormonal therapy involving aromatase inhibitors in the management of
women with breast cancer.
Ingle JN, Suman VJ, Jordan VC, Dowsett M.
Mayo Clinic, Rochester, Minnesota 55905, USA.
Numerous comparative clinical trials have been conducted evaluating combination
hormonal therapy involving the aromatase inhibitor aminoglutethimide, but there
is no evidence for any superiority of this approach over single-agent therapy
alone. The advent of new aromatase inhibitors with greater potency, selectivity,
and better tolerability has prompted a reconsideration of the combined therapy
approach, with attention being focused on pharmacologic and endocrinologic
clinical research. The value of combining newer aromatase inhibitors with other
hormonal agents remains to be established.
Publication Types:
Review
Review, Tutorial
PMID: 10731119 [PubMed - indexed for MEDLINE]
111: Endocr Relat Cancer 1999 Jun;6(2):259-63
Aromatase inhibitors and their use in the sequential setting.
Coombes RC, Harper-Wynne C, Dowsett M.
Cancer Research Campaign, Department of Cancer Medicine, Imperial College School
of Medicine, Charing Cross Hospital, London, UK.
Over the past decade several novel aromatase inhibitors have been introduced
into clinical practice. The discovery of these drugs followed on from the
observation that the main mechanism of action of aminogluthemide was via
inhibition of the enzyme aromatase thereby reducing peripheral levels of
oestradiol in postmenopausal patients. The second-generation drug,
4-hydroxyandrostenedione (formestane), was introduced in 1990 and although its
use was limited by its need to be given parenterally it was found to be a
well-tolerated form of endocrine therapy. Third-generation inhibitors include
vorozole, letrozole, anastrozole and exemestane, the former three being
non-steroidal inhibitors, the latter being a steroidal inhibitor. All are
capable of inhibiting aromatase action by >95% compared with 80% in the case of
4-hydroxyandrostenedione. The sequential use of different generations of
aromatase inhibitors in the same patients is discussed. Studies suggest that an
optimal sequence of these compounds may well result in longer remission in
patients with hormone receptor positive tumours.
Publication Types:
Review
Review, Tutorial
PMID: 10731118 [PubMed - indexed for MEDLINE]
112: Endocr Relat Cancer 1999 Jun;6(2):245-9
Aromatase inhibitors: a dose-response effect?
Smith IE.
Section of Medicine, Royal Marsden Hospital and Institute of Cancer Research,
London, UK.
Publication Types:
Review
Review, Tutorial
PMID: 10731116 [PubMed - indexed for MEDLINE]
113: Endocr Relat Cancer 1999 Jun;6(2):231-4
Use of aromatase inhibitors in the adjuvant treatment of breast cancer.
Baum M.
Institute of Surgical Studies, University College London, UK.
The value of endocrine treatment of early breast cancer has been illustrated by
the antioestrogen, tamoxifen, which has now been available for nearly 30 years.
However, if the recognised side effects and pharmacological properties of
tamoxifen are taken into consideration, it is possible that other endocrine
treatments that are now available can provide equal or superior efficacy, along
with improved tolerability. One such group of agents is the aromatase inhibitors
specifically the new-generation triazole aromatase inhibitors, such as
anastrozole and letrozole, which have both shown tolerability and efficacy
advantages over standard treatments in postmenopausal women with advanced breast
cancer. There are convincing reasons why the new generation of aromatase
inhibitors have advantages over tamoxifen. For instance, from their agonist
properties, the effects on the endometrium and tumour stimulation seen with
tamoxifen would not be expected, nor would the visual disturbances that have
been associated with the triphenylethylene compounds, including tamoxifen. A
number of aromatase inhibitors, for instance, anastrozole, letrozole and
exemestane, are currently being investigated for treatment of early breast
cancer. The results of the trials of aromatase inhibitors and tamoxifen will, in
the next few years, define whether or not the new-generation aromatase
inhibitors have a role to play in the treatment of postmenopausal women with
early breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 10731114 [PubMed - indexed for MEDLINE]
114: Endocr Relat Cancer 1999 Jun;6(2):227-30
Lessons from the use of aromatase inhibitors in the neoadjuvant setting.
Dixon JM, Love CD, Renshaw L, Bellamy C, Cameron DA, Miller WR, Leonard RC.
Edinburgh Breast Unit, Western General Hospital, UK.
Postmenopausal patients with oestrogen receptor-positive locally advanced T4b,
N0-1, M0 and large operable breast cancers T2>3 cm, T3, T4, N0-1 and M0 have
been treated with 2.5 mg letrozole (12 patients), 10 mg letrozole (12 patients),
1 or 10 mg anastrozole (24 patients) and 20 mg tamoxifen (65 patients). There
was no apparent difference in response rate between 2.5 and 10 mg letrozole.
Only 17 patients with anastrozole have so far completed the 3-month treatment
period. Median clinical, mammographic and ultrasound reductions in tumour
volumes for patients treated with letrozole were 81% (95% confidence interval
(CI) 66-88), 77% (95% CI 64-82) and 81% (95% CI 69-86) respectively and for
anastrozole, values were 87% (95% CI 59-97), 73% (95% CI 58-82) and 64% (95% CI
52-76) respectively. This compares with a median reduction in tumour volume for
tamoxifen-treated patients as assessed by ultrasound of 48% (95% CI 27-48).
There were seven complete clinical responses (CR), sixteen patients who achieved
50% or greater reduction in tumour volume (PR) and one no change (NC) for
letrozole and four CRs, twelve PRs and one progressive disease for anastrozole.
Best radiological responses were one CR, twenty PRs and three NCs for letrozole
and one CR, fifteen PRs and one NC for anastrozole. This study has shown that
the new aromatase inhibitors, letrozole and anastrozole, are highly effective
agents in the neoadjuvant setting and they should now be compared with tamoxifen
as first-line treatment in a randomised study.
Publication Types:
Review
Review, Tutorial
PMID: 10731113 [PubMed - indexed for MEDLINE]
115: Endocr Relat Cancer 1999 Jun;6(2):219-25
Role of aromatase inhibitors in advanced breast cancer.
Buzdar AU.
Department of Medical Oncology, The University of Texas, MD Anderson University
Cancer Center, Houston 77030, USA.
A number of potent and selective non-steroidal aromatase inhibitors are now
available for treatment of advanced breast cancer in postmenopausal women, of
which anastrozole and letrozole, in particular, represent a significant
advantage over the earlier agents in terms of both efficacy and tolerability.
These agents are rapidly becoming established as the second-line therapy of
choice in postmenopausal women with advanced disease, progressing on tamoxifen,
and data on their efficacy as first-line treatment compared with tamoxifen will
be available in the near future. Exemestane, a new, steroidal aromatase
inhibitor which potentially lacks cross-resistance with non-steroidal agents is
still in clinical development. The full potential of the new-generation
aromatase inhibitors in the treatment of breast cancer is currently being
investigated in a large program of clinical trials evaluating their use as
adjuvant treatment following surgery in postmenopausal patients with early
disease.
Publication Types:
Review
Review, Tutorial
PMID: 10731112 [PubMed - indexed for MEDLINE]
116: Endocr Relat Cancer 1999 Jun;6(2):205-10
Aromatase inhibitors and their antitumor effects in model systems.
Brodie A, Lu Q, Liu Y, Long B.
Department of Pharmacology and Experimental Therapeutics, and Greenebaum Cancer
Center, School of Medicine, University of Maryland, Baltimore 21201, USA.
The potential of aromatase (estrogen synthetase) within the breast to provide a
significant source of estrogen mediating tumor proliferation is suggested by
studies reporting 4- to 6-fold higher estrogen levels in tumors than in plasma
of postmenopausal patients with breast cancer. Recent studies in our laboratory
have identified aromatase and its mRNA in tumor epithelial cells using
immunocytochemistry and in situ hybridization. In addition, significant
aromatase activity, which was stimulated 7-fold by dexamethasone, was measured
in metastatic cells isolated from a breast cancer patient. Increase in
proliferation, as measured by proliferating cell nuclear antigen immunostaining
in tumor sections and by thymidine incorporation into DNA in response to
testosterone, was observed in histocultures of breast cancer samples. This
latter effect could be inhibited by 4-hydroxyandrostenedione. These results
imply that intratumoral aromatase has functional significance and may be an
important target for successful inhibitor treatment of breast cancer patients.
To investigate treatment strategies with aromatase inhibitors and antiestrogens,
we developed an intratumoral aromatase model to simulate the hormone responsive
postmenopausal breast cancer patient. Tumors of estrogen receptor positive human
breast carcinoma cells (MCF-7) transfected with the human aromatase gene are
grown in ovariectomized nude mice. These cells synthesize sufficient estrogen to
stimulate tumor formation. We have utilized this model to investigate the
effects on tumor growth of the antiestrogens, tamoxifen and ICI 182780, and the
aromatase inhibitors, letrozole and anastrozole (arimidex), alone and in
combination. Both the aromatase inhibitors and the antiestrogens were effective
in suppressing tumor growth. However, letrozole was significantly more effective
than the antiestrogens. When the aromatase inhibitors were combined with the
antiestrogen, tamoxifen, tumor growth was suppressed to about the same extent as
with the aromatase inhibitors alone. Furthermore, the results do not suggest any
benefit from combining tamoxifen with the pure antiestrogen, ICI 182780. Thus
sequential use of these agents is likely to be more advantageous to the patient
in terms of longer duration of effective treatment.
PMID: 10731110 [PubMed - indexed for MEDLINE]
117: Endocr Relat Cancer 1999 Jun;6(2):187-95
Biology of aromatase inhibitors: pharmacology/endocrinology within the breast.
Miller WR.
Breast Research Unit, Western General Hospital, Edinburgh, UK.
Both mammary adipose tissue and breast cancers have the ability to aromatize
androgens into oestrogens. Such potential may maintain the growth of
hormone-dependent tumours. It has therefore been important to determine the
effects of new aromatase inhibitors such as formestane, exemestane, anastrozole
and letrozole on oestrogen biosynthesis and concentrations of endogenous
hormones within the breast. Studies based on in vitro incubations of breast
cancer and cultures of mammary adipose tissue fibroblasts demonstrate that these
drugs are highly effective inhibitors, with IC50 values ranging between 1 and 50
nM (although the relative efficacy varies between tissues and test systems).
Despite this potential, in vitro incubations of breast tissues from patients
treated with type II inhibitors such as aminoglutethimide and letrozole can
display paradoxically high aromatase activity; this appears to be caused by the
reversible nature of the inhibition, coupled with induction/stabilization of the
aromatase enzyme. To assess in situ effects within the breast, postmenopausal
women with large primary breast cancers have been treated neoadjuvantly with
aromatase inhibitors using a protocol that included (i) breast biopsy before
treatment, (ii) definitive surgery after 3 months of treatment and (iii)
infusion of [3H]androstenedione and [14C]oestrone in the 18 h immediately before
biopsy and surgery. With this study design, it has been shown that drugs such as
letrozole profoundly inhibit in situ aromatase activity and reduce endogenous
oestrogens within the breast.
PMID: 10731108 [PubMed - indexed for MEDLINE]
118: Endocr Relat Cancer 1999 Jun;6(2):181-5
Drug and hormone interactions of aromatase inhibitors.
Dowsett M.
Academic Department of Biochemistry, The Royal Marsden NHS Trust, London, UK.
The clinical development of aromatase inhibitors has been largely confined to
postmenopausal breast cancer patients and strongly guided by pharmacological
data. Comparative oestrogen suppression has been helpful in circumstances in
which at least one of the comparitors has caused substantially non-maximal
aromatase inhibition. However, the triazole inhibitors, letrozole and
anastrozole, and the steroidal inhibitor, exemestane, all cause >95% inhibition.
Comparisons between these drugs therefore require more sensitive approaches such
as the direct measurement of enzyme activity by isotopic means. None of these
three agents has significant effects on other endocrine pathways at its
clinically applied doses. Pharmacokinetic analyses of the combination of
tamoxifen and letrozole have revealed that these drugs interact, resulting in
letrozole concentrations approximately 35-40% lower than when letrozole is used
alone.
Publication Types:
Review
Review, Tutorial
PMID: 10731107 [PubMed - indexed for MEDLINE]
119: Steroids 2000 Apr;65(4):171-9
Aromatase inhibitors and their application in breast cancer treatment*.
Brodie AM, Njar VC.
Department of Pharmacology, School of Medicine, University of Maryland, 685 West
Baltimore Street, Baltimore, MD, USA. [email protected]
Estrogens are known to be important in the growth of breast cancers in both pre-
and postmenopausal women. The number of breast cancer patients with
hormone-dependent disease increases with age, as does the incidence of breast
cancer. Although estrogens are no longer made in the ovaries after menopause,
peripheral tissues produce sufficient concentrations to stimulate tumor growth.
Because aromatase catalyzes the rate-limiting step in the biosynthesis of
estrogen, inhibitors of this enzyme have been developed in the last few years as
a logical treatment strategy. Two classes of aromatase inhibitors, steroidal and
nonsteroidal compounds, are now in use. Among the steroid substrate analogs,
formestane and examestane have been shown to be effective in breast cancer
patients with advanced disease. Highly potent and selective nonsteroidal
inhibitors have recently been found to suppress plasma and urinary estrogens by
more than 95% in breast cancer patients. Two of these compounds recently were
approved in the United States and have been shown to be more effective than
other second-line agents in terms of overall response rates and treatment
failure, as well as better tolerated. Although studies of the efficacy of these
agents in earlier stage disease are awaited, it is evident that aromatase
inhibitors can extend the duration of treatment in breast cancer patients.
Publication Types:
Review
Review, Tutorial
PMID: 10713305 [PubMed - indexed for MEDLINE]
120: Am J Obstet Gynecol 2000 Feb;182(2):432-8
The role of estrogen in the maintenance of primate pregnancy.
Albrecht ED, Aberdeen GW, Pepe GJ.
Department of Obstetrics, Gynecology, and Reproductive Sciences, Center for
Studies in Reproduction, the University of Maryland School of Medicine,
Baltimore 21201, USA.
OBJECTIVE: The aim of this study was to determine the role of estrogen in
pregnancy maintenance in baboons by suppressing estrogen synthesis through
administration of a highly specific nonsteroidal aromatase inhibitor, CGS 20267.
STUDY DESIGN: CGS 20267 was administered subcutaneously at maximal dosages of
2.0 mg/d to pregnant baboons (n = 24) daily beginning on either day 30 (n = 8),
day 60 (n = 8), or day 100 (n = 8) of gestation (normal length of gestation is
184 days) until animals miscarried or were delivered abdominally on days 160
through 168 of gestation. CGS 20267 and estradiol (n = 9), each at maximal
dosages of 2 mg/d, were administered at the same intervals of gestation. Twenty
baboons served as untreated control animals. Serum estradiol and progesterone
levels were determined by radioimmunoassay from serum samples obtained at 1- to
3-day intervals from a maternal peripheral vein. RESULTS: Within 1 to 3 days of
the initiation of CGS 20267 administration, maternal serum estradiol
concentration decreased to and remained at a level that was substantially lower
(mean +/- SE, 0. 096 +/- 0.003 ng/mL) than in the untreated control animals
throughout gestation (0.35-4.0 ng/mL; P <.001). Although pregnancy was
maintained in 19 of the 20 untreated control baboons (95%), only 12 of the 24
animals that received CGS 20267 (50%) maintained pregnancy. In contrast, all the
baboons treated concomitantly with estradiol and CGS 20267 (9/9) maintained
pregnancy. Thus estradiol alone prevented the high rate of miscarriage induced
by the antiestrogenic agent CGS 20267. Serum progesterone concentrations were
not significantly different throughout the experimental period between the CGS
20267-treated baboons that maintained pregnancy (12. 9 +/- 1.4 ng/mL) and those
that miscarried (13.6 +/- 1.6 ng/mL) and were not lower in antiestrogen-treated
baboons than in untreated control baboons (10.6 +/- 0.8 ng/mL). CONCLUSION:
Estrogen, acting directly, indirectly, or both through a factor or factors other
than the level of progesterone, plays a critically important physiologic role in
the maintenance of primate pregnancy.
PMID: 10694348 [PubMed - indexed for MEDLINE]
121: Vopr Onkol 1999;45(5):504-10
[Aromatase gene expression and its modifying factors in breast tumor tissue]
[Article in Russian]
Berstein LM, Larionov AA, Pauley RJ, Chernitsa OI, Semiglazov VF, Yue W,
Edamatsu Kh, Ito Kh, Santen R.
N.N. Petrov Research Institute of Oncology, St. Petersburg, Russia.
Aromatase (CYP 19) gene expression was studied in 70 breast tumors. When
RNA-dot-blot or rt-polymerase chain reaction were used expression frequency was
60.4 and 91.7%, respectively. An analysis of individual variants of non-coding
exon of aromatase gene confirmed that, unlike normal mammary tissue, tumor
switched from activation of exon I.4 ("sensitive" to glucocorticoids) to exons
II ("sensitive" to cAMP) or I.3. This difference was relatively somewhat more
pronounced in the Russian material. Direct correlation between aromatase
enzymatic activity and expression of exons II and I.3 in tumor tissue appeared
more significant than that of aromatase gene coding site. An evaluation of the
expression of adenylate cyclase G-protein alpha-subunit genes established an
inverse correlation between expression of Gi2a and exon I.3. Breast tumors with
elevated basal aromatase activity were more sensitive to aromatase inhibitors
(letrozole, 4-OHA) in vitro although no relationship between use of CYP19
(aromatase) 5' exon variant and in vitro inhibition of aromatase was detected. A
correlation was observed between expression of aromatase gene and variants of
its 5' exon, on the one hand, and age, tumor grade, steroid receptor presence
and tumor lymphocytic infiltration, on the other. To summarize, local estrogen
production in breast tumor tissue is regulated by a wide range of factors
expression both aromatase gene influencing and its enzymatic activity, thus
providing leverage on both.
PMID: 10629706 [PubMed - indexed for MEDLINE]
122: Pharmacoeconomics 1999 Oct;16(4):379-97
Cost effectiveness of letrozole in the treatment of advanced breast cancer in
postmenopausal women in the UK.
Nuijten M, Meester L, Waibel F, Wait S.
MEDTAP, Amsterdam, The Netherlands. [email protected]
OBJECTIVE: To simulate the treatment of postmenopausal women with advanced
breast cancer from second-line hormone therapy to death, and to generate
estimates of the cost and effectiveness of letrozole and megestrol in order to
determine the incremental cost effectiveness of letrozole, expressed as cost per
life-years gained. DESIGN: A decision-analytic model, using Markov process
techniques, was designed to evaluate the lifetime clinical and economic
consequences of treatment with letrozole compared with standard care with
megestrol. The model was based on clinical trial results showing a clear
advantage of letrozole in terms of time to progression and duration of response.
SETTING: The setting of the study was that of the UK healthcare system in 1996.
PATIENTS AND PARTICIPANTS: A hypothetical cohort of patients, identical to the
patients recruited for the AR/BC2 clinical trial, who were postmenopausal women
with advanced breast cancer who had previously failed to respond to first-line
or adjuvant anti-estrogen therapy. INTERVENTIONS: The dosages of medications
were 2.5 and 160 mg/day for letrozole and megestrol, respectively. The analysis
covered the period from treatment initiation until death (lifetime model).
Effectiveness was expressed as survival and time without progression, and the
model also included all relevant economic measures. MAIN OUTCOME MEASURES AND
RESULTS: Based on the model, the average survival time of the letrozole group
was 2.1 years (25.3 months) versus 1.9 years (21.5 months) for the megestrol
group, a gain in survival of 2.4 months (10.5%). The average time without
progression, cumulatively calculated over the different treatment options,
amounted to 20.2 months for letrozole and 17.8 months for megestrol, an increase
of 13.7% for the former patients. The total average cost per patient for the
treatment of advanced breast cancer starting from second-line hormone therapy
until death was higher in the letrozole group at 7547 Pounds versus 6820 Pounds
for the megestrol group (discounted at an annual rate of 5%), leading to an
incremental cost-effectiveness ratio of 3588 Pounds per life-year gained (1996
values). CONCLUSIONS: Based on the assumptions used in this model, letrozole
offers a suitable alternative to megestrol in the treatment of second-line
hormone therapy.
PMID: 10623366 [PubMed - indexed for MEDLINE]
123: Breast Cancer Res Treat 1999 Sep;57(2):183-92
The effect of combining aromatase inhibitors with antiestrogens on tumor growth
in a nude mouse model for breast cancer.
Lu Q, Liu Y, Long BJ, Grigoryev D, Gimbel M, Brodie A.
Department of Pharmacology and Experimental Therapeutics, University of
Maryland, School of Medicine, Baltimore 21201, USA.
We have previously established a model for postmenopausal, hormone-dependent
breast cancer in nude mice which is responsive to both antiestrogens and
aromatase inhibitors. In this model, MCF-7 human breast carcinoma cells
transfected with the aromatase gene (MCF-7CA) synthesize sufficient estrogen to
form tumors in ovariectomized nude mice. In the present study we used this
intratumoral aromatase model to investigate the effects on tumor growth of the
new nonsteroidal aromatase inhibitors letrozole (CGS 20,267) and anastrozole (ZD
1033) and the antiestrogens tamoxifen (ICI 47,474) and faslodex (ICI 182,780).
Furthermore, we determined whether the inhibition of estrogen synthesis together
with inhibition of estrogen action would be more effective in controlling breast
tumor growth. The results of our studies indicate that the aromatase inhibitors
anastrozole and letrozole, as well as the new pure antiestrogen faslodex, have
potent antitumor effects in the mouse model. In the treatment of mice with
mammary tumors, letrozole was more effective in suppressing tumor growth than
anastrozole. This was consistent with the Ki values of these inhibitors against
placental aromatase and the IC50 values in cell culture (MCF-7CA), which
indicated the greater potency of letrozole as an aromatase inhibitor. Letrozole
also had greater antitumor effects than tamoxifen and faslodex. The antitumor
effect of letrozole was substantial, making it difficult to detect any
additional effect on the tumors when letrozole was combined with the
antiestrogens. However, the combined treatment of anastrozole + tamoxifen and
anastrozole + faslodex also did not increase efficacy compared to the aromatase
inhibitor alone. In addition, combining the two antiestrogens did not suppress
tumor growth more effectively than faslodex alone. Our results show that
treatment with the combinations of aromatase inhibitors with either tamoxifen or
faslodex are not more effective in blocking estrogen stimulation of tumor growth
than the aromatase inhibitors alone.
PMID: 10598045 [PubMed - indexed for MEDLINE]
124: Drugs Aging 1999 Oct;15(4):271-83
Aromatase inhibitors in the treatment of postmenopausal breast cancer.
Bajetta E, Zilembo N, Bichisao E.
Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
[email protected]
Anastrozole, letrozole and vorozole are new aromatase inhibitors with a
nonsteroidal structure (NSS), and have been demonstrated to be highly effective
and better tolerated than standard endocrine therapy with megestrol (megestrol
acetate) and aminoglutethimide (AG). These agents are very potent and selective:
all of them are capable of suppressing estrone (E1) and estradiol (E2) to the
limit of sensitivity methods, and plasma estrone sulfate (E1S) levels are also
suppressed. However, the fact that this potency has not led to any greater
clinical efficacy, and that there is no relationship between estrogen
suppression and clinical response, suggests that aromatase inhibitors may have
additional mechanisms of action. A number of international, multicentre clinical
trials have compared anastrozole, letrozole and vorozole with megestrol 160
mg/day or AG 500 mg/day plus hydrocortisone in patients with advanced breast
cancer. Letrozole proved to be significantly more effective than megestrol but
anastrozole had a greater effect on survival than either agent. However,
letrozole therapy led to longer survival than that observed in patients treated
with AG. The activity of vorozole was similar to that of megestrol and AG. These
results have raised a number of questions. The first is how should the clinical
results be evaluated, given that 'disease stabilisation lasting > or =6 months'
has been considered a response? The second is how should these drugs be used,
and whether there is a rationale for using them in combination or sequentially
in the treatment of patients with advanced breast cancer? Finally, is the
possible effect of formestane and vorozole on intratumoral aromatase an
alternative or concomitant mechanism of action? Anastrozole, letrozole and
vorozole will be compared with tamoxifen in postmenopausal patients with breast
cancer in adjuvant and primary settings. However, we feel that concomitant
biological and clinical studies should also be carried out in order to clarify
the properties of these drugs and avoid possible risks for patients over time.
