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

Background: The study compares letrozole and aminoglutethimide (AG), astandard therapy for postmenopausal women with advanced breast cancer,previously treated with anti-oestrogens.Patients and methods: 555 women were randomly assigned letrozole 2.5 mgonce daily (n = 185), letrozole 0.5 mg once daily (n = 192) oraminoglutethimide 250 mg twice daily with corticosteroid support (n = 178)in an open-label, multicentre trial. The primary endpoint was objectiveresponse rate (ORR), with time events as secondary. ORR was analysed ninemonths after enrolment of the last patient, while survival was analysed 15months after the last patient was enrolled. We report the results of theseanalyses plus an extended period of observation (covering a total durationof approximately 45 months) to determine the duration of response andclinical benefit.Results: Overall objective response rates (complete + partial) of19.5%, 16.7% and 12.4% were seen for letrozole 2.5 mg,0.5 mg and AG respectively. Median duration of response and stable diseasewas 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 timeto 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 frequentevent 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 mgletrozole).Conclusions: Letrozole 2.5 mg offers longer disease control thanaminoglutethimide and letrozole 0.5 mg in the treatment of postmenopausalwomen with advanced breast cancer, previously treated with anti-oestrogens.     

Efficacy of first-line letrozole versus tamoxifen as a function of age in postmenopausal women with advanced breast cancer

PURPOSE: To compare the efficacy, in regard to time to progression (TTP) and objective response rate (ORR), of letrozole (Femara; Novartis Pharma AG; Basel Switzerland), an oral aromatase inhibitor, with that of tamoxifen (Tamofen; Leiras OY; Turku, Finland) as first-line therapy in younger (<70 years) and older (>/=70 years) postmenopausal women with advanced breast cancer. MATERIALS AND METHODS: Nine hundred seven patients with advanced breast cancer were randomly assigned to receive 2.5 mg letrozole (n = 453) or 20 mg tamoxifen (n = 454) once daily in a double-blind, multicenter, international trial. Among the prospectively planned analyses were analyses of TTP and ORR by age (<70 and >/=70 years). The results of these prospectively planned analyses are reported here. RESULTS: Letrozole was as effective in older postmenopausal women (>/=70 years of age) as it was in younger postmenopausal women (<70 years of age). The overall ORR in the older subgroup was significantly higher in patients treated with letrozole (38%) than in patients treated with tamoxifen (18%). In the younger subgroup of postmenopausal patients, the ORRs were not significantly different (letrozole, 26%; tamoxifen, 22%). TTP was significantly longer for letrozole than for tamoxifen in both age groups (younger: letrozole median TTP, 8.8 months; tamoxifen, 6.0 months; older: letrozole median TTP, 12.2 months; tamoxifen, 5.8 months). Although age was independently prognostic of TTP, there was no significant effect of age on ORR in the presence of other factors. CONCLUSION: The data show that letrozole, 2.5 mg once daily, is as effective in older, postmenopausal women as it is in younger postmenopausal women with advanced breast cancer. In addition, letrozole was more effective than tamoxifen in both younger and older patients.     

Approval summary: letrozole in the treatment of postmenopausal women with advanced breast cancer.

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 >or=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.     

来曲唑与氨鲁米特对照治疗绝经后晚期乳腺癌113例

目的 对比来曲唑和氨鲁米特治疗妇女绝经后晚期乳腺癌患者的有效性和耐受性。 方法 采用开放、随机、多中心对照研究。患者随机分组接受口服来曲唑2．5mg．d-1或氨鲁米特1g．d-1的对照治疗。 结果 来曲唑组(n=59)有效率23．73％(CR 2例，PR 12例，ITT有效率21．88％)，SD 20．31％(13例)。氨鲁米特组(n=54)有效 率11．11％(CR 1例，PR 5例，ITT有效率10．17％)，SD 20．34％(12例)，2组疗效无统计学差异(P>0．05)。来曲唑组和氨鲁米特 组不良反应发生率分别为18．64％和42．11％，与治疗相关的不良反应发生率分别为13．56％和33．33％。比较2组总的和与治疗 相关的不良反应发生率均以来曲唑组明显较低，P值均为0．002。 结论 来曲唑对绝经后、ER／PR阳性或不明的晚期乳腺癌患者有效率为23．73％，与氨鲁米特比较无统计学差异。但来曲唑不良 反应较氨鲁米特明显低，可以代替氨鲁米特用于晚期绝经后受体阳性或不明乳癌患者的治疗。     

