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.

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.     

Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma.

BACKGROUND: Two randomized, double-blind trials have compared tamoxifen 20 mg daily and the selective, nonsteroidal aromatase inhibitor anastrozole 1 mg daily as first-line therapy for advanced breast carcinoma (ABC) in postmenopausal women. The trials were prospectively designed to allow for combined data analyses. METHODS: The combined study population included 1021 postmenopausal women (median age, 67 years [range, 30-92]) with ABC whose tumors were either estrogen and/or progesterone receptor positive or of unknown receptor status. Primary endpoints were time to progression (TTP), objective response, and tolerability. RESULTS: At a median duration of follow-up of 18.2 months, anastrozole was at least equivalent to tamoxifen in terms of median TTP (8.5 and 7.0 months, respectively; estimated hazard ratio [tamoxifen relative to anastrozole], 1.13 [lower 95% confidence level, 1.00]). In a retrospective subgroup analysis, anastrozole was superior to tamoxifen with respect to TTP (median values of 10.7 and 6.4 months for anastrozole and tamoxifen, respectively, two-sided P = 0.022) in patients with estrogen and/or progesterone receptor positive tumors (60% of combined trial population). In terms of objective response, 29.0% of anastrozole and 27.1% of tamoxifen patients achieved either a complete response (CR) or a partial response (PR). Clinical benefit (CR + PR + stabilization of > or = 24 weeks) rates were 57.1% and 52.0% for anastrozole and tamoxifen, respectively. Both anastrozole and tamoxifen were well tolerated. Anastrozole led to significantly fewer venous thromboembolic (P = 0.043; not adjusted for multiple comparisons) events, and vaginal bleeding was reported in fewer patients treated with anastrozole than with tamoxifen. CONCLUSIONS: In postmenopausal women with hormonally sensitive ABC, anastrozole should be considered as the new standard first-line treatment.     

Anastrozole (Arimidex) versus tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: survival analysis and updated safety results

We present an initial survival analysis and an update of the safety data of the North American and Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability (TARGET) double-blind, randomised, multicentre studies which compared anastrozole with tamoxifen as first-line treatment in postmenopausal patients with oestrogen receptor and/or progesterone receptor-positive (ER+/PR+) or receptor-unknown advanced breast cancer (ABC). At a median follow-up of 43.7 months, 56.0% of patients in the anastrozole group and 56.1% of patients in the tamoxifen group had died. The proportion of patients dead at 2 years was 31.1 and 32.0% in the anastrozole and tamoxifen groups, respectively. In the ER+/PR+ subgroup, 55.1 and 55.9% of patients had died and median time to deaths (TTD) were 40.8 and 41.3 months in the anastrozole and tamoxifen groups, respectively. Both agents remained well tolerated, with fewer reports of vaginal bleeding (anastrozole versus tamoxifen, 1.0% versus 2.5%) and thromboembolic events (anastrozole versus tamoxifen, 5.3% versus 9.0%) in the anastrozole group versus the tamoxifen group. Hot flushes and vaginal dryness were reported marginally less in the tamoxifen group compared with the Anastrozole group. Although no improvement in survival was observed, the favourable profile of anastrozole with respect to efficacy (TTP) and tolerability [Cancer 92 (2001) 2247] support the use of anastrozole in advance of tamoxifen as the first-line therapy choice in postmenopausal women with ABC.     

Randomised study of anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women

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.     

Efficacy of tamoxifen following anastrozole ('Arimidex') compared with anastrozole following tamoxifen as first-line treatment for advanced breast cancer in postmenopausal women

Anastrozole ('Arimidex') is indicated for the treatment of advanced breast cancer in postmenopausal women. Combined analysis of two international randomised, double-blind trials (n=1021) showed that in patients with hormone receptor-positive tumours, first-line treatment with anastrozole significantly prolonged the time to progression (TTP) compared with tamoxifen (median TTP: 10.7 versus 6.4 months, respectively; P=0.022). Second-line tamoxifen following anastrozole, or vice versa, in this trial population was unblinded. The treatments were crossed over and then efficacy was assessed using a questionnaire. Of 511 patients randomised to anastrozole, 137 (26.8%) received second-line tamoxifen. Questionnaire data were available for 119 patients; 58 (48.7%) gained clinical benefit (CB=complete+partial response (CR+PR)+(stable disease (SD) >/=24 weeks)), while 12 (10.1%) had an objective response (OR=CR+PR). Of 510 patients randomised to tamoxifen, 134 (26.3%) received second-line anastrozole. Questionnaire data from 95 patients showed that 54 (56.8%) gained CB and 7 of the patients gaining CB (7.4%) had an OR. Previous studies showed anastrozole is effective after first-line tamoxifen. These data show that the sequential administration of first-line anastrozole followed by tamoxifen provides effective use of these drugs in the treatment of postmenopausal women with advanced breast cancer.     

