Endocrinological and clinical evaluation of exemestane, a new steroidal aromatase inhibitor.

The androstenedione derivative, exemestane (FCE 24304), is a new orally active irreversible aromatase inhibitor. Fifty-six post-menopausal advanced breast cancer patients entered this study to evaluate the activity of four low exemestane doses in reducing oestrogen levels. The drug''s tolerability and clinical efficacy were also assessed. Exemestane was orally administered to four consecutive groups at daily doses of 25, 12.5, 5 and 2.5 mg, and the changes in oestrogen, gonadotrophins, sex-hormone binding globulin and dehydroepiandrosterone sulphate levels were evaluated. Drug selectivity was studied by measuring 17-hydroxycorticosteroid urinary levels. After 7 days of treatment, mean oestrone and oestradiol levels had decreased by respectively 64% and 65% (a decrease which was maintained over time); in the 2.5 mg group, oestrone sulphate levels also decreased by 74%. Gonadotrophin levels were significantly higher, whereas no changes in the other serum hormone levels or any interference with adrenal synthesis were detected. Treatment tolerability was satisfactory: nausea and dyspepsia were reported in 16% of patients. The overall objective response rate was 18%. In conclusion, exemestane is effective in reducing oestrogen levels at all of the tested doses and shows interesting clinical activity.     

Efficacy of exemestane after nonsteroidal aromatase inhibitor use in metastatic breast cancer patients

Background: Previous studies have suggested a lack of complete cross-resistance between steroidal (exemestane) and non-steroidal aromatase inhibitors (nSAI). Methods: Eighty-eight metastatic breast cancer (MBC) patients who received 25 mg of exemestane orally once a day at the National Cancer Center, Korea, between 2003 and 2009, were reviewed retrospectively. All patients had received nSAI for metastatic disease prior to exemestane therapy. Results: The median age was 52 years (range, 33–79), and 13 (14.8%) patients were premenopausal who concomitantly received GnRH agonist. Exemestane was given as a second- (80.7%) or third-line (19.3%) hormone therapy. The clinical benefit (CB) rate (complete response + partial response + stable disease ≥ 24 weeks) was 30.7%, with a median CB duration of 10.0 months (range, 6.3–78.7). The median progression-free survival (PFS) was 3.0 months (95% confidence interval [CI], 1.99–4.01) and the overall survival (OS) 21.5 months (95% CI, 17.96–25.04), with a median follow-up of 50.3 months. Patients who achieved CB had longer OS than those patients who did not (29.6 vs 17.9 months; P = 0.002). On univariate analysis of predictive factors, patients who had achieved CB from previous nSAI tended to show lower CB rate (24.6% vs 44.4%, respectively; P = 0.063) and shorter PFS (2.8 vs 4.8 months, respectively; p = 0.233) than patients who had not. Achieving CB from previous nSAI became independent predictive factor for CBR to exemestane on multivariable analysis (Odds ratio = 2.852, P = 0.040). Conclusions: Exemestane after nSAI failure was effective in prolonging CB duration. The drug’s efficacy seemed to be inferior in patients who had benefit from previous nSAI use.     

Effects of steroidal and nonsteroidal aromatase inhibitors on markers of bone turnover in healthy postmenopausal women

Introduction  

In contrast to nonsteroidal aromatase inhibitors, the steroidal aromatase inactivator exemestane does not have detrimental effects on bone in animal models. This study was designed to compare the effects of exemestane with the nonsteroidal aromatase inhibitors anastrozole and letrozole on serum and urine levels of biomarkers of bone turnover in healthy postmenopausal women.     

Effects of the antiestrogen tamoxifen and the aromatase inhibitor letrozole on serum hormones and bone characteristics in a preclinical tumor model for breast cancer.

