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.     

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.     

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。     

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.     

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.     

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.     

Stage and treatment variation with age in postmenopausal women with breast cancer: compliance with guidelines

Breast cancer-specific mortality is static in older women despite having fallen in younger age groups, possibly due to lack of screening and differences in treatment. This study compared stage and treatment between two cohorts of postmenopausal women (55-69 vs >70 years) in a single cancer network over 6 months. A total of 378 patients were studied (>70: N=167, 55-69 years: N=210). Older women presented with more advanced disease (>70: metastatic/locally advanced 12%, 55-69 years: 3%, P<0.01). Those with operable cancer had a worse prognosis (Nottingham Prognostic Index (NPI) >70: median NPI 4.4, 55-69 years: 4.25, P<0.03). These stage differences were partially explained by higher screening rates in the younger cohort. Primary endocrine therapy was used in 42% of older patients compared with 3% in the younger group (P<0.001). Older women with cancers suitable for breast conservation were more likely to choose mastectomy (>70: 57.5% mastectomy rate vs 55-69 years: 20.6%, P<0.01). Nodal surgery was less frequent in older patients (>70: 6.7% no nodal surgery, 55-69 years: 0.5%, P<0.01) and was more likely to be inadequate (>70: 10.7% <4 nodes excised, 55-69 years: 3.4%, P<0.02). In summary, older women presented with more advanced breast cancer, than younger postmenopausal women and were treated less comprehensively.     

Letrozole in the neoadjuvant setting: the P024 trial

Neoadjuvant chemotherapy trials have consistently reported lower response rates in hormone receptor-positive (HR+) breast cancer when compared with HR- cases. Preoperative endocrine therapy has therefore become a logical alternative and has gained considerable momentum from the finding that aromatase inhibitors (AIs) are more effective than tamoxifen for HR+ breast cancer in both the neoadjuvant and adjuvant settings. The most convincing neoadjuvant trial to demonstrate the superiority of an AI versus tamoxifen was the P024 study, a large multinational double-blind trial in postmenopausal women with HR+ breast cancer ineligible for breast-conserving surgery. The overall response rate (ORR) was 55% for letrozole and 36% for tamoxifen (P<0.001). Significantly more letrozole-treated patients underwent breast-conserving surgery (45 vs. 35%, respectively; P=0.022). In addition, ORR was significantly higher with letrozole than tamoxifen in the human epidermal growth factor receptor HER1/HER2+ subgroup (P=0.0004). The clinical efficacy of letrozole in HER2+ breast cancer was confirmed by fluorescent in situ hybridization analysis and was found to be comparable to that of HER2- cases (ORR 71% in both subsets). Biomarker studies confirmed the superiority of letrozole in centrally assessed estrogen receptor-positive (ER+) tumors and found a strong relationship with the degree of ER positivity for both agents. Interestingly, letrozole was effective even in marginally ER+ tumors and, unlike tamoxifen, consistently reduced the expression from estrogen-regulated genes (progesterone receptor and trefoil factor 1). Furthermore, when analyzed by Ki67 immunohistochemistry, letrozole was significantly more effective than tamoxifen in reducing tumor proliferation (P=0.0009). Thus, neoadjuvant letrozole is safe and superior to tamoxifen in the treatment of postmenopausal women with HR+ locally advanced breast cancer.     

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.     

