Breaking the 5-year barrier: Results from the MA.17 extended adjuvant trial in women who have completed adjuvant tamoxifen treatment

Abstract The selective estrogen-receptor modulator, tamoxifen, has been the mainstay of adjuvant endocrine therapy for several decades, significantly improving outcomes for numerous women with hormone-receptor-positive (HR+) early breast cancer. However, tamoxifen is associated with acquired resistance: efficacy appears to decrease gradually with prolonged use, whereas the incidence of troublesome adverse events, such as thromboembolic disease and endometrial cancer, persists. Hence, long-term exposure to tamoxifen is associated with an unfavorable risk:benefit profile, limiting adjuvant tamoxifen therapy to 5 years. The majority of breast cancer recurrences and deaths occur more than 5 years after surgery, demonstrating the need for new treatment strategies for women who have completed tamoxifen therapy. Furthermore, the risk of late relapse is particularly high among women with HR+ disease, who are thus ideal candidates for further endocrine therapy. In 2003, the first interim analysis of the MA.17 trial was published, identifying letrozole as the first agent to significantly reduce the risk of recurrence in women who had completed standard adjuvant tamoxifen therapy. Over 5000 women with HR+ breast cancer were randomized to receive either letrozole or placebo within 3 months of stopping tamoxifen therapy. The trial was unblinded at the first planned interim analysis because of a highly significant ( p = 0.00008) 43% reduction in the relative risk of recurrence at a median follow-up of 28.8 months. The final analysis (median follow-up 30 months) confirmed these findings, with letrozole reducing the relative risk of recurrence by 42%, equating to an absolute reduction in the risk of relapse of 4.6% at 4 years. The beneficial effect of letrozole was seen regardless of nodal status, previous chemotherapy or duration of tamoxifen treatment (>5 years or ⩽5 years), and increased with duration of therapy. Letrozole also reduced the risk of distant recurrence, and significantly improved overall survival in patients with node-positive, but not node-negative disease, becoming the first aromatase inhibitor to improve survival compared with standard treatment in early-stage breast cancer. Letrozole therapy was well tolerated: no significant detrimental effects were seen on the cardiovascular system (5.8% vs 5.6% p = 0.76), lipid metabolism (16% vs 16% p = 0.79) or global quality of life scores compared with placebo. Musculoskeletal side effects, including patient-reported new osteoporosis, were more common in patients taking letrozole. Patient-reported new osteoporosis was not associated with an increased fracture risk. Letrozole is the first agent shown to reduce the risk of late relapse after completion of tamoxifen therapy, in what is now known as the extended adjuvant setting. Letrozole is, therefore, a highly effective and well-tolerated endocrine therapy that significantly improves outcomes for women with HR+ early breast cancer. Letrozole has improved treatment options for women with early breast cancer, extending the duration of adjuvant therapy to at least 10 years.