Anastrozole versus tamoxifen as first-line therapy in postmenopausal patients with hormone-dependent advanced breast cancer: a prospective,randomized, phase III study

A prospective phase III trial comparing anastrozole with tamoxifen as first-line therapy in postmenopausal, hormone-dependent, advanced breast cancer (ABC). Patients were randomized to anastrozole 1 mg daily (n = 121) or tamoxifen 40 mg daily (n = 117). Efficacy and tolerability were evaluated after 3 months' therapy, and survival was evaluated at median time of follow-up. At a median follow-up of 13.3 months, clinical benefit (CB) was achieved in 83% and 56% of anastrozole and tamoxifen patients, respectively (p < 0.001); median time to disease progression (TTP) in patients achieving CB was 18.0 months and 7.0 months, respectively, (hazard ratio [HR] = 0.13, 95% CI = 0.08-0.20, p < 0.01). At data cutoff, 89% of tamoxifen patients had died, compared with 60% of anastrozole patients; median time to death was 17.4 months and 16.0 months, respectively (HR = 0.64, 95% CI = 0.47-0.86, p = 0.003). Therapy was well tolerated in both groups. Anastrozole showed significant advantages over tamoxifen for CB, median TTP in patients gaining CB, and survival. These data further support routine use of anastrozole as first-line treatment for postmenopausal hormone-dependent ABC.     

Anastrozole (Arimidex™) in clinical practice versus the old ‘gold standard’, tamoxifen

For the past 25 years, the estrogen antagonist tamoxifen has been considered the ‘gold standard’ for the treatment of breast cancer, despite certain tolerability issues and the risk of developing resistance. The aromatase inhibitors work by blocking the conversion of androgens to estrogen and were developed for use in patients where ovarian function had ceased (naturally, surgically or pharmacologically). Anastrozole, a third-generation nonsteroidal aromatase inhibitor that is a highly potent and selective inhibitor of the aromatase enzyme, has been shown to be superior to the gold standard tamoxifen for the first-line treatment of postmenopausal women with advanced breast cancer . As second-line therapy, anastrozole has shown superior survival compared with megestrol acetate and is also efficacious as neoadjuvant treatment in postmenopausal women and in combination with goserelin for the treatment of premenopausal women with advanced breast cancer. More recently, the results of the ATAC (anastrozole, tamoxifen, alone or in combination) trial, a large study in 9366 patients, demonstrated that anastrozole was significantly superior to tamoxifen for the treatment of postmenopausal women with early breast cancer, with regards to disease-free survival (p = 0.013) and incidence of contralateral breast cancer (p = 0.007). In addition, anastrozole was shown to be significantly better tolerated than tamoxifen with respect to endometrial cancer (p = 0.02), vaginal bleeding/discharge (p < 0.0001 for both), ischaemic cerebrovascular events (p = 0.0006), thromboembolic events (p = 0.0006) and hot flushes (p < 0.0001), while tamoxifen was associated with significantly less musculoskeletal disorders and fractures than anastrozole (p < 0.0001 for both). This review focuses on both the clinical pharmacology and the clinical data of anastrozole with emphasis on its future applications.     

Anastrozole (Arimidex) in clinical practice versus the old 'gold standard', tamoxifen