PURPOSE: The purpose of this study was to evaluate and compare the effects of the antiestrogen tamoxifen and the aromatase inhibitor letrozole on tumor growth, serum hormones, uterine weight, body composition, and bone characteristics in mice. EXPERIMENTAL DESIGN: Human estrogen-dependent breast cancer cells stably transfected with the aromatase gene (MCF-7CA cells) were inoculated in Matrigel subcutaneously into ovariectomized nude mice. This model represents postmenopausal breast cancer in many respects, including the fact that estrogen is no longer produced by the ovaries and is not under feedback regulation by gonadotropins. Mice that received subcutaneously implanted MCF-7CA cancer cells were then treated with tamoxifen or letrozole for 7 weeks. RESULTS: As reported previously, tumor growth was markedly inhibited by both tamoxifen (100 microg/day) and letrozole (10 microg/day). Tamoxifen treatment led to increased bone mineral density (BMD) and hyperplastic uteri. Mice treated with letrozole had significantly smaller uteri than the controls and tamoxifen-treated mice. Letrozole did not affect BMD. There was no significant difference in systemic leptin and insulin-like growth factor I levels as a result of tamoxifen or letrozole treatment. CONCLUSIONS: Tamoxifen treatment inhibited breast cancer cell growth and increased BMD but caused uterine hypertrophy in this preclinical model of postmenopausal breast cancer. Letrozole inhibited tumor growth without inducing uterine hypertrophy. In addition, letrozole had no effect on BMD. These findings provide experimental evidence that letrozole is an effective and safe (in terms of risk of endometrial cancer risk and osteoporosis) alternative or complement to tamoxifen treatment for breast cancer.     

依西美坦在非甾体类芳香化酶抑制剂经治失败的晚期乳腺癌患者中的临床应用

背景与目的：依西美坦为甾体类芳香化酶灭活剂,能不可逆地结合到芳香化酶与雄激素底物的结合位点上,引起酶永久失活,阻断雄激素向雌激素的转化。依西美坦对激素受体阳性绝经后复发转移性乳腺癌具有明显的疗效,且有研究表明,依西美坦与其他内分泌药物包括非甾体类芳香化酶抑制剂之间无明显交叉耐药反应。本研究旨在评价依西美坦在采用非甾体类芳香化酶抑制剂治疗失败的晚期乳腺癌患者中的临床应用价值。方法：33例雌激素（estrogen receptor,ER）和（或）孕激素受体（progesterone receptor,PR）阳性或不明的绝经后晚期乳腺癌患者,且均为既往接受过非甾体类芳香化酶抑制剂治疗进展的患者,口服依西美坦,1次/d,每次25mg,28d为1个周期,评价疗效和不良反应。结果：全组33例患者中,无CR病例,PR2例（6.0%）,SD19例（57.6%）,其中稳定持续时间≥24周者13例,PD12例（36.4%）,有效率（CR＋PR）为6.0%,临床获益率（CR＋PR＋SD≥24周）为45.5%,中位无进展生存期（PFS）为5.9个月（1～29.3个月）。年龄≥60岁患者的临床获益率高于年龄〈60岁患者,既往未接受过化疗（不包括辅助化疗）患者出现进展的比例低于接受过化疗患者,差异均有统计学意义（P〈0.05）。所有患者均无严重不良反应发生。结论：依西美坦在非甾体类芳香化酶抑制剂治疗失败的绝经后内分泌治疗反应型晚期乳腺癌患者中仍能取得较好的临床疗效。     

