FACE: the barefaced facts of AI potency

The use of third-generation aromatase inhibitors (AIs), such as anastrozole and letrozole, as initial adjuvant hormonal therapy in postmenopausal women (PMW) with hormone receptor-positive (HR+) breast cancer offers a significant benefit over tamoxifen for reducing recurrence risk. Clinical studies, including the Arimidex Tamoxifen Alone or in Combination (ATAC) and the Breast International Group (BIG) 1-98 trials, have proven that both anastrozole and letrozole are, respectively, superior to tamoxifen in improving disease-free survival. Although differing in design, objectives, and follow-up time, these trials offer some insight into the comparative clinical efficacy of these two nonsteroidal AIs. In particular, results from BIG 1-98 show that letrozole significantly reduces early distant metastatic (DM) events, which constitute the majority of early recurrence events. Subsequently, there is a beneficial overall survival effect emerging in the trial, whereas survival is unchanged with anastrozole after 100 months of follow-up in ATAC. Significant differences in the potency of these two drugs, vis-à-vis their degree of aromatase inhibition, have been observed in comparative trials and show that letrozole causes a more complete suppression of estrogen levels than does anastrozole. Whether this difference in potency is relevant to reductions in DM events during adjuvant therapy remains unclear. The Femara Anastrozole Clinical Evaluation trial is addressing this issue in a more unequivocal manner by comparing initial adjuvant treatment with anastrozole or letrozole in a population of breast cancer patients at high risk of recurrence: PMW with HR+ disease and axillary lymph node involvement.