来曲唑与氨鲁米特对照治疗绝经后晚期乳腺癌113例

目的对比来曲唑和氨鲁米特治疗妇女绝经后晚期乳腺癌患者的有效性和耐受性。方法采用开放、随机、多中心对照研究。患者随机分组接受口服来曲唑2.5mg.d~(-1)或氨鲁米特1g.d(-1)的对照治疗。结果来曲唑组(n=59)有效率23.73%(CR 2例,PR 12例,ITT 有效率21.88%),SD 20.31%(13例)。氨鲁米特组(n=54)有效率11.11%(CR 1例,PR 5例,ITT 有效率10.17%),SD 20.34%(12例),2组疗效无统计学差异(P>0.05)。来曲唑组和氨鲁米特组不良反应发生率分别为18.64%和42.11%,与治疗相关的不良反应发生率分别为13.56%和33.33%。比较2组总的和与治疗相关的不良反应发生率均以来曲唑组明显较低,P 值均为0.002。结论来曲唑对绝经后、ER/PR 阳性或不明的晚期乳腺癌患者有效率为23.73%,与氨鲁米特比较无统计学差异。但来曲唑不良反应较氨鲁米特明显低,可以代替氨鲁米特用于晚期绝经后受体阳性或不明乳癌患者的治疗。     

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.

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.     

Letrozole in advanced breast cancer: the PO25 trial

Tamoxifen has been a standard first-line endocrine therapy for post-menopausal women with hormone-responsive advanced breast cancer, but more than half of patients fail to respond and time to progression is less than 12 months in responders. The third-generation aromatase inhibitors were developed to provide more effective alternatives to tamoxifen. In the Femara Study PO25, post-menopausal women with advanced breast cancer were randomized to receive letrozole 2.5 mg (n=453) or tamoxifen 20 mg (n=454) given orally daily until progressive disease occurred. Patients were permitted to cross over to the other treatment at progression. In the primary efficacy analysis, median time to progression (TTP) was significantly longer with letrozole than with tamoxifen (9.4 months vs. 6.0 months, respectively; P<0.0001). The objective response rate (ORR) was significantly higher for letrozole than for tamoxifen (32% vs. 21%; P=0.0002). Prospectively planned analyses of the intent-to-treat population showed that letrozole significantly improved overall survival (OS) compared with tamoxifen over the first 24 months of the trial. An exploratory analysis of patients, who did not cross over, indicated a median OS benefit of 14 months for letrozole compared with tamoxifen. Letrozole is the only third-generation aromatase inhibitor that has demonstrated significant improvements in ORR, TTP, and early OS.     

Double-blind randomised trial comparing the non-steroidal aromatase inhibitors letrozole and fadrozole in postmenopausal women with advanced breast cancer.

BACKGROUND: To compare the efficacy, safety and tolerability of letrozole, an advanced non-steroidal aromatase inhibitor, and fadrozole hydrochloride, an older-generation drug in this class, we conducted a randomised double-blind trial in postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: One hundred and fifty-seven postmenopausal women with advanced breast cancer were enrolled and randomly assigned to receive letrozole or fadrozole in a multicentre, randomised double-blind trial in Japan. One hundred and fifty-four eligible patients were treated with either letrozole 1.0 mg once daily (n = 77) or fadrozole 1.0 mg twice daily (n = 77), for a minimum of 8 weeks. RESULTS: Letrozole showed a significantly higher overall objective response rate [complete response (CR) + partial response (PR)] than fadrozole (31.2% and 13.0%, respectively; P = 0.011, Fisher's exact test). Clinical benefits defined as CR, PR and stable disease (no change in status for more than 24 weeks) were also higher in patients treated with letrozole (50.6%) than fadrozole (35.1%). Letrozole was significantly superior to fadrozole in terms of the dominant lesion in soft tissue, bone and viscera (P = 0.011, stratified Mantel-Haenszel test). Median time to progression was 211 days in the letrozole group and 113 days in the fadrozole group with no significant difference (P = 0.175, log-rank test). Letrozole markedly reduced the estradiol, estrone and estrone sulfate levels in peripheral blood within 4 weeks. The suppressive effect of fadrozole on these hormone levels was insufficient. Adverse drug reactions were observed in 35.9% of the patients treated with letrozole and in 39.5% of those treated with fadrozole with no significant difference between the two groups (P = 0.74, Fisher's exact test). Most of the adverse drug reactions were rated as grade 1 or 2. CONCLUSIONS: The results show letrozole at a dose of 1.0 mg once daily to be more effective in treating postmenopausal women with advanced breast cancer than fadrozole at 1.0 mg twice daily, with similar safety and tolerability profiles.     

