Third-generation aromatase inhibitors: Differences between the agents and their role in reducing the risk of distant metastasis and improving survival
There are now several efficacious treatments for early-stage hormone-receptor-positive breast cancer. Although tamoxifen reduces disease recurrence and death from breast cancer and previously was the standard of care for decades, third-generation aromatase inhibitors (AIs) are now the treatment of choice for postmenopausal women with early-stage breast cancer (ESBC). There are three commercially available AIs: letrozole, anastrozole, and exemestane. All three have been shown to bemore effective and at least as well tolerated as tamoxifen when used as adjuvant therapy. Preclinical studies suggest letrozole is the most potent inhibitor of aromatase and results in greater suppression of estrogen levels when compared to other AIs. However, the relationship between aromatase activity and clinical efficacy is unclear. In the absence of direct head-to-head comparisons between the AIs, cross-trial comparisons have been used to try to elucidate differences between the AIs. There is a wealth of data comparing each AI with tamoxifen; however, across these trials, differences in study populations, definition of trial endpoints, and treatment schedules exist. Definitive conclusions remain unreached; however, differences between the agents are emerging. Upfront letrozole appears particularly effective when used in the adjuvant setting, particularly for the prevention of early distant metastasis. Distant metastasis is associated with significant morbidity and is strongly associated with breast-cancer-related death. This article explores the clinical efficacy of the AIs, differences between the agents, and their safety profiles in addition to discussing optimal ESBC clinical trial endpoints.
