Aromatase inhibitors in the early adjuvant setting – the latest evidence

Abstract

In early breast cancer, adjuvant therapy significantly reduces the risk of recurrence after complete surgical resection of the tumor mass. For over a decade, 5 years of adjuvant endocrine therapy with the selective estrogen receptor modulator tamoxifen has been the gold standard in hormone-receptor-positive (HR+) disease. Despite therapy with tamoxifen, relapses still occur, and the rate of relapse is particularly high in the first 2–3 years after surgery. More effective therapies are urgently required to prevent these relapses, particularly in patients with higher-risk disease. The third-generation aromatase inhibitors (AIs), letrozole , anastrozole and exemestane , have shown greater efficacy than tamoxifen, with comparable tolerability, in large, randomized, phase III trials in the early adjuvant setting. On the basis of these findings, AIs are now displacing tamoxifen as the preferred adjuvant endocrine therapy for HR+ early breast cancer in postmenopausal women . Two treatment strategies have been used to investigate AI efficacy in the early adjuvant setting, both with 5 years’ tamoxifen as the comparator: upfront AI for 5 years, or switching to an AI after completing between 2 and 3 years of tamoxifen. When given upfront, anastrozole (ATAC trial) and letrozole (BIG 1-98 trial) have been shown to significantly improve disease-free survival compared with tamoxifen. Letrozole also significantly reduced the risk of distant recurrence, a well-recognized predictor of breast cancer death. Indirect comparisons suggest that these two AIs may not be clinically equivalent, but a direct comparison of letrozole and anastrozole in a prospective, randomized trial is required to prove whether these two AIs do differ clinically. Switching to exemestane or anastrozole therapy after 2–3 years of tamoxifen has also been shown to significantly reduce the risk of relapse compared with 5 years of tamoxifen therapy. However, in these trials, randomization and/or analyses were initiated at the time of switching therapy, including only patients who remained disease-free at this time, thus excluding patients with higher-risk disease who had experienced early relapse, and selecting a more favorable patient population. Trials comparing upfront AIs with the sequential approaches are ongoing: BIG 1-98 and amended TEAM. Of note BIG 1-98 is the only trial to include both switching strategies: tamoxifen followed by letrozole and letrozole followed by tamoxifen. Trials in the early adjuvant setting have revealed that AIs are generally well tolerated: side effects are predictable and manageable. Although further studies are required to determine the optimum treatment strategy and duration of AI therapy, the third-generation AIs are proving highly effective agents in the treatment of HR+ early breast cancer, and bring into question the validity of tamoxifen as the gold standard for adjuvant therapy. Recently updated international guidelines now recommend that early adjuvant therapy should include an AI.