The prognostic significance of single hormone receptor positive metastatic breast cancer: an analysis of three randomised phase III trials of aromatase inhibitors.

We analysed the outcomes of women with metastatic breast cancer (MBC) from three randomised phase III trials of aromatase inhibitors according to oestrogen receptor (ER) and progesterone receptor (PgR) status. Both receptors were analysed in 1010 of the 1870 women (54%), including 31 that were ER-/PgR-, which were excluded. Of the remaining 979, 726 (74%) were ER+/PgR+ but 253 were single hormone receptor positive (213 ER+/PgR-, 40 ER-/PgR+). Although there were no differences in clinical benefit or time to progression, the median overall survival of women with ER+/PgR+ tumours was significantly longer than those with single HR positive tumours (800 versus 600 days, p=0.01). In women with ER+ tumours, the median overall survival of those with tumours that were also PgR+ was significantly longer than those that were PgR- (800 versus 625 days, p=0.02). The PgR status is an important prognostic factor for survival in MBC.

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.

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.

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.

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.

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.

Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study.

BACKGROUND: A randomized, double-blind, multicenter study was conducted to compare the anti-tumor activity of letrozole vs. tamoxifen in postmenopausal women with ER and/or PgR positive primary untreated breast cancer. PATIENTS AND METHODS: Three hundred thirty-seven postmenopausal women with ER and/or PgR positive primary untreated breast cancer were randomly assigned once daily treatment with either letrozole 2.5 mg or tamoxifen 20 mg for four months. At baseline none of the patients were considered to be candidates for breast-conserving surgery (BCS) and 14% of the patients were considered inoperable. The primary endpoint was to compare overall objective response (CR + PR) determined by clinical palpation. Secondary endpoints included overall objective response on ultrasound and mammography and the number of patients who qualified for BCS. RESULTS: Overall objective response rate (clinical palpation) was statistically significantly superior in the letrozole group, 55% compared to tamoxifen, 36% (P < 0.001). Secondary endpoints of ultrasound response, 35% vs. 25% (P = 0.042), mammographic response, 34% vs. 16% (P < 0.001), and BCS, 45% vs. 35% (P = 0.022) between the letrozole and tamoxifen groups, respectively, showed letrozole to be significantly superior. Both treatments were well tolerated. CONCLUSIONS: This study shows that letrozole is more effective than tamoxifen as preoperative therapy in postmenopausal patients with ER and/or PgR positive primary untreated breast cancer and is at least as well tolerated.