For the past 25 years, the estrogen antagonist tamoxifen has been considered the 'gold standard' for the treatment of breast cancer, despite certain tolerability issues and the risk of developing resistance. The aromatase inhibitors work by blocking the conversion of androgens to estrogen and were developed for use in patients where ovarian function had ceased (naturally, surgically or pharmacologically). Anastrozole, a third-generation nonsteroidal aromatase inhibitor that is a highly potent and selective inhibitor of the aromatase enzyme, has been shown to be superior to the gold standard tamoxifen for the first-line treatment of postmenopausal women with advanced breast cancer. As second-line therapy, anastrozole has shown superior survival compared with megestrol acetate and is also efficacious as neoadjuvant treatment in postmenopausal women and in combination with goserelin for the treatment of premenopausal women with advanced breast cancer. More recently, the results of the ATAC (anastrozole, tamoxifen, alone or in combination) trial, a large study in 9366 patients, demonstrated that anastrozole was significantly superior to tamoxifen for the treatment of postmenopausal women with early breast cancer, with regards to disease-free survival (p = 0.013) and incidence of contralateral breast cancer (p = 0.007). In addition, anastrozole was shown to be significantly better tolerated than tamoxifen with respect to endometrial cancer (p = 0.02), vaginal bleeding/discharge (p < 0.0001 for both), ischaemic cerebrovascular events (p = 0.0006), thromboembolic events (p = 0.0006) and hot flushes (p < 0.0001), while tamoxifen was associated with significantly less musculoskeletal disorders and fractures than anastrozole (p < 0.0001 for both). This review focuses on both the clinical pharmacology and the clinical data of anastrozole with emphasis on its future applications.     

The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial: an update

Until recently, tamoxifen was the only adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early-stage breast cancer. However, the first efficacy update from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial has introduced a choice of adjuvant therapy in this setting. After a median follow-up of 47 months, these data indicated that anastrozole continued to show superior efficacy compared with tamoxifen, including significantly greater disease-free survival, a longer median time to recurrence, and a reduced incidence of contralateral breast cancer. Anastrozole also exhibited a number of important tolerability benefits compared with tamoxifen, including reduced incidences of thromboembolic events, vaginal bleeding, and endometrial cancer. Additional ATAC subprotocols included the examination of bone mineral density and its associated sequelae, endometrial abnormalities, and quality of life. The results of these studies support the primary conclusions of the main efficacy and safety analyses: the efficacy benefits of anastrozole were not at the expense of quality of life, anastrozole was associated with reduced endometrial stimulation compared with tamoxifen, and only patients receiving tamoxifen had endometrial atypical hyperplasia. Anastrozole was associated with a modest loss of bone mineral density and an initial increase of fractures compared with tamoxifen. However, the fracture rate with anastrozole stabilizes after 2 years, and indirect comparison suggests that any increased fracture risk with anastrozole is modest. This review concludes that, based on the overall risk-benefit profile from the ATAC study, anastrozole is a rational alternative to tamoxifen for the adjuvant treatment of women with hormone-sensitive early-stage breast cancer.     

Development of a novel aromatase inhibitor, anastrozole (Arimidex)--its basic and clinical studies

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.     

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.     

Three years' follow-up from the ATAC trial is sufficient to change clinical practice: a debate

Tamoxifen is currently the adjuvant treatment of choice for postmenopausal women with hormone-sensitive breast cancer. However, in the treatment of postmenopausal women with advanced disease, the third-generation aromatase inhibitor anastrozole ('Arimidex') has been shown to be at least as effective as tamoxifen, and to be more effective than tamoxifen in patients with estrogen receptor-positive disease. Furthermore, anastrozole is well tolerated and is associated with fewer adverse reactions (such as thromboembolic events, vaginal bleeding, and endometrial cancer) compared with tamoxifen. A change in clinical practice has now emerged for the first-line treatment of postmenopausal advanced disease in patients, with tamoxifen becoming the second- or third-line choice for many clinicians. These data have raised questions about the optimal adjuvant treatment for postmenopausal women with early breast cancer. The 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial has compared the efficacy and safety of tamoxifen and anastrozole in the adjuvant treatment of postmenopausal women with early breast cancer. At 3 years' follow-up in the overall population, anastrozole demonstrated a significant benefit compared with tamoxifen for disease-free survival (DFS) (89.4% vs. 87.4%; p = 0.013), time to recurrence (hazard ratio = 0.79; p = 0.008), and contralateral breast cancers (odds ratio = 0.42; 95% confidence interval: 0.22-0.79; p = 0.007). Anastrozole produced improvements in quality of life similar to tamoxifen and was better tolerated for a number of predefined adverse events. Of course, a large body of evidence is available regarding the safety profile of tamoxifen and some feel that more data are needed from the ATAC trial to demonstrate that the early advantages of anastrozole over tamoxifen can be maintained in the longer term. However, a follow-up analysis at 47 months has confirmed that the tolerability profile and the absolute benefit of anastrozole were maintained over the extended follow-up period, demonstrating that the benefits of anastrozole are likely to be maintained over the long term. This review assesses these and other data from the ATAC trial and presents the arguments for and against whether 3 years' follow-up is sufficient to inform a change in clinical practice for the adjuvant treatment of postmenopausal women with early breast cancer.     

Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment.

PURPOSE: To compare the efficacy and tolerability of fulvestrant (formerly ICI 182,780) and anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. PATIENTS AND METHODS: Patients (n = 451) with advanced breast cancer were randomized to receive fulvestrant 250 mg as a once-monthly (one x 5 mL) intramuscular injection or an oral dose of anastrozole 1 mg in this open, parallel-group, multicenter trial. The primary end point was time to progression (TTP). Secondary end points included objective response (OR) rates, defined as complete response (CR) or partial response (PR), duration of response (DOR), and tolerability. RESULTS: Patients were followed for a median period of 14.4 months. In terms of TTP, fulvestrant was as effective as anastrozole (hazard ratio, 0.98; confidence interval [CI], 0.80 to 1.21; P =.84). Median TTP was 5.5 months for fulvestrant and 5.1 months for anastrozole. OR rates showed a numerical advantage for fulvestrant (20.7%) over anastrozole (15.7%) (odds ratio, 1.38; CI, 0.84 to 2.29; P =.20). Clinical benefit rates (CR + PR + stable disease > or = 24 weeks) were 44.6% for fulvestrant and 45.0% for anastrozole. Median DOR was 14.3 months for fulvestrant and 14.0 months for anastrozole. Both treatments were well tolerated, with 3.2% and 1.3% of fulvestrant- and anastrozole-treated patients, respectively, withdrawn from treatment because of an adverse event. CONCLUSION: Fulvestrant was as effective as anastrozole. These data confirm that fulvestrant is an additional, effective, and well-tolerated treatment for advanced breast cancer in postmenopausal women whose disease progressed on prior endocrine therapy.     

阿那曲唑治疗绝经后晚期乳腺癌的临床疗效分析

目的探讨阿那曲唑治疗绝经后晚期乳腺癌的临床疗效。方法回顾性分析阿那曲唑一线治疗301例绝经后晚期乳腺癌全国多中心的临床资料及疗效。结果 301例均可评价疗效,中位显效时间为2～3个月。CR为11.6%（35/301）,PR为38.2%（115/301）。总客观缓解率（ORR）为49.8%（150/301）。中位疾病进展时间（TTP）为12个月。≥70岁者TTP为12个月,ORR为64.2%,均优于〈70岁者。非内脏转移组（TTP为12个月,ORR为61.9%）优于肝脏以外内脏转移组（TTP为6个月,ORR为37.9%）;肝脏以外内脏转移组TTP和ORR优于肝脏转移组（TTP3个月,ORR为7.1%）。激素受体双阳性组TTP为12个月和ORR为57.8%,明显优于激素受体单阳性组[ER（＋）PR（-）、ER（-）PR（＋）组];ER（＋）PR（-）组TTP、ORR与ER（-）PR（＋）组比较无显著性差异。结论阿那曲唑作为绝经后晚期乳腺癌患者内分泌一线治疗选择,能够有效提高疾病客观缓解率和延长疾病进展时间。     

Anastrozole as adjuvant therapy for early-stage breast cancer: implications of the ATAC trial

Tamoxifen has been the gold standard adjuvant therapeutic agent for postmenopausal women with hormone-sensitive breast cancer for > 25 years. Although it continues to play an important role in treating premenopausal women, tamoxifen's association with some serious safety and tolerability issues, including increased incidence of endometrial cancer and thromboembolic events, may be cause to limit its use in postmenopausal women. Anastrozole was the first drug to show improved efficacy and safety compared with standard therapies for first- and second-line therapy of hormone-sensitive advanced breast cancer in postmenopausal women. This article provides a review of the results of the first major analysis of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) early-stage breast cancer trial, initiated in 1996, and discusses the implications for the use of anastrozole in the adjuvant setting. This randomized, double-blind, multicenter trial compared tamoxifen (20 mg once daily) with anastrozole (1 mg) alone and in combination with tamoxifen, as adjuvant endocrine treatment for postmenopausal patients with operable, invasive, early-stage breast cancer. The results of the ATAC trial show anastrozole to be more effective and better tolerated than tamoxifen in this group of patients, and an updated follow-up suggests the therapeutic index for anastrozole will continue to remain superior to that of tamoxifen. Anastrozole is now emerging as a new standard for the adjuvant treatment of postmenopausal women with hormone-sensitive early-stage breast cancer. New adjuvant trials are currently using anastrozole in the control arm.     

Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial.

PURPOSE: To compare the efficacy and tolerability of fulvestrant (formerly ICI 182,780) with anastrozole in the treatment of advanced breast cancer in patients whose disease progresses on prior endocrine treatment. PATIENTS AND METHODS: In this double-blind, double-dummy, parallel-group study, postmenopausal patients were randomized to receive either an intramuscular injection of fulvestrant 250 mg once monthly or a daily oral dose of anastrozole 1 mg. The primary end point was time to progression (TTP). Secondary end points included objective response (OR) rate, duration of response (DOR), and tolerability. RESULTS: Patients (n = 400) were followed for a median period of 16.8 months. Fulvestrant was as effective as anastrozole in terms of TTP (hazard ratio, 0.92; 95.14% confidence interval [CI], 0.74 to 1.14; P =.43); median TTP was 5.4 months with fulvestrant and 3.4 months with anastrozole. OR rates were 17.5% with both treatments. Clinical benefit rates (complete response + partial response + stable disease > or = 24 weeks) were 42.2% for fulvestrant and 36.1% for anastrozole (95% CI, -4.00% to 16.41%; P =.26). In responding patients, median DOR (from randomization to progression) was 19.0 months for fulvestrant and 10.8 months for anastrozole. Using all patients, DOR was significantly greater for fulvestrant compared with anastrozole; the ratio of average response durations was 1.35 (95% CI, 1.10 to 1.67; P < 0.01). Both treatments were well tolerated. CONCLUSION: Fulvestrant was at least as effective as anastrozole, with efficacy end points slightly favoring fulvestrant. Fulvestrant represents an additional treatment option for postmenopausal women with advanced breast cancer whose disease progresses on tamoxifen therapy.     

Anastrozole (‘Arimidex’) versus tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer: Results of the double-blind cross-over SAKK trial 21/95 - a sub-study of the TARGET (Tamoxifen or ‘Arimidex’ Randomized Group Efficacy and Tolerability) trial

It is desirable to identify the most effective sequence of endocrine therapies for the treatment of postmenopausal women with advanced, hormone-responsive breast cancer. In a retrospective analysis of two large, randomized, comparative Phase III trials in this patient population, the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability (TARGET) trial and the North American trial, we ascertained that tumors responding to anastrozole as first-line therapy may subsequently respond to tamoxifen as second-line therapy. In a double-blind cross-over trial, the SAKK 21/95 sub-trial (including patients from the Swiss centres in the TARGET trial), we further investigated the clinical impact of anastrozole followed by tamoxifen compared with that of tamoxifen followed by anastrozole. Patients with locally advanced or metastatic breast cancer who had continued on randomized treatment until objective disease progression and were still considered suitable for endocrine therapy, could continue on blinded therapy crossing-over to the alternative treatment. They were assessed for time to progression (TTP) from treatment randomization, TTP after crossing-over treatments, time from randomization to progression after crossing-over treatments and overall survival. Median TTP from randomization for patients receiving first-line treatment with anastrozole (n= 31) and tamoxifen (n= 29) was 11.3 and 8.3 months, respectively, p= 0.75. Median TTP from treatment cross-over was 6.7 months for tamoxifen after progression on anastrozole (n= 19) and 5.7 months for anastrozole after progression on tamoxifen (n= 18), while median time from randomization to second progression was 28.2 and 19.5 months, respectively. Overall survival from randomization for the anastrozole-tamoxifen sequence and the tamoxifen-anastrozole sequence was 69.7 versus 59.3 months, respectively, p= 0.10. The relative risk of death was higher for the tamoxifen followed by anastrozole sequence (1.63; 95% confidence interval [CI] 0.89–2.98). Tamoxifen is an effective second-line therapy after anastrozole. Our data, together with the better tolerability profile of anastrozole compared with tamoxifen, support the use of anastrozole as first-line therapy for advanced breast cancer in postmenopausal women with hormone receptor-positive tumors. Treatment with tamoxifen may still be useful upon subsequent progression.     