Publication Types:
Review
Review, Tutorial
PMID: 10582774 [PubMed - indexed for MEDLINE]
125: J Clin Oncol 1999 Dec;17(12):3856-60
Comment in:
J Clin Oncol. 2000 Apr;18(8):1802-3.
Comment on:
J Clin Oncol. 1998 Feb;16(2):453-61.
Letrozole: updated duration of response.
Chaudri HA, Trunet PF.
Publication Types:
Comment
Letter
PMID: 10577865 [PubMed - indexed for MEDLINE]
126: Bull Cancer 1999 Oct;86(10):821-7
[Aromatase inhibitors]
[Article in French]
Feutrie ML, Bonneterre J.
Hopital civil d'Armentieres, 112, rue Sadi-Carnot, 59285 Armentieres.
Aromatase inhibitors used in breast cancer, are drugs that inhibit the
transformation of androstenedione and testosterone, respectively in estradiol
and estrone. Two classes have been described: steroidal inhibitors which act
competitively and irreversibly and non steroidal inhibitors which block the P
450 cytochrome. The first one is aminoglutethimide which has an adrenal effect
on 11, 18 and 21 hydroxylase. Rogletimide, less powerful and less specific is a
aminoglutethimide analogue. The response rates obtained with formestane is not
different. The clinical development has been stopped due to a lack of
specificity. Letrozole, vorozole, exemestane and anastrozole are more powerful
and more specific. Letrozole and vorozole are at least as efficient and better
tolerated than aminoglutethimide. Anastrozole, letrozole and vorozole are at
least as efficient as megestrol acetate and better tolerated in advanced breast
cancer patients receiving a second line hormone therapy.
Publication Types:
Review
Review, Tutorial
PMID: 10572233 [PubMed - indexed for MEDLINE]
127: Vopr Onkol 1999;45(4):361-8
[Letrozole (Femara), a new aromatase inhibitor for advanced breast cancer]
[Article in Russian]
Gershanovich M, Chaudri Kh, Campos D, Lurie H, Bonaventura A, Jeffrey M, Buzzi
F, Bodrogi I, Ludwig H, Reichard P, O'Higgins NO, Romieu G, Friedrich P, Lassus
M.
N.N. Petrov Research Institute of Oncology, Ministry of Health of the RF, St.
Petersburg, Russia.
The study compares letrozole (Femara and aminoglutethimide (AG), a standard
therapy for postmenopausal women with advanced breast cancer, previously treated
with anti-estrogens. 555 women were randomly assigned letrozole 2.5 mg once
daily (n = 185), letrozole 0.5 mg once daily (n = 192) or aminoglutethimide 250
mg twice daily with corticosteroid support (n = 178) in an open-label,
multicenter trial. The primary end-point was objective response rate (ORR), with
time events as secondary. ORR was analysed nine months after enrollment of the
last patient, while survival was analysed 15 months after the last patients was
enrolled. We report the results of these analyses plus an extended period of
observation (covering a total duration of approximately 45 months) to determine
the duration of response and clinical benefit. Overall objective response rates
(complete + partial) of 19.5%, 16.7% and 12.4% were seen for letrozole 2.5 mg,
0.5 mg and AG respectively. Median duration of response and stable disease was
longest for letrozole 2.5 mg (21 months) compared with letrozole 0.5 mg (18
months) and AG (14 months). Letrozole 2.5 mg was superior to AG in time to
progression, time to treatment failure and overall survival. Treatment-related
adverse events occurred in fewer patients on letrozole (33%) than on AG (46%).
Letrozole 2.5 mg offers longer disease control than aminoglutethimide and
letrozole 0.5 mg in the treatment of postmenopausal women with advanced breast
cancer, previously treated with anti-estrogens.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 10532092 [PubMed - indexed for MEDLINE]
128: J Steroid Biochem Mol Biol 1999 Jul-Aug;70(1-3):89-95
Rainbow trout, Oncorhynchus mykiss, as a model for aromatase inhibition.
Shilling AD, Carlson DB, Williams DE.
Department of Environmental and Molecular Toxicology and Marine/Freshwater
Biomedical Sciences Center, Oregon State University, Corvallis, 97331-6601, USA.
The feasibility of utilizing rainbow trout, Oncorhynchus mykiss, as an
alternative model for studying the inhibition of aromatase (CYP 19) was
investigated. The suppression of estrogen-dependent tumors by aromatase
inhibitors has been important in the treatment of breast cancer. Estrogens,
estrogen precursors and xenoestrogens have been found to promote liver cancer in
the trout model. A steroid, 4-hydroxy-4-androstene-3,17-dione (4-OHA), and
non-steroids, aminoglutethimide (AG) and Letrozole (CGS 20267), all of which are
known aromatase inhibitors in rats and humans, were examined in vitro for
activity in trout ovarian microsomes. Aromatase activity was quantified as the
release of 3H2O from the conversion of [3H]-4-androstene-3,17-dione to
17beta-estradiol and estrone. Trout ovarian microsomes exhibited activity
between 39-60 fmol mg(-1) min(-1) with a calculated Vmax of 71.1 fmol mg(-1)
min(-1) when incubated at 25 degrees C with 200 nM 4-androstene-3,17-dione (K(M)
= 435 nM). Significant inhibition by 4-OHA up to 80% was seen at 1.5 microM. At
2000 microM, AG decreased aromatase activity by up to 82%. Letrozole reduced
aromatase activity a maximum of 90% in a dose-dependent manner, but the Ki (2.3
microM) was 1000-fold higher than reported in human trials. Indole-3-carbinol
and some of its derivatives, two DDE isomers and four flavones (except
alpha-naphthoflavone) at 1000 microM did not significantly inhibit aromatase in
vitro. Letrozole and clotrimazole, fed to juvenile rainbow trout at doses up to
1000 ppm for 2 weeks, were not effective in suppressing dehydroepiandrosterone
(DHEA) induced increases in vitellogenin and 17beta-estradiol levels. These
results document that trout aromatase is sensitive to inhibition in vitro by
known inhibitors of the mammalian enzyme. The mechanism(s) for lack of
inhibition in vivo is currently unknown and must be further investigated in
order to develop a trout model for studying the role of aromatase in
carcinogenesis.
PMID: 10529006 [PubMed - indexed for MEDLINE]
129: Drug Saf 1999 Oct;21(4):297-309
Risks and benefits of aromatase inhibitors in postmenopausal breast cancer.
Michaud LB, Buzdar AU.
Division of Pharmacy, The University of Texas M.D. Anderson Cancer Center,
Houston 77030, USA.
Aromatase inhibitors were first reported in the early 1970s and have been used
to treat breast cancer since that time. Until recently, essentially the only
agent available in this class was aminoglutethimide, a nonspecific inhibitor
with multiple adverse effects and drug interactions. Selective and potent
aromatase inhibitors are now available (formestane, exemestane, fadrozole,
anastrozole and letrozole), and we review the risks and benefits of these agents
in order to assist clinicians in making treatment decisions. Formestane is an
injectable steroidal aromatase inhibitor with significant activity against
metastatic breast cancer. It has been shown to have similar efficacy and
superior tolerability compared with megestrol, and is similar to tamoxifen in
the metastatic setting. Exemestane is an oral steroidal aromatase inhibitor. It
has been shown to be effective third-line therapy after tamoxifen and megestrol
in postmenopausal patients with metastatic breast cancer. All the nonsteroidal
(imidazole/triazole) aromatase inhibitors are orally available. Fadrozole has
similar activity to megestrol and tamoxifen in the setting of metastasis, but
has been shown in phase II trials to inhibit cortisol and aldosterone
production. Anastrozole and letrozole have similar toxicity profiles. Compared
with megestrol, anastrozole improves overall survival and has superior
tolerability. Letrozole is superior to megestrol and aminoglutethimide in terms
of overall survival and time to progression, and is also better tolerated.
Although there is a strong rationale for using these agents in the treatment of
breast cancer, the information presently available is insufficient to recommend
any one agent over another. Direct comparative studies are lacking, and
comparing agents across studies is limited by many biases and may not be valid.
Formestane is only available as an injection and exemestane is not commercially
available in many countries, making these agents more difficult to recommend
over the other 3 agents. Fadrozole is less potent and less selective in
inhibiting aromatase than letrozole. The efficacies of fadrozole, megestrol and
tamoxifen appear to be similar; however, comparative data show no advantage of
fadrozole over letrozole. Anastrozole and letrozole are generally considered to
be similar agents. The clinical future of the selective aromatase inhibitors is
promising, and these agents may change the way postmenopausal breast cancer is
treated at all stages of the disease.
Publication Types:
Review
Review, Tutorial
PMID: 10514021 [PubMed - indexed for MEDLINE]
130: Clin Cancer Res 1999 Sep;5(9):2338-43
Impact of tamoxifen on the pharmacokinetics and endocrine effects of the
aromatase inhibitor letrozole in postmenopausal women with breast cancer.
Dowsett M, Pfister C, Johnston SR, Miles DW, Houston SJ, Verbeek JA, Gundacker
H, Sioufi A, Smith IE.
Department of Biochemistry, Royal Marsden Hospital, London, United Kingdom.
This study examined whether the addition of tamoxifen to the treatment regimen
of patients with advanced breast cancer being treated with the aromatase
inhibitor letrozole led to any pharmacokinetic or pharmacodynamic interaction.
Twelve of 17 patients completed the core period of the trial in which 2.5 mg/day
letrozole was administered alone for 6 weeks and in combination with 20 mg/day
tamoxifen for the subsequent 6 weeks. Patients responding to treatment continued
on the combination until progression of disease or any other reason for
discontinuation. Plasma levels of letrozole were measured at the end of the
6-week periods of treatment with letrozole alone and the combination and once
more between 4 and 8 months on combination therapy. No further measurements were
done thereafter. Hormone levels were measured at 2-week intervals throughout the
core period. Marked suppression of estradiol, estrone, and estrone sulfate
occurred with letrozole treatment, and this was not significantly affected by
the addition of tamoxifen. However, plasma levels of letrozole were reduced by a
mean 37.6% during combination therapy (P<0.0001), and this reduction persisted
after 4-8 months of combination therapy. Letrozole is the first drug to be
described in which this pharmacokinetic interaction occurs with tamoxifen. The
mechanism is likely to be a consequence of an induction of
letrozole-metabolizing enzymes by tamoxifen but was not further addressed in
this study. It is possible that the antitumor efficacy of letrozole may be
affected. Thus, sequential therapy may be preferable with these two drugs. It is
not known whether tamoxifen interacts with other members of this class of drugs
or with other drugs in combination.
Publication Types:
Clinical Trial
Multicenter Study
PMID: 10499602 [PubMed - indexed for MEDLINE]
131: Neth J Med 1999 Aug;55(2):50-8
New aromatase inhibitors for the treatment of advanced breast cancer in
postmenopausal women.
de Jong PC, Blijham GH.
Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The
Netherlands.
Inhibition of the enzyme aromatase, the rate limiting step in estrogen
production, is an effective endocrine treatment of advanced postmenopausal
breast cancer. Recently, several new aromatase inhibitors have been developed to
improve efficacy and reduce toxicity compared to the prototype aromatase
inhibitor aminoglutethimide. Aromatase inhibitors can be divided into two types.
The first are the non-steroidal inhibitors that have a mechanism of action
similar to aminoglutethimide. The second are the steroidal inhibitors that
function as a false substrate for aromatase. Of the non-steroidal aromatase
inhibitors, two drugs, anastrozole and letrozole, have recently been registered
for the second line endocrine treatment of advanced postmenopausal breast cancer
after failure on tamoxifen. The phase III studies of these drugs indicate at
least equal efficacy compared to current second line treatment with
aminoglutethimide or megestrol acetate. Their toxicity profile, however, is much
more favourable. This makes them the drugs of choice for the second line
endocrine treatment of advanced breast cancer in postmenopausal patients, who
failed during adjuvant or first line treatment with tamoxifen. Of the steroidal
aromatase inhibitors, the orally active drug exemestane is still in phase III
clinical study; the registration is expected in 1999.
Publication Types:
Review
Review, Tutorial
PMID: 10474272 [PubMed - indexed for MEDLINE]
132: Drugs 1999 Aug;58(2):233-55
Comprehensive pharmacology and clinical efficacy of aromatase inhibitors.
Njar VC, Brodie AM.
Department of Pharmacology and Experimental Therapeutics, School of Medicine,
University of Maryland, Baltimore 21201, USA.
The goal of hormone therapy is to deprive breast tumours of estrogens, since
estrogens have been implicated in the development or progression of tumours.
This can be accomplished by the use of antiestrogens that block estrogen action
or by inhibiting aromatase, the enzyme that catalyses the final and
rate-limiting step in estrogen biosynthesis. A number of steroidal and
nonsteroidal compounds have been developed as aromatase inhibitors. This review
highlights the valuable role that a few of these aromatase inhibitors have
played, and continue to play, in the treatment of breast cancer. Following
background information regarding the biochemistry of aromatase, the rationale
for its inhibition, and an outline of the test systems for evaluating and
characterising aromatase inhibitors, the discussion focuses on the new
generation of aromatase inhibitors that are in clinical trials or clinically
available. Specifically, it discusses the pharmacology and clinical efficacy of
formestane, exemestane, rogletimide, fadrozole, vorozole, anastrozole and
letrozole. The role of these agents as the optimal second-line agents (after
tamoxifen) for the treatment of advanced breast cancer has been established;
their prospects in other clinical settings and as potential breast cancer
chemopreventives are warranted but are yet to be fully determined.
Publication Types:
Review
Review, Academic
PMID: 10473018 [PubMed - indexed for MEDLINE]
133: Ann Ital Chir 1999 May-Jun;70(3):377-89
[Treatment of metastatic breast carcinoma]
[Article in Italian]
Puglisi F, Sobrero A.
Dipartimento di Ricerche Mediche e Morfologiche, Cattedra di Oncologia Medica,
Universita degli Studi di Udine.
In spite of major advances in early detection and adjuvant therapy, metastatic
breast cancer remains a major clinical problem affecting a significant number of
patients. Metastatic disease is generally considered incurable and conventional
therapy is used mainly with palliative intent. Therefore, the choice of
appropriate therapeutic approach requires a reasoned evaluation of the
likelihood of benefit from therapy balanced with the impact of therapy on the
patient's quality of life. The estimated aggressiveness of the tumour and
indicators of response to therapy (e.g. the status of hormonal receptors) are
useful parameters to take into account before selecting a given treatment.
Endocrine therapy is an important option in the management of stage IV disease,
with tamoxifen the most widely used first-line drug in postmenopausal women. For
progressing patients, the third generation of aromatase inhibitors (letrozole,
anastrazole) are considered good second-line endocrine agents. The LH-RH
agonists represent the initial choice in premenopausal patients candidate to
receive hormonal therapy, with the use of tamoxifen as a valuable alternative.
Combination chemotherapy regimens (e.g. CMF or CAF) are usually used for
first-line treatment of patients with aggressive, steroid receptor-negative
disease. Recently, several relatively new agents have shown significant activity
in metastatic breast cancer. In particular, the taxanes (paclitaxel and
docetaxel) are particularly promising as single agents but also in combination
with other drugs, especially anthracyclines. Finally, another class of agents,
the d mention because they represent an important new treatment modality in the
management of metastatic.
Publication Types:
Review
Review, Tutorial
PMID: 10466241 [PubMed - indexed for MEDLINE]
134: Eur J Cancer 1999 Feb;35(2):208-13
Double-blind, randomised, multicentre endocrine trial comparing two letrozole
doses, in postmenopausal breast cancer patients.
Bajetta E, Zilembo N, Dowsett M, Guillevin L, Di Leo A, Celio L, Martinetti A,
Marchiano A, Pozzi P, Stani S, Bichisao E.
Division of Medical Oncology B, Istituto Nazionale per lo Studio e la Cura dei
Tumori, Milan, Italy.
Letrozole is an orally competitive aromatase inhibitor. This double-blind,
randomised, multicentre trial was carried out to evaluate the endocrine effects
of two doses of letrozole, 0.5 mg versus 2.5 mg orally daily, in postmenopausal
advanced breast cancer patients progressing after tamoxifen. The
pharmacokinetics of letrozole was also assessed. 46 patients entered the trial,
22 on letrozole 0.5 mg and 24 on 2.5 mg. A significant suppression of oestrone
and oestradiol levels was achieved by both letrozole doses. Neither letrozole
dose induced any changes in cortisol and aldosterone production at rest or after
Synacthen stimulation. Androstenedione, testosterone, 17 alpha-OH progesterone,
triiodothyronine (T3) thyroxine, (T4) and thyroid-stimulating hormone (TSH)
plasma levels did not show any significant changes. Sex hormone binding globulin
(SHBG), follicle-stimulating hormone (FSH) and luteinising hormone (LH) levels
increased significantly over time. Plasma letrozole concentrations increased
until reaching steady-state values after 1 month at the dose of 0.5 mg and after
2 months at 2.5 mg. In conclusion, both letrozole doses suppressed oestrogen
levels without affecting adrenal activity.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 10448261 [PubMed - indexed for MEDLINE]
135: Clin Cancer Res 1999 Jul;5(7):1642-9
Evaluation of tamoxifen plus letrozole with assessment of pharmacokinetic
interaction in postmenopausal women with metastatic breast cancer.
Ingle JN, Suman VJ, Johnson PA, Krook JE, Mailliard JA, Wheeler RH, Loprinzi CL,
Perez EA, Jordan VC, Dowsett M.
Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
[email protected]
The goals of this clinical trial involving postmenopausal women with metastatic
breast cancer were to: (a) examine the effects of letrozole on tamoxifen (TAM)
pharmacokinetics; (b) examine estrogen suppression in patients receiving TAM
plus letrozole; and (c) evaluate tolerability, toxicity, objective response, and
time to progression for the combination. Postmenopausal women with measurable or
evaluable metastatic breast cancer received TAM (20 mg daily) for 6 weeks, and
then letrozole (2.5 mg daily) was added. To examine for any effect of letrozole
on the levels of TAM and two metabolites [N-desmethyl-TAM and 4-hydroxy-TAM],
serum samples were obtained at 6, 12, 18, and 24 weeks. To examine for aromatase
inhibition, serum samples were obtained before treatment and at 6, 12, 18, and
24 weeks for estradiol, estrone (E1) E1 sulfate, and sex hormone-binding
globulin. A total of 34 patients were entered on this trial, and 23 patients
were still on study at week 24, 18 of whom had blood samples available at both
week 6 and week 24. The 95% confidence interval for the mean difference between
levels at week 24 and levels at week 6 was -34 to 15 ng/ml for TAM, -35 to 45
ng/ml for N-desmethyl-TAM, and -1 to 2 for 4-hydroxy-TAM. For estradiol, a
significant decrease (median, 88.5%; range, 73.7-95.2%) was identified after 6
weeks of letrozole, which was maintained for an additional 12 weeks. Similar
significant reductions were identified for E1. E1 sulfate levels increased after
6 weeks of TAM alone but then decreased significantly after the addition of
letrozole. Sex hormone-binding globulin levels were significantly elevated after
6 weeks of TAM alone and remained elevated after the addition of letrozole. Six
of the 34 patients (17.6%) achieved an objective response (95% confidence
interval, 6.8-34.5%), with a median time to disease progression of 7.6 months.
There was no indication of a systematic decrease in TAM, N-desmethyl-TAM, or
4-hydroxy-TAM after the additional of letrozole. Estrogen suppression induced by
letrozole was substantial despite the concomitant administration of TAM. The
antitumor effect of TAM plus letrozole was less than expected.
Publication Types:
Clinical Trial
Clinical Trial, Phase II
PMID: 10430063 [PubMed - indexed for MEDLINE]
136: J Steroid Biochem Mol Biol 1999 Apr-Jun;69(1-6):205-10
Aromatase and its inhibitors.
Brodie A, Lu Q, Long B.
Department of Pharmacology and Experimental Therapeutics, School of Medicine,
University of Maryland, Baltimore 21201, USA. [email protected]
Inhibitors of aromatase (estrogen synthetase) have been developed as treatment
for postmenopausal breast cancer. Both steroidal substrate analogs, type I
inhibitors, which inactivate the enzyme and non-steroidal competitive
reversible, type II inhibitors, are now available. 4-hydroxyandrostenedione
(4-OHA), the first selective aromatase inhibitor, has been shown to reduce serum
estrogen concentrations and cause complete and partial responses in
approximately 25% of patients with hormone responsive disease who have relapsed
from previous endocrine treatment. Letrozole (CGS 20, 269) and anastrozole (ZN
1033) have been recently approved for treatment. Both suppress serum estrogen
levels to the limit of assay detection. Letrozole has been shown to be
significantly superior to megace in overall response rates and time to treatment
failure, whereas anastrozole was found to improve survival in comparison to
megace. Both were better tolerated than the latter. The potential of aromatase
within the breast as a significant source of estrogen mediating tumor
proliferation and which might determine the outcome of inhibitor treatment was
explored. Using immunocytochemistry and in situ hybridization, aromatase and
mRNAarom was detected mainly in the epithelial cells of the terminal ductal
lobular units (TDLU) of the normal breast and also in breast tumor epithelial
cells as well as some stromal cells. Increase in proliferation, measured by
increased thymidine incorporation into DNA and by PCNA immunostaining in
response to testosterone was observed in histocultures of breast cancer samples.
This effect could be inhibited by 4-OHA and implies that intratumoral aromatase
has functional significance. An intratumoral aromatase model in the
ovariectomized nude mouse was developed which simulated the hormone responsive
postmenopausal breast cancer patient. This model also allows evaluation of the
efficacy of aromatase inhibitors and antiestrogens in tumors of estrogen
receptor positive, human breast carcinoma cells transfected with the human
aromatase gene. Thus, the cells synthesized estrogen which stimulated tumor
formation. Both aromatase inhibitors and antiestrogens were effective in
suppressing tumor growth in this model. However, letrozole was more effective
than tamoxifen. When the aromatase inhibitors were combined with tamoxifen,
tumor growth was suppressed to about the same extent as with the aromatase
inhibitors alone. Thus, there was no additive or synergistic effects of
combining tamoxifen with aromatase inhibitors. This suggests that sequential
treatment with these agents is likely to be more beneficial to the patient in
terms of longer response to treatment.
Publication Types:
Review
Review, Tutorial
PMID: 10418994 [PubMed - indexed for MEDLINE]
137: Oncologist 1998;3(2):129-130
Molecular Action and Clinical Relevance of Aromatase Inhibitors.
Murphy MJ Jr.
AlphaMed Press, Miamisburg, Ohio, 45342-3758, USA. mjm@alphamed press.com
BREAST CANCER: HIGH PREVALENCE AND RISING INCIDENCE: Breast cancer is the most
common form of cancer among women in Europe, North and South America and
Australasia; approximately 1 in 10 women in Western countries will develop
breast cancer during their lifetime. It is estimated that the disease will
affect five million women worldwide over the next decade, and the incidence of
breast cancer is increasing on average by about 1% per year in industrialized
countries and at a greater rate in developing countries. COMPLEX ETIOLOGY:
Although the specific etiology of breast cancer remains unknown, a number of
factors are recognized which increase a woman's risk of developing the disease.