An open randomised trial of second-line endocrine therapy in advanced breast cancer. comparison of the aromatase inhibitors letrozole and anastrozole

It was previously shown that letrozole (Femara) was significantly more potent than anastrozole (Arimidex) in inhibiting aromatase activity in vitro and in inhibiting total body aromatisation in patients with breast cancer. The objective of this study was to compare letrozole (2.5 mg per day) and anastrozole (1 mg per day) as endocrine therapy in postmenopausal women with advanced breast cancer previously treated with an anti-oestrogen. This randomised, multicentre and multinational open-label phase IIIb/IV study enrolled 713 patients. Treatment was for advanced breast cancer that had progressed either during anti-oestrogen therapy or within 12 months of completing that therapy. Patients had tumours that were either positive for oestrogen and/or progesterone receptors (48%) or of unknown receptor status (52%). The primary efficacy endpoint was time to progression (TTP). Secondary endpoints included objective response, duration of response, rate and duration of overall clinical benefit (responses and long-term stable disease), time to treatment failure, and overall survival, as well as general safety. There was no difference between the treatment arms in TTP; median times were the same for both treatments. Letrozole was significantly superior to anastrozole in the overall response rate (ORR) (19.1% versus 12.3%, P=0.013), including in predefined subgroups (receptor status-unknown, and soft-tissue- and viscera-dominant site of disease). There were no significant differences between the treatment arms in the rate of clinical benefit, median duration of response, duration of clinical benefit, time to treatment failure or overall survival. Both agents were well tolerated and there were no significant differences in safety. These results support previous data documenting the greater aromatase-inhibiting activity of letrozole and indicate that advanced breast cancer is more responsive to letrozole than to anastrozole as second-line endocrine therapy.     

Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group.

PURPOSE: To analyze overall survival (OS) and update efficacy data for letrozole versus tamoxifen as first-line therapy in postmenopausal women with locally advanced or metastatic breast cancer. PATIENTS AND METHODS: This multicenter phase III trial randomly assigned 916 patients with hormone receptor-positive or unknown tumors letrozole 2.5 mg (n = 458) or tamoxifen 20 mg (n = 458) daily until disease progression. Optional cross-over was permitted at the treating physician's discretion. This report updates efficacy at a median follow-up of 32 months. RESULTS: The superiority of letrozole to tamoxifen was confirmed for time to progression (median, 9.4 v 6.0 months, respectively; P <.0001), time to treatment failure (median, 9 v 5.7 months, respectively; P <.0001), overall objective response rate (32% v 21%, respectively; P =.0002), and overall clinical benefit. Median OS was slightly prolonged for the randomized letrozole arm (34 v 30 months, respectively). Although this difference in OS is not significant, survival was improved in the randomized letrozole arm over the first 2 years of the study. Approximately one half of the patients in each arm crossed over. Total duration of endocrine therapy ("time to chemotherapy") was significantly longer (P =.005) for patients initially on letrozole (median, 16 months) than for patients initially on tamoxifen (median, 9 months). Time to worsening of Karnofsky performance score was significantly delayed with letrozole compared with tamoxifen (P =.001). CONCLUSION: This study documents the superiority of letrozole over tamoxifen in first-line endocrine therapy in postmenopausal women with advanced breast cancer.     