Letrozole in the neoadjuvant setting: the P024 trial

Neoadjuvant chemotherapy trials have consistently reported lower response rates in hormone receptor-positive (HR+) breast cancer when compared with HR? cases. Preoperative endocrine therapy has therefore become a logical alternative and has gained considerable momentum from the finding that aromatase inhibitors (AIs) are more effective than tamoxifen for HR+ breast cancer in both the neoadjuvant and adjuvant settings. The most convincing neoadjuvant trial to demonstrate the superiority of an AI versus tamoxifen was the P024 study, a large multinational double-blind trial in postmenopausal women with HR+ breast cancer ineligible for breast-conserving surgery. The overall response rate (ORR) was 55% for letrozole and 36% for tamoxifen (P < 0.001). Significantly more letrozole-treated patients underwent breast-conserving surgery (45 vs. 35%, respectively; P = 0.022). In addition, ORR was significantly higher with letrozole than tamoxifen in the human epidermal growth factor receptor HER1/HER2+ subgroup (P = 0.0004). The clinical efficacy of letrozole in HER2+ breast cancer was confirmed by fluorescent in situ hybridization analysis and was found to be comparable to that of HER2? cases (ORR 71% in both subsets). Biomarker studies confirmed the superiority of letrozole in centrally assessed estrogen receptor-positive (ER+) tumors and found a strong relationship with the degree of ER positivity for both agents. Interestingly, letrozole was effective even in marginally ER+ tumors and, unlike tamoxifen, consistently reduced the expression from estrogen-regulated genes (progesterone receptor and trefoil factor 1). Furthermore, when analyzed by Ki67 immunohistochemistry, letrozole was significantly more effective than tamoxifen in reducing tumor proliferation (P = 0.0009). Thus, neoadjuvant letrozole is safe and superior to tamoxifen in the treatment of postmenopausal women with HR+ locally advanced breast cancer.     

The breast cancer continuum in hormone-receptor-positive breast cancer in postmenopausal women: evolving management options focusing on aromatase inhibitors.

There are now a number of highly effective options for the treatment of hormone-receptor-positive breast cancer. Although tamoxifen was the standard hormonal treatment for many years, we now have another option for postmenopausal women: the third-generation aromatase inhibitors (AIs) anastrozole, exemestane and letrozole. A number of trials have investigated the use of third-generation AIs compared with tamoxifen throughout the continuum of treatment settings for postmenopausal women with breast cancer. In the neoadjuvant setting, letrozole, given for 4 months, resulted in better overall clinical response and breast-conserving surgery rates than tamoxifen. The Immediate Preoperative Anastrozole Tamoxifen or Combined with Tamoxifen trial gave anastrozole for 3 months with no difference in clinical response but significantly improved breast-conserving surgery rates. Compared with tamoxifen, anastrozole and letrozole significantly improved disease-free survival as early adjuvant treatment for hormone-receptor-positive disease. Switching to anastrozole or exemestane after 2 to 3 years of adjuvant tamoxifen for a total of 5 years of therapy was also more effective than continued tamoxifen. All three agents are approved in the early adjuvant or switching setting in the USA. Letrozole following 5 years of tamoxifen as extended adjuvant treatment improved disease-free survival and, in the node-positive subgroup, overall survival when compared with placebo. Anastrozole and letrozole are both approved for the first-line treatment of hormone-sensitive advanced breast cancer in postmenopausal women; letrozole showed an improved response rate compared with tamoxifen. Anastrozole, letrozole and exemestane are all indicated for the second-line treatment of advanced breast cancer. In summary, third-generation AIs have been shown to have superior efficacy over tamoxifen in the metastatic, neoadjuvant and adjuvant settings and to improve outcome as extended adjuvant therapy following 5 years of tamoxifen. Ongoing studies will further define the role of sequential adjuvant treatment. Appropriate duration of treatment is another important area of investigation. This review will cover hormonal therapy for postmenopausal women with breast cancer and will not address the treatment of premenopausal women.     

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.     

Maintenance hormone therapy with letrozole after first-line chemotherapy for advanced breast cancer

OBJECTIVES: Maintenance hormone therapy after first-line chemotherapy is routinely used by many clinicians in advanced breast cancer patients with potentially hormone-sensitive tumors, although there are insufficient evidences in the literature to support this practice. We investigated the effects of the third-generation aromatase inhibitor letrozole as a maintenance therapy in postmenopausal patients who had responded or had stable disease with first-line chemotherapy. METHODS: Fifty-eight patients (median age 62 years, range 31-80) were recruited and received letrozole, 2.5 mg/day starting within 8 weeks since the last cycle of chemotherapy. Estrogen and/or progesterone receptor status was positive in 81% of the patients, unknown in 19%; 57% of the patients had visceral disease. First-line chemotherapy included anthracyclines and/or taxanes in 74% of cases. RESULTS: The median time to progression (TTP) from starting letrozole was 18.5 months. A shorter TTP was found in patients with abnormal CA 15-3 levels at the start of maintenance letrozole (median TTP, 9.9 months: p = 0.01), or with levels increasing >25% from baseline during the first 6 months of letrozole therapy (median TTP, 8.2 months: p < 0.0001). Response status improved during letrozole in 15.5% of patients who had obtained less than a complete response to chemotherapy. Maintenance treatment was well tolerated and had no significant impact on quality of life scores. CONCLUSIONS: This study provides evidence in support of the common clinical practice of maintenance hormone therapy after chemotherapy in suitably selected patients with advanced breast cancer.     