Genetic predisposition, or family history of breast cancer, is known to be
responsible for 5% of all cases. However, the variation in incidence throughout
populations, and changes relating to population migration and adoption of
altered lifestyles, all point to the critical importance of nongenetic
determinants. Such factors include early menarche, late menopause, late age at
birth of first child or nulliparity, a history of benign breast disease, and
diet. There is also evidence that hormones play a major role in the etiology of
breast cancer, with the risk of developing malignancies related to the
cumulative exposure of the breast to estrogen and progesterone, which stimulate
the growth of tumor cells. TREATMENT FOR EARLY BREAST CANCER: SURGERY -/+
ADJUVANT THERAPY: At the time of diagnosis, approximately 50% of patients will
be diagnosed with early breast cancer. This proportion is increasing as a
consequence of the introduction of early detection programs. Surgery remains the
primary treatment for early breast cancer, and the frequency of radical
mastectomy has been replaced by breast conserving surgery. After surgery, other
therapeutic modalities such as radiation, chemotherapy or endocrine therapy may
be given in the adjuvant setting. Surgical cure rates vary for patients with
early breast cancer; the US figure is approximately 40%, and there are no
definitive means to predict those who will be cured and those who will have
recurrent disease. As a result, following primary surgical treatment, adjuvant
therapy is usually recommended to destroy any remaining cancer cells at the
primary site, to control micrometastases and to prolong disease-free survival,
with the ultimate aim of providing an overall survival benefit. Upon disease
recurrence in the remaining 60% of patients, endocrine therapy and chemotherapy
represent the two general classes of treatment. One of the principle decisions
to be taken in advanced breast cancer is which therapy to select in order to
maximize patient benefit. The choice is largely dependent upon prognostic
factors and whether the patient is pre- or postmenopausal. ENDOCRINE THERAPY OR
CHEMOTHERAPY IN ADVANCED BREAST CANCER: Unlike chemotherapy, endocrine therapy
is not cytotoxic and is therefore better tolerated by the patient. A recent
study comparing therapy for prognostically different groups showed that patients
benefiting most from the use of sequential endocrine agents are those regarded
as low risk. The preferred sequence of treatment has been suggested to be
tamoxifen followed by selective aromatase inhibitor and then a progestin.
ENDOCRINES AND ENZYMES OFFER NEW TREATMENTS FOR ADVANCED BREAST CANCER:
ESTROGEN-DRIVEN BREAST CANCER: Since 1896, when Sir George Beatson demonstrated
that ovariectomy induced regression of mammary tumors in women, the aim of
endocrine breast cancer therapy has been to selectively deprive the body of
estrogen. Ovariectomy accomplished this by removing the gland that is the
predominant source of estrogens in premenopausal women. Since the avoidance of
such surgery is preferable, emphasis is devoted to the pharmacological
inhibitors of estrogen production. ENDOCRINE PATHWAY REVEALS "ACHILLES' HEEL":
Like other steroid hormones, the two circulating estrogens-estrone and
estradiol-are produced from cholesterol. Inhibiting the enzymes that are
involved at earlier steps in the branching pathway of steroidogenesis could have
an undesirable impact on the production of other physiologically important
hormones such as aldosterone and cortisol. Since aromatase catalyzes the last
step in estrogen production, it makes an ideal target for the development of
selective and potent inhibitors (Fig. 1). STRUCTURE OF AROMATASE REVEALS SECRETS
OF SELECTIVE INHIBITION: Aromatase is a cytochrome P450 enzyme, with both an
iron-containing and a steroid-binding site. The substrate, androstenedione, sits
in the enzyme's steroid-binding site, that site which otherwise catalyzes the
formation of estrogen. From this structural relationship, there are, therefore,
two reasonable ways to inhibit aromatase: * by occupying the steroid-binding
site of the enzyme with a compound such as formestane (Lentaron®), or * by
binding the iron with nitrogen-containing compounds such as aminoglutethimide
(Orimeten®), the oldest aromatase inhibitor. AROMATASE INHIBITORS: STEROIDAL
AND NON-STEROIDAL: Formestane (Lentaron®) is the only commercially available
steroidal compound which inhibits aromatase and must be administered
parenterally. Other new aromatase inhibitors such as fadrozole (Afema®) and
letrozole (Femara®) are orally active nitrogen-containing compounds that
bind the heme iron of aromatase. AMINOGLUTETHIMIDE VERSUS LETROZOLE: OLD VERSUS
NEW: Although aminoglutethimide has long been used to treat advanced breast
cancer, its aromatase inhibition is not selective. Consequently,
aminoglutethimide also binds to and thereby inhibits several other cytochrome
P450 enzymes in the steroidogenesis pathway. An ideal aromatase inhibitor would
fit the catalytic site of aromatase optimally and would thus interact only with
aromatase. The affinity of letrozole (Femara®) for the heme group of
aromatase makes it a selective and potent inhibitor (Fig. 2). In fact, studies
show that Femara® has little effect on the other adrenal steroids, and is
the most selective aromatase inhibitor available today.
PMID: 10388095 [PubMed - as supplied by publisher]
138: Ann Oncol 1999 Apr;10(4):377-84
The third-generation non-steroidal aromatase inhibitors: a review of their
clinical benefits in the second-line hormonal treatment of advanced breast
cancer.
Hamilton A, Piccart M.
Institut Jules Bordet, Brussels, Belgium.
Three new aromatase inhibitors have recently completed phase III evaluation as
treatment of metastatic breast cancer in post-menopausal women whose disease has
progressed despite tamoxifen therapy: anastrozole (ARIMIDEX, Zeneca), letrozole
(FEMARA, Novartis) and vorozole (RIVIZOR, Janssen). All belong to the third
generation of non-steroidal aromatase inhibitors, and each is superior to
previous generations in terms of potency and selectivity. The trials that have
been performed compare each agent to megestrol acetate, and letrozole and
vorozole to aminoglutethimide. Although the studies are not directly comparable
due to differing study designs and patient populations, it has been demonstrated
each of these drugs provides single agent, once-daily, oral palliation of
hormone-responsive, post-menopausal metastatic breast cancer. Letrozole is
clearly more effective than megestrol acetate, and anastrozole and vorozole are
possibly so. All three are better tolerated than the progestin, particularly in
terms of weight gain. Both letrozole and vorozole are significantly more
effective, and better tolerated than aminoglutethimide. Overall, this most
recent generation of aromatase inhibitors is a clear improvement on our current
standard second-line therapies. In 1999, tamoxifen remains the first choice in
the hormonal therapy of breast cancer. Following tamoxifen failure, the optimal
second-line hormonal therapy remains undefined, but aminoglutethimide and
megestrol acetate are no longer optimal therapy in this setting. The
third-generation non-steroidal aromatase inhibitors must now be compared to each
other, to the steroidal aromatase inhibitors, to the pure anti-oestrogens, and
to tamoxifen.
Publication Types:
Review
Review, Academic
PMID: 10370778 [PubMed - indexed for MEDLINE]
139: Ross Fiziol Zh Im I M Sechenova 1998 Nov;84(11):1242-6
[Metabolism of the androgenic precursor androstenedione and effects of aromatase
inhibitors in cultured blood lymphocytes]
[Article in Russian]
Bershtein LM, Poroshina TE, Larionov AA, Zimarina TS.
Petrov Research Institute of Oncology, St. Petersburg.
Blood lymphocytes from 26 women were cultivated in RPMI-1640 for 72 hrs with or
without dexamethasone, dbcAMP, and TPA. Androstenedione conversion was most
often activated by the dbcAMP, then by Dex and TPA. Response to dbcAMP was most
obvious in women under 50, whereas response to Dex--in women over 50. Aromatase
inhibitor fadrosol displayed a tendency towards prevention of the activation of
androstenedione conversion in cultivated lymphocytes. A possibility of aromatase
gene induction in cultivated lymphocytes cannot be completely excluded and
demands further investigation with the aid of molecular-genetic methods.
PMID: 10204168 [PubMed - indexed for MEDLINE]
140: J Steroid Biochem Mol Biol 1998 Dec;67(5-6):403-11
Macrophages, estrogen and the microenvironment of breast cancer.
Mor G, Yue W, Santen RJ, Gutierrez L, Eliza M, Berstein LM, Harada N, Wang J,
Lysiak J, Diano S, Naftolin F.
Department of Obstetrics and Gynecology, Center for Research in Reproductive
Biology, Yale University School of Medicine, New Haven, CT 06520, USA.
Estrogen is a major mitogenic stimulus to established breast cancer. Estrogen
sources include ovarian, extraglandular sites and breast tissue. Which source
primarily maintains benign and breast cancer tissue estrogen concentrations
remains unclear. While macrophages may comprise up to 50% of the mass of breast
carcinomas, previous studies neglected to study them as possible sources of
estrogen. We present evidence that breast macrophages constitute an in situ
source of estradiol and that the amount produced is sufficient to mediate
cellular proliferation. We utilized immunohistochemistry and RT-PCR to study
cell-specific aromatase expression in (i) 29 breast biopsies, (ii) human
monocytes/macrophages and (iii) a myeloid cell line (THP-1) capable of
differentiating into macrophages. Use of a breast cancer cell line (MCF-7)
provided biologic confirmation of the role of aromatization in cell
proliferation. We demonstrated considerable amounts of immunoreactive-aromatase
(irARO) in breast tissue macrophages and a positive correlation between the
proportion of irARO present in macrophages and lesion severity. Using in vitro
techniques, we demonstrated that monocytes and THP-1 cells require
differentiation into macrophages to produce aromatase in amounts approaching
placental levels. The amount of estrogen produced by THP-1 cells stimulated
MCF-7 cells to proliferate, an effect blocked by aromatase inhibitors. Estrogen
production by macrophages in breast tissue appears sufficient to stimulate the
proliferation of adjacent epithelial cells and to autoregulate cytokine
production. These findings represent a new dimension of cellular regulation in
breast tissue with major biologic implications, amenable to pharmacological
manipulation.
PMID: 10030689 [PubMed - indexed for MEDLINE]
141: Recent Results Cancer Res 1998;152:277-84
Aromatase inhibitors and their use in the adjuvant setting.
Coombes RC.
Department of Cancer Medicine, Imperial College School of Medicine, Charing
Cross Hospital, London, UK.
Over the past decade several novel aromatase inhibitors have been introduced
into clinical practice. The discovery of these drugs followed on from the
observation that the main mechanism of action of aminoglutethemide was via
inhibition of the enzyme aromatase, thereby reducing peripheral levels of
estradiol in post-menopausal patients. The second-generation drug
4-hydroxyandrostenedione was introduced in 1990, and although its use was
limited by its need to be given parenterally, it was found to be a
well-tolerated form of endocrine therapy. The third-generation inhibitors
include vorozole, letrozole, anastrozole and exemestane, the former three being
non-steroidal inhibitors, the latter being a steroidal inhibitor. All these
compounds are capable of reducing estrogen levels to within 5%-10% of baseline
levels compared with 20%-30% base line levels in the case of
4-hydroxyandrostenedione. Studies are currently in progress to determine the
value of these third-generation aromatase inhibitors in the adjuvant setting.
These studies include head-to-head comparison of aromatase inhibitor with
tamoxifen, sequential aromatase inhibitor after tamoxifen and first-line
aromatase inhibitor followed by adjuvant tamoxifen. Current issues revolve
around the toxicity of these compounds in terms of effects on the cardiovascular
system and bone.
Publication Types:
Review
Review, Tutorial
PMID: 9928565 [PubMed - indexed for MEDLINE]
142: Presse Med 1998 Dec 12;27(39):2049-54
[Breast cancer: new therapeutic strategies]
[Article in French]
Espie M.
Hopital St Louis, Centre des Maladies du Sein, Paris. [email protected]
NEED FOR NEW CHEMOTHERAPY AGENTS: Metastasic breast cancer is an excellent model
for studying anticancer agents: chemotherapy or hormonotherapy or compounds
modifying the organism's response. If no adjuvant treatment is given after
locoregional treatment of breast cancer, metastasis will develop within 10 years
in 30% of the patients free of initial nodal invasion and within 5 years in 50%
of the patients with initial nodal invasion. ADJUVANT TREATMENTS: Hormonotherapy
and chemotherapy reduce mortality due to breast cancer by 10%. New adjuvant
agents have been recently introduced. Taxans (docetaxel, paclitaxel) are the
most active molecules since antracyclines. New aromataase inhibitors include
letrozole and anastrozole. Their efficacy has been demonstrated in phase II and
phase III trials, allowing their experimentation as adjuvant treatments.
Publication Types:
Clinical Trial
Clinical Trial, Phase II
Clinical Trial, Phase III
Randomized Controlled Trial
PMID: 9893697 [PubMed - indexed for MEDLINE]
143: J Steroid Biochem Mol Biol 1998 Nov;67(4):293-304
The steroidal antiestrogen ICI 182,780 is an inhibitor of cellular aromatase
activity.
Long BJ, Tilghman SL, Yue W, Thiantanawat A, Grigoryev DN, Brodie AM.
Department of Pharmacology and Experimental Therapeutics, The University of
Maryland School of Medicine, Baltimore 21201, USA.
Two types of endocrine therapy that have been successfully applied to patients
with hormone-dependent breast cancer are the non-steroidal antiestrogen
tamoxifen, and inhibitors of aromatase, the enzyme that synthesizes estrogens.
The major drawback with tamoxifen is that it acts as a partial estrogen-agonist
and this is believed to mediate, at least in part, acquired tumor resistance to
the drug as well as endometrial hyperplasia and carcinoma in some patients. The
newer and more potent antiestrogen ICI 182,780 is a steroidal molecule that is
devoid of estrogenic activity. We now report that ICI 182,780 is also an
inhibitor of aromatase activity in fibroblasts isolated from the normal human
breast as well as other carcinoma cell lines that express aromatase (MCF-7Ca
breast cancer and JEG-3 choriocarcinoma). ICI 182,780 (1 microM) did not affect
aromatase activity levels in human placental microsomes and only inhibited
aromatase activity in each of the cell lines following a prolonged incubation
period. In the fibroblasts, inhibition of aromatase activity by ICI 182,780 was
shown to be time and dose-dependent. In contrast, tamoxifen and 17beta-estradiol
were shown to have no effect on aromatase activity levels. ICI 182,780 inhibited
aromatase activity levels with IC50 values of 16.80 nM in MCF-7Ca cells, 125.50
nM in JEG-3 cells and 386.1 nM in breast fibroblasts. These values were compared
to those for known aromatase inhibitors, and in each of the cell lines the order
of potency was letrozole>4-OHA>anastrozole>ICI 182,780. The inhibition of
aromatase activity by ICI 182,780 was sustained even after the antiestrogen was
removed from the cells indicating that ICI 182,780 may be remaining bound to the
enzyme. Although ICI 182,780 had no effect on the proliferation of the
fibroblasts, or JEG-3 cells, it significantly inhibited the growth of MCF-7Ca
cells. This growth inhibition appeared to be due to the antiestrogenic activity
of ICI 182,780 and not to its aromatase inhibiting effects. ICI 182,780 did not
inhibit aromatase activity by down-regulating levels of the aromatase
transcript. These results show that in addition to being a potent antiestrogen,
ICI 182,780 is also an inhibitor of cellular aromatase activity, and suggest
that by interfering with the actions of estrogen by two distinct mechanisms, ICI
182,780 may be a suitable drug for treating patients with hormone-dependent
breast cancer.
PMID: 9883986 [PubMed - indexed for MEDLINE]
144: Drugs 1998 Dec;56(6):1125-40
Letrozole. A review of its use in postmenopausal women with advanced breast
cancer.
Lamb HM, Adkins JC.
Adis International Limited, Auckland, New Zealand. [email protected]
Letrozole is an oral reversible nonsteroidal aromatase inhibitor. Clinical
tracer studies show that it inhibits peripheral aromatase by over 98% and
suppresses blood and urinary estrogen levels by over 95% after 2 weeks of
treatment in postmenopausal women. Letrozole also significantly inhibits
intratumoral aromatase in vivo. The action of letrozole appears to be selective
for aromatase; long term administration did not affect basal levels of 17
alpha-hydroxyprogesterone or aldosterone, although slight decreases in cortisol
levels were observed in 2 studies, these did not appear to be clinically
significant. In 2 phase IIb/III trials, letrozole 2.5 mg/day achieved objective
response rates of 19.5 and 23.6% which were sustained for a median duration of
24 and 33 months, respectively. The median duration of response compared
favourably with both comparator agents, aminoglutethimide and megestrol (15 and
18 months, respectively), as did objective response rates (12.4 and 16.4%).
Letrozole 2.5 mg/day was associated with an increase in median survival time of
8 and 3 months compared with aminoglutethimide and megestrol, respectively.
According to analyses of overall function, letrozole 2.5 mg/day was
significantly superior to both comparators with respect to duration of response
and aminoglutethimide with respect to survival. Letrozole has a good short term
tolerability profile. The adverse events reported most commonly in association
with letrozole 2.5 mg/day in the 2 phase IIb/III trials were headache (1.1 and
7%), nausea (6 and 10.3%), fatigue (3.2 and 5%), hot flushes (4.9 and 5%) and
peripheral oedema (6%). Events were usually mild to moderate in severity;
adverse events necessitated discontinuation of treatment in 3% of letrozole 2.5
mg/day recipients. CONCLUSIONS: Letrozole, in common with vorozole and
anastrozole, offers greater selectivity and potency of aromatase inhibition than
the prototype aromatase inhibitor, aminoglutethimide, and can be administered
once daily. Available clinical data suggest that letrozole achieves a
significantly longer duration of response than megestrol and aminoglutethimide
and longer overall survival than aminoglutethimide. However, direct comparisons
are required to distinguish between the newer aromatase inhibitors. For this
reason, letrozole should be recommended as a second-line treatment in
postmenopausal women with advanced breast cancer whose disease has progressed on
or failed to respond to antiestrogen therapy.
Publication Types:
Review
Review, Tutorial
PMID: 9878997 [PubMed - indexed for MEDLINE]
145: Cancer Pract 1998 Nov-Dec;6(6):349-52
Drug update: letrozole: A new aromatase inhibitor for metastatic breast cancer.
Mays-Holland T.
Pharmacy Practice, College of Pharmacy, University of Utah, Salt Lake City.
Publication Types:
Review
Review Literature
PMID: 9824427 [PubMed - indexed for MEDLINE]
146: Clin Cancer Res 1995 Dec;1(12):1511-5
In vivo measurement of aromatase inhibition by letrozole (CGS 20267) in
postmenopausal patients with breast cancer.
Dowsett M, Jones A, Johnston SR, Jacobs S, Trunet P, Smith IE.
Academic Department of Biochemistry and Department of Medicine, Royal Marsden
National Health Service Trust, Fulham Road, London SW3 6JJ, United Kingdom.
Thirteen postmenopausal women with advanced breast cancer were enrolled in an
open randomized Phase I trial of a new p.o. active aromatase inhibitor, CGS
20267 (letrozole). The primary aim of the trial was to assess the impact of two
doses of letrozole (0.5 and 2. 5 mg/day) on the peripheral aromatization of
androstenedione to estrone. An in vivo isotopic technique was used to measure
peripheral aromatization in each patient before treatment. The patients were
then randomly assigned to one of the two doses, and measurements of
aromatization were repeated after 6 weeks. At 0.5 mg and 2.5 mg/day, letrozole
inhibited aromatization by 98.4% (97.3 to >99.1) and >98.9% (98.5 to >99.1;
geometric means and ranges), respectively. Plasma estrogen levels were also
measured before and during treatment. At the dose of 0.5 mg/day estrone and
estradiol levels fell by 82.0% and 84.1% (geometric means), respectively. At the
dose of 2.5 mg/ day, the estrogens fell by 80.8% and 68.1%, respectively. There
were no significant differences between the doses in aromatase inhibition. No
formal statistical analysis was performed on the estrogen data. Letrozole is
therefore a highly effective inhibitor of aromatase, causing near complete
inhibition of the enzyme in peripheral tissues at the doses investigated. The
falls in estrogen levels were greater than those seen with earlier generation
aromatase inhibitors.
Publication Types:
Clinical Trial
Clinical Trial, Phase I
Randomized Controlled Trial
PMID: 9815951 [PubMed - indexed for MEDLINE]
147: Drugs Aging 1998 Oct;13(4):321-32
Anastrozole. A review of its use in the management of postmenopausal women with
advanced breast cancer.
Wiseman LR, Adkins JC.
Adis International Limited, Auckland, New Zealand. [email protected]
Anastrozole is a new oral nonsteroidal aromatase inhibitor indicated for the
second-line endocrine treatment of postmenopausal women with advanced breast
cancer. In postmenopausal women, anastrozole significantly reduces plasma
estrogen levels; maximal suppression is achieved at dosages > or = 1 mg/day and
levels remain suppressed during long term therapy. In two phase III clinical
trials, anastrozole 1 or 10 mg/day showed similar clinical efficacy to that of
oral megestrol (megestrol acetate) 160 mg/day in postmenopausal women with
advanced breast cancer. Primary end-points [including time to disease
progression (120 to 170 days) and overall response rates (complete and partial
response and stable disease lasting > or = 24 weeks: 29 to 37%)] and secondary
end-points [time to treatment failure (115 to 168 days) and duration of response
(257 to 261 days)] did not differ significantly between treatment groups.
However, a significant survival advantage was observed in patients treated with
anastrozole 1 mg/day compared with megestrol in a follow-up combined analysis of
patients enrolled in both studies (median time to death 26.7 vs 22.5 months).
Quality of life parameters were generally improved to a similar extent in all
treatment groups. Anastrozole is generally well tolerated in the majority of
patients, the most common adverse events being gastrointestinal (GI)
disturbances (incidence 29 to 33%). These events are generally mild or moderate
and transient. Other adverse events reported with anastrozole include headache
(< or = 18%), asthenia (< or = 16%), pain (< or = 15%), hot flushes and bone
pain (both < or = 12%), back pain and dyspnoea (both < or = 11%) and peripheral
oedema (< or = 9%). GI disturbance tended to be more common with anastrozole
than megestrol, particularly at the 10 mg/day dosage; however, compared with
megestrol, anastrozole is less frequently associated with weight gain.
CONCLUSIONS: Anastrozole, with its apparent survival advantage versus megestrol
(demonstrated in a combined analysis of phase III studies), convenient once
daily oral administration and acceptable short term tolerability profile, is a
second-line treatment option for postmenopausal patients with
tamoxifenrefractory advanced breast cancer. The results of ongoing comparative
trials with tamoxifen will determine the relative efficacy of anastrozole as
first-line endocrine therapy for advanced breast cancer and as adjuvant therapy
for early disease. In addition, direct comparative studies are required to
determine the efficacy of anastrozole relative to that of other oral aromatase
inhibitors such as letrozole and vorozole.
Publication Types:
Review
Review, Tutorial
PMID: 9805213 [PubMed - indexed for MEDLINE]
148: Breast Cancer Res Treat 1998 Jul;50(1):63-71
The effects of aromatase inhibitors and antiestrogens in the nude mouse model.
Lu Q, Yue W, Wang J, Liu Y, Long B, Brodie A.
Department of Pharmacology & Experimental Therapeutics, and Greenbaum Cancer
Center, School of Medicine, University of Maryland, Baltimore 21201, USA.
