A conventional carcinogenesis study in mice at doses of 0.6 to 60 mg/kg/day (about 1 to 100 times the daily maximum recommended human dose on a mg/m 2 basis) administered by oral gavage for up to 2 years revealed a dose-related increase in the incidence of benign ovarian stromal tumors. The incidence of combined hepatocellular adenoma and carcinoma showed a significant trend in females when the high dose group was excluded due to low survival. In a separate study, plasma AUC 0-12hr levels in mice at 60 mg/kg/day were 55 times higher than the AUC 0-24hr level in breast cancer patients at the recommended dose. The carcinogenicity study in rats at oral doses of 0.1 to 10 mg/kg/day (about 0.4 to 40 times the daily maximum recommended human dose on a mg/m 2 basis) for up to 2 years also produced an increase in the incidence of benign ovarian stromal tumors at 10 mg/kg/day. Ovarian hyperplasia was observed in females at doses equal to or greater than 0.1 mg/kg/day. At 10 mg/kg/day, plasma AUC 0-24hr levels in rats were 80 times higher than the level in breast cancer patients at the recommended dose.The benign ovarian stromal tumors observed in mice and rats were considered to be related to the pharmacological inhibition of estrogen synthesis and may be due to increased luteinizing hormone resulting from the decrease in circulating estrogen.
Letrozole was not mutagenic in in vitro tests (Ames and E.coli bacterial tests) but was observed to be a potential clastogen in in vitro assays (CHO K1 and CCL 61 Chinese hamster ovary cells). Letrozole was not clastogenic in vivo (micronucleus test in rats).
In a fertility and early embryonic development toxicity study in female rats, oral administration of letrozole starting 2 weeks before mating until pregnancy day 6 resulted in an increase in pre-implantation loss at doses ≥ 0.03 mg/kg/day (approximately 0.1 times the maximum recommended human dose on a mg/m 2 basis). In repeat-dose toxicity studies, administration of letrozole caused sexual inactivity in females and atrophy of the reproductive tract in males and females at doses of 0.6, 0.1 and 0.03 mg/kg in mice, rats and dogs, respectively (approximately 1, 0.4 and 0.4 times the daily maximum recommended human dose on a mg/m 2 basis, respectively).
In a multicenter study (BIG 1-98, NCT00004205) enrolling over 8,000 postmenopausal women with resected, receptor-positive early breast cancer, one of the following treatments was randomized in a double-blind manner:
- tamoxifen for 5 years
- Letrozole for 5 years
- tamoxifen for 2 years followed by letrozole for 3 years
- Letrozole for 2 years followed by tamoxifen for 3 years
- tamoxifen for 5 years
- Letrozole for 5 years
The study in the adjuvant setting, BIG 1-98 was designed to answer two primary questions: whether letrozole for 5 years was superior to Tamoxifen for 5 years (Primary Core Analysis) and whether switching endocrine treatments at 2 years was superior to continuing the same agent for a total of 5 years (Sequential Treatments Analysis). Selected baseline characteristics for the study population are shown in Table 6.
The primary endpoint of this trial was disease-free survival (DFS) (i.e., interval between randomization and earliest occurrence of a local, regional, or distant recurrence, or invasive contralateral breast cancer, or death from any cause). The secondary endpoints were overall survival (OS), systemic disease-free survival (SDFS), invasive contralateral breast cancer, time to breast cancer recurrence (TBR) and time to distant metastasis (TDM).
The Primary Core Analysis (PCA) included all patients and all follow-up in the monotherapy arms in both randomization options, but follow-up in the two sequential treatments arms was truncated 30 days after switching treatments. The PCA was conducted at a median treatment duration of 24 months and a median follow-up of 26 months. Letrozole was superior to tamoxifen in all endpoints except overall survival and contralateral breast cancer [e.g., DFS: hazard ratio, HR 0.79; 95% CI (0.68, 0.92); P =0.002; SDFS: HR 0.83; 95% CI (0.70, 0.97); TDM: HR 0.73; 95% CI (0.60, 0.88); OS: HR 0.86; 95% CI (0.70, 1.06).
In 2005, based on recommendations by the independent Data Monitoring Committee, the tamoxifen arms were unblinded and patients were allowed to complete initial adjuvant therapy with letrozole (if they had received tamoxifen for at least 2 years) or to start extended adjuvant treatment with letrozole (if they had received tamoxifen for at least 4.5 years) if they remained alive and disease-free. In total, 632 patients crossed to letrozole or another aromatase inhibitor. Approximately 70% (448) of these 632 patients crossed to letrozole to complete initial adjuvant therapy and most of these crossed in years 3 to 4. All of these patients were in Option 1. A total of 184 patients started extended adjuvant therapy with letrozole (172 patients) or with another aromatase inhibitor (12 patients). To explore the impact of this selective crossover, results from analyses censoring follow-up at the date of the selective crossover (in the tamoxifen arm) are presented for the MAA.
