Reducing the risk of late recurrence in hormone-responsive breast cancer

Women with early breast cancer are exposed to an ongoing risk of relapse, even after successful surgical resection of the primary tumor and, where given, radiotherapy. Adjuvant chemotherapy and/or endocrine therapy can further help to prevent relapses by targeting metastatic disease deposits, which may be present but clinically undetectable. The benefits of adjuvant therapy are well documented, and millions of relapses have undoubtedly been prevented by treatment in this setting. Adjuvant tamoxifen has proven particularly effective in preventing relapses in hormone-receptor-positive (HR+) disease, and has been the standard treatment for affected women for over 30 years. However, long-term exposure to tamoxifen is associated with an unfavorable risk: benefit profile due to decreasing efficacy and an increasing incidence of harmful side effects. Although the risk of relapse is highest during the first 2-3 years after surgery, a residual risk remains indefinitely for those women who do not experience disease relapse in these early years, and the majority of all breast cancer recurrences and deaths occur after completion of 5 years of adjuvant tamoxifen. Hence, there is a great need for additional adjuvant therapies to reduce the considerable risk of late relapses in patients with HR+ disease: until recently no agent had been shown to provide a significant benefit over no further treatment. In 2003, upon publication of the first interim analysis of the MA.17 trial, letrozole became the first agent to be shown to significantly reduce relapses in women with HR+ early breast cancer who had completed 5 years of adjuvant tamoxifen. Subsequent analyses confirmed that letrozole significantly reduced recurrences, including distant metastases, and, in patients with node-positive disease, the agent also significantly improved overall survival, with the benefit of letrozole increasing with duration of therapy, at least up to 48 months. Preliminary results from a small, open-label study suggest that extended anastrozole therapy can also improve outcomes after completion of standard adjuvant tamoxifen. Ongoing analyses from MA.17, investigating how estrogen and progesterone receptor status and the length of time since finishing tamoxifen influence the effectiveness of letrozole, and studies evaluating the safety and efficacy of 10 years of extended aromatase inhibitor therapy, will help to optimize extended adjuvant therapy and improve outcomes for women with HR+ early breast cancer.