The effects of antiestrogens, tamoxifen and ICI 182,780, and aromatase
inhibitors, arimidex (anastrozole ZD1033) and letrozole (CGS 20,267), on the
growth of tumors were studied in nude mice. In this model, estrogen dependent
MCF-7 human breast cancer cells stably transfected with the aromatase gene were
inoculated in four sites per mouse. Sufficient estrogen is produced from
aromatization of androstenedione supplement (0.1 mg/mouse/day) by the cells to
stimulate their proliferation, tumor formation, and maintain the uterus similar
to that of the intact mouse. Once the tumors reached a measurable size, the mice
were injected with antiestrogen or inhibitor for 35-56 days. Tumor volumes were
measured weekly. At autopsy, the tumors were removed, cleaned, and weighed.
Statistical data was determined from tumor weights. Both antiestrogens were
effective in reducing tumor growth in these mice. Tamoxifen appears to be more
effective than ICI 182,780, although the former stimulated the uterine weight
whereas the pure antiestrogen did not. However, both aromatase inhibitors were
more effective than the antiestrogens. Tumor regression was observed with
letrozole. Thus, after-treatment tumor weights were less than those of a group
of mice at the start of treatment. The aromatase inhibitors also reduced the
weight of the uterus, suggesting that these compounds, as well as the pure
antiestrogen, may not cause endometrial proliferation, unlike tamoxifen. These
aromatase inhibitors may not only benefit patients who have relapsed from
tamoxifen, but may be more effective in patients as first line agents for
suppressing the effects of estrogen.
PMID: 9802621 [PubMed - indexed for MEDLINE]
149: Breast Cancer Res Treat 1998;49 Suppl 1:S93-9; discussion S109-19
Demonstration of aromatase activity and its regulation in breast tumor and
benign breast fibroblasts.
Santen RJ, Martel J, Hoagland M, Naftolin F, Roa L, Harada N, Hafer L, Zaino R,
Pauley R, Santner S.
Department of Internal Medicine, University of Virginia School of Medicine,
Charlottesville, USA.
Breast tumors from post-menopausal women contain higher amounts of estradiol
than would be predicted from levels circulating in plasma. This observation
raised the hypothesis that tumors may synthesize estradiol in situ and increase
their tissue estradiol levels via this mechanism. The key enzyme involved in
tissue estrogen synthesis, aromatase, is present in breast tumors but, according
to some investigators, not in sufficient concentration to be biologically
meaningful. We postulated that foci of cells in breast tumors might contain high
amounts of aromatase and this locally produced estrogen might act in a paracrine
or autocrine fashion. To test this hypothesis, we utilized immunohistochemistry
to localize the aromatase enzyme, an histological scoring system to quantitate
it, and culture of isolated breast cells to demonstrate its potential
regulation. In 26 archival breast tumors, 16 (62%) contained aromatase by
radiometric assay. With the immunohistochemical method, we detected areas with
staining in the stroma as well as tumor epithelial cells. Staining ranged from
the intensity approaching that seen in placenta to levels just distinguishable
from background. We adopted an histological scoring system (H-score) from that
used to quantitate progesterone receptor levels in tissue and used it to
quantitate aromatase activity. A higher histologic score was found in stromal
spindle cells (13) than in tumor epithelial cells (4.8). The biochemical
aromatase results correlated with the H-score of stromal but not epithelial
cells. To further study stromal cells from tumors, we isolated stromal cells
from breast tumors and the benign areas of breast distal to the tumor and grew
them in culture. Addition of dexamethasone, phorbol esters, and cyclic AMP
analogues stimulated aromatase enzyme and messenger RNA levels substantially.
Use of aromatase enzyme inhibitors such as letrozole blocked estrogen production
but did not alter aromatase message levels. Epithelial cells, whether
nonmalignant or cancer derived, exhibited no regulation by dexamethasone,
phorbol esters, or cAMP analogues. These data, taken together, suggest that
stromal cells may be more important than epithelial cancer cells for estrogen
production in breast tumors. The ability to stimulate aromatase activity
substantially with various enhancers of aromatase provides further credence for
an important biologic role of estrogen production in tumor tissue.
PMID: 9797023 [PubMed - indexed for MEDLINE]
150: Breast Cancer Res Treat 1998;49 Suppl 1:S67-71; discussion S73-7
Fadrozole and letrozole in advanced breast cancer: clinical and biochemical
effects.
Smith IE, Norton A.
Breast Unit, Section of Medicine, Royal Marsden Hospital, London, UK.
Publication Types:
Review
Review, Tutorial
PMID: 9797020 [PubMed - indexed for MEDLINE]
151: Breast Cancer Res Treat 1998;49 Suppl 1:S39-44; discussion S73-7
Theoretical considerations for the ideal aromatase inhibitor.
Dowsett M.
Royal Marsden Hospital, London, UK. [email protected]
A definition of the theoretical components of an ideal aromatase inhibitor is
developed, one aspect of which is completeness of enzyme inhibition. The three
triazole inhibitors, letrozole, vorozole and anastrozole all inhibit whole body
aromatisation by > 96% at their clinically used doses and vorozole and letrozole
were more effective in Phase III clinical trials than aminoglutethimide (250 mg
bd) which achieves < 90% inhibition. The possibility is considered that the
apparent small differences between the triazoles may be associated with
differences in clinical effectiveness. These new compounds merit consideration
for studies of breast cancer prevention.
Publication Types:
Review
Review, Tutorial
PMID: 9797016 [PubMed - indexed for MEDLINE]
152: Breast Cancer Res Treat 1998;49 Suppl 1:S27-32; discussion S33-7
Clinical importance of intratumoral aromatase.
Miller WR, Mullen P, Telford J, Dixon JM.
Breast Unit, Western General Hospital, Edinburgh, UK.
Evidence to support the contention that estrogen biosynthesis in breast cancers
is of clinical significance has been sought by relating activity to (i) clinical
response to aromatase inhibitors and (ii) tumor concentrations of estrogens.
Significant correlations have been reported between the presence/high levels of
tumor aromatase in vitro and likelihood of response to aminoglutethimide in
patients with advanced breast cancer, but the association is not absolute and it
has been more difficult to demonstrate similar relationships in patients with
earlier stages of cancers treated with other more potent inhibitors. There are
however data to suggest that in vitro measurements of aromatase may not reflect
in situ estrogen synthesis. For example mammary adipose tissue fibroblasts
preincubated with reversible aromatase inhibitors may paradoxically display
elevated in vitro aromatase activity. Similar enhanced in vitro activity may be
observed in breast material taken from patients treated neo-adjuvantly with
aromatase inhibitors such as aminoglutethamide and letrozole. That this is an
artifact of in vitro systems can be demonstrated by performing in situ
assessments of aromatase activity in patients before and after treatment with
aromatase inhibitors. Thus it can be shown that letrozole markedly inhibits in
situ aromatase and reduces tumor levels of estrogens.
Publication Types:
Review
Review, Tutorial
PMID: 9797015 [PubMed - indexed for MEDLINE]
153: Breast Cancer Res Treat 1998;49 Suppl 1:S23-6; discussion S33-7
Intratumoral aromatase model: the effects of letrozole (CGS 20267).
Brodie A, Lu Q, Yue W, Wang J, Liu Y.
Department of Pharmacology and Experimental Therapeutics, Greenebaum Cancer
Center, School of Medicine, University of Maryland, Baltimore 21201, USA.
An intratumoral aromatase model in the ovariectomized nude mouse was developed
which simulated the hormone responsive postmenopausal breast cancer patient.
MCF-7, human breast cancer cells transfected with the aromatase gene, inoculated
into ovariectomized nude mice are able to synthesize sufficient estrogens to
enhance cell proliferation and the development of tumors. These tumors are
responsive to both antiestrogens and aromatase inhibitors. However, letrozole
was found to be more effective than tamoxifen and caused tumor regression, a
result not previously noted in nude mice with endocrine treatments. When the
aromatase inhibitors were combined with tamoxifen, tumor growth was suppressed
to about the same extent as treatment with the aromatase inhibitors alone. Thus,
there was no additive or synergistic effects of combining tamoxifen with
aromatase inhibitors. These results suggest that letrozole has the potential to
be more effective than tamoxifen for achieving greater reduction in estrogenic
effects on tumors and uterus in postmenopausal breast cancer patients. In
addition, sequential treatment with these agents is likely to be more beneficial
to the patient in terms of longer response to treatment.
PMID: 9797014 [PubMed - indexed for MEDLINE]
154: J Clin Pharmacol 1998 Aug;38(8):727-35
Plasma protein binding of letrozole, a new nonsteroidal aromatase enzyme
inhibitor.
Colussi DM, Parisot CY, Lefevre GY.
Department of Drug Metabolism and Pharmacokinetics, Novartis Pharma S.A.,
Rueil-Malmaison, France.
The protein binding characteristics of the nonsteroidal aromatase inhibitor
letrozole were determined using 14C-labeled letrozole. The binding of letrozole
in human serum was 60.1 +/- 2.9% as a mean obtained in six individual sera and
was similar in human plasma. The binding in human serum remained constant at
concentrations of letrozole ranging from 10 to 500 ng/mL. A similar binding
value in human serum was obtained using equilibrium dialysis and ultrafiltration
technique. Albumin (binding 55.1 +/- 1.4%) is the main protein involved in the
drug binding to plasma proteins. Increases in letrozole concentration (10-500
ng/mL) had no effect on binding. Albumin binding appeared to be nonsaturable
with a binding capacity of 2 L/mmol. Binding to alpha1-acid glycoprotein and to
gamma globulins was lower than 10%. The fraction in erythrocytes with a
hematocrit of 0.4 was found to be 35.2 +/- 2.7%. Letrozole binding to serum
proteins of rat, dog, mouse, and rabbit was approximately 10% lower than that in
human serum and approximately 20% lower than that in baboons. Tamoxifen
(100-1,500 ng/mL) had no effect on the in vitro binding of letrozole. Ex vivo
binding in plasma from patients after repeated administration of letrozole alone
(61.4 +/- 2.6%) was the same as after combined administration of letrozole and
tamoxifen (60.0 +/- 3.2%).
PMID: 9725549 [PubMed - indexed for MEDLINE]
155: J Clin Oncol 1998 Aug;16(8):2892-3
Comment on:
J Clin Oncol. 1998 Feb;16(2):453-61.
Letrozole for advanced breast cancer.
Hoctin-Boes G, Yates R, Steinberg M.
Publication Types:
Comment
Letter
PMID: 9704745 [PubMed - indexed for MEDLINE]
156: Ann Oncol 1998 Jun;9(6):639-45
Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg
daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced
breast cancer. Letrozole International Trial Group (AR/BC3).
Gershanovich M, Chaudri HA, Campos D, Lurie H, Bonaventura A, Jeffrey M, Buzzi
F, Bodrogi I, Ludwig H, Reichardt P, O'Higgins N, Romieu G, Friederich P, Lassus
M.
N. N. Petrov Research Institute of Oncology, St. Petersburg, Russia.
BACKGROUND: The study compares letrozole and aminoglutethimide (AG), a standard
therapy for postmenopausal women with advanced breast cancer, previously treated
with antioestrogens. PATIENTS AND METHODS: 555 women were randomly assigned
letrozole 2.5 mg once daily (n = 185), letrozole 0.5 mg once daily (n = 192) or
aminoglutethimide 250 mg twice daily with corticosteroid support (n = 178) in an
open-label, multicentre trial. The primary endpoint was objective response rate
(ORR), with time events as secondary. ORR was analysed nine months after
enrollment of the last patient, while survival was analysed 15 months after the
last patient was enrolled. We report the results of these analyses plus an
extended period of observation (covering a total duration of approximately 45
months) to determine the duration of response and clinical benefit. RESULTS:
Overall objective response rates (complete + partial) of 19.5%, 16.7% and 12.4%
were seen for letrozole 2.5 mg, 0.5 mg and AG respectively. Median duration of
response and stable disease was longest for letrozole 2.5 mg (21 months)
compared with letrozole 0.5 mg (18 months) and AG (14 months). Letrozole 2.5 mg
was superior to AG in time to progression, time to treatment failure and overall
survival. Treatment-related adverse events occurred in fewer patients on
letrozole (33%) than on AG (46%). Transient nausea was the most frequent event
with letrozole (7% on 0.5 mg, 10% on 2.5 mg, 10% on AG), rash with AG (11%, 1%
on 0.5 mg, 3% on 2.5 mg letrozole). CONCLUSIONS: Letrozole 2.5 mg offers longer
disease control than aminoglutethimide and letrozole 0.5 mg in the treatment of
postmenopausal women with advanced breast cancer, previously treated with
anti-oestrogens.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 9681078 [PubMed - indexed for MEDLINE]
157: Schweiz Rundsch Med Prax 1998 Apr 22;87(17):584-8
[Aromatase inhibitors--new possibilities in treatment of breast carcinoma]
[Article in German]
Friedrichs K, Janicke F.
Frauenklinik und Poliklinik, Universitats-Krankenhaus Eppendorf, Hamburg.
Aromatase inhibition is now an acknowledged second line treatment modality for
advanced breast cancer in postmenopausal women. Aminoglutethimide is an
inhibitor of adrenal steroid biosynthesis and blocks the conversion of
cholesterol to pregnenolone, and therefore reduces levels of adrenal androgens,
which are a source of estrogens in both premenopausal and postmenopausal women.
Aminoglutethimide has produced antitumor response rates of 35% in unselected
patients, most of whom have undergone prior therapy with either chemotherapy or
hormonal manipulation. As is true of other hormonal responses, high response
rates of up to 70% are observed in patients who are ER and/or PR positive. The
reason why these drugs are currently used after tamoxifen is mainly due to the
side effects of aminoglutethimide, which impairs the mineralocorticoid and
glucocorticoid synthesis. New, less toxic compounds appear, which block the
conversion of androstenedione to estrone and efficiently suppress plasma
estrogen levels., e.g. formestane, anastrozole and letrozole. Aromatase
inhibitors are now being compared to tamoxifen as first-line endocrine treatment
in relapsing patients. If these trials confirm a similar or better response rate
to new aromatase inhibitors compared to tamoxifen, the time will come to study
them as the first line adjuvant treatment in non-metastatic disease.
Publication Types:
Review
Review, Tutorial
PMID: 9623325 [PubMed - indexed for MEDLINE]
158: Minerva Ginecol 1998 Mar;50(3):51-63
[Current status and prospectives of aromatase inhibitors in the treatment of
advanced breast cancer]
[Article in Italian]
Boccardo F.
Servizio di Oncologia Medica II, Istituto Nazionale per la Ricerca sul Cancro,
Genova.
Endocrine therapy represents one of the most effective instruments for the
palliative and adjuvant treatment of breast cancer, in particular in
postmenopausal patients. While tamoxifen still forms the treatment of choice
during the adjuvant phase and the first-line treatment during the metastatic
phase, aromatase inhibitors undoubtedly represent the treatment of choice for
patients who do not respond to antiestrogen treatment. These drugs represent a
heterogeneous family of compounds able to provide more or less selective
inhibition of aromatases by forming an irreversible bond with the catalytic site
of the enzymatic complex (type I inhibitors) or using a competitive mechanism
(type II inhibitors). Among the type I drugs, 4-hydroxyandrostenedione and
hexamestane are those that probably attract greatest clinical interest. These
drugs can significantly reduce the circulating levels of estrone and estradiol,
and have been shown to be active in 20% of patients pretreated with tamoxifen.
Moreover, hexamestane was also effective in patients pretreated with type II
inhibitors, of which the parent drug is aminoglutethimide. This drug is still
used in the second and third-line treatment of breast cancer but, since it
causes collateral effects in a substantial percentage of patients, above all
when used at higher doses in combination with hydrocortisone, it will soon be
replaced by second and third generation inhibitors, like letrozole, fadrozole,
vorozole and anastrozole. These drugs have been shown to be significantly more
active than aminoglutethimide, both in vitro and in vivo, and above all more
selective. In particular, even at high doses anastrozole has not been found to
interfere with steroidogenesis at a corticoadrenal level. Moreover, anastrozole
has been shown to be very active even at relatively modest doses given in a
single daily dose. Two recent controlled studies, including a total of over 600
patients, recently demonstrated that, if used in second line in patients who no
longer responded to adjuvant or palliative tamoxifen therapy, anastrozole is
just as effective but probably better tolerated than megestrol acetate. Studies
are now in progress or are currently being launched to evaluate the possible
value of anastrozole and other third generation inhibitors both as first-line
treatment and as adjuvant treatment as an alternative or in combination with
tamoxifen.
Publication Types:
Review
Review Literature
PMID: 9595916 [PubMed - indexed for MEDLINE]
159: Med Lett Drugs Ther 1998 Apr 10;40(1024):43-5
Toremifene and letrozole for advanced breast cancer.
PMID: 9580744 [PubMed - indexed for MEDLINE]
160: Clin Cancer Res 1998 Mar;4(3):697-711
Tamoxifen-resistant fibroblast growth factor-transfected MCF-7 cells are
cross-resistant in vivo to the antiestrogen ICI 182,780 and two aromatase
inhibitors.
McLeskey SW, Zhang L, El-Ashry D, Trock BJ, Lopez CA, Kharbanda S, Tobias CA,
Lorant LA, Hannum RS, Dickson RB, Kern FG.
Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC
20007, USA.
Although the antiestrogen tamoxifen has been the mainstay of therapy for
estrogen receptor (ER)-positive breast cancer, successful treatment of
responsive tumors is often followed by the acquisition of tamoxifen resistance.
Subsequently, only 30-40% of patients have a positive response to second
hormonal therapies. This lack of response might be explained by mechanisms for
tamoxifen resistance that sensitize ER pathways to small amounts of estrogenic
activity present in tamoxifen or that bypass ER pathways completely. To
elucidate one possible mechanism of tamoxifen resistance, we treated
ovariectomized tumor-bearing mice injected with fibroblast growth factor
(FGF)-transfected MCF-7 breast carcinoma cells with the steroidal antiestrogen
ICI 182,780 or one of two aromatase inhibitors, 4-OHA or letrozole. These
treatments did not slow estrogen-independent growth or prevent metastasis of
tumors produced by FGF-transfected MCF-7 cells in ovariectomized nude mice.
FGF-transfected cells had diminished responses to ICI 182,780 in vitro,
suggesting that autocrine activity of the transfected FGF may be replacing
estrogen as a mitogenic stimulus for tumor growth. ER levels in FGF
transfectants were not down-regulated, and basal levels of transcripts for
estrogen-induced genes or of ER-mediated transcription of estrogen response
element (ERE) luciferase reporter constructs in the FGF expressing cells were
not higher than parental cells, implying that altered hormonal responses are not
due to down-regulation of ER or to FGF-mediated activation of ER. These studies
indicate that estrogen independence may be achieved through FGF signaling
pathways independent of ER pathways. If so, therapies directed at the operative
mechanism might produce a therapeutic response or allow a response to a second
course of antiestrogen treatment.
PMID: 9533540 [PubMed - indexed for MEDLINE]
161: Anticancer Res 1998 Jan-Feb;18(1A):171-6
Antitumor effects of SEF19, a new nonsteroidal aromatase inhibitor, on
7,12-dimethylbenz[a]anthracene-induced mammary tumors in rats.
Iino Y, Karakida T, Sugamata N, Andoh T, Takei H, Takahashi M, Yaguchi S,
Matsuno T, Takehara M, Sakato M, Kawashima S, Morishita Y.
Department of Emergency and Critical Care Medicine, Gunma University School of
Medicine, Japan.
The antitumor and endocrine effects of a new nonsteroidal aromatase inhibitor,
2-(imidazol-1-yl)-4,6-dimorphorino-l, 3, 5-triazine (SEF19) were examined in
female Sprague-Dawley rats bearing estrogen dependent
7,12-dimethylbenz[a]anthracene(DMBA)-induced mammary tumors, and the effects
were compared with those of CGS20267. The rats bearing DMBA-induced mammary
tumors within 6-15 weeks after the DMBA administration were divided into the
treatment groups once a week every week, and they were treated with SEF19,
CGS20267 and vehicle for 4 weeks. One hundred rats were sacrificed 4 hours after
the last administration, and the remaining 60 rats were sacrificed after a
4-week recovery period. During the treatment and recovery period, the tumor size
was generally smaller in the SEF19 and CGS20267-treated subgroups than in the
control subgroup. Tumor sizes in the subgroups treated with high doses of SEF19
(25 mg/kg/day and 50 mg/kg/2 days) were reduced to the size of the
CGS20267-treated subgroup. The CGS20267-treated rats showed decrease in the
serum estradiol level and an increase in the serum testosterone level. Their
uterine weights were reduced. SEF19 treatment failed to show any effect on the
serum levels of estrone, estradiol, testosterone and androstenedione, but it
suppressed uterine weight in a dose-dependent manner. After the recovery period,
no effect was detected in the serum concentrations of steroid hormones and the
weight of the organs. At every dose used in the present study the aromatase
inhibitory activity of SEF19 was weaker than that of CGS20267, but the
inhibitory effect on mammary tumor growth of SEF19 at high doses was comparable
to that of CGS20267. We conclude that the antitumor effect of SEF19 is not due
to aromatase inhibition but mainly to its direct cytotoxicity.
PMID: 9568073 [PubMed - indexed for MEDLINE]
162: Oncology (Huntingt) 1998 Mar;12(3 Suppl 5):41-4
Pivotal trials of letrozole: a new aromatase inhibitor.
Smith IE.
Breast Unit, Royal Marsden Hospital, London, England.
Letrozole (Femara) is a nonsteroidal aromatase inhibitor that is approximately
10,000 times as potent as aminoglutethimide in vivo. Two pivotal multinational
phase III trials have compared letrozole (0.5 and 2.5 mg/d) against megestrol
acetate and aminoglutethimide, respectively, in patients with locally advanced
or metastatic breast cancer. The letrozole vs megestrol acetate trial showed the
superiority of letrozole (2.5 mg/d) over megestrol acetate with respect to
response rate, response duration, duration of overall clinical benefit (complete
response plus partial response plus stable disease > or = 6 months), time to
progression, and time to treatment failure. The letrozole-treated patients also
showed a nonsignificant trend toward better survival. In the letrozole vs
aminoglutethimide trial, letrozole (2.5 mg/d) was significantly superior in
terms of duration of overall clinical benefit and survival. There were also
strong trends favoring letrozole with regard to objective response rate and
duration of response. Unexpectedly, both trials demonstrated a dose-response
effect for 2.5 mg of letrozole over 0.5 mg in terms of response and overall
survival. This finding raises the possibility that intratumoral aromatase
suppression may be more relevant in breast cancer therapy than are plasma
estrogen levels.
Publication Types:
Review
Review, Tutorial
PMID: 9556791 [PubMed - indexed for MEDLINE]
163: Oncology (Huntingt) 1998 Mar;12(3 Suppl 5):36-40
Preclinical studies using the intratumoral aromatase model for postmenopausal
breast cancer.
Brodie A, Lu Q, Liu Y, Long B, Wang JP, Yue W.
Department of Pharmacology, School of Medicine, University of Maryland,
Baltimore, USA.