弗隆和氨鲁米特治疗绝经后妇女晚期乳腺癌临床观察

目的:观察弗隆和氨鲁米特治疗绝经后晚期乳腺癌的疗效和不良反应.方法:50例绝经后晚期乳腺癌患者随机进入弗隆组26例和氨鲁米特组24例.弗隆2.5mg口服,每天1次.氨鲁米特,第1周125mg口服,每日2次;第2周,250mg,每日2次;第3周250mg,每日3次;从第4周开始,250mg,每日4次.治疗30天为1周期.结果:弗隆组有效患者(CR PR)7例(26.9%),高于氨鲁米特组3例(12.5%),但差异无显著性(P=0.294).两组病情稳定(SD)患者分别有14例(53.8%)和12例(50.0%);病情进展(PD)患者分别有5例(19.2%)和9倒(37.5%).两药疗效在不同受体状态、无病间期、病变部位和治疗阶段的分层比较,差异均无显著性(P值均＞0.05).弗隆组主要的不良反应有乏力(15.4%)、食欲下降(11.5%),头晕、恶心、头痛、嗜睡发生率均＜8%,且程度较轻;氨鲁米特组恶心(25.0%)、呕吐(1 6 7%)发生明显高于弗隆组,差异有显著性(P值分别为0.045和0.046);头晕(25.0%)、乏力(20.8%)、食欲下降(16.7%)、嗜睡(12.5%)、皮肤瘙痒(12.5%)的发生也均高于弗隆组,但差异无显著性(P值均＞0.05),另外有1例患者出现过敏性皮疹.结论:弗隆治疗绝经后晚期乳腺癌有一定疗效,部分不良反应比氨鲁米特轻,患者耐受性强.     

Double-blind,randomised, multicentre endocrine trial comparing two letrozole doses,in postmenopausal breast cancer patients

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, 17α-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.     

来曲唑及去势联合来曲唑综合治疗晚期乳腺癌46例分析

目的观察来曲唑组及去势联合来曲唑治疗组间治疗晚期乳腺癌的疗效及不良反应。方法来曲唑组36例绝经后晚期乳腺癌患者接受来曲唑2.5mg口服,每日1次;去势联合来曲唑治疗组10例绝经前晚期乳腺癌接受去势治疗和来曲唑治疗,部分患者加用局部放疗。结果来曲唑组及去势联合来曲唑组治疗晚期乳腺癌均有较好效果。但来曲唑组较去势联合来曲唑组在平均生存时间(37.1个月对26.1个月)以及两年生存率(94.0%对60.0%)均有优势。结论来曲唑治疗晚期乳腺癌效果较好,药物不良反应轻。绝经前女性通过去势联合来曲唑也可以取得满意效果。     

Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate.

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.     

弗隆和氨鲁米特治疗绝经后妇女晚期乳腺癌临床观察

目的观察弗隆和氨鲁米特治疗绝经后晚期乳腺癌的疗效和不良反应。方法50例绝经后晚期乳腺癌患者随机进入弗隆组26例和氨鲁米特组24例。弗隆2.5mg口服,每天1次。氨鲁米特,第1周125mg口服,每日2次;第2周,250mg,每日2次;第3周250mg,每日3次;从第4周开始,250mg,每日4次。治疗30天为1周期。结果弗隆组有效患者(CR PR)7例(26.9%),高于氨鲁米特组3例(12.5%),但差异无显著性(P=0.294)。两组病情稳定(SD)患者分别有14例(53.8%)和12例(50.0%);病情进展(PD)患者分别有5例(19.2%)和9例(37.5%)。两药疗效在不同受体状态、无病间期、病变部位和治疗阶段的分层比较,差异均无显著性(P值均>0.05)。弗隆组主要的不良反应有乏力(15.4%)、食欲下降(11.5%)、头晕、恶心、头痛、嗜睡发生率均<8%,且程度较轻;氨鲁米特组恶心(25.0%)、呕吐(16.7%)发生明显高于弗隆组,差异有显著性(P值分别为0.045和0.046),头晕(25.0%)、乏力(20.8%)、食欲下降(16.7%)、嗜睡(12.5%)、皮肤瘙痒(12.5%)的发生也均高于弗隆组,但差异无显著性(P值均>0.05),另外有1例患者出现过敏性皮疹。结论弗隆治疗绝经后晚期乳腺癌有一定疗效,部分不良反应比氨鲁米特轻,患者耐受性强。     

Superiority of letrozole to tamoxifen in the first-line treatment of advanced breast cancer: evidence from metastatic subgroups and a test of functional ability

