Breast Cancer Res Treat (2007) 105:67–74 DOI 10.1007/s10549-007-9702-9 R E V I E W A decade of letrozole: FACE Joyce O’Shaughnessy Received: 15 January 2007 / Accepted: 17 July 2007 Springer Science+Business Media, LLC 2007 Abstract Third-generation nonsteroidal aromatase inhibitors (AIs), letrozole and anastrozole, are superior to tamoxifen as initial therapy for early breast cancer but have not been directly compared in a head-to-head adjuvant trial. Cumu- lative evidence suggests that AIs are not equivalent in terms of potency of estrogen suppression and that there may be differences in clinical efﬁcacy. Thus, with no data from head-to-head comparisons of the AIs as adjuvant therapy yet available, the question of whether there are efﬁcacy differences between the AIs remains. To help answer this question, the Femara versus Anastrozole Clinical Evaluation (FACE) is a phase IIIb open-label, randomized, multicenter trial designed to test whether letrozole or anastrozole has superior efﬁcacy as adjuvant treatment of postmenopausal women with hormone receptor (HR)- and lymph node- positive breast cancer. Eligible patients (target accrual, N = 4,000) are randomized to receive either letrozole 2.5 mg or anastrozole 1 mg daily for up to 5 years. The primary objective is to compare disease-free survival at 5 years. Secondary end points include safety, overall sur- vival, time to distant metastases, and time to contralateral breast cancer. The FACE trial will determine whether or not letrozole offers a greater clinical beneﬁt to postmenopausal women with HR+ early breast cancer at increased risk of early recurrence compared with anastrozole. Keywords Anastrozole Breast cancer Femara Aromatase inhibitors Letrozole Tamoxifen J. O’Shaughnessy (&) Texas Oncology, P.A, Baylor Sammons Cancer Center and US Oncology, 3535 Worth Street, Ste. 500, Dallas, TX 75246, USA e-mail: Joyce.O’Shaughnessy@usoncology.com Introduction The aromatase inhibitors (AIs) have proven to be a pow- erful drug class for use in hormone-sensitive breast cancer and have shown superiority over the selective estrogen- receptor modulator (SERM) tamoxifen in preclinical models of hormone-dependent breast cancer [1] and in randomized controlled trials in patients with advanced breast cancer [2] and early breast cancer [3, 4]. Initial adjuvant therapy with either letrozole (Femara1) or anas- trozole (Arimidex1) was shown to be signiﬁcantly more effective than tamoxifen in both the Breast International Group (BIG) 1-98 and Anastrozole and Tamoxifen Alone or in Combination (ATAC) randomized controlled trials in postmenopausal women with localized breast cancer [3, 4]. In the BIG 1-98 primary core analysis, patients with hormone receptor-positive (HR+) tumors randomized to receive letrozole initially were compared with those assigned to receive tamoxifen initially (N = 8,010). After a median follow-up of 25.8 months, 351 events had occurred in the letrozole group (n = 4,003) and 428 events in the tamoxifen group (n = 4,007), with 5–year disease-free survival (DFS) estimates of 84.0% and 81.4%, respec- tively. Letrozole signiﬁcantly reduced the risk of breast cancer recurrence (hazard ratio = 0.81; 95% conﬁdence interval [CI] 0.70, 0.93; P = 0.003), especially the risk of distant recurrence (hazard ratio = 0.73; 95% CI 0.60, 0.88; P = 0.001) [3]. An analysis limited to patients randomized to either letrozole-only or tamoxifen-only arms (N = 4,922) was recently published and allows for more direct comparisons with results from other trials of con- tinuous therapy with a single endocrine agent [5]. Results from the letrozole-only or tamoxifen-only arms were con- sistent with those published for the primary core analysis and showed that letrozole signiﬁcantly reduced the risk of 123