Are all aromatase inhibitors alike?

The anti-estrogen tamoxifen was the gold-standard adjuvant therapy for hormone-receptor-positive (HR+) early breast cancer for several decades, but has recently been displaced by the third-generation aromatase inhibitors (AIs). Three AIs are commercially available: letrozole, anastrozole and exemestane. All are more effective and at least as well tolerated as tamoxifen as adjuvant therapy for HR+ breast cancer in postmenopausal women. Despite the wealth of data comparing AIs with tamoxifen, it is unclear whether the three AIs are clinically equivalent, owing to the lack of head-to-head trials directly comparing them. Preclinical and small clinical studies suggest that letrozole is the most potent inhibitor of aromatase, reducing circulating estrogen levels to a greater degree than the other agents. However, whether this greater activity translates into superior clinical efficacy remains to be determined. In the absence of direct comparative data, cross-trial comparisons have been used to gain insights into any safety or efficacy differences. All three AIs have been compared directly with tamoxifen, and efficacy relative to tamoxifen has been compared across trials, although such analyses are complicated by differences in treatment schedules, patient populations and trial designs. Definitive conclusions cannot yet be drawn, but some important differences are coming to light, with upfront letrozole appearing particularly effective at preventing early distant metastasis, an event strongly associated with breast-cancer-related death. No safety differences between the AIs have yet been identified. This article explores the pharmacologic and clinical differences between the AIs, based on data from clinical and preclinical studies.