Effects of adjuvant aromatase inhibitor therapy on lipid profiles

How aromatase inhibitors affect lipids is of great interest. Compared with tamoxifen, adjuvant anastrozole and letrozole are associated with increased incidences of hypercholesterolemia, while similar data are lacking for exemestane in the adjuvant setting. No significant differences in lipid profiles occurred with extended adjuvant exemestane compared with placebo, but total cholesterol and low-density lipoprotein levels increased significantly above baseline in both groups over 6 months. Likewise, no significant differences in hypercholesterolemia rates occurred between extended adjuvant letrozole and placebo. A lipid substudy further confirmed that letrozole did not significantly alter serum lipids for 36 months compared with placebo. Thus, although aromatase inhibitors lack the lipid-lowering properties of tamoxifen, no significant worsening of lipid levels occurs with their use. Patients would benefit from lifestyle changes and routine monitoring of serum lipids. Breast cancer therapy trials often report serum lipid parameters, but assessing the quality and overall significance of the data can be difficult. Methodology of data collection varies among trials and the concomitant use of lipid-modifying medication is often not reported. This review discusses the current understanding of the influence of lipid levels on cardiovascular risk in women and presents key findings on the effects of adjuvant aromatase inhibitor therapy on lipid profiles.     

Effects of adjuvant aromatase inhibitor therapy on lipid profiles

How aromatase inhibitors affect lipids is of great interest. Compared with tamoxifen, adjuvant anastrozole and letrozole are associated with increased incidences of hypercholesterolemia, while similar data are lacking for exemestane in the adjuvant setting. No significant differences in lipid profiles occurred with extended adjuvant exemestane compared with placebo, but total cholesterol and low-density lipoprotein levels increased significantly above baseline in both groups over 6 months. Likewise, no significant differences in hypercholesterolemia rates occurred between extended adjuvant letrozole and placebo. A lipid substudy further confirmed that letrozole did not significantly alter serum lipids for 36 months compared with placebo. Thus, although aromatase inhibitors lack the lipid-lowering properties of tamoxifen, no significant worsening of lipid levels occurs with their use. Patients would benefit from lifestyle changes and routine monitoring of serum lipids. Breast cancer therapy trials often report serum lipid parameters, but assessing the quality and overall significance of the data can be difficult. Methodology of data collection varies among trials and the concomitant use of lipid-modifying medication is often not reported. This review discusses the current understanding of the influence of lipid levels on cardiovascular risk in women and presents key findings on the effects of adjuvant aromatase inhibitor therapy on lipid profiles.     

An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole,letrozole, and exemestane

BACKGROUND: The newer generation, nonsteroidal aromatase inhibitors (AIs) anastrozole and letrozole have shown superior efficacy compared with tamoxifen as first-line treatments and compared with megestrol acetate as second-line therapy in postmenopausal women with advanced breast carcinoma. In an open-label, Phase II trial, it was reported that exemestane showed numerical superiority compared with tamoxifen for objective response and clinical benefit. Because these agents ultimately may be administered for periods of up to 5 years in the adjuvant setting, it is of increasing importance to assess their tolerability and pharmacologic profiles. METHODS: In the absence of data from direct clinical comparisons, the published literature was reviewed for the clinical pharmacology, pharmacokinetic characteristics, and selectivity profiles of anastrozole, letrozole, and exemestane. RESULTS: At clinically administered doses, the plasma half-lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and exemestane (25 mg once daily) were 41-48 hours, 2-4 days, and 27 hours, respectively. The time to steady-state plasma levels was 7 days for both anastrozole and exemestane and 60 days for letrozole. Androgenic side effects have been reported only with exemestane. Anastrozole treatment had no impact on plasma lipid levels, whereas both letrozole and exemestane had an unfavorable effect on plasma lipid levels. In indirect comparisons, anastrozole showed the highest degree of selectivity compared with letrozole and exemestane in terms of a lack of effect on adrenosteroidogenesis. CONCLUSIONS: All three AIs demonstrated clinical efficacy over preexisting treatments. However, there were differences in terms of pharmacokinetics and effects on lipid levels and adrenosteroidogenesis. The long-term clinical significance of these differences remains to be elucidated.     