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.     

The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L).

BACKGROUND: The purpose of this study was to evaluate changes in serum lipid parameters {cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and lipoprotein(a) [Lp(a)]}, in postmenopausal women receiving letrozole or placebo after adjuvant tamoxifen for early stage breast cancer (NCIC CTG MA.17L). PATIENTS AND METHODS: MA.17L is a substudy of MA.17, a randomized, double-blind, placebo-controlled trial of letrozole 2.5 mg taken daily for 5 years in postmenopausal women with primary breast cancer completing approximately 5 years of prior adjuvant tamoxifen. Patients consenting to participate in this companion study had blood drawn and lipid parameters (total cholesterol, HDL cholesterol, LDL cholesterol, Lp(a), triglycerides) evaluated at baseline, 6 months, 12 months and yearly thereafter until completion of protocol therapy. It was required that women be non-hyperlipidemic and not taking lipid-lowering drugs at time of entry on this trial. RESULTS: Three hundred and forty seven women were enrolled in the study. The letrozole and the placebo groups demonstrated marginally significant differences in the percentage change from baseline in HDL cholesterol at 6 months (P=0.049), in LDL cholesterol at 12 months (P=0.033) and triglycerides at 24 months (P=0.036). All comparisons of lipid parameters at other time points were not significantly different between the two treatment groups. No statistically significant differences in the number of patients exceeding the thresholds defined for the lipid parameters were found between the two treatment groups. CONCLUSIONS: The MA.17 trial demonstrated a significant improvement in disease-free survival with the use of letrozole as extended adjuvant therapy post tamoxifen. Results from this study suggests that letrozole does not significantly alter serum cholesterol, HDL cholesterol, LDL cholesterol, triglycerides or Lp(a) in non-hyperlidiemic postmenopausal women with primary breast cancer treated up to 36 months following at least 5 years of adjuvant tamoxifen therapy. These findings further support the tolerability of extended adjuvant letrozole in postmenopausal women following standard tamoxifen therapy.     

Quality-adjusted survival in a crossover trial of letrozole versus tamoxifen in postmenopausal women with advanced breast cancer.

BACKGROUND: Results from a phase III study of postmenopausal women with advanced breast cancer demonstrated longer time to disease progression for patients taking letrozole versus tamoxifen. This analysis compares the trade-offs between progression-free survival and toxicity. DESIGN: Quality-adjusted survival was calculated using Q-TWiST (quality-adjusted time without symptoms or toxicity). Survival curves were partitioned into three health states: toxicity (TOX), disease progression (PROG) and periods without toxicity or disease progression (TWiST). The utility-weighted sum of the health state durations was derived and compared. RESULTS: There was not a significant difference in mean duration of serious adverse events prior to progression between the letrozole (n=453) and tamoxifen (n=454) groups (2.2 and 2 months, respectively). For TWiST, the mean duration for letrozole was 11.5 months, versus 8.5 months for tamoxifen (P <0.001). The mean duration of PROG was 11.5 months for letrozole and 12.7 months for tamoxifen (P=0.047). Using utility weights of 0.5 for TOX and PROG resulted in a 2.5-month difference in quality-adjusted survival favoring letrozole (P <0.0001). CONCLUSIONS: The longer time to disease progression with letrozole versus tamoxifen was achieved without increased time with adverse events and resulted in more quality-adjusted survival for patients on letrozole.     

Exemestane versus anastrozole as front-line endocrine therapy in postmenopausal patients with hormone receptor-positive, advanced breast cancer: final results from the Spanish Breast Cancer Group 2001-03 phase 2 randomized trial

BACKGROUND:

Several aromatase inhibitor studies have reported variations in the inhibitory potency of these agents that could lead to differences in clinical outcomes. In the current study, the authors formally evaluated the activity of anastrozole and exemestane in postmenopausal women with hormone‐responsive, advanced breast cancer.

