Are all aromatase inhibitors the same? A review of controlled clinical trials in breast cancer

Background: Five years of tamoxifen therapy has been the standard of care for the adjuvant treatment of estrogen receptor-positive early-stage breast cancer for many years and was the first hormonal treatment for postmenopausal women with advanced or metastatic disease. The third-generation aromatase inhibitors (Als) anastrozole, exemestane, and letrozole offer new treatment options, although their efficacy has not been compared directly in randomized, double-blind, controlled trials in any breast cancer treatment setting. Objective: The goal of this article was to review the results of recent randomized, controlled clinical trials of the Als in the settings of neoadjuvant, adjuvant, and advanced/metastatic breast cancer. Methods: MEDLINE was searched for descriptions of randomized, controlled clinical trials published from 1990 to 200S using the terms breast cancer, aromatase, aromatase inhibitor, anastrozole, exemestane, and letrozole. Abstracts from the proceedings of several oncology meetings held between 2001 and 2005 were searched to capture relevant emerging data. Results: In 2 Phase III trials comparing an AI with tamoxifen for the adjuvant treatment of breast cancer in postmenopausal women, disease-free survival was significantly improved with anastrozole and letrozole compared with tamoxifen as initial adjuvant treatment (P = 0.01 and P = 0.003, respectively). A switch to either anastrozole (2 Phase III trials) or exemestane (1 Phase III trial) after 2 to 3 years of adjuvant tamoxifen therapy was more effective in reducing the risk of recurrence than continued tamoxifen therapy (P = 0.006, P < 0.002, and P < 0.001, respectively); data on switching to letrozole are expected soon. In another Phase III trial, letrozole was found to improve disease-free survival in the extended adjuvant setting (P 0.001) and was the only AI consistently more effective than tamoxifen in the neoadjuvant setting. In 3 Phase III studies (I letrozole vs tamoxifen, 2 anastrozole vs tamoxifen), both anastrozole and letrozole were more efficacious than tamoxifen in the first-line setting, and some patients receiving letrozole had better overall response rates compared with those receiving anastrozole in the second-line setting (19.1% vs 12.3%, respectively; P = 0.013). In a patient-preference study, those receiving letrozole reported fewer adverse events than those receiving anastrozole (43% vs 65%; P < 0.003), and more patients preferred letrozole to anastrozole (68% vs 32%; P < 0.01). Conclusions: Currently, anastrozole and letrozole are associated with the most complete data over the breast cancer care continuum, with efficacy In early-stage, locally advanced, and metastatic disease. Indirect comparisons suggest stronger evidence for the use of letrozole compared with other Als for breast cancer in postmenopausal women who require estrogen-deprivation therapy. Data from randomized, double-blind comparative studies will help clarify the differences between Als.