Extending the benefits of adjuvant therapy in early HR+ breast cancer.

The benefits of adjuvant tamoxifen are well documented, but therapy is limited to 5 years because of reports of an unfavorable risk: benefit profile in later years. However, the risk of relapse continues beyond the end of therapy. Before the MA.17 trial, no agent given after the standard 5 years of adjuvant tamoxifen had been shown to provide additional benefit, leaving women unprotected against the ongoing risk of late recurrences of breast cancer. In the MA.17 trial, starting letrozole within 3 months of completing tamoxifen significantly reduced the risk of relapse (including distant metastases) compared with placebo, and also significantly improved survival in patients who had node-positive disease at diagnosis. On the basis of data from the first interim analysis, the MA.17 trial was unblinded, and all patients in the placebo arm were offered letrozole: approximately two-thirds accepted. Early study unblinding left some important questions unanswered (including the long-term safety of extended adjuvant letrozole), but provided an opportunity to assess the benefits of starting letrozole after a prolonged period without active therapy. Even after a prolonged tamoxifen-free period, starting letrozole improved disease-free survival and distant disease-free survival, and reduced the occurrence of new, contralateral primary breast cancer, compared with observation and no active therapy. In subsequent intention-to-treat analyses, the benefit of letrozole persisted, despite a significant proportion of patients in the placebo arm having crossed over onto late extended adjuvant letrozole. In additional pre-unblinding, retrospective analyses derived from the core MA.17 data, the benefits of extended adjuvant letrozole increased with treatment duration, at least upto 4 years, and the efficacy of letrozole appeared to vary in defined patient subgroups. Current data strongly support the use of extended adjuvant letrozole to protect postmenopausal women with HR+ early breast cancer against the risk of late recurrence of disease, and suggest that all women should be considered for letrozole, even if several years have elapsed since tamoxifen was completed.