To determine the most effective strategies for the treatment of postmenopausal
hormone dependent breast cancer, we recently developed a model system in nude
mice. In this model, estrogen receptor-positive human breast cancer cells
(MCF-7) stably transfected with the aromatase gene are inoculated into
ovariectomized, immunosuppressed (nude) mice. These cells synthesize sufficient
estrogen from androgen substrate to stimulate their proliferation and the
development of tumors. Moreover, estrogen secreted by the tumor cells maintains
uterine weight comparable to that of the intact mouse. In the present study, we
employed this model to investigate the effects of the aromatase inhibitor,
letrozole (CGS 20267 [Femara]) on mammary tumor growth and on the uterus. We
also used this model to predict the effects of combining two aromatase
inhibitors, letrozole and anastrozole (Arimidex), with the antiestrogen
tamoxifen (Nolvadex). Letrozole was found to be a highly potent inhibitor of
tumor proliferation and more effective than tamoxifen. No stimulation of uterine
growth was observed with the aromatase inhibitors. However, the combination of
letrozole or anastrozole and tamoxifen was no more effective than either
aromatase inhibitor alone. The agonistic effect of tamoxifen on the uterus was
observed when it was given alone and when combined with the aromatase
inhibitors. Furthermore, letrozole had the most potent antitumor activity when
compared to other aromatase inhibitors and antiestrogens. No additional benefit
was observed by combining these agents with tamoxifen over treatment with
aromatase inhibitors alone.
PMID: 9556790 [PubMed - indexed for MEDLINE]
164: Oncology (Huntingt) 1998 Mar;12(3 Suppl 5):32-5
Emerging role of aromatase inhibitors in the treatment of breast cancer.
Harvey HA.
Section of Hematology-Oncology, Hershey Medical Center, Penn State Geissinger
Health Systems, Hershey, Pennsylvania, USA.
The new generation of potent steroidal and nonsteroidal inhibitors of the enzyme
aromatase act by decreasing estrogen production throughout the body in
postmenopausal women. The most potent of these agents may also inhibit estrogen
synthesis within metastatic breast cancer tissue. The newly developed, orally
administered, nonsteroidal competitive inhibitors, such as anastrozole
(Arimidex), letrozole (Femara), and vorozole (Rizivor), are a thousand times
more potent inhibitors of aromatase than is aminoglutethimide. Furthermore,
these agents are highly selective. In several large randomized trials, the new
inhibitors produced similar response rates as megestrol acetate (160 mg/d) in
postmenopausal women with hormone-dependent breast cancer, but showed a trend
toward improved response duration and survival. They also produced less weight
gain and fewer cardiovascular and thromboembolic side effects. In addition,
letrozole proved superior to aminoglutethimide in another randomized trial. Both
anastrozole (1.0 mg/d) and letrozole (2.5 mg/d) have now been approved as
second-line treatment for hormone-dependent breast cancer in postmenopausal
women in whom disease has progressed following tamoxifen treatment. Either drug
should replace the routine use of megestrol acetate in this setting. Ongoing
clinical studies are comparing anastrozole and letrozole to antiestrogens as
first-line endocrine therapy for metastatic breast cancer. Other trials will
study the possible roles of these compounds as adjuvant therapy and
chemoprevention for breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 9556789 [PubMed - indexed for MEDLINE]
165: Breast Cancer Res Treat 1998 Mar;48(1):45-51
Effect of CGS 20267 on ovarian aromatase and gonadotropin levels in the rat.
Sinha S, Kaseta J, Santner SJ, Demers LM, Bremmer WJ, Santen RJ.
Department of Medicine, The Pennsylvania State University, The Milton S. Hershey
Medical Center, Hershey 17033, USA.
Aromatase catalyzes the rate limiting step that converts androgens to estrogens.
Postmenopausal women with hormone dependent breast cancer respond to first
generation aromatase inhibitors such as aminoglutethimide with a marked
suppression of circulating estradiol levels. In contrast, premenopausal women
appear to be resistant to first generation aromatase inhibitors. The inability
to block ovarian aromatase results from the low affinity of first generation
inhibitors for the active site of the enzyme. Under these circumstances, the
high substrate levels in the premenopausal ovary compete effectively with these
inhibitors and do not allow binding of inhibitor to the active site of the
enzyme. Second and third generation aromatase inhibitors with higher affinity
for aromatase have now been developed and potentially could block ovarian
aromatase. To test this possibility, we administered CGS 20267 (letrozole), a
highly potent aromatase inhibitor, to cycling female rats. A dose dependent
inhibition of uterine weight occurred with maximum effects produced by the 5
mg/kg/day dosage. During a period of 4 weeks, uterine weight was reduced to
levels induced by ovariectomy. Ovarian tissue estradiol levels were inhibited by
approximately 80%. As a reflection of inhibition of ovarian aromatase activity,
the levels of androstenedione in the ovary increased by an order of magnitude.
Both LH and FSH plasma levels increased but not to those observed after
ovariectomy. The rise in gonadotropin levels induced a statistically significant
but relatively small increase in ovarian weights. These results demonstrate the
ability to persistently block ovarian aromatase activity in cycling rats with a
potent aromatase inhibitor. This study provides a rationale for clinical trials
of potent aromatase inhibitors in pre-menopausal women with breast cancer.
PMID: 9541188 [PubMed - indexed for MEDLINE]
166: Endocrinology 1998 Mar;139(3):1038-45
The regulation of gonadotropin-releasing hormone-induced calcium signals in male
rat gonadotrophs by testosterone is mediated by dihydrotestosterone.
Tobin VA, Canny BJ.
Department of Physiology, Monash University, Clayton, Victoria, Australia.
The biological effects of testosterone (T) may be mediated directly by T or
indirectly by its metabolites, dihydrotestosterone (DHT) and estradiol. The
present study examined whether the metabolism of T is involved in the regulation
of GnRH-induced Ca2+ signaling at the pituitary. In gonadotrophs from castrated
rats, a significantly greater percentage of gonadotrophs demonstrated
oscillatory Ca2+ responses to 100 nM GnRH than cells from intact rats (72% vs.
24%; P < 0.05). This increase was prevented by the administration of T
propionate (0.1 mg/kg x day), DHT benzoate (2 mg/kg x day,), estradiol benzoate
(EB; 5 microg/kg x day), or the combination of the above doses of DHT benzoate
and EB. In all cases the proportion of gonadotrophs from the steroid-treated
rats having oscillatory Ca2+ responses to 100 nM GnRH was between 21-25% (P >
0.05, compared with intact rats). To assess the importance of T metabolism,
intact male rats were treated with the aromatase inhibitor letrozole (1 mg/kg x
day), the 5alpha-reductase inhibitor finasteride (50 mg/kg x day), or their
respective vehicles for 7 days. Letrozole had no effect on GnRH-induced Ca2+
signals, serum LH concentrations, or ventral prostate or testes weight.
Finasteride treatment, however, mimicked the effects of castration, with
significantly more gonadotrophs exhibiting Ca2+ oscillations in response to 100
nM GnRH than gonadotrophs from the vehicle-treated group (71% vs. 20%
respectively; P < 0.05). Finasteride also caused a significant (P < 0.05)
decrease in prostatic weight and DHT concentration, but had no significant
effect on either prostatic T or serum LH concentrations. These findings suggest
that in the intact male rat, the effects of T on GnRH-induced Ca2+ signaling are
preferentially mediated via DHT. The results of this study also show that in the
absence of androgens, estradiol may regulate GnRH-induced Ca2+ signaling in the
male rat pituitary.
PMID: 9492036 [PubMed - indexed for MEDLINE]
167: J Clin Oncol 1998 Feb;16(2):453-61
Comment in:
J Clin Oncol. 1998 Aug;16(8):2892-3.
J Clin Oncol. 1999 Dec;17(12):3856-60.
J Clin Oncol. 2000 Apr;18(8):1802-3.
Letrozole, a new oral aromatase inhibitor for advanced breast cancer:
double-blind randomized trial showing a dose effect and improved efficacy and
tolerability compared with megestrol acetate.
Dombernowsky P, Smith I, Falkson G, Leonard R, Panasci L, Bellmunt J, Bezwoda W,
Gardin G, Gudgeon A, Morgan M, Fornasiero A, Hoffmann W, Michel J, Hatschek T,
Tjabbes T, Chaudri HA, Hornberger U, Trunet PF.
PURPOSE: To compare two doses of letrozole and megestrol acetate (MA) as
second-line therapy in postmenopausal women with advanced breast cancer
previously treated with antiestrogens. PATIENTS AND METHODS: Five hundred
fifty-one patients with locally advanced, locoregionally recurrent or metastatic
breast cancer were randomly assigned to receive letrozole 2.5 mg (n = 174),
letrozole 0.5 mg (n = 188), or MA 160 mg (n = 189) once daily in a double-blind,
multicenter trial. Data were analyzed for tumor response and safety variables up
to 33 months of follow-up evaluation and for survival up to 45 months. RESULTS:
Letrozole 2.5 mg produced a significantly higher overall objective response rate
(24%) compared with MA (16%; logistic regression, P = .04) or letrozole 0.5 mg
(13%; P = .004). Duration of objective response was significantly longer for
letrozole 2.5 mg compared with MA (Cox regression, P = .02). Letrozole 2.5 mg
was significantly superior to MA and letrozole 0.5 mg in time to treatment
failure (P = .04 and P = .002, respectively). For time to progression, letrozole
2.5 mg was superior to letrozole 0.5 mg (P = .02), but not to MA (P = .07).
There was a significant dose effect in overall survival in favor of letrozole
2.5 mg (P = .03) compared with letrozole 0.5 mg. Letrozole was significantly
better tolerated than MA with respect to serious adverse experiences,
discontinuation due to poor tolerability, cardiovascular side effects, and
weight gain. CONCLUSION: The data show letrozole 2.5 mg once daily to be more
effective and better tolerated than MA in the treatment of postmenopausal women
with advanced breast cancer previously treated with antiestrogens.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 9469328 [PubMed - indexed for MEDLINE]
168: J Steroid Biochem Mol Biol 1997 Nov-Dec;63(4-6):261-7
The aromatase inhibitor letrozole in advanced breast cancer: effects on serum
insulin-like growth factor (IGF)-I and IGF-binding protein-3 levels.
Bajetta E, Ferrari L, Celio L, Mariani L, Miceli R, Di Leo A, Zilembo N, Buzzoni
R, Spagnoli I, Martinetti A, Bichisao E, Seregni E.
Medical Oncology B Division, Istituto Nazionale per lo Studio e la Cura dei
Tumori, Milan, Italy.
Serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 levels were
measured in two groups of postmenopausal women with advanced breast cancer, who
received the aromatase inhibitor letrozole 0.5 or 2.5 mg p.o. once daily. Blood
samples were obtained from 15 patients in each dose group at baseline, and one
and three months after starting therapy. Circulating IGF-I and IGFBP-3
concentrations were determined by means of radioimmunoassay. In both dosage
groups a statistically significant increase in the IGF-I levels was observed
during three months of letrozole treatment (P=0.003). In addition, the multiple
testing procedure yielded in the whole patient population a significant result
in the comparison between mean IGF-I values after three months of therapy and
those observed at baseline (P=0.004), the estimated average increase being of
24%. No significant result was obtained in the analysis for the dose effect
(P=0.077) and for the time x dose interaction (P=0.208). Circulating IGFBP-3
levels did not appear to be affected by letrozole treatment in either of the
dose groups. This is the first report concerning the short-term effects of
letrozole on components of the IGF system in breast cancer patients; further
investigations are warranted in order to confirm these preliminary data.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 9459192 [PubMed - indexed for MEDLINE]
169: Cancer Epidemiol Biomarkers Prev 1998 Jan;7(1):65-78
Aromatase inhibitors as potential cancer chemopreventives.
Kelloff GJ, Lubet RA, Lieberman R, Eisenhauer K, Steele VE, Crowell JA, Hawk ET,
Boone CW, Sigman CC.
Chemoprevention Branch, Division of Cancer Prevention and Control, National
Cancer Institute, Bethesda, Maryland 20852, USA.
Epidemiological and experimental evidence strongly supports a role for estrogens
in the development and growth of breast tumors. A role for estrogen in prostate
neoplasia has also been postulated. Therefore, one chemopreventive strategy for
breast and prostate cancers is to decrease estrogen production. This can be
accomplished by inhibiting aromatase, the enzyme that catalyzes the final,
rate-limiting step in estrogen biosynthesis. The use of aromatase inhibitors is
of clinical interest for cancer therapy, and selective, potent aromatase
inhibitors have been developed. Several of these agents have demonstrated
chemopreventive efficacy in animal models. The rationale for the use of
aromatase inhibitors as chemopreventives and identification of inhibitors to
serve as potential chemopreventive agents are the subjects of this review. After
background information regarding aromatase is presented, the data for each
inhibitor are summarized separately. The discussion focuses on those inhibitors
that are clinically available or in clinical trials, including:
aminoglutethimide (Cytadren), rogletimide, fadrozole hydrochloride, liarozole
hydrochloride, anastrozole (Arimidex), letrozole, vorozole, formestane,
exemestane, and atamestane. On the basis of results from preclinical studies,
aromatase inhibitors may be promising agents for clinical trials in populations
at high risk for developing estrogen-dependent cancers. Total suppression of
aromatase may have adverse effects, as is evident in postmenopausal women
(increased osteoporosis, cardiovascular disease, and urogenital atrophy).
However, on the basis of preclinical studies of chemopreventive efficacy and
chemotherapeutic applications of aromatase inhibitors showing dose-response
efficacy, it may be possible to obtain chemopreventive effects without total
suppression of aromatase and circulating estrogen levels. Suppressing local
estrogen production may be an alternative strategy, as suggested by the
discovery of a unique transcriptional promoter of aromatase gene expression,
I.4, in breast adipose tissue. The development of drugs that target this
promoter region may be possible.
Publication Types:
Review
Review, Tutorial
PMID: 9456245 [PubMed - indexed for MEDLINE]
170: Biopharm Drug Dispos 1997 Dec;18(9):779-89
Absolute bioavailability of letrozole in healthy postmenopausal women.
Sioufi A, Gauducheau N, Pineau V, Marfil F, Jaouen A, Cardot JM, Godbillon J,
Czendlik C, Howald H, Pfister C, Vreeland F.
Laboratoires Ciba-Geigy, Bioanalytics and Pharmacokinetics, Rueil-Malmaison,
France.
Letrozole is a new non-steroidal inhibitor of the aromatase enzyme system. It is
currently under development for the treatment of postmenopausal women with
advanced breast cancer. Absolute bioavailability of letrozole when given orally
as one 2.5 mg film-coated tablet in comparison to the same dose given
intravenously as a bolus injection was studied in 12 healthy postmenopausal
women. Letrozole absolute systemic bioavailability after p.o. administration was
99.9 +/- 16.3%. Elimination of letrozole was slow. Total-body clearance of
letrozole from plasma after i.v. administration was low (2.21 L h-1). The
calculated distribution volume at steady state (1.87 L kg-1) suggests a rather
high tissue distribution. Biotransformation of letrozole is the main elimination
mechanism with the glucuronide conjugate of the secondary alcohol metabolite
being the predominant species found in urine. The two study treatments were
tolerated equally well.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 9429742 [PubMed - indexed for MEDLINE]
171: Oncology 1997;54 Suppl 2:11-4
Anastrozole--a new generation in aromatase inhibition: clinical pharmacology.
Dowsett M, Lonning PE.
Department of Academic Biochemistry, Royal Marsden Hospital, London, UK.
Use of the aromatase inhibitor aminoglutethimide is limited by its lack of
selectivity for aromatase and its toxicity. Newer agents are more selective, but
do not always offer improved inhibition of aromatase. Indirect comparison of
their activity in inhibiting aromatase and suppressing plasma oestrogens
indicates that aminoglutethimide, rogletimide, formestane, and fadrozole
inhibited aromatase activity by 74-91%, with reported falls in oestradiol level
of 58-76%. In contrast, the new-generation oral once-daily aromatase inhibitors
anastrozole (Arimidex) and letrozole were of a similar activity, inhibiting
aromatase activity by over 96%, with a concomitant fall in oestradiol and
oestrone levels of at least 80%. Anastrozole at the recommended clinical dose of
1 mg daily also suppressed oestrone sulphate levels by 93.5%; activity with
anastrozole 10 mg daily was not statistically significantly different. The new
generation of aromatase inhibitors, as typified by anastrozole, thus offers
effective and convenient aromatase inhibition which correlates well with
decreases in the levels of plasma oestrogens.
Publication Types:
Review
Review, Tutorial
PMID: 9394854 [PubMed - indexed for MEDLINE]
172: J Surg Oncol 1997 Nov;66(3):215-20
Use of aromatase inhibitors in postmenopausal women with advanced breast cancer.
Roseman BJ, Buzdar AU, Singletary SE.
Department of Surgical Oncology, University of Texas M.D. Anderson Cancer
Center, Houston 77030, USA.
Surgeons have been involved in the management of metastatic breast cancer since
the technique of ovarian ablation was introduced in 1896. However, as newer
hormonal and chemotherapeutic regimens were developed, drug therapy gradually
replaced surgery as the preferred treatment for metastatic breast cancer. Thus,
management of metastatic breast cancer has largely shifted from surgeons to
medical oncologists. Advances in hormonal pharmacology have placed hormonal
therapy alongside surgery and radiation therapy as a standard treatment option
for women with advanced breast cancer. The purpose of this article is to update
surgeons on the current use of hormonal agents for treatment of advanced breast
cancer in postmenopausal women, and to review the aromatase inhibitors, a new
line of hormonal agents for the treatment of advanced breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 9369969 [PubMed - indexed for MEDLINE]
173: J Steroid Biochem Mol Biol 1997 Apr;61(3-6):315-22
Sex differences in the regulation of embryonic brain aromatase.
Hutchison JB, Beyer C, Hutchison RE, Wozniak A.
MRC Neuroendocrine Development and Behaviour Group, The Babraham Institute,
Cambridge, U.K.
Oestrogen formed from androgen by aromatization plays a critical role in the
sexual differentiation of the male brain and behaviour. A question which has
still to be answered is what regulates the gender-specific changes in aromatase
activity forming oestrogen during sensitive periods of brain growth. Using a
primary cell culture technique and sexed embryos, we have shown that in the
fetal mouse brain, oestrogen formation in the male is neuronal rather than glial
and aromatase activity is regionally localized, being higher in the hypothalamus
than in the cortex. The aromatase activity measured from cells in culture has
the same enzyme binding affinity (apparent Km approximately 40 nM) as intact
brain samples. Neurones developing in the embryonic male brain (embryonic day
(ED) 15) contain higher aromatase activity (Vmax, 895 fmol/h/mg protein) than
the female (Vmax, 604). Although a sex difference exists at early stages of
embryonic development (ED 13), the embryonic aromatase system is regulated by
steroids later in fetal development. The developing aromatase-containing
neuroblasts probably form processes which connect to other aromatase neurones.
Immunoreactive staining with an aromatase polyclonal antibody identifies an
increase in numbers of aromatase-immunoreactive hypothalamic neuronal cell
bodies following testosterone treatment. Testosterone treatment also causes both
stimulation of neurite growth and branching as well as functional maturation of
aromatase neurones. In particular, there is an increase in aromatase activity
per neurone as well as a dramatic increase in the number of neurones expressing
the enzyme. Both the functional and morphological changes depend on androgen
receptor stimulation for several days in vitro. This conclusion is supported by
colocalization studies which reveal a high number of fetal hypothalamic
aromatase neurones co-expressing androgen receptor. We conclude that
testosterone influences the growth of male hypothalamic neurones containing
aromatase at a sensitive period of brain development. Endogenous steroid
inhibitors of aromatase, probably formed within the neuroglia, also play a role
in the control of oestrogen production. An endogenous 5alpha-reduced metabolite
of testosterone, 5alpha-androstanedione, is almost as potent in inhibiting
neuronal hypothalamic aromatase activity (Ki = 23 nM) as the synthetic
non-steroidal inhibitors such as the imidazole, fadrozole, and the triazoles,
arimidex and letrozole. It is clear that the oestrogen-forming capacity of the
male hypothalamus has the special characteristics and plasticity of regulation
which could affect brain differentiation at specific steroid-sensitive stages in
ontogeny.
Publication Types:
Review
Review, Tutorial
PMID: 9365207 [PubMed - indexed for MEDLINE]
174: J Steroid Biochem Mol Biol 1997 Apr;61(3-6):241-5
Clinical use of aromatase inhibitors in the treatment of advanced breast cancer.
Trunet PF, Vreeland F, Royce C, Chaudri HA, Cooper J, Bhatnagar AS.
Department of Research and Medicine, Ciba-Geigy Ltd, Rueil-Malmaison, France.
The aim of endocrine therapy is to reduce the estrogenic stimulus for tumour
growth. After failure of tamoxifen--the standard "first-line" hormonotherapy for
advanced breast cancer (ABC)--the most frequently prescribed endocrine therapies
are progestins and aromatase inhibitors (AIs) ("second-line" hormonotherapy).
Estrogen deprivation through AIs provides effective treatment of
hormone-dependent ABC in postmenopausal (PMP) women. Over the past few years,
the goals of our research programme were to develop more potent, more selective
and better tolerated AIs than our first AI, aminoglutethimide (AG). Lentaron
(4-hydroxyandrostenedione, formestane), a highly selective steroidal compound
was the first of the new AIs to be used in clinical trials. It is a substrate
analogue, administered as an i.m. injection every 2 weeks. It is effective in
the treatment of ABC with an objective response rate (ORR) similar to tamoxifen
and megestrol acetate (MA) and is generally well tolerated; rare instances of
injection site reactions have been reported. Afema (fadrozole HCl), a
non-steroidal AI is active orally, and effectively suppresses estrogen levels in
PMP women, but it is not completely selective for aromatase when administered at
higher than therapeutic doses. At the therapeutic dose of 1 mg twice a day it
has an anti-tumour efficacy similar to MA, a good tolerability and no clinically
relevant effects on other hormones of the endocrine system. Letrozole is the
fourth of our AIs in clinical development. It is a non-steroidal, achiral,
orally active, potent and highly selective competitive AI. Clinical endocrine
studies have shown that the dose of 0.5 mg a day is the lowest dose achieving
maximum estrogen suppression. Over a wide dose range, a lack of clinically
relevant effects on other hormones of the endocrine system has confirmed its
high selectivity. In four phase Ib/IIa studies in PMP patients with ABC who
failed previous therapy, letrozole produced ORRs of 9, 31, 33 and 36%. One phase
IIb/III study has been completed and two others are ongoing, comparing two doses
of letrozole with MA or AG to confirm the anti-tumour efficacy of letrozole in
the treatment of ABC in PMP women after treatment with anti-estrogens.
Preliminary results from the completed trial show that letrozole 2.5 mg is
superior to 0.5 mg in terms of ORR, time to progression and time to treatment
failure, and is superior to the standard dose of MA in terms of ORR and
tolerability. Therefore letrozole 2.5 mg can be recommended as a first choice
for the treatment of PMP patients with hormone receptor-positive or unknown ABC
after anti-estrogen therapy.
Publication Types:
Review
Review, Tutorial
PMID: 9365196 [PubMed - indexed for MEDLINE]
175: J Steroid Biochem Mol Biol 1997 Apr;61(3-6):193-202
Regulation of aromatase activity within the breast.
Miller WR, Mullen P, Sourdaine P, Watson C, Dixon JM, Telford J.
University Dept. of Clinical Oncology, Western General Hospital, Edinburgh, U.K.
Local oestrogen biosynthesis within the breast can be highly variable, in vitro
aromatase activity both in breast cancers and mammary adipose tissue displaying
over a 40-fold range between the highest and lowest levels. Evidence is
presented to show that: (i) transcriptional activity may influence oestrogen
biosynthesis within breast cancers in that both aromatase mRNA and STAT nuclear
binding are correlated positively to in vitro aromatase activity; (ii) the local
presence of cancer may enhance aromatase activity in particulate fractions and
primary fibroblast cultures from mammary adipose tissue; (iii) tumour extracts
and breast cyst fluids may induce aromatase in cultured fibroblasts, the active
principles responsible for these effects being incompletely defined (although
the combination of interleukin (IL)-6 and its soluble receptor dramatically
enhances aromatase activity, it is unclear whether this particular cytokine
system can account for the stimulatory effects of breast extracts and fluids);
(iv) the aromatase activities in both breast cancer and adipose tissues are
susceptible to classical aromatase inhibitors such as aminoglutethimide and
4-hydroxyandrostenedione (and to newer inhibitors such as CGS16949 and CGS20267
at low nanomolar concentrations) but reduced sensitivity to
4-hydroxyandrostenedione may be observed in certain breast cancers. These
findings may have important implications for the development and progression of
hormone-dependent cancers within the breast.