Comparison of the effects of the irreversible aromatase inhibitor exemestane with atamestane and MDL 18962 in rats with DMBA-induced mammary tumours

The antitumour activity of the steroidal aromatase inhibitors exemestane (FCE 24304), MDL 18962 and atamestane (SH 489) was evaluated on 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumours in rats. The compounds were given subcutaneously at daily doses of 10 and 50 mg/kg for 4 weeks. Exemestane was also given orally, at daily doses of 100 and 200 mg/kg. Subcutaneous exemestane induced 30% (10 mg/kg) and 73% (50 mg/kg) regressions of established tumours and strongly reduced the appearance of new tumours. Conversely, atamestane, MDL 18962 and oral exemestane did not affect growth of established tumours nor influenced the appearance of new neoplasms. Aromatase activity of ovarian microsomes (OAA) was reduced by 85%–93% after subcutaneous exemestane and by 25%–59% after MDL 18962, and was unaffected after atamestane. Oral exemestane caused a reduction in OAA of 72%–74%. Serum luteinising hormone (LH) levels were reduced at both the subcutaneous doses of exemestane and at the higher dose of MDL 18962. Atamestane caused an increase in LH levels, while no effect was observed with oral exemestane. The LH-lowering effect of subcutaneous exemestane, the less marked effect of MDL 18962, and the ineffectiveness of oral exemestane were also observed after 10 days of treatment in ovariectomised rats. The antigonadotrophic effect of subcutaneous exemestane, which is probably due to its slight androgenic effect, could contribute to its antitumour activity in the DMBA tumour model in intact rats, through a counteraction of the negative feedback of oestrogens on gonadotropin secretion.     

Serum HER-2/neu and response to the aromatase inhibitor letrozole versus tamoxifen.

PURPOSE: To determine the effect of elevated serum HER-2/neu on the response of metastatic breast cancer patients to an aromatase inhibitor versus an antiestrogen. PATIENTS AND METHODS: Five hundred sixty-two estrogen receptor-positive metastatic breast cancer patients were randomized to first-line hormone therapy with either letrozole or tamoxifen. An automated enzyme-linked immunosorbent assay was used to detect serum HER-2/neu. RESULTS: For patients with normal serum HER-2/neu (70.5%), objective response rate (ORR; 39% in letrozole-treated patients v 26% in tamoxifen-treated patients; P =.008), clinical benefit (CB; 57% v 45%; P =.016), time to progression (TTP; median, 12.2 v 8.5 months; P =.0019), and time to treatment failure (TTF; median, 11.6 v 6.2 months; P =.0066) were significantly better in patients treated with letrozole. In the elevated HER-2/neu group (29.5%), there was no significant difference in ORR (17% in letrozole-treated patients v 13% in tamoxifen-treated patients; P =.45) or CB (33% v 26%; P =.31), but there was a strong trend in favor of a longer TTP with letrozole (median, 6.1 v 3.3 months; P =.0596) and a significantly longer TTF with letrozole (median, 6.0 v 3.2 months; P =.0418). Multivariate analysis revealed that elevated serum HER-2/neu was a negative predictor for ORR and TTP. CONCLUSION: Patients with normal serum HER-2/neu receiving letrozole demonstrated a significantly greater ORR and CB and longer TTP and TTF than patients receiving tamoxifen. Although in patients with elevated serum HER-2/neu there was no significant difference between letrozole and tamoxifen in ORR or CB, there was a strong trend favoring longer TTP and significantly longer TTF with letrozole.     

Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: a phase II trial.

PURPOSE: To evaluate the antitumor activity and toxicity of a new steroidal aromatase inactivator, exemestane, in postmenopausal women with metastatic breast cancer who had progressive disease (PD) after treatment with a nonsteroidal aromatase inhibitor. PATIENTS AND METHODS: In this phase II trial, eligible patients were treated with exemestane 25 mg daily (n = 241) followed, at the time PD was determined, by exemestane 100 mg daily (n = 58). RESULTS: On the basis of the intent-to-treat analysis by independent review, exemestane 25 mg produced objective responses in 6.6% of patients (95% confidence interval [CI], 3.8% to 10.6%) and overall success (complete response + partial response + no change for 24 weeks or longer) in 24.3% (95% CI, 19.0% to 30.2%). The median durations of objective response and overall success were 58.4 weeks (95% CI, 49.7 to 71.1 weeks) and 37.0 weeks (95% CI, 35.0 to 39.4 weeks), respectively. Increasing the dose of exemestane to 100 mg upon the development of PD produced one partial response (1.7%; 95% CI, 0.0% to 9.2%). Both dosages were well tolerated and were discontinued because of adverse events in only 1.7% of patients. CONCLUSION: Exemestane 25 mg once daily seems to be an attractive alternative to chemotherapy for the treatment of patients with metastatic breast cancer after multiple hormonal therapies have failed.     

