Longer-Term Outcomes of Letrozole Versus Placebo After 5 Years of Tamoxifen in the NCIC CTG MA.17 Trial: Analyses Adjusting for Treatment Crossover

Abstract

Purpose The interim analysis of the National Cancer Institute of Canada Clinical Trials Group MA.17 trial showed that letrozole was significantly better than placebo in disease-free survival (DFS) for postmenopausal women with hormone receptor–positive breast cancer following about 5 years of tamoxifen therapy. When patients were unblinded, those on placebo were offered letrozole. Longer-term efficacy of letrozole, especially survival, was of particular interest because the median follow-up of the first interim analysis was only 2.5 years. Efficacy was difficult to assess because more than 60% of placebo patients crossed over to letrozole after being unblinded. Patients and Methods Two statistical approaches were used to adjust for the potential effects of treatment crossover: one was based on the inverse probability of censoring weighted (IPCW) Cox model and the other on a Cox model with time-dependent covariates. Results With a median follow-up of 64 months, the hazard ratios (HRs) of letrozole and placebo from the IPCW analyses were HR of 0.52 (95% CI, 0.45 to 0.61; P < .001) for DFS, HR of 0.51 (95% CI, 0.42 to 0.61; P < .001) for distant disease-free survival (DDFS), and HR of 0.61 (95% CI, 0.52 to 0.71; P < .001) for overall survival (OS). The results from the analyses based on the Cox model with time-dependent covariates were similar for letrozole and placebo: HR of 0.58 (95% CI, 0.47 to 0.72; P < .001) for DFS, HR of 0.68 (95% CI, 0.52 to 0.88; P = .004) for DDFS, and HR of 0.76 (95% CI, 0.60 to 0.96; P = .02) for OS. Conclusion Exploratory analyses based on longer follow-up and adjusting for treatment crossover suggest that extended adjuvant letrozole was superior to placebo in DFS, DDFS, and OS.

NCCN Guidelines Insights: Breast Cancer, Version 1.2017

“…In the MA-17 trial, postmenopausal women with hormone receptor-positive, early-stage breast cancer who had completed 4.5 to 6 years of adjuvant tamoxifen were randomized to extended therapy with letrozole or not. [68][69][70] With a median followup of 64 months, letrozole was associated with improved DFS (HR, 0.52; 95% CI, 0.45-0.61) and OS (HR, 0.61; 95% CI, 0.52-0.71) compared with placebo. 70 The ATLAS trial randomly allocated premenopausal and postmenopausal women to either 5 or 10 years (extended therapy) of tamoxifen.…”

“…[68][69][70] With a median followup of 64 months, letrozole was associated with improved DFS (HR, 0.52; 95% CI, 0.45-0.61) and OS (HR, 0.61; 95% CI, 0.52-0.71) compared with placebo. 70 The ATLAS trial randomly allocated premenopausal and postmenopausal women to either 5 or 10 years (extended therapy) of tamoxifen. The outcome analyses of 6,846 women with ER-positive disease showed that by extending adjuvant treatment to 10 years, the risk of relapse and breast cancer-related mortality was reduced.…”

Hormonal therapy in breast cancer: A model disease for the personalization of cancer care

“…Generally the therapy was well-tolerated, and the incidence of fracture was the same in each arm, suggesting that the risk of fracture seen in the above studies when compared to tamoxifen reflected the anti-osteopenic effects of tamoxifen (Goss et al, 2005(Goss et al, , 2008. When adjusted for cross-over that occurred after unblinding, there was also a significant improvement in overall survival observed in the entire population (HR 0.61, P < 0.001) (Jin et al, 2011) The EBCTCG has evaluated the use of aromatase inhibitors as compared to tamoxifen in a recent meta-analysis involving 19,000 patients. As was seen in the individual studies the use of an aromatase inhibitor whether upfront or sequentially with tamoxifen results in significantly reduced risk of recurrence, with absolute benefit of approximately 3%.…”

Adjuvant Endocrine Therapy for Early Breast Cancer: A Systematic Review of the Evidence for the 2014 Cancer Care Ontario Systemic Therapy Guideline

“…Although not definitive, the foregoing studies, together with the ma.17 trial [28][29][30][31][32][33][34][35][36] , suggest that hormonal treatment could be beneficial for some patients even after a delay of several years.…”

“…Supplementary Tables 3 and 4 present results from the ebctcg meta-analyses 40,41 , and Supplementary Table 5 presents results from the literature search [4][5][6][28][29][30][31][32][33][34][35][36] .…”