PMID: 9365190 [PubMed - indexed for MEDLINE]
176: J Steroid Biochem Mol Biol 1997 Apr;61(3-6):157-66
Effect of estrogen deprivation on the reproductive physiology of male and female
primates.
Shetty G, Krishnamurthy H, Krishnamurthy HN, Bhatnagar S, Moudgal RN.
Center for Reproductive Biology and Molecular Endocrinology, Indian Institute of
Science, Bangalore.
The availability of CGS 16949A, CGS 20267 and CGP 47645, a series of aromatase
inhibitors (AIs) having high specific activity and specificity, made possible
this study wherein the need for estrogen (E) for regulating (a) follicular
maturation/ovulation, luteal function and pregnancy establishment, and (b)
testicular function of the bonnet monkey (Macaca radiata) has been examined.
Generally these compounds, used in the range of 500 microg to 2.5 mg/day did not
inhibit follicular maturation although they did reduce E levels. Although low
doses had no effect on ovulation it appears that relatively high doses of CGS
20267 and CGP 47645 could be inhibiting it. Three oral doses of letrozole (CGS
20267, each dose of 2 mg) during the follicular phase resulted in the formation
of multiple follicles in cycling females, and these could be ovulated by
exogenous hCG (1000 IU) treatment. Although administration of AI during the
early luteal phase had no effect on progesterone (P) production, it prevented
pregnancy establishment. Whereas AI administration in the female had no
significant effect on luteinizing hormone (LH) and follicle stimulating hormone
(FSH) levels (except at high drug dosages), it significantly increased serum
testosterone (T) levels in the male. Sustained high levels of T (30-50 ng/ml)
could be maintained for 100 days by administering 2.5 mg of CGP 47465 orally
once in 5 days. Blockade of E synthesis in the male led to the disruption of
testicular germ cell transformation, which in turn resulted in a significant
reduction in sperm production. These studies with aromatase inhibitors in the
monkey suggest that these compounds have a potential for use as fertility
regulating agents in both the male and female primate.
PMID: 9365186 [PubMed - indexed for MEDLINE]
177: Cancer 1997 Oct 15;80(8 Suppl):1646-51
Issues concerning the role of chemotherapy and hormonal therapy of bone
metastases from breast carcinoma.
Harvey HA.
Division of Hematology-Oncology, The Milton S. Hershey Medical Center,
Pennsylvania 17033, USA.
A significant percentage (50-70%) of patients with metastatic breast carcinoma
(MBC) will have disease involving the bony skeleton. Clonal selection mediated
by parathyroid hormone-related protein and other factors may explain the high
incidence of osseous metastases in MBC. The presence of specific growth factors
and cytokines in the microenvironment of bone may contribute to the successful
establishment and growth of metastatic lesions and also might determine response
or resistance of these lesions to chemotherapy or hormonal therapy. Osteolytic
bone lesions in MBC frequently give rise to serious clinical problems including
bone pain, pathologic fracture, hypercalcemia, and neurologic complications. MBC
often is treated with systemic chemotherapy or hormonal therapy. The purpose of
this article was to review the recent published literature describing the impact
of systemic chemotherapy and hormonal therapy of MBC on the response of bone
lesions and their clinical course and complications. Evaluating the response of
bone lesions can be problematic and may be complicated by the phenomenon of
"tumor flare" that may be observed with either chemotherapy or hormonal therapy.
Use of the International Union Against Cancer criteria for the response of bone
lesions is recommended. Several studies report objective responses (20-60%) of
lytic bone metastases to standard combination chemotherapy regimens such as
cyclophosphamide, methotrexate, and 5-fluorouracil and cyclophosphamide,
doxorubicin, and 5-fluorouracil, mitoxantrone and 5-FU, newer combinations, and
single agents including paclitaxel and docitaxel but responses to vinorelbine
may be less frequent. Complete responses of bone lesions to chemotherapy are
rare but partial responses and disease stabilization can lead to long term
patient benefit. A series from the M. D. Anderson Cancer Center of patients with
bone metastases treated with 5-FU, doxorubicin, and cyclophosphamide
chemotherapy reported a median duration of response of 14 months. In a recent
multicenter study of 195 patients with lytic lesions from MBC treated with
chemotherapy, the objective response rate (complete response + partial response)
in bone was 18% and 65% of the patients developed at least 1 morbid skeletal
event with a median onset of 7.0 months from the start of chemotherapy.
Hormone-dependent breast carcinoma has a proclivity to metastasize to bone. In
earlier studies comparing aminoglutethimide or medroxyprogesterone acetate with
tamoxifen, a higher response rate of bone metastases was observed for the first
two agents. However, in more recent studies comparing newer aromatase
inhibitors, such as anastrozole, fadrozole, and letrozole, with megestrol
acetate, there were no significant differences in rates of response in bone.
Patients with MBC with bony lesions respond to both chemotherapy and hormonal
therapy and can have a prolonged survival. Therefore such patients are in a more
favorable position to benefit from adjunctive supportive therapy such as
bisphosphonates intended to reduce skeletal morbidity.
Publication Types:
Review
Review, Tutorial
PMID: 9362431 [PubMed - indexed for MEDLINE]
178: Gan To Kagaku Ryoho 1997 Oct;24(13):1910-6
[New drugs in metastatic breast cancer--1997]
[Article in Japanese]
Enomoto K.
Dept. of Surgery, Keio University, Tokyo, Japan.
The introduction of new drugs may offer significant hope for improvement in the
treatment of breast cancer. They include new cytotoxic agents such as Taxanes,
Topoisomerase inhibitor, MDR modulator, new hormone such as 3rd generation
nonsteroidal aromatase inhibitor, pure antiestrogen for patients with refractory
metastatic breast cancer and new bisphosphonates for those who have metastases
to bone. Therefore, some reports evaluating such new drugs were reviewed.
Japanese studies revealed response rate of Taxanes in the treatment of
metastatic breast cancer as follows; Six out of 22 (27%) with 1 CR for 24 hours
infusion, 21 out of 52 (34%) with 2 CR for 3 hours infusion of paclitaxel
respectively, 21 out of 31 (41%) with 2 CR for 1 hour infusion, and 32 out of 72
(44%) with 5 CR for 1 hour infusion of Docetaxel, In addition, the MTD of the
combination was reached at dose level with 60 mg/sqm of Docetaxel and 400 mg/sqm
of cyclophosphamide. As regards hormone therapy, thirty four out of 176 (19%)
with 5 CR were observed in phase II study of Fadrozol but results from the phase
II study of 3rd generation aromatase inhibitor is not yet accomplished in Japan.
However, any european reports did not show a difference in response rate in
patients with tamoxifen refractory breast cancer between newer aromatase
inhibitor and megasterol, and a good choice of hormones in the treatment of
metastatic breast cancer appears to be difficult.
Publication Types:
Review
Review, Tutorial
PMID: 9350235 [PubMed - indexed for MEDLINE]
179: Drugs Aging 1997 Sep;11(3):245-50; discussion 251-2
Vorozole.
Wiseman LR, Spencer CM.
Adis International Limited, Auckland, New Zealand. [email protected]
Vorozole is a triazole derivative which binds to the cytochrome P450 moiety of
aromatase, thus causing reversible inhibition of the enzyme. Plasma estradiol
levels are reduced by about 90% in postmenopausal women treated with vorozole.
Phase II clinical studies found vorozole to be an effective agent for the
treatment of postmenopausal women with advanced breast cancer, achieving
objective responses in up to 35% of patients. In 2 large phase III studies,
vorozole 2.5 mg/day demonstrated favourable clinical efficacy compared with
aminoglutethimide and megestrol. Vorozole improved patients' quality of life to
a greater extent than aminoglutethimide. Clinical trials to date indicate that
the tolerability of vorozole is better than that of aminoglutethimide. Vorozole
also appears to be at least as well tolerated as megestrol (although
inappropriate bodyweight gain is more common in megestrol recipients). The most
common adverse events with vorozole are hot flushes, and nausea, which are
generally mild in severity.
Publication Types:
Review
Review, Tutorial
PMID: 9303282 [PubMed - indexed for MEDLINE]
180: Ann Oncol 1997 Jul;8(7):631-2
Aromatase inhibitors come of age.
Dowsett M.
Publication Types:
Editorial
PMID: 9296213 [PubMed - indexed for MEDLINE]
181: Biopharm Drug Dispos 1997 Aug;18(6):489-97
Comparative bioavailability of letrozole under fed and fasting conditions in 12
healthy subjects after a 2.5 mg single oral administration.
Sioufi A, Sandrenan N, Godbillon J, Trunet P, Czendlik C, Howald H, Pfister C,
Ezzet F.
Laboratoires Ciba-Geigy, Bioanalytics and Pharmacokinetics, Medical Department,
Rueil-Malmaison, France.
Letrozole is a new non-steroidal inhibitor of the aromatase enzyme system. It is
currently under development for the treatment of postmenopausal women with
advanced breast cancer. To investigate the influence of food on the
bioavailability of letrozole, 12 healthy male volunteers were treated under fed
and fasted conditions with single oral doses of 2.5 mg letrozole in film-coated
tablets. Plasma concentration profiles were determined. No significant
difference in the extent of absorption (AUC or AUC0-8 h) was observed between
the two treatments but the rate of letrozole absorption decreased slightly under
fed conditions. However, in view of the half-life of about 2 d this small change
in the absorption rate is not considered to be of clinical relevance for
treatment with repeated administrations.
Publication Types:
Clinical Trial
Controlled Clinical Trial
PMID: 9267682 [PubMed - indexed for MEDLINE]
182: Cancer 1997 Jul 15;80(2):218-24
A randomized phase II trial of two dosage levels of letrozole as third-line
hormonal therapy for women with metastatic breast carcinoma.
Ingle JN, Johnson PA, Suman VJ, Gerstner JB, Mailliard JA, Camoriano JK, Gesme
DH Jr, Loprinzi CL, Hatfield AK, Hartmann LC.
Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
BACKGROUND: It is common practice to utilize a series of different hormonal
agents in the treatment of postmenopausal women who, despite disease
progression, continue to be candidates for hormonal therapy on a clinical basis.
Letrozole is a new highly selective and potent aromatase inhibitor. There are
limited data on third-line hormonal therapy in general, and this study was
undertaken to evaluate letrozole in this context. METHODS: A randomized trial
involving two independent Phase II trials of two letrozole dosage levels, 0.5 mg
and 2.5 mg per day, was performed. Eligibility requirements included failure on
two prior hormonal therapies and measurable or evaluable disease. RESULTS:
Ninety-one patients, 46 receiving 0.5 mg and 45 receiving 2.5 mg of letrozole
per day, were assessable for response. At the lower dose, 9 patients (20%)
achieved an objective response; 6 patients (13%) had this documented on 2
occasions separated by 3 months. At the higher dose, 10 patients (22%) achieved
a response; 8 patients (18%) had this documented on 2 occasions separated by 3
months. The median times to progression were 97 days for the lower dose and 154
days for the higher dose. Toxicity was considered acceptable. CONCLUSIONS:
Letrozole has definite antitumor activity as third-line hormonal therapy for
women with metastatic breast carcinoma at doses of 0.5 and 2.5 mg per day. It is
an effective and generally well-tolerated hormonal agent.
Publication Types:
Clinical Trial
Clinical Trial, Phase II
Randomized Controlled Trial
PMID: 9217033 [PubMed - indexed for MEDLINE]
183: Drug Ther Bull 1997 Jul;35(7):55-6
New aromatase inhibitors for breast cancer.
Anastrozole (Arimidex-Zeneca) and letrozole (Femara-Novartis) are the first
selective, oral, non-steroidal aromatase inhibitors. They are licensed for the
treatment of advanced breast cancer in postmenopausal women where tamoxifen or
other anti-oestrogen therapy has failed. The manufacturers of both drugs claim
that their products are more effective, less toxic and better tolerated than the
progestogen megestrol acetate, the standard therapy in this clinical situation.
We assess these claims.
Publication Types:
Review
Review, Tutorial
PMID: 9282426 [PubMed - indexed for MEDLINE]
184: Tumori 1996 Sep-Oct;82(5):417-22
Novel non-steroidal aromatase inhibitors: are there new perspectives in the
treatment of breast cancer?
Bajetta E, Celio L, Buzzoni R, Bichisao E.
Division of Medical Oncology B, Istituto Nazionale per lo Studio e la Cura dei
Tumori, Milan, Italy.
Breast cancer is the most common malignant neoplasm affecting women in Western
countries, and most new cases are manifested during the postmenopausal period.
The clinical results obtained with aminoglutethimide, and later with formestane,
have established aromatase inhibition as one of the major therapeutic options in
hormone-dependent advanced disease. Nevertheless, the lack of specificity of
aminoglutethimide and the less than optimal oral activity of formestane soon led
to further efforts to find a potent, highly selective, orally active,
side-effect-free aromatase inhibitor for use in postmenopausal women with
advanced breast cancer. Here we review the available data on three new,
competitive non-steroidal aromatase inhibitors--letrozole, vorozole and
anastrozole--which are approaching the point of detailed pharmacologic and
clinical evaluation. Preliminary data have confirmed the high potency and
selectivity of these endocrine agents, but their antitumor activity still
remains to be completely defined. Challenges given by these novel aromatase
inhibitors are discussed taking into account the biologic implications related
to their mechanism of action and their future use in the management of breast
cancer.
Publication Types:
Review
Review, Tutorial
PMID: 9063515 [PubMed - indexed for MEDLINE]
185: J Endocrinol 1996 Sep;150 Suppl:S59-63
Oestrogen formation in breast: clinical and biological importance.
Dowsett M, Detre S, Rowlands M, Grimshaw R.
Royal Marsden Hospital, London, UK.
It has been known for many years that many breast carcinomas can synthesize
oestrogens from androgens via the action of the enzyme aromatase. There has been
widespread speculation on the possibility that this acts as an important
intracrine source of growth stimulation. For example, there are data which
indicate that clinical response to aromatase inhibitors is far more common in
tumours which possess measurable amounts of aromatase. In addition, aromatase
activity in the quadrant of the normal breast surrounding breast carcinomas is
generally higher than in the other quadrants. However, these data are only
suggestive and the case for a significant role for intratumoural aromatase in
breast cancer growth remains unproven. We have recently explored this
possibility by the transfection of human breast cancer cells with aromatase. By
a series of experiments in athymic mice we have demonstrated that growth is
supported by this intracrine source in the absence of endocrine oestrogen
stimulation.
PMID: 8943788 [PubMed - indexed for MEDLINE]
186: J Chromatogr B Biomed Appl 1996 Aug 30;683(2):251-8
High-performance liquid chromatography of the aromatase inhibitor, letrozole,
and its metabolite in biological fluids with automated liquid-solid extraction
and fluorescence detection.
Marfil F, Pineau V, Sioufi A, Godbillon SJ.
Laboratory Ciba-Geigy, Rueil-Malmaison, France.
An analytical method for the determination of letrozole (CGS 20,267) in plasma
and of letrozole and its metabolite, CGP 44,645, in urine is described.
Automated liquid-solid extraction of compounds from plasma and urine was
performed on disposable 100-mg C8 columns using the ASPEC system. The separation
was achieved on an ODS Hypersil C18 column using acetonitrile-phosphate buffer,
pH 7, as the mobile phase at a flow-rate of 1.5 ml/min. A fluorescence detector
was used for the quantitation. The excitation and emission wavelengths were 230
and 295 nm, respectively. The limits of quantitation (LOQ) of letrozole in
plasma and in urine were 1.40 nmol/l (0.4 ng/ml) and 2.80 nmol/l, respectively.
The respective mean recoveries and coefficient of variation (C.V.) were 96.5%
(9.8%) in plasma and 104% (7.7%) in urine. The LOQ of CGP 44645 in urine was
8.54 nmol/l (2 ng/ml). The mean recovery was 108% (6.3%). The compounds were
well separated from co-extracted endogenous components and no interferences were
observed at the retention times of compounds. The sensitivity of this method for
letrozole in plasma should be sufficient for kinetic studies in humans with
single doses of 0.5 mg and possibly less.
PMID: 8891923 [PubMed - indexed for MEDLINE]
187: J Steroid Biochem Mol Biol 1996 Jul;58(4):411-5
Paradoxical effect of an aromatase inhibitor, CGS 20267, on aromatase activity
in guinea pig brain.
Choate JV, Resko JA.
Department of Physiology and Pharmacology, Oregon Health Sciences University,
Portland 97201, U.S.A.
To determine the effect of in vivo treatment of guinea pigs with a non-steroidal
aromatase inhibitor (CGS 20267; letrozole), we treated subjects with
subcutaneous Silastic implants containing crystalline letrozole. We studied four
treatment groups: intact, intact letrozole-treated, castrate and castrate
letrozole-treated. After treatment for 1 week, brain tissues (preoptic area,
septum, medial basal hypothalamus, amygdala and parietal cortex) were removed,
and microsomal aromatase activity (AA) was determined by an in vitro 3H2O assay
using 1beta-3H-androstenedione as substrate. Kinetic experiments were performed
to determine the competitive nature of letrozole and an approximate Ki was
calculated. Letrozole appears to be a reversible, competitive inhibitor of
aromatase activity with an apparent Ki of 1.2 nM. Aromatase activity in intact
letrozole-treated animals was elevated compared to untreated controls in all
brain areas tested (P< 0.05). Letrozole also stimulated AA in the brains of
letrozole-treated castrated guinea pigs compared to untreated castrated animals
(P< 0.05). These data indicate that letrozole administered in vivo causes an
increase in AA. Possible mechanisms include an autoregulatory mechanism which is
interrupted by enzyme inhibition, or an effect of the inhibitor on turnover
rates of P450 aromatase.
PMID: 8903425 [PubMed - indexed for MEDLINE]
188: Differentiation 1996 Jul;60(4):193-201
The ovary retains male potential after the thermosensitive period for sex
determination in the turtle Emys orbicularis.
Dorizzi M, Richard-Mercier N, Pieau C.
Institut Jacques Monod, CNRS, Paris, France.
Emys orbicularis is a turtle with temperature-dependent sex determination. The
thermosensitive period (TSP) lies between embryonic stages 16 and 22. Gonadal
differentiation begins during this period involving oestrogens. Treatment with
oestrogens during TSP results in the differentiation of ovaries at a
male-producing temperature (25 degrees C), whereas treatment with an
antioestrogen (tamoxifen) or with nonsteroidal aromatase inhibitors results in
gonadal masculinization at a female-producing temperature (30 degrees C). The
present study examines the effects on the ovary of inhibiting aromatase activity
after TSP. Eggs of E. orbicularis incubated at 30 degrees C were given five or
seven applications of 10 micrograms aromatase inhibitor Letrozole (CGS 20267) in
ethanol, between stages 22+ and 24-25 when ovarian aromatase activity strongly
increases. Individuals which received five applications were sacrificed at
stages 24(+)-25. Those which received seven applications were sacrificed either
at stage 25+ (close to hatching), or 34-36 days after hatching. Gonadal
aromatase activity and related gonadal structure were studied in each
individual. In the three series, the gonadal aromatase activity in individuals
treated with Letrozole varied from similar or close to that in controls to much
lower, and the gonadal structure varied from ovary-like to ovotestis. Ovotestes
had the lowest levels of aromatase activity, under 4 fmoles/h/gonad, close to
testis levels. They were found in 7 out of 26 individuals given Letrozole.
Besides ovotestes, gonads presenting various degrees of masculinization, with
enlarged epithelial cords and lacunae in the medulla, were found. Therefore, by
inhibiting aromatase activity and thus estrogen synthesis, we were able to
obtain the differentiation of testis-like cords or tubes in ovaries of E.
orbicularis, after the period of temperature sensitivity. These results show
that the ovary retains male potential after this period. Thus, besides their
implication during the critical embryonic period for gonadal sex
differentiation, oestrogens play a role in maintaining the ovarian structure
after this period. A decrease in oestrogen levels could explain some other cases
of ovarian masculinization known in vertebrates.
PMID: 8765049 [PubMed - indexed for MEDLINE]
189: Acta Oncol 1996;35 Suppl 5:38-43
Aromatase inhibition for breast cancer treatment.
Lonning PE.
Department of Oncology, Haukeland University Hospital, Bergen, Norway.
While the first generation aromatase inhibitor aminoglutethimide and second- and
third generation inhibitors like formestane and fadrozole all have been found to
inhibit in vivo aromatization by 85-93%, the novel aromatase inhibitors
letrozole and arimidex inhibit in vivo aromatization by 97-99%. However, we do
not know whether these drugs cause a higher response rate or a longer duration
of remission compared with less potent aromatase inhibitors. Lack of
cross-resistance to steroidal and non-steroidal aromatase inhibitors suggests
that these drugs may have partially different mechanisms of action, probably by
influencing the intratumour aromatase enzyme. Recent studies have shown that
breast cancer cells may adapt to alterations in oestrogen concentration in vitro
by increasing their sensitivity. The observation that patients suffering relapse
following castration, hypophysectomy or adrenalectomy may respond to treatment
with aromatase inhibitors suggests that similar mechanisms could be responsible
for acquired resistance to oestrogen deprivation.
Publication Types:
Review
Review, Tutorial
PMID: 9142963 [PubMed - indexed for MEDLINE]
190: Acta Oncol 1996;35 Suppl 5:15-8
Letrozole (CGS 20267), a new oral aromatase inhibitor for the treatment of
advanced breast cancer in postmenopausal patients.
Trunet PF, Bhatnagar AS, Chaudri HA, Hornberger U.
Department of Research, Pharmaceuticals Division, Ciba-Geigy Limited, Basel,
Switzerland.
Letrozole is a new orally, active, potent, and highly specific non-steroidal
aromatase inhibitor. Letrozole is about 200 and 10000 times as potent as
aminoglutethimide (AG) in vitro and in vivo, respectively. Letrozole was tested
in healthy men and postmenopausal women and in postmenopausal patients with
advanced breast cancer (ABC). Levels of circulating estrogens decreased by more
than 75 to 95% from pre-treatment levels have been observed in patients treated
with daily doses of 0.1 to 5 mg letrozole. No clinically relevant changes in
other hormones of the endocrine system were found. In four phase Ib/IIa trials,
letrozole has shown anti-tumor activity in postmenopausal patients with ABC
previously treated with hormonotherapy and/or chemotherapy. Letrozole was well
tolerated. Phase IIb/III studies are on going to compare two doses of letrozole
with megestrol acetate or AG in order to confirm the anti-tumor efficacy of
letrozole in the treatment of ABC in postmenopausal patients who
progressed/relapsed following treatment with anti-estrogens.
Publication Types:
Review
Review, Tutorial
PMID: 9142959 [PubMed - indexed for MEDLINE]
191: Ann Oncol 1996 Jan;7(1):99-102
Letrozole, a new oral non-steroidal aromastase inhibitor in treating
postmenopausal patients with advanced breast cancer. A pilot study.
Bisagni G, Cocconi G, Scaglione F, Fraschini F, Pfister C, Trunet PF.
Medical Oncology Division, University Hospital, Parma.