Effect of the irreversible aromatase inhibitor FCE 24304 on DMBA-induced mammary tumors in ovariectomized rats treated with testosterone

Summary The antitumor activity of the irreversible aromatase inhibitor FCE 24304 (6-methylenandrosta-1,4-diene-3,17-dione) was studied in ovariectomized, testosterone propionate (TP)-treated rats with 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumors that were used as a postmenopausal tumor model. When given s.c. at 20 mg/kg per day, 3 days a week for 4 weeks, TP was effective in maintaining tumor growth in ovariectomized rats (51% tumor regression in control animals vs 94% in ovariectomized rats). FCE 24304 given s.c. twice daily at 100 mg/kg per day, 6 days a week for 4 weeks, induced 96% regression, thus inhibiting the growth-promoting effect of TP. When the effect of various doses of FCE 24304 was evaluated, in comparison with a 52% tumor regression rate in control (ovariectomized, TP-treated) rats, tumor regressions amounted to 88% and 96% at s.c. FCE 24304 doses of 10 and 50 mg/kg per day, respectively, and to 76%, 88%, and 81% at oral doses of 10, 50, and 100 mg/kg per day, respectively. When FCE 24304 was given alone to ovariectomized rats, it did not affect ovariectomy-induced tumor regression (87% vs 94%). In conclusion, FCE 24304 was effective by both the s.c. and oral routes against DMBA-induced mammary tumors in ovariectomized TP-treated rats, a postmenopausal mammary tumor model.     

Antitumor activity of the aromatase inhibitor FCE 24928 on DMBA-induced mammary tumors in ovariectomized rats treated with testosterone

Summary The antitumor activity of the irreversible aromatase inhibitor FCE 24928 (4-aminoandrosta-1,4,6-triene-3,17-dione) was studied in ovariectomized and testosterone propionate (TP)-treated rats bearing 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumors. This experimental condition was used as a model of postmenopausal breast cancer. TP was given s.c. three times per week for 4 weeks at a dose of 20 mg/kg per day, a treatment that is effective in maintaining tumor growth in ovariectomized rats (89% growing tumors). FCE 24928 given s.c. twice daily 6 days/week for 4 weeks at doses of 10 and 30 mg/kg per day inhibited the tumor growth-promoting effect of TP as shown by 81% and 80% tumor-regression rates. When FCE 24928 was given at various dose levels either s.c. (3, 10, and 30 mg/kg daily) or orally (10, 30, and 100 mg/kg per day), tumor regression were observed at all doses, amounting to 63%–93% and 63%–72%, respectively. In addition, FCE 24928 given alone (30 mg/kg daily s.c.) to ovariectomized rats did not affect ovariectomy-induced tumor regression. In conclusion, following both s.c. and oral administration, FCE 24928 was effective against DMBA-induced mammary tumors in ovariectomized TP-treated rats, a postmenopausal mammary tumor model.     