METHODS:

Postmenopausal women who had measurable disease according to Response Evaluation Criteria in Solid Tumors and had not received previous endocrine therapy for advanced breast cancer were randomized to receive either oral exemestane 25 mg daily or oral anastrozole 1 mg daily until they had disease progression. The primary endpoint was the objective response rate (ORR), and secondary endpoints included the clinical benefit rate (CBR), time to progression (TTP), overall survival, and safety. Crossover to the other aromatase inhibitor was permitted at the time of disease progression; ORR, CBR, and TTP after second‐line treatment also were explored.

RESULTS:

In total, 103 patients were enrolled. The median patient age was 71.6 years, 52.4% of patients had visceral disease, and 75.8% of patients had ≥2 disease sites. Half of the patients had received previous tamoxifen, and 60% had received previous chemotherapy. The efficacy observed in the exemestane and anastrozole groups was an ORR of 36.2% and 46%, respectively; a CBR of 59.6% and 68%, respectively, and a TTP of 6.1 months and 12.1 months, respectively. At progression, 28 patients crossed over to the other aromatase inhibitor, including 16 patients who switched to exemestane (CBR, 43.7%; TTP, 4.4 months) and 12 patients who switched to anastrozole (CBR, 8.3%; TTP, 2 months). Both drugs were generally well tolerated, and no study drug‐related serious adverse events were reported.

CONCLUSIONS:

In this phase 2 randomized trial, no significant differences in clinical activity were observed in favor of exemestane to justify a superiority phase 3 trial design in the first‐line setting. Cancer 2012;. © 2011 American Cancer Society.     

Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial

BackgroundTo compare the incidence and timing of bone fractures in postmenopausal women treated with 5 years of adjuvant tamoxifen or letrozole for endocrine-responsive early breast cancer in the Breast International Group (BIG) 1-98 trial.MethodsWe evaluated 4895 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial who received at least some study medication (median follow-up 60.3 months). Bone fracture information (grade, cause, site) was collected every 6 months during trial treatment.ResultsThe incidence of bone fractures was higher among patients treated with letrozole [228 of 2448 women (9.3%)] versus tamoxifen [160 of 2447 women (6.5%)]. The wrist was the most common site of fracture in both treatment groups. Statistically significant risk factors for bone fractures during treatment included age, smoking history, osteoporosis at baseline, previous bone fracture, and previous hormone replacement therapy.ConclusionsConsistent with other trials comparing aromatase inhibitors to tamoxifen, letrozole was associated with an increase in bone fractures. Benefits of superior disease control associated with letrozole and lower incidence of fracture with tamoxifen should be considered with the risk profile for individual patients.     

Letrozole (Femara), a new aromatase inhibitor for advanced breast cancer]

The study compares letrozole (Femara and aminoglutethimide (AG), a standard therapy for postmenopausal women with advanced breast cancer, previously treated with anti-estrogens. 555 women were randomly assigned letrozole 2.5 mg once daily (n = 185), letrozole 0.5 mg once daily (n = 192) or aminoglutethimide 250 mg twice daily with corticosteroid support (n = 178) in an open-label, multicenter trial. The primary end-point was objective response rate (ORR), with time events as secondary. ORR was analysed nine months after enrollment of the last patient, while survival was analysed 15 months after the last patients was enrolled. We report the results of these analyses plus an extended period of observation (covering a total duration of approximately 45 months) to determine the duration of response and clinical benefit. Overall objective response rates (complete + partial) of 19.5%, 16.7% and 12.4% were seen for letrozole 2.5 mg, 0.5 mg and AG respectively. Median duration of response and stable disease was longest for letrozole 2.5 mg (21 months) compared with letrozole 0.5 mg (18 months) and AG (14 months). Letrozole 2.5 mg was superior to AG in time to progression, time to treatment failure and overall survival. Treatment-related adverse events occurred in fewer patients on letrozole (33%) than on AG (46%). Letrozole 2.5 mg offers longer disease control than aminoglutethimide and letrozole 0.5 mg in the treatment of postmenopausal women with advanced breast cancer, previously treated with anti-estrogens.