PURPOSE: To evaluate the endocrine effects as well as the pharmacokinetic
parameters, efficacy and safety of letrozole, a new fourth-generation
non-steroidal aromatase inhibitor. PATIENTS AND METHODS: Fourteen postmenopausal
women with progressive metastatic breast cancer, previously treated with
endocrine therapy and/or chemotherapy for advanced disease, were treated with
0.5 mg daily doses of letrozole, orally. Endocrine and pharmacokinetic
measurements were made before treatment and on days 14, 28, 56, and 84 of
therapy. RESULTS: Letrozole induced a >86% decrease in plasma estrone and a
approximately 67% reduction in circulating estradiol from day 14 on. There was a
statistically significant decrease in plasma cortisol, which appeared clinically
irrelevant since all values remained within the normal range. No significant
changes in aldosterone concentration were noted. One patient achieved a complete
response (CR) and 4 patients a partial response (PR), with an objective response
rate of 36% (95% CI 13% to 65%). Median duration of response was 24 months,
ranging from 4 to 44 months. No toxic effects attributable to letrozole were
noted in any patient. CONCLUSION: Letrozole appears to be a very promising new
antiaromatase drug. The characteristics of the patients more likely to respond,
taking into account prior systemic treatment, should be defined by future
studies. Further phase II and phase III studies comparing letrozole to other
available second or even first-line endocrine-therapy agents, are warranted.
Publication Types:
Clinical Trial
PMID: 9081401 [PubMed - indexed for MEDLINE]
192: J Steroid Biochem Mol Biol 1996 Jan;56(1-6 Spec No):145-50
The control and biological importance of intratumoural aromatase in breast
cancer.
Dowsett M, Lee K, Macaulay VM, Detre S, Rowlands M, Grimshaw R.
Royal Marsden Hospital, London, U.K.
The existence of aromatase activity in human breast carcinomas has been
established for about 20 years but the clinical and biological importance of
this remains unclear. A number of studies in clinical material suggest that
aromatase activity may be a prerequisite of response to aromatase inhibitors and
that aromatase activity may be enhanced in those tumours relapsing during
treatment with one such inhibitor, aminoglutethimide. These results would carry
more significance, however, if it was demonstrable that the growth of breast
carcinomas is affected by the conversion of androgens to oestrogens by
intratumoural aromatase. We have tried to address this by establishing model
systems with aromatase-transfected MCF7 breast cancer cells. We have
demonstrated that these cells can be stimulated mitogenically with androgen and
that this proliferation is suppressible with aromatase inhibitors. Similarly the
growth of aromatase transfected cells but not wild type cells as xenografts is
supported by androstenedione and inhibitable by both the steroidal aromatase
inhibitor, 4-hydroxyandrostenedione and non-steroidal inhibitor, CGS 20267. Work
with the former of these, which is a suicide inhibitor allowed us to demonstrate
that growth can proceed with aromatase activity approximating to the highest
level seen in breast carcinomas indicating that at least at this extreme level
the intratumoural conversion of androgens to oestrogens may indeed be able to
support tumour growth. Further work with this mode system should allow us to
define the minimal amount of intratumoural activity which can support tumour
growth.
Publication Types:
Review
Review, Tutorial
PMID: 8603035 [PubMed - indexed for MEDLINE]
193: Gen Comp Endocrinol 1995 Dec;100(3):314-26
Endocrine sex reversal of gonads by the aromatase inhibitor Letrozole (CGS
20267) in Emys orbicularis, a turtle with temperature-dependent sex
determination.
Richard-Mercier N, Dorizzi M, Desvages G, Girondot M, Pieau C.
Institut Jacques Monod, CNRS et Universite Paris, France.
In embryos of Emys orbicularis, the sexual differentiation of gonads is
influenced by the incubation temperature of eggs. Estrogens administered during
the thermosensitive period result in the feminization of gonads at 25 degrees
(male-producing temperature), whereas an antiestrogen or aromatase inhibitors
masculinize the gonads at 30 degrees (female-producing temperature). The
nonsteroidal aromatase inhibitor Letrozole induces gonads with different degrees
of masculinization, from ovary-like to testis-like. The present study examines
the endocrine function of such masculinized gonads, at the end of embryonic
life. Aromatase activity (which is involved in estrogen synthesis in ovary) and
the status of Mullerian ducts (the regression of which reflects the secretion of
a putative anti-Mullerian hormone by the Sertoli cells) were examined. One month
after treatment with Letrozole, the gonads of embryos presented various levels
of aromatase activity. There was a strong correlation among aromatase activity,
gonadal structure, and Mullerian duct status; high levels of aromatase (similar
or close to those in control females) were found in ovary-like gonads;
intermediate levels were found in gonads (masculinized ovaries or ovotestes?)
exhibiting a cortex and a composite medulla containing a mixture of ovarian
lacunae and testicular cord-like structures; low levels (similar or close to
those in control males) were found in strongly masculinized gonads (testis-like
or ovotestes). Mullerian ducts were regressing in the majority of embryos with
gonads containing low levels of aromatase activity. In these individuals, gonads
functioned as embryonic testes. These results confirm the implication of
estrogens in gonadal differentiation. The origin of these hormones is
controversial, so that the aromatase activity was compared in gonads, in the
undissociated adrenal-mesonephric complex (AM), and in different parts of this
complex during the thermosensitive period. At the female-producing temperature,
the aromatase activity per unit of tissue increased in differentiating ovaries
but it was low in AM and similar to that found in AM at male-producing
temperature. In embryos whose gonads had been masculinized by early treatment
with Letrozole, aromatase activity was unchanged in AM. These results suggest
that the main source of estrogens involved in ovarian differentiation is the
gonad itself.
PMID: 8775058 [PubMed - indexed for MEDLINE]
194: Curr Opin Oncol 1995 Nov;7(6):523-6
Metastatic breast cancer.
Rubens RD.
Imperial Cancer Research Fund, Clinical Oncology Unit, Guy's Hospital, London,
UK.
Tamoxifen as adjuvant systemic treatment after first isolated locoregional
recurrence of breast cancer has been shown to decrease the subsequent
locoregional relapse rate, but it affects neither distant metastases nor
survival. In metastatic disease, tamoxifen has not improved response when added
to ablation of ovarian function. The cyclical sequential use of tamoxifen with
megestrol acetate has not increased the response over tamoxifen alone. Aromatase
inhibitors are an expanding field; formestane and vorozole are effective agents,
and letrozole shows promise. In chemotherapy, major interest has focused on the
use of taxoids, with high activity being reported for both paclitaxel and
docetaxel, the latter being particularly effective as a second-line treatment.
Reports continue to reaffirm the effectiveness of vinorelbine. The in vitro
ability of quinidine to reverse resistance to anthracyclines has not been
repeatable in a clinical setting. The evaluation of high-dose chemotherapy with
bone marrow support continues to be explored, but this approach has thus far not
been demonstrated to improve clinical outcome in advanced disease. The
intra-arterial administration of chemotherapy appears to have a useful
palliative role in selected patients with locoregional disease.
Publication Types:
Clinical Trial
Review
Review, Tutorial
PMID: 8547400 [PubMed - indexed for MEDLINE]
195: Gen Comp Endocrinol 1995 Sep;99(3):316-22
Making males from females: the effects of aromatase inhibitors on a
parthenogenetic species of whiptail lizard.
Wennstrom KL, Crews D.
Department of Zoology, University of Texas at Austin 78712, USA.
The parthenogenetic whiptail lizard Cnemidophorus uniparens provides a good
model for the study of sex determination and sexual differentiation because
genetic variation is minimal and all unmanipulated embryos will develop as
females. Thus any deviation from the established course of development can be
identified as a treatment effect. Previous work has shown that early prenatal
treatment with CGS16949A, a nonsteroidal aromatase inhibitor, causes hatchlings
to develop as males. The present study explores more fully the effects of dosage
and timing of application of CGS16949A and examines the sex-reversing potential
of CGS20267, a new and reputedly more potent aromatase inhibitor. Eggs were
treated with a range of dosages of the aromatase inhibitors. Hatchlings that
received 1 microgram or more of either inhibitor were all male, while those that
received 0.1 microgram or less were all female. No difference in potency between
the two compounds was detected. Animals treated with 100 micrograms of CGS16949A
on Day 20 of incubation or later were all female, while those treated on Day 5
were all male. Seven sex-reversed male parthenogens have been raised to sexual
maturity. The animals appear similar morphologically and behaviorally to males
of the sexually reproducing whiptail species. Spermatogenesis and spermiogenesis
have been confirmed by histological examination of the testes and by
postcopulatory cloacal swabs. Application of aromatase inhibitors has been shown
to sex-reverse both avian and reptilian species. In mammals, the
male-determining gene of the Y chromosome (SRY) may code for an intrinsic
aromatase inhibitor. Studies show the gene's product has a binding domain which
recognizes regulatory elements in the promoter of the aromatase gene.(ABSTRACT
TRUNCATED AT 250 WORDS)
PMID: 8536943 [PubMed - indexed for MEDLINE]
196: J Clin Endocrinol Metab 1995 Sep;80(9):2658-60
Use of ultrasensitive recombinant cell bioassay to measure estrogen levels in
women with breast cancer receiving the aromatase inhibitor, letrozole.
Klein KO, Demers LM, Santner SJ, Baron J, Cutler GB Jr, Santen RJ.
Children's Hospital of Orange County, California 92668, USA.
The development of well tolerated, potent, specific, and nontoxic aromatase
inhibitors for the treatment of postmenopausal women with estrogen-dependent
breast cancer has been a major goal of recent studies. The third generation
inhibitors now under investigation are nearly 10,000-fold more potent than first
generation compounds. Currently available RIAs for plasma estradiol lack
sufficient sensitivity to measure levels during aromatase inhibition and, thus,
to assess drug potency precisely. The availability of an ultrasensitive bioassay
for estradiol provided the opportunity to accurately assess the potency of a new
third generation triazole aromatase inhibitor, letrozole (CGS 20267). We used
this assay to measure estradiol levels in 14 women with metastatic breast cancer
given letrozole at doses of 100 micrograms to 5.0 mg/day over a 12-week period.
The lack of differences between doses and sampling times allowed pooling of
data. Basal estradiol levels of 7.2 +/- 1.9 pmol/L (mean +/- SEM, 1.95 +/- 0.52
pg/mL) fell to 0.26 +/- 0.11 pmol/L (0.07 +/- 0.03 pg/mL) during the first 6
weeks of therapy and to 0.48 +/- 0.18 pmol/L (0.13 +/- 0.05 pg/mL) during the
second 6 weeks of therapy. Although plasma estradiol levels measured by RIA were
significantly correlated with levels measured by bioassay (r = 0.79; P < 0.01),
the degree of suppression assessed by the bioassay (95 +/- 2% after 6 weeks) was
greater than that determined by the RIA (81 +/- 4%), presumably due to improved
ability to measure very low estradiol levels. We conclude that plasma estradiol
is suppressed by letrozole to lower levels than previously observed, with
equivalent suppression at all doses studied. A slight, although not
statistically significant, rebound in estradiol levels occurs during the second
6 weeks of therapy compared to the first 6 weeks. Maximum inhibition of
aromatase is achieved at letrozole doses as low as 100 micrograms.
Publication Types:
Clinical Trial
PMID: 7673408 [PubMed - indexed for MEDLINE]
197: Int J Cancer 1995 Jul 28;62(3):297-302
An in vivo model of intratumoural aromatase using aromatase-transfected MCF7
human breast cancer cells.
Lee K, Macaulay VM, Nicholls JE, Detre S, Ashworth A, Dowsett M.
Academic Department of Biochemistry, Royal Marsden Hospital, London, UK.
About two-thirds of human breast carcinomas contain detectable levels of
aromatase, the enzyme which converts androgens to oestrogens. Assessment of the
importance of this enzyme to breast cancer growth has been hampered by the
absence of an adequate model system. We have previously reported that MCF7 human
hormone-dependent breast cancer cells transfected with human aromatase cDNA
(Arom1 cells) showed a growth response in vitro to exogenous androgens and this
effect was blocked by aromatase inhibitors. We report here our use of these
cells to develop a xenograft model in athymic nude mice. Neither MCF7 cells nor
Arom1 cells formed tumours in oophorectomised (ovx) nude mice unless provided
with oestradiol (E2) support. Once established, Arom1, but not MCF7, tumours
could be grown in ovx females supplemented with androstenedione (delta 4A). The
mean plasma level of delta 4A was 14 nmol/L in supplemented animals and < 0.5
nmol/L in unsupplemented animals. Similarly, unsupplemented male nude mice were
able to support the growth of Arom1 tumours but not MCF7 tumours. The potent and
highly specific aromatase inhibitor CGS20267 (letrozole) significantly decreased
tumour growth at 2 mg/kg/day and completely inhibited growth at 20 mg/kg/day in
delta 4A-supplemented but not E2-supplemented animals. Our results indicate that
delta 4A-dependent growth of Arom1 tumours in vivo is mediated through the
action of intratumoural aromatase. This model should allow an assessment of the
critical levels of aromatase required for tumour growth support.
PMID: 7628871 [PubMed - indexed for MEDLINE]
198: Cancer Res 1995 Jul 15;55(14):3073-7
Effect of aromatase inhibitors on growth of mammary tumors in a nude mouse
model.
Yue W, Wang J, Savinov A, Brodie A.
Department of Pharmacology and Experimental Therapeutics, School of Medicine,
University of Maryland, Baltimore 21201, USA.
The effects of aromatase inhibitors 4-hydroxyandrostenedione (4-OHA), CGS
16949A, and CGS 20267, and of the antiestrogen tamoxifen (TAM), were studied on
the growth of human breast carcinoma in a nude mouse model. To simulate the
postmenopausal breast cancer patient, tumors were formed from inoculates of
MCF-7 cells transfected with the human aromatase gene to provide a source of
non-ovarian estrogen in ovariectomized mice. Tumor growth was significantly
inhibited by all treatments (P < 0.05). Greater reduction in growth occurred in
mice treated with TAM combined with aromatase inhibitors than with TAM alone.
Tumor progesterone receptor concentrations were unaltered by TAM treatment but
were reduced by aromatase inhibitors. Progesterone receptor concentrations
correlated with tumor growth. The greatest reduction occurred in tumors of CGS
20267-treated mice in which no progesterone receptors were detected. In the
ovariectomized mice used in these studies, uterine weight was maintained by
estrogen produced from the tumor. Uterine weight was reduced by aromatase
inhibitors but not by TAM treatment. However, there was a significant increase
in uterine weight in mice treated with the combination of TAM and 4-OHA. Thus,
the agonist effect of TAM was evident when estrogen synthesis was inhibited. The
results indicate that aromatase inhibitors have potent effects on mammary tumor
growth but lack the estrogenic effects on the uterus observed with TAM. There
appeared to be no significant benefit in combining TAM with 4-OHA over 4-OHA
treatment alone.
PMID: 7606729 [PubMed - indexed for MEDLINE]
199: Cancer 1995 Apr 15;75(8):2132-8
Letrozole (CGS 20267). A phase I study of a new potent oral aromatase inhibitor
of breast cancer.
Lipton A, Demers LM, Harvey HA, Kambic KB, Grossberg H, Brady C, Adlercruetz H,
Trunet PF, Santen RJ.
Department of Medicine, M. S. Hershey Medical Center, Pennsylvania State
University, Hershey 17033, USA.
BACKGROUND. Letrozole (CGS 20267), a triazole derivative, is a new, once-daily,
oral nonsteroidal inhibitor of aromatase activity. METHODS. In this Phase I
trial, 23 heavily pretreated postmenopausal patients with metastatic breast
cancer received letrozole at doses ranging from 0.1 to 5.0 mg once daily.
RESULTS. No hematologic, biochemical, or significant clinical toxicity was
encountered. Serial steroid measurements were determined in 19 of these
patients. Letrozole at all doses tested produced a marked suppression of plasma
estrone, estradiol, estrone sulfate, and urine estrone and estradiol. This was
observed within 24 hours of the initial dose of letrozole and resulted in a
greater than 90% suppression of plasma and urinary estrogen levels within 2
weeks. Letrozole appears to be highly selective in its action and does not
compromise glucocorticoid or mineralocorticoid production or thyroid function.
Of the 21 evaluable patients, there were 2 with partial responses and 7 with
stable disease. CONCLUSIONS. Letrozole is a well tolerated, potent, and specific
inhibitor of estrogen biosynthesis in postmenopausal patients with metastatic
breast cancer.
Publication Types:
Clinical Trial
Clinical Trial, Phase I
PMID: 7697604 [PubMed - indexed for MEDLINE]
200: J Endocrinol 1994 Nov;143(2):279-89
Role of reductase and aromatase in sex determination in the red-eared slider
(Trachemys scripta), a turtle with temperature-dependent sex determination.
Crews D, Bergeron JM.
Department of Zoology, University of Texas at Austin 78712.
In many turtles the temperature during the middle of incubation determines the
gonadal sex of the hatchling. In the red-eared slider turtle (Trachemys
scripta), an incubation temperature of 26 degrees C results in all male
offspring, whereas an incubation temperature of 31 degrees C results in all
female offspring; at temperatures intermediate to these (e.g. 29, 29.2, 29.4
degrees C) a mixed sex ratio is obtained. Administration of exogenous oestrogens
will overcome the effects of an all-male producing incubation temperature to
cause female sex determination, whereas administration of exogenous
dihydrotestosterone (DHT) or testosterone to eggs incubating at an all-female
temperature will have no discernible effect. Administration of DHT will cause
male sex determination only if administered at intermediate incubation
temperatures whereas administration of testosterone to eggs incubating at all
male-producing and male-biased intermediate temperatures results in a
significant number of female offspring, an effect presumably due to
aromatization of testosterone to oestradiol (OE2). Since testosterone serves as
the precursor to both DHT and OE2, being metabolized by reductase and aromatase
respectively, three experiments were conducted to determine whether various
putative reductase and aromatase inhibitors would overcome the effect of
incubation temperature. First, while administration of testosterone to eggs
incubating at all male-producing and male-biased intermediate temperatures
produced females in a dose- and temperature-dependent manner, significant
numbers of intersex individuals resulted from high dosage testosterone treatment
to eggs incubating at a female-biased intermediate temperature. The reductase
inhibitors 4MA and MK906 were capable of producing female offspring if
administered at intermediate temperatures, but not in a dose-dependent fashion.
Administration of the aromatase inhibitors CGS16949A and CGS20267 resulted in
male offspring at both female-biased intermediate and at all female-producing
temperatures in a dose-dependent fashion. Second, similar findings were obtained
with combined doses of testosterone and reductase or aromatase inhibitors.
Combined treatment of eggs at male-biased intermediate incubation temperatures
with testosterone and reductase inhibitor resulted in female hatchlings, whereas
combined treatment of testosterone and aromatase inhibitor at both female-biased
intermediate and at all female-producing temperatures resulted in male
hatchlings.(ABSTRACT TRUNCATED AT 400 WORDS)
PMID: 7829992 [PubMed - indexed for MEDLINE]
201: Exp Toxicol Pathol 1994 Aug;46(3):211-3
Changes induced by treatment with aromatase inhibitors in testicular Leydig
cells of rats and dogs.
Junker Walker U, Nogues V.
Preclinical Safety, Pathology, Pharma Division, Ciba-Geigy AG, Basel,
Switzerland.
Treatment of male rats and dogs with CGP 32,349 (formestane), a steroidal
aromatase inhibitor, and CGS 20,267 (letrozole), a non-steroidal aromatase
inhibitor, induced different alterations in testicular interstitial Leydig cells
in the two species. Whereas in dogs Leydig cells were hypertrophic and
hyperplastic, in rats either no effect (CGS 20,267) or atrophy of Leydig cells
(CGP 32,349) was reported. The different response of the two species can be
explained by different regulating mechanisms of gonadotropin secretion by the
anterior pituitary.
PMID: 8000241 [PubMed - indexed for MEDLINE]
202: J Steroid Biochem Mol Biol 1994 Jun;49(4-6):281-7
Aromatase inhibitors in the treatment of breast cancer.
Brodie AM.
Department of Pharmacology & Experimental Therapeutics, School of Medicine,
University of Maryland, Baltimore 21201.
A number of inhibitors of estrogen synthesis are now becoming available which
could be of value in the treatment of breast cancer. 4-Hydroxyandrostenedione
(4-OHA), the first of these compounds to enter the clinic has been found to be
effective in postmenopausal patients who have relapsed from tamoxifen. Thus, in
studies of 240 patients, 26% patients experienced partial or complete response
to treatment. An additional 25% patients had disease stabilization. 4-OHA is a
potent selective, steroidal inhibitor which causes inactivation of aromatase in
vitro. It is effective in reducing concentrations of ovarian estrogens in rats
and of ovarian and peripheral estrogens in non-human primate species. The
compound has been shown to lower serum estrogen levels in postmenopausal breast
cancer patients. However, not all of these patients experienced disease
remission, suggesting that their tumors were hormone insensitive rather than
that the dose of 4-OHA was suboptimal. In trials of patients who had not
received prior tamoxifen treatment, 4-OHA (250 mg i.m. every 2 weeks) was found
to induce complete or partial tumor regression in 33% of patients. The response
of patients was not significantly different from that observed in patients
treated with tamoxifen (30 mg o.d) of 37%. No significant difference between
treatments was observed for disease stabilization, the duration of response or
median survival. Several other steroidal aromatase inhibitors have been studied,
such as 7 alpha-substituted androstenedione derivatives. MDL 18962
[10-(2-propynyl)estr-4-ene-3,17-dione] and FCE 24304
(6-methylen-androsta-1,4-diene-3,17-dione) are currently in clinical trials.
Non-steroidal inhibitors of cytochrome P-450 enzymes, such as imidazole and
triazole derivatives have been developed which are highly selective for
aromatase. Three triazoles which are very potent and selective inhibitors are
vorazole (6-[(4-chlorophenyl)(1H-1,2,4-triazol-1-yl)-methyl]1-methyl-1H-
benzotriazole R 76713, arimidex 2,2'[5-(1H-1,2,4-triazol-1-yl
methyl)-1,3-phenylene]bis(2-methylpropiononitrile) (ZD1033) and letrozole
4-[1-(cyanophenyl)-1-(1,2,4-triazolyl)methyl]benzonitril (CGS 20267). These
compounds reduce serum estradiol concentration to undetectable levels in breast
cancer patients. These highly potent inhibitors provide the opportunity to
determine whether a further degree of estrogen suppression will be important in
producing greater clinical response.(ABSTRACT TRUNCATED AT 400 WORDS)
Publication Types:
Review
Review, Tutorial
PMID: 8043490 [PubMed - indexed for MEDLINE]
203: J Pharm Sci 1994 Apr;83(4):520-4
Development, application and comparison of an enzyme immunoassay and a
high-performance liquid chromatography method for the determination of the
aromatase inhibitor CGS 20,267 in biological fluids.
Pfister CU, Duval M, Godbillon J, Gosset G, Gygax D, Marfil F, Sioufi A, Winkler
B.
Ciba-Geigy Ltd., Pharma Research and Development, Basle, Switzerland.
CGS 20,267 is a new potent and selective, nonsteroidal, oral aromatase
inhibitor. For its determination in human plasma and urine, an enzyme
immunoassay (EIA) and an HPLC method were developed. The EIA showed good
precision and accuracy (intra- and interassay variation between 3.0 and 17.7%,
recoveries between 81 and 106%) and a quantitation limit of 0.7 nmol/L. A strong
cross reactivity of the antibodies with the hydroxy metabolite of CGS 20,267
(CGP 44,645) was observed. The HPLC method showed a quantitation limit in plasma
of 28 and 34 nmol/L for CGS 20,267 and CGP 44,645, respectively. For urine,
concentrations down to 180 nmol/L (CGS 20,267) and 210 nmol/L (CGP 44,645) could
be measured. A cross check between EIA and HPLC on plasma samples from healthy
male volunteers or breast cancer patients treated orally with CGS 20,267
revealed an excellent correlation (slope = 0.934, intercept = 26, r = 0.991).
