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.