Pharmacological profiles of exemestane and formestane,steroidal aromatase inhibitors used for treatment of postmenopausal breast cancer

Steroidal aromatase inhibitors like formestane and exemestane are useful drugs for endocrine treatment of postmenopausal breast cancer. In addition, these drugs should be considered valuable probes to explore the biology of breast cancer with particular emphasis on possible relations between the degree of estrogen suppression and clinical efficacy and the possible role of intratumor estrogen synthesis. The fact that steroidal and non-steroidal aromatase inhibitors bind to different parts of the aromatase enzyme suggests these drugs may act in concert aggravating plasma estrogen suppression. Thus, use of a steroidal and a non-steroidal aromatase inhibitors in concert may be one way to improve breast cancer treatment and may also provide important information to a better understanding of the dose-response relationship between estrogen suppression and clinical effects. Further, the finding that patients progressing on non-steroidal aromatase inhibitors may respond to formestane as well as exemestane suggests these drugs may have differential effects, probably on the aromatization in the tumor tissue. Further studies are warranted to explore the influence of steroidal and non-steroidal aromatase inhibitors on intratumor aromatase activity and intratumor estrogen concentrations and to correlate these findings to intratumor drug concentrations. The findings that steroidal aromatase inhibitors may have clinical effects in patients progressing on treatment with the non-steroidal aromatase inhibitor aminoglutethimide is challenging, and suggest further studies to evaluate possible benefits of using different novel aromatase inhibitors in concert or sequence.     

Effects of third generation aromatase inhibitors on bone health and other safety parameters: results of an open, randomised, multi-centre study of letrozole, exemestane and anastrozole in healthy postmenopausal women

Given potential differences between the skeletal and other effects of the third generation aromatase inhibitors (AIs), we conducted an open, randomised Phase I study, comparing the effects of three licensed AIs on bone turnover markers, lipid profiles and adrenal function. Treatment comparisons were undertaken in 90 healthy postmenopausal women with normal bone mineral density who received once daily oral anastrozole (1mg, n=29), letrozole (2.5mg, n=29) or exemestane (25mg, n=32) for 24weeks with a subsequent 12week washout period. All three AIs induced increases in bone resorption markers, but no significant differences were observed in their effects on bone turnover markers. Greater differences were observed in lipid metabolism. Notably, exemestane, but not anastrozole or letrozole, significantly increased the LDL:HDL cholesterol ratio by 12weeks, largely mediated by a decrease in HDL-cholesterol. Further, long-term clinical studies are required to determine the impact, if any, of the differences observed between the AIs     

Impact of tamoxifen on the pharmacokinetics and endocrine effects of the aromatase inhibitor letrozole in postmenopausal women with breast cancer.

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.     

A single-nucleotide polymorphism in the aromatase gene is associated with the efficacy of the aromatase inhibitor letrozole in advanced breast carcinoma

PURPOSE: To evaluate the efficacy of treatment with the aromatase inhibitor letrozole in breast cancer patients segregated with respect to DNA polymorphisms of the aromatase gene CYP19. Patients and Methods: Postmenopausal patients (n = 67) with hormone receptor-positive metastatic breast cancer were treated with the aromatase inhibitor letrozole. PCR allelic discrimination was used to examine three single-nucleotide polymorphisms (SNP) in DNA obtained from breast carcinoma tissue. Two SNPs analyzed (rs10046 and rs4646) were located in the 3' untranslated region and one (rs727479) was in the intron of the aromatase CYP19 gene. The primary end point of treatment efficacy was time to progression (TTP). RESULTS: Median age was 62 years and median number of metastatic sites was 2. Observed allelic SNP frequencies were rs10046, 71%; rs4646, 46%; and rs727479, 63%. Of the 67 patients, 65 were evaluable for efficacy. Median TTP was 12.1 months. We observed no relationship between TTP and the rs10046 or rs727479 variants. In contrast, we found that TTP was significantly improved in patients with the rs4646 variant, compared with the wild-type gene (17.2 versus 6.4 months; P = 0.02). CONCLUSION: In patients with hormone receptor-positive metastatic breast cancer treated with the aromatase inhibitor letrozole, the presence of a SNP in the 3' untranslated region of the CYP19 aromatase gene is associated with improved treatment efficacy. Testing for the CYP19 rs4646 SNP as a predictive tool for breast cancer patients on antiaromatase therapy deserves prospective evaluation.