However, the EIA measurements of urine samples yielded 3-25 times higher
concentrations than those obtained by HPLC. Further, HPLC analysis revealed the
presence of CGS 20,267 and cross-reacting metabolites in urine but not in
plasma. Therefore, the EIA can only be used for the determination of CGS 20,267
in plasma samples.
PMID: 8046607 [PubMed - indexed for MEDLINE]
204: Breast Cancer Res Treat 1994;30(1):95-102
Effects of Fadrozole (CGS 16949A) and Letrozole (CGS 20267) on the inhibition of
aromatase activity in breast cancer patients.
Demers LM.
Department of Pathology and Medicine, M.S. Hershey Medical Center, Pennsylvania
State University, Hershey 17033.
Fadrozole Hydrochloride (CGS 16949A) and Letrozole (CGS 20267), are two of the
newest non-steroidal, orally active aromatase inhibitors currently being
evaluated as second line treatment of patients with hormone dependent forms of
metastatic breast cancer. In a phase I clinical efficacy study, we examined the
ability of these two imidazole derivatives to suppress the synthesis of estrogen
in a cohort of postmenopausal patients with metastatic breast cancer. Both
medications at relatively low doses were potent and rapid inhibitors of
aromatase activity as evidenced by their ability to suppress the level of blood
and urine estradiol and estrone as well as blood estrone sulfate in these
patients. Letrozole appeared to be the more potent of the two, with over 95%
suppression of both plasma and urinary estrogens observed within 2 weeks of
therapy. Letrozole appeared to be more selective than Fadrozole in inhibiting
aromatase activity in that no compromise in cortisol and aldosterone output was
evident with Letrozole therapy at all of the doses tested, a compromise clearly
seen with Fadrozole. The inhibition of aromatase activity by these imidazole
derivatives as second line therapy for patients with hormone dependent breast
cancer appears to be a favorable alternative form of hormone ablative therapy
and holds considerable promise for the treatment of this malignancy.
Publication Types:
Clinical Trial
Clinical Trial, Phase I
Controlled Clinical Trial
PMID: 7949208 [PubMed - indexed for MEDLINE]
205: J Steroid Biochem Mol Biol 1993 Dec;47(1-6):161-6
The role of estrogen in the feedback regulation of follicle-stimulating hormone
secretion in the female rat.
Bhatnagar AS, Batzl C, Hausler A, Nogues V.
Research Department, Pharmaceuticals Division, CIBA-GEIGY Limited, Basel,
Switzerland.
Letrozole (CGS 20267) is a non-steroidal aromatase inhibitor which, at its
maximally effective dose of 1 mg/kg p.o., elicits endocrine effects equivalent
to those seen after ovariectomy. Adult, female cyclic rats were administered
letrozole (1 mg/kg p.o.) once daily for 14 days. A control group of animals was
ovariectomized on day 1 of treatment and a third group of animals served as
untreated controls. During the experiment, vaginal smears were taken daily and
at the end of 14 days all animals were sacrificed, trunk blood was taken for
serum estradiol, LH and FSH measurements and the uterus and ovaries were removed
and weighed. The ovaries were then fixed and prepared for histological
examination. Serum hormone measurements showed that after treatment with
letrozole, serum estradiol levels were reduced by 76% of untreated controls and
serum LH was elevated to 378% of control values. These compared favorably with
those seen after ovariectomy, serum estradiol was reduced by 78% and serum LH
was elevated to 485% of untreated controls. However, FSH was unchanged after
letrozole treatment (125% of control), whereas after ovariectomy FSH rose to
398% of control. Uterine weight was suppressed in the letrozole-treated animals
as well as the ovariectomized animals by 60 and 70%, respectively. The histology
of the ovaries of animals treated with letrozole were consistent with the serum
hormone findings. Except for the effects on serum FSH, these results confirm
previous findings that treatment with letrozole elicits endocrine effects
similar to those seen after ovariectomy. Furthermore, these results demonstrate
that FSH secretion is not under the control of estradiol whereas LH secretion is
under feedback control of ovarian estrogen.
PMID: 8274431 [PubMed - indexed for MEDLINE]
206: J Clin Endocrinol Metab 1993 Aug;77(2):324-31
Comment in:
J Clin Endocrinol Metab. 1993 Aug;77(2):316-7
Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in healthy
postmenopausal women.
Iveson TJ, Smith IE, Ahern J, Smithers DA, Trunet PF, Dowsett M.
Breast Unit, Royal Marsden Hospital, London, United Kingdom.
We have performed a phase I study of the effect of a single dose of CGS 20267,
an oral nonsteroidal aromatase inhibitor, in 12 healthy volunteer postmenopausal
women. Each subject received 2 single doses of CGS 20267 (0.1, 0.5, or 2.5 mg)
or placebo separated by a washout period of at least 6 weeks. There was
statistically significant suppression of serum estrone and estradiol at all
three doses of CGS 20267 tested. Serum estrone and estradiol concentrations were
maximally suppressed by 76% and 79% from baseline levels, respectively. Urinary
excretion of estrone and estradiol was also suppressed, although this did not
reach statistical significance. Serum concentrations of aldosterone, cortisol,
17 alpha-hydroxyprogesterone, androstenedione, testosterone, FSH, LH, and TSH
were unaffected by CGS 20267. The drug was well tolerated, with no significant
side-effects. This study has shown CGS 20267 to be a potent and specific
aromatase inhibitor, and further studies are now needed to assess its clinical
efficacy.
Publication Types:
Clinical Trial
Clinical Trial, Phase I
Randomized Controlled Trial
PMID: 8345035 [PubMed - indexed for MEDLINE]
207: J Clin Endocrinol Metab 1993 Aug;77(2):319-23
Comment in:
J Clin Endocrinol Metab. 1993 Aug;77(2):316-7
Open dose-finding study of a new potent and selective nonsteroidal aromatase
inhibitor, CGS 20 267, in healthy male subjects.
Trunet PF, Mueller P, Bhatnagar AS, Dickes I, Monnet G, White G.
Research and Development Department, CIBA-GEIGY Limited, Basel, Switzerland.
The aim of this open, dose-finding study was to evaluate the effects of single
dose CGS 20 267, a new oral nonsteroidal aromatase inhibitor, on the inhibition
of estrogen production and also on the production of adrenal and testicular
steroids in healthy male subjects. Nine dose levels ranging from 0.02-30 mg and
placebo were tested, each dose being given to 3 subjects only. A total of 18
subjects were included; 12 of them received 2 single administration, the
remaining 6 were exposed only once to one of the 2 highest dose levels. A
reduction in serum estrogen levels when compared to baseline was already
observed after 2 h, reaching maximum suppression between 10 and 48 h after
administration. After 24 h, a suppression of estrone levels by 60-85% from
baseline was achieved with all tested doses. A reduction in estradiol levels by
about 30% from baseline was observed at the lowest dose (0.02 mg). This
reduction was further enhanced dose dependently to a maximum of about 90% from
baseline at 24 h after administration of the highest dose (30 mg). With the
higher doses (10 and 30 mg), estrogen suppression was maintained up to 3 days. A
dose-dependent increase of testosterone, LH, and FSH was observed and was most
pronounced in the 10- and 30-mg dose groups, which can be considered as a
consequence of the long-lasting aromatase inhibition achieved with these high
doses. No effect on serum cortisol and aldosterone levels was observed up to the
highest dose. No clinically relevant changes were observed in blood chemistry
and hematology tests. The systemic and subjective tolerability of CGS 20 267 was
good at all doses. This study has shown that CGS 20 267 is a well tolerated,
potent, selective, and long-acting inhibitor of the aromatase enzyme after
single administration.
Publication Types:
Clinical Trial
Controlled Clinical Trial
PMID: 8345034 [PubMed - indexed for MEDLINE]
208: J Clin Endocrinol Metab 1993 Aug;77(2):316-8
Comment on:
J Clin Endocrinol Metab. 1993 Aug;77(2):319-23
J Clin Endocrinol Metab. 1993 Aug;77(2):324-31
Estrogen synthesis inhibitors: from "off the rack" to haute couture.
Santen RJ.
Publication Types:
Comment
Editorial
PMID: 8345033 [PubMed - indexed for MEDLINE]
209: J Steroid Biochem Mol Biol 1993 Mar;44(4-6):687-91
The efficacy of CGS 20267 in suppressing estrogen biosynthesis in patients with
advanced stage breast cancer.
Demers LM, Lipton A, Harvey HA, Kambic KB, Grossberg H, Brady C, Santen RJ.
Department of Medicine, Pennsylvania State University, Milton S. Hershey Medical
Center, Hershey 17033.
The pharmacologic inhibition of aromatase activity has been the focus of
clinical trials in patients with advanced stage breast cancer. Recent
developments with imidazole compounds that inhibit aromatase activity suggest
their clinical use as potent inhibitors of estrogen biosynthesis in
postmenopausal breast cancer patients. In this Phase I, open-label, dose-range
finding study, we examined the inhibitory potency of CGS 20267 on blood and
urine levels of estradiol, estrone and estrone sulfate in 8 patients with
metastatic breast cancer. Studies included evaluation of adrenal and thyroid
function to look for evidence of general hydroxylase inhibition at dose levels
effective for aromatase blockade. Patients were administered CGS 20267 at doses
of 0.1 and 0.25 mg, once a day in ascending doses over a 12-week period.
Preliminary data reveal that CGS 20267 elicits a striking suppression in plasma
estradiol, estrone and estrone sulphate which was observed in some patients as
quickly as within 24 h of the first dose. Estrogen suppression of over 90% was
achieved within 2 weeks of therapy. No alterations in either baseline or ACTH
(cortrosyn) stimulated cortisol and aldosterone levels were observed through the
12 weeks of therapy. In addition, 24 h urine sodium and potassium values were
not appreciably altered during therapy. We conclude that CGS 20267 is a potent,
specific inhibitor of estrogen biosynthesis in postmenopausal patients with
metastatic breast cancer and effectively reduces blood and urine estrogens to
undetectable levels.
Publication Types:
Clinical Trial
Clinical Trial, Phase I
PMID: 8476785 [PubMed - indexed for MEDLINE]
210: J Steroid Biochem Mol Biol 1993 Mar;44(4-6):633-6
Anti-tumor and endocrine effects of non-steroidal aromatase inhibitors on
estrogen-dependent rat mammary tumors.
Schieweck K, Bhatnagar AS, Batzl C, Lang M.
Research Department, CIBA-GEIGY Limited, Basel, Switzerland.
The non-steroidal aromatase inhibitor CGS 20,267, at maximally effective doses
in non-tumor bearing adult female rats, elicits endocrine effects mimicking
those seen after surgical ovariectomy and thus induces a "medical" ovariectomy.
We now report on studies characterizing the anti-tumor and endocrine effects of
three orally active non-steroidal aromatase inhibitors, CGS 20,267, CGP 45,688
and CGP 47,645, in adult female rats bearing estrogen-dependent DMBA-induced
mammary tumors. Doses ranging from 3 to 3000 micrograms/kg were given by gavage
once daily for 6 weeks. After 6 weeks of treatment, the ED50 for suppression of
tumor volume was 10-30, 100 and 3-10 micrograms/kg for CGS 20,267, CGP 45,688
and CGP 47,645, respectively. The maximally effective dose for anti-tumor
efficacy was 300, 1000 and 100 micrograms/kg for each of the three inhibitors,
respectively. The observed potent anti-tumor efficacy was accompanied by potent
endocrine effects. Thus, disruption of ovarian cyclicity (at maximal doses rats
remained in constant diestrus) was observed in all animals from the 2nd or 3rd
week of treatment to the end of the 6-week treatment period. Uterine weight, at
the maximally effective doses for each of the three inhibitors, was suppressed
to between 42 and 28% of pre-treatment levels. This suppression was similar to
the suppression of uterine weight (27% of pre-treatment) seen after ovariectomy.
Serum estradiol concentrations in rats treated with 300 micrograms/kg CGS 20,267
were significantly suppressed to 12% of pre-treatment levels and serum
luteinizing hormone (LH) concentrations were elevated 3 to 4-fold over
pre-treatment levels. Thus the potent anti-tumor efficacy seen with each of the
three non-steroidal aromatase inhibitors was accompanied in each case by a
variety of endocrine effects corresponding to those seen after ovariectomy.
PMID: 8476774 [PubMed - indexed for MEDLINE]
211: J Steroid Biochem Mol Biol 1993 Mar;44(4-6):421-8
Structure-activity relationships and binding model of novel aromatase
inhibitors.
Lang M, Batzl C, Furet P, Bowman R, Hausler A, Bhatnagar AS.
Pharmaceutical Research Department, CIBA-GEIGY Limited, Basel, Switzerland.
The use of aromatase inhibitors is an established therapy for
oestrogen-dependent breast cancer in postmenopausal women. However, the sole
commercially available aromatase inhibitor, aminoglutethimide, is not very
selective. We have therefore developed fadrozole hydrochloride and CGS 20,267,
which are both currently under clinical evaluation. This report will present an
analysis of structure-activity relationships in the azole series of inhibitors
and give an account of the further optimization of our development compounds,
starting from CGS 20,267 over CGP 45,688 and leading to CGP 47,645, the most
potent aromatase inhibitor in vivo reported to date. In addition, on the basis
of comparisons of these azole-type inhibitors with the most potent steroidal
inhibitors published in the literature, we propose a CAMM-generated model
describing the relative binding modes of these two classes of compounds at the
active site of the enzyme.
PMID: 8476755 [PubMed - indexed for MEDLINE]
212: Cancer Res 1993 Jan 15;53(2):266-70
Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in
postmenopausal patients with advanced breast cancer.
Iveson TJ, Smith IE, Ahern J, Smithers DA, Trunet PF, Dowsett M.
Breast Unit, Royal Marsden Hospital, London, England.
A phase I study was performed of CGS 20267, an oral nonsteroidal, highly potent,
and selective aromatase inhibitor, in 21 postmenopausal patients with advanced
breast cancer. The patients were recruited in 3 successive groups of 7,
receiving 0.1, 0.5, and 2.5 mg p.o./day, respectively. All patients had received
at least one prior endocrine treatment (range, 1-4), and six patients had
received prior chemotherapy. The treatment was very well tolerated, and no
toxicity was seen at any of the three doses. There was a statistically
significant suppression of estradiol (E2) and estrone (E1) levels by 74% and 79%
from baseline levels, respectively (P < 0.0001). Suppression occurred in all
three patient groups, with many patients having serum concentrations of
estradiol and estrone, which were below the limit of detection of the assays (3
and 10 pM, respectively), which corresponds to a maximum measurable estrogen
suppression of 86%. CGS 20267 had no significant effect on serum levels of
follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating hormone,
cortisol, 17 alpha-hydroxyprogesterone, androstenedione, and aldosterone. Seven
(33%, 95% confidence interval, 15-57%) of the 21 patients have responded to
treatment (one complete remission, 6 partial remissions according to criteria of
the Union Internationale contre le Cancer), and 6 are still responding to CGS
20267 (duration of response; 4+, 6+, 6+, 9+, 9, 12+, and 12+ months). Five have
had stable disease for more than 3 months, and 9 had progressive disease. These
results suggest that CGS 20267 is a very potent and specific aromatase
inhibitor, and phase II studies are now required to confirm its clinical
efficacy.
Publication Types:
Clinical Trial
Clinical Trial, Phase I
PMID: 8417819 [PubMed - indexed for MEDLINE]
213: J Cell Biochem Suppl 1993;17G:242-6
Clinical use of aromatase inhibitors in the treatment of breast cancers.
Manni A.
Milton S. Hershey Medical Center, Department of Medicine, Pennsylvania State
University, Hershey 17033.
Estrogens are the major hormones supporting the growth of human breast cancer.
Aromatization of androgen precursors in peripheral tissues, including the breast
cancer itself, is the major source of estrogens in postmenopausal women.
Therefore, inhibition of the aromatase enzyme offers an effective means of
inducing regression of hormone-responsive breast cancer. Aminoglutethimide, the
first and most widely tested aromatase inhibitor, suppresses estrogen production
to the level of adrenalectomy and exerts an anti-tumor action comparable to
other standard endocrine therapies such as tamoxifen. However, conventional
doses of the drug (1000 mg daily) cause moderate toxicity and inhibit other
critical cytochrome P-450 steroidogenic enzymes, thus requiring concomitant
glucocorticoid administration. New non-steroidal, competitive aromatase
inhibitors with greater selectivity and less toxicity are being developed. The
second generation compound, fadrazole (CGS 16949), lowers estrogen production to
a degree similar to aminoglutethimide (50-80%), but at much lower doses
(approximately 2 mg daily) and is associated with minimal toxicity. Although not
totally specific, this drug is sufficiently selective not to require
simultaneous cortisol replacement. CGS 16949 has been shown to possess
significant anti-tumor action in pilot studies and is currently being tested in
Phase III trials. Recently, a third generation inhibitor, CGS 20267, has been
found to have virtually complete selectivity for the aromatase enzyme.
Furthermore, this drug suppresses estrogen biosynthesis to a greater extent
(approximately 90%) than previously observed with other aromatase inhibitors.
Such enhanced activity may lead to a superior anti-tumor action, and may extend
the use of this drug to a variety of other conditions where optimal suppression
of estrogen biosynthesis is desired.
Publication Types:
Review
Review, Tutorial
PMID: 8007705 [PubMed - indexed for MEDLINE]
214: J Int Med Res 1992 Aug;20(4):303-12
Aromatase inhibitors: clinical pharmacology and therapeutic implications in
breast cancer.
Perez N, Borja J.
Medical Department, Ciba-Geigy SA, Barcelona, Spain.
Aminoglutethimide was the first aromatase inhibitor to be used in breast cancer
therapy but, since it interacts with the synthetic glucocorticoids,
hydrocortisone must also be given as a replacement. The most important
side-effects of aminoglutethimide are at the level of the central nervous
system. Other aromatase inhibitors with greater potency and selectivity are
being developed. Pyridoglutethimide, a compound resulting from modifications to
the structure of aminoglutethimide, seems to be devoid of sedative properties
according to preliminary tests on the central nervous system.
4-Hydroxyandrostenedione is significantly more potent and better tolerated than
aminoglutethimide. Fadrozole (CGS 16,949 A) is 200-400 times more potent than
aminoglutethimide and is now in phase II of its clinical development. CGS 20,267
has no effect on adrenal steroidogenesis and is currently in phase I of its
clinical development. Availability of newer aromatase inhibitors could make a
worthwhile contribution to endocrine therapy in breast cancer.
Publication Types:
Review
Review, Tutorial
PMID: 1387368 [PubMed - indexed for MEDLINE]
215: J Steroid Biochem Mol Biol 1992 Mar;41(3-8):437-43
Inhibition of estrogen biosynthesis and its consequences on gonadotrophin
secretion in the male.
Bhatnagar AS, Muller P, Schenkel L, Trunet PF, Beh I, Schieweck K.
Department of Research and Development, Pharmaceuticals Division CIBA-GEIGY
Limited, Basel, Switzerland.
Of the gonadal steroids in the male, testosterone is the most important
regulator of gonadotrophin secretion. However, whether testosterone affects
gonadotrophin secretion directly or whether it must first be aromatized to
estrogens is controversial. We have reported extensively on the endocrine and
anti-tumor effects of the non-steroidal aromatase inhibitors CGS 16949A and CGS
20267 in adult female rats. In these animals, both inhibitors potently and
selectively inhibit estrogen biosynthesis. Thus these agents can be effectively
used in studying estrogen-dependent processes. CGS 16949A was administered for
14 days to adult male rats, over a dose range which in females suppresses
estradiol and elevates LH. In male rats a suppression of estradiol was seen,
however, there was no significant effect on either serum LH or on the weights of
androgen-dependent organs. CGS 16949A, when administered to healthy men at a
dose of 1 mg b.i.d. for 10 days, causes a significant fall in plasma estradiol
and significant elevations of plasma FSH and testosterone. Dose-dependent
suppression of serum estradiol and an increase in serum testosterone and LH are
seen after administration of single oral doses of CGS 20267. These results
indicate that in the male rat, inhibition of aromatization of testosterone to
estrogens does not influence gonadotrophin secretion whereas in men the negative
feedback exerted by testosterone on gonadotrophin secretion is dependent on the
aromatization of testosterone to estrogens.
PMID: 1532903 [PubMed - indexed for MEDLINE]
216: J Steroid Biochem Mol Biol 1990 Dec 20;37(6):1021-7
Highly selective inhibition of estrogen biosynthesis by CGS 20267, a new
non-steroidal aromatase inhibitor.
Bhatnagar AS, Hausler A, Schieweck K, Lang M, Bowman R.
Research Department, Ciba-Geigy Limited, CH-4002 Basel, Switzerland.
CGS 20267 is a new non-steroidal compound which potently inhibits aromatase in
vitro (IC50 of 11.5 nM) and in vivo (ED50 of 1-3 micrograms/kg p.o.), CGS 20267
maximally inhibits estradiol production in vitro in LH-stimulated hamster
ovarian tissue at 0.1 microM with an IC50 of 0.02 microM and does not
significantly affect progesterone production up to 350 microM. In
ACTH-stimulated rat adrenal tissue in vitro, aldosterone production was
inhibited with an IC50 of 210 microM (10,000 times higher than the IC50 for
estradiol production); no significant effect on corticosterone production was
seen at 350 microM. In vivo, in ACTH-treated rats, CGS 20267 does not affect
plasma levels of corticosterone or aldosterone at a dose of 4 mg/kg p.o. (1000
times higher than the ED50 for aromatase inhibition in vivo). In adult female
rats, a 14-day treatment with 1 mg/kg p.o. daily, completely interrupts ovarian
cyclicity and suppresses uterine weight to that seen 14 days after ovariectomy.
In adult female rats bearing estrogen-dependent DMBA-induced mammary tumors, 0.1
mg/kg p.o. given daily for 42 days caused almost complete regression of tumors
present at the start of treatment. Thus compared to each other, CGS 16949A and
CGS 20267 are both highly potent in inhibiting estrogen biosynthesis in vitro
and in vivo. The striking difference between them is that unlike CGS 16949A, CGS
20267 does not affect adrenal steroidogenesis in vitro or in vivo, at
concentrations and doses several orders of magnitude higher than those required
to inhibit estrogen biosynthesis.
Publication Types:
Review
Review, Tutorial
PMID: 2149502 [PubMed - indexed for MEDLINE]
hehe, yeah, hopefully this thread will trigger some more conversing.
Once again, I feel the IGF-1 issue to be of little importance and should not take precedence as ones primary influence when chosing an anti-e. Ones main concern should be protection against estrogen.
Once again, I feel the IGF-1 issue to be of little importance and should not take precedence as ones primary influence when chosing an anti-e. Ones main concern should be protection against estrogen.
Thanks for compiling and posting all that. I've only just skimmed some of the studies I haven't seen before, but one mentioned a new oral "pure antiestrogen" SR16234. That will be interesting.
This comment is interesting as well;
..."In contrast, type II anti-aromatase agents (eg, aminoglutethimide, anastrozole, and letrozole) often caused a paradoxical increase in aromatase activity when measured under similar conditions." I wonder what the significance of this is, if any?
Good stuff. Thanks
This comment is interesting as well;
..."In contrast, type II anti-aromatase agents (eg, aminoglutethimide, anastrozole, and letrozole) often caused a paradoxical increase in aromatase activity when measured under similar conditions." I wonder what the significance of this is, if any?
Good stuff. Thanks