Advances in endocrine treatments for postmenopausal women with metastatic and early breast cancer

For the past 25 years, the estrogen antagonist tamoxifen has been the hormonal treatment of choice for postmenopausal patients with hormone-sensitive metastatic and early breast cancer (EBC). However, tamoxifen is associated with certain tolerability and safety concerns. In addition, the hormonal options after progression are limited, and thus, alternative endocrine treatments have been developed. This review provides a synopsis of the newer alternatives in endocrine therapy of breast cancer: the aromatase inhibitors (AIs) and fulvestrant Faslodex), the estrogen receptor antagonist that downregulates estrogen and progesterone receptors and has no known agonist activity. The third-generation AIs, anastrozole and letrozole, have been shown to be as effective or more effective than megestrol acetate and tamoxifen as second- and first-line therapies for the treatment of postmenopausal patients with metastatic breast cancer, and exemestane has been approved for second-line use. Fulvestrant has been shown to be as effective as anastrozole as second-line therapy for metastatic breast cancer and has been approved in the U.S. for the treatment of postmenopausal women with hormone-receptor-positive metastatic breast cancer following progression on antiestrogen therapy. Anastrozole is the only AI with published clinical trial data and U.S. Food and Drug Administration approval for adjuvant therapy of postmenopausal women with EBC. The 'Arimidex,' Tamoxifen, Alone or in Combination (ATAC) trial, a double-blind, multicenter trial with 9,366 patients, compared tamoxifen with anastrozole, alone and in combination, as adjuvant endocrine treatment for postmenopausal patients with operable, invasive, EBC. The first analysis (at a median follow-up of 33.3 months) showed longer disease-free survival and, in general, better tolerability with anastrozole than with tamoxifen. This pattern was maintained at later analyses with a median follow-up of 47 months for efficacy and 37 months for safety and tolerability. Although longer follow-up is warranted, anastrozole appears to be a well-documented choice of endocrine adjuvant therapy for postmenopausal women with hormone-responsive breast cancer.     

Role of anastrozole across the breast cancer continuum: from advanced to early disease and prevention

Breast tumorigenesis is a continuum from preinvasive lesions to early breast cancer and advanced disease. In this article the data supporting the use of the aromatase inhibitor anastrozole in postmenopausal women across this continuum are reviewed. In advanced disease, anastrozole has a significant survival benefit and tolerability advantage compared with megestrol acetate when used as second-line treatment. As first-line therapy, anastrozole significantly prolongs time to progression compared with tamoxifen in women with hormone receptor-positive (HR+) disease. In the adjuvant setting, anastrozole has superior efficacy and tolerability compared with tamoxifen in newly diagnosed patients and those who have already received 2-3 years' prior adjuvant tamoxifen. Therefore, anastrozole should be considered a preferred treatment option for postmenopausal women with HR+ early breast cancer. Furthermore, anastrozole has preoperative efficacy in HR+ large or locally advanced tumors. Finally, anastrozole substantially reduces the incidence of contralateral breast cancer compared with tamoxifen in women with HR+ early breast cancer and, therefore, is a potential chemopreventive agent. Anastrozole is thus positioned to become the standard care for postmenopausal women with HR+ disease across the whole breast cancer continuum. Additional data from ongoing studies will further clarify the role of anastrozole across the continuum and answer outstanding questions regarding the optimal timing and duration of treatment.     

他莫昔芬治疗芳香化酶抑制剂耐药的激素受体阳性绝经后转移性乳腺癌患者的临床研究

目的:探讨他莫昔芬治疗芳香化酶抑制剂（AIs）耐药的激素受体阳性（HR+）绝经后转移性乳腺癌（MBC）患者的疗效和安全性。方法:回顾性分析他莫昔芬治疗AIs耐药的30例HR+绝经后MBC患者的临床资料,观察终点为缓解率（RR）、临床获益率（CBR）、疾病进展时间（TTP）和安全性。结果:30例患者中,CR 1例,PR 9例,SD 15例,RR为33.3%,CBR 为50%,中位TTP 6.1个月。23例骨和/或软组织转移患者中,RR为34.8%,CBR为52.2%,中位TTP 7.3个月;7例肝脏和/或肺部转移患者中,RR为28.6%,CBR为42.8%,中位TTP 4.8个月（P=0.019）。不良反应多为面部潮红、阴道干燥、白带增多、阴道出血、恶心、呕吐、腹泻等,均为I、II级。结论:他莫昔芬治疗AIs耐药的HR+绝经后MBC患者安全有效,可改善患者预后。