PURPOSE: The letrozole study 025 is a large (n = 907), international, double-blind, randomized, phase III trial in postmenopausal women with advanced breast cancer. This subanalysis compares the efficacies of letrozole and tamoxifen as first-line therapy in postmenopausual women with advanced breast cancer according to site of metastatic lesions and Karnofsky Performance Status (KPS). MATERIALS AND METHODS: Nine hundred seven patients with advanced breast cancer were randomly assigned to once-daily oral letrozole (2.5 mg; Femara; Novartis Pharma AG; Basel, Switzerland) or tamoxifen (20 mg; Tamofen; Leiras OY; Turku, Finland). Time to progression (TTP) was estimated using the Kaplan-Meier product-limit method. Treatments were compared by Cox proportional hazards regression models. RESULTS: Letrozole treatment significantly prolonged TTP in all subsets of patients: those with nonvisceral metastases, those with visceral metastases without liver involvement, and those with liver metastases. The reduction in risk of progression ranged from 25%, for patients with nonvisceral metastases, to 36%, for patients with liver metastases. The distributions of baseline KPS scores for both treatment groups were similar (57% had KPS scores >/=90). Time to worsening of 20 points or more in KPS score was significantly longer with letrozole than with tamoxifen, but modest numbers of patients experienced such deterioration (letrozole, 20%, tamoxifen, 22%, in patients without visceral metastases; 23%-24% in patients with liver metastases; and letrozole, 14%, tamoxifen, 30%, in patients with visceral metastases without liver involvement). CONCLUSION: These data demonstrate the consistent superiority of letrozole over tamoxifen and support the use of letrozole as a new standard of endocrine therapy in postmenopausal women with advanced breast cancer.     

弗隆和氨鲁米特治疗绝经后妇女晚期乳腺癌临床观察(英文)

目的观察弗隆和氨鲁米特治疗绝经后晚期乳腺癌的疗效和不良反应。方法 50例绝经后晚期乳腺癌患者随机进入弗隆组26例和氨鲁米特组24例。弗隆2.5mg 口服,每天1次。氨鲁米特,第1周125mg 口服,每日2次;第2周,250mg,每日2次;第3周250mg,每日3次;从第4周开始,250mg,每日4次。治疗30天为1周期。结果弗隆组有效患者(CR+PR)7例(26.9%),高于氨鲁米特组3例(12.5%),但差异无显著性(P=0.294)。两组病情稳定(SD)患者分别有14例(53.8%)和12例(50.0%);病情进展(PD)患者分别有5例(19.2%)和9例(37.5%)。两药疗效在不同受体状态、无病间期、病变部位和治疗阶段的分层比较,差异均无显著性(P 值均>0.05)。弗隆组主要的不良反应有乏力(15.4%),食欲下降(11.5%)、头晕、恶心、头痛、嗜睡发生率均<8%,且程度较轻;氦鲁米特组恶心(25.0%)、呕吐(16.7%)发生明显高于弗隆组,差异有显著性(P 值分别为0.045和0.046),头晕(25.0%)、乏力(20.8%)、食欲下降(16.7%)、嗜睡(12.5%)、皮肤瘙痒(12.5%)的发生也均高于弗隆组,但差异无显著性(P 值均>0.05),另外有1例患者出现过敏性皮疹。结论弗隆治疗绝经后晚期乳腺癌有一定疗效,部分不良反应比氨鲁米特轻,患者耐受性强。     

Letrozole, a new oral non-steroidal aromastase inhibitor in treating postmenopausal patients with advanced breast cancer. A pilot study

PURPOSE: To evaluate the endocrine effects as well as the pharmacokineticparameters, efficacy and safety of letrozole, a new fourth-generationnon-steroidal aromatase in hibitor. Patients and methods: Fourteen postrnenopausal women with progressivemetastatic breast cancer, previously treated with endocrinetherapy and/or chemotherapy for advanced disease, were treatedwith 0.5 mg daily doses of letrozole, orally. Endocrine andpharmacokinetic measurements were made before treatment andon days 14, 28, 56, and 84 of therapy. RESULTS: Letrozole induced a >86% decrease in plasma estrone and a=67% reduction in circulating estradiol from day 14 on. Therewas a statistically significant decrease in plasma cortisol,which appeared clinically irrelevant since all values remainedwithin the normal range. No significant changes in aldosteroneconcentration were noted. One patient achieved a complete response(CR) and 4 patients a partial response (PR), with an objectiveresponse rate of 36% (95% CI 13% to 6 5%). Median duration ofresponse was 24 months, ranging from 4 to 44 months. No toxiceffects 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 definedby future studies. Further phase II and phase III studies comparingletrozole to other available second or even first-line endocrine-therapyagents, are war ranted. aromatase inhibitors, breast carconoma, endocrine therapy, letrozole     