The PCA allowed the results of letrozole for 5 years compared with tamoxifen for 5 years to be reported in 2005 after a median follow-up of only 26 months. The design of the PCA is not optimal to evaluate the effect of letrozole after a longer time (because follow-up was truncated in two arms at around 25 months). The MAA (ignoring the two sequential treatment arms) provided follow-up equally as long in each treatment and did not over-emphasize early recurrences as the PCA did. The MAA thus provides the clinically appropriate updated efficacy results in answer to the first primary question, despite the confounding of the tamoxifen reference arm by the selective crossover to letrozole. The updated results for the MAA are summarized in Table 7. Median follow-up for this analysis is 73 months.
The Sequential Treatments Analysis (STA) addresses the second primary question of the study. The primary analysis for the STA was from switch (or equivalent time-point in monotherapy arms) + 30 days (STA-S) with a two-sided test applied to each pair-wise comparison at the 2.5% level. Additional analyses were conducted from randomization (STA-R) but these comparisons (added in light of changing medical practice) were under-powered for efficacy.
|Primary Core Analysis (PCA)||Monotherapy Arms Analysis (MAA)|
|Characteristic||n (%)||n (%)||n (%)||n (%)|
|Age (median, years)||61||61||61||61|
|Age range (years)||38 to 89||39 to 90||38 to 88||39 to 90|
|Hormone receptor status (%)|
|ER+ and/or PgR+||99.7||99.7||99.7||99.7|
|Nodal status (%)|
|Nodal status unknown||7||7||7||7|
|Prior adjuvant chemotherapy (%)||24||24||24||24|
|Letrozole N=2463||Tamoxifen N=2459||Hazard ratio|
|Events (%)||5-year rate||Events (%)||5-year rate||(95% CI)||P|
|Disease-free survival 1||ITT||445 (18.1)||87.4||500 (20.3)||84.7||0.87 (0.76, 0.99)||0.03|
|Censor||445||87.4||483||84.2||0.84 (0.73, 0.95)|
|0 positive nodes||ITT||165||92.2||189||90.3||0.88 (0.72, 1.09)|
|1 to 3 positive nodes||ITT||151||85.6||163||83.0||0.85 (0.68, 1.06)|
|>=4 positive nodes||ITT||123||71.2||142||62.6||0.81 (0.64, 1.03)|
|Adjuvant chemotherapy||ITT||119||86.4||150||80.6||0.77 (0.60, 0.98)|
|No chemotherapy||ITT||326||87.8||350||86.1||0.91 (0.78, 1.06)|
|Systemic DFS 2||ITT||401||88.5||446||86.6||0.88 (0.77,1.01)|
|Time to distant metastasis 3||ITT||257||92.4||298||90.1||0.85 (0.72, 1.00)|
|Adjuvant chemotherapy||ITT||84||–||109||–||0.75(0.56 to 1.00)|
|No chemotherapy||ITT||173||–||189||–||0.90 (0.73,1.11)|
|Distant DFS 4||ITT||385||89.0||432||87.1||0.87 (0.76,1.00)|
|Contralateral breast cancer||ITT||34||99.2||44||98.6||0.76 (0.49, 1.19)|
|Overall survival||ITT||303||91.8||343||90.9||0.87 (0.75, 1.02)|
|Censor||303||91.8||338||90.1||0.82 (0.70, 0.96)|
|0 positive nodes||ITT||107||95.2||121||94.8||0.90 (0.69,1.16)|
|1 to 3 positive nodes||ITT||99||90.8||114||90.6||0.81 (0.62,1.06)|
|>=4 positive nodes||ITT||92||80.2||104||73.6||0.86 (0.65, 1.14)|
|Adjuvant chemotherapy||ITT||76||91.5||96||88.4||0.79 (0.58, 1.06)|
|No chemotherapy||ITT||227||91.9||247||91.8||0.91 (0.76, 1.08)|
|Definition of: 1 Disease-free survival: Interval from randomization to earliest event of invasive loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death without a prior event 2 Systemic disease-free survival: Interval from randomization to invasive regional recurrence, distant metastasis, or death without a prior cancer event 3 Time to distant metastasis: Interval from randomization to distant metastasis 4 Distant disease-free survival: Interval from randomization to earlier event of relapse in a distant site or death from any cause|
ITT analysis ignores selective crossover in tamoxifen arms Censored analysis censors follow-up at the date of selective crossover in 632 patients who crossed to letrozole or another aromatase inhibitor after the tamoxifen arms were unblinded in 2005
Figure 1 shows the Kaplan-Meier curves for Disease-Free Survival Monotherapy Analysis
DFS events defined as loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death from any cause (i.e., definition excludes second non-breast primary cancers).
The medians of overall survival for both arms were not reached for the MAA. There was no statistically significant difference in overall survival. The hazard ratio for survival in the letrozole arm compared to the tamoxifen arm was 0.87, with 95% CI (0.75, 1.02) (see Table 7). There were no significant differences in DFS, OS, SDFS, and Distant DFS from switch in the Sequential Treatments Analysis with respect to either monotherapy (e.g., [tamoxifen 2 years followed by] letrozole 3 years versus tamoxifen beyond 2 years, DFS HR 0.89; 97.5% CI 0.68, 1.15 and [letrozole 2 years followed by] tamoxifen 3 years versus letrozole beyond 2 years, DFS HR 0.93; 97.5% CI 0.71, 1.22). There were no significant differences in DFS, OS, SDFS, and Distant DFS from randomization in the Sequential Treatments Analyses.
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