Aromatase inhibitors: Effective endocrine therapy in the early adjuvant setting for postmenopausal women with hormone-responsive breast cancer

Early breast cancer now has a relatively good prognosis, with many affected women surviving for over a decade. In hormone-receptor-positive (HR+) disease, adjuvant tamoxifen therapy has had a particularly strong impact on outcomes over the past 30 years, preventing approximately half of all expected recurrences and a third of all breast cancer deaths. For many years, adjuvant tamoxifen for 5 years was the standard treatment for HR+ disease. However, de novo and acquired resistance is common, and many patients will experience a relapse while on tamoxifen, indicating the need for more effective agents to treat HR+ breast cancer. Furthermore, tamoxifen is associated with potentially life-threatening side effects, including thromboembolic disease and endometrial cancer which, together with decreasing efficacy, limit tamoxifen to 5 years. In recent years, the third-generation aromatase inhibitors (AI) have demonstrated superior efficacy to tamoxifen as adjuvant therapy for HR+ early breast cancer in postmenopausal women. In large, randomized, controlled trials, upfront substitution of tamoxifen with an AI for 5 years or switching to an AI after 2-3 years of tamoxifen have been shown to significantly reduce recurrences compared with 5 years of tamoxifen. The benefits of sequential endocrine therapy with tamoxifen followed by an AI and vice versa are unconfirmed. Adjuvant AI therapy was well tolerated, with side effects being generally predictable and more manageable than those associated with tamoxifen. Whether clinical differences exist between anastrozole, letrozole and exemestane has yet to be confirmed in head-to-head trials, but available data suggest that letrozole may be particularly effective in patients with node-positive disease or those who have received adjuvant chemotherapy, that is, patients at increased risk of an early relapse. Furthermore, upfront letrozole, but not anastrozole, significantly reduced distant metastases, a well-recognized predictor of breast cancer death. The optimal treatment regimen requires clarification, and ongoing studies will provide further information regarding the optimum treatment strategy to gain the greatest clinical impact from the AIs in the adjuvant setting.