A randomized,placebo-controlled trial (NCIC CTG MAP1) examining the effects of letrozole on mammographic breast density and other end organs in postmenopausal women

Mammographically detected breast density has been correlated with breast cancer risk. Breast density appears to be influenced by hormonal factors including increasing age, postmenopausal status, number of pregnancies, lower body weight, hormone replacement therapy, and tamoxifen therapy. The aromatase inhibitor letrozole profoundly reduces breast and circulating estrogen levels in postmenopausal women. We hypothesize that letrozole may reduce breast density and report here on its effects on mammographic breast density, bone mineral density (BMD), bone biomarkers, plasma hormone, and serum lipid levels. MAP1 was a multicenter, randomized, double-blind, placebo-controlled, feasibility trial in which postmenopausal women with or without prior invasive breast cancer were randomized in a 2:1 ratio of letrozole (2.5 mg daily) or placebo for 12 months and followed for a total of 24 months. Eligible women had an estimated >25% breast density on baseline mammogram. The primary endpoint was change in percent breast density (PD) between the baseline and 12-month mammograms as estimated by a computer-assisted thresholding program. Baseline and 12-month mammographic density was also assessed in a blinded manner by visual inspection. Secondary endpoints included changes in serum hormones, plasma lipid levels, bone biomarkers, and BMD. Data are available for 67 women (44 on letrozole and 23 on placebo). No significant changes in PD were noted between the treatment arms at either 12 or 24 months. No distinguishable difference in density measurements by visual inspection were noted between baseline and 12-month mammograms. A significant decrease in percentage change in T-score of the femoral neck at 12 months was noted in the letrozole arm without other significant changes in BMD parameters. Lipid values did not differ between treatment groups except for a borderline significant decrease in total cholesterol at 3 months among women treated with letrozole. Letrozole therapy was associated with a significant reduction in mean serum estradiol, estrone, and estrone sulfate levels at 12 months, but not at 24 months. A significant increase in serum IGF-1 levels was also noted in the letrozole group compared to the placebo group at both 12 and 24 months. To conclude, compared with placebo, 12 months of letrozole therapy does not appear to have a significant effect on mammographic PD. Twelve months of letrozole was associated with a decrease of uncertain clinical significance in the T-score of the femoral neck at 12 months which was reversible at 24 months with recovery of estrogen levels. Letrozole therapy was found to increase IGF-1 levels at 12 and 24 months.     

High circulating HER2 extracellular domain levels correlate with reduced efficacy of an aromatase inhibitor in hormone receptor-positive metastatic breast cancer: a confirmatory prospective study

BACKGROUND: In this specifically designed, prospective study, the authors addressed the predictive value of circulating levels of the extracellular domain (ECD) of HER2 in patients with metastatic breast cancer who were treated with letrozole. METHODS: Two hundred twenty-six patients with hormone receptor-positive, metastatic breast cancer received letrozole (2.5 mg daily) until they developed either disease progression or unacceptable toxicity. Efficacy was measured primarily as the time to progression (TTP) and, secondarily, as the objective response rate (ORR) and overall survival. HER2 ECD levels were determined by using a sandwich enzyme HER2/neu immunoassay before letrozole treatment was initiated. Positive HER2 ECD status was correlated with treatment efficacy. RESULTS: Forty-two patients (19%) had elevated HER2 ECD levels, which were associated with primary tumor HER2 expression (P < .001) but not with age, performance status, location, or number of metastatic sites. The median TTP was significantly shorter among patients who had elevated HER2 ECD compared with the median TTP among patients who had normal levels (4 months vs 14 months; P = .0004), and the ORR was lower in the group with elevated HER2 ECD levels (14% vs 30%; P < .036). Overall survival was significantly shorter among patients with elevated serum HER-2 ECD (P < .0005). CONCLUSIONS: Elevated HER2 ECD concentrations predicted poorer outcomes in postmenopausal women with metastatic hormone receptor-positive breast cancer who were treated with aromatase inhibitors like letrozole.