Update on the MA.17 extended adjuvant trial

For women with early breast cancer, a substantial risk of relapse remains after surgical resection of the primary tumor, despite adjuvant therapy. Adjuvant endocrine therapy with tamoxifen has been used for many years in the treatment of hormone-receptor-positive (HR+) disease, but exposure to the agent is limited to 5 years due to an unfavorable risk:benefit profile in later years. Despite the beneficial carry-over effects of tamoxifen, the majority of breast cancer recurrences and deaths occur after completion of adjuvant tamoxifen, that is, more than 5 years after initial diagnosis. Hence, additional endocrine therapy could greatly improve outcomes for women with HR+ early breast cancer, but until recently, no agent had been shown to provide a significant benefit over no further treatment. The first interim analysis of the NCIC CTG MA.17 trial showed that the third-generation aromatase inhibitor, letrozole, significantly reduced the risk of relapse, including distant metastases, compared with placebo in women who remained disease-free for up to 3 months after completion of standard adjuvant tamoxifen. On the basis of these results, the trial was stopped and unblinded. Final analysis confirmed these findings and also showed that letrozole significantly improved overall survival in patients with node-positive disease at diagnosis. Retrospective analysis of MA.17 data has shown that the benefit achieved with letrozole increases with the duration of therapy, at least up to 48 months, raising important questions regarding the optimal duration of extended adjuvant letrozole. Additional retrospective analyses investigating the impact of estrogen- and progesterone-receptor status on response to therapy, and whether letrozole is effective following a prolonged treatment-free interval after stopping tamoxifen, are ongoing, and will help to optimize the use of letrozole in women who have completed tamoxifen.