68 DFS events (hazard ratio = 0.82; 95% CI 0.71, 0.95; P = 0.007) [5, 6] and the risk of distant metastases. After a median follow-up of 51 months, 352 DFS events (14.3%) were observed in the letrozole-only group (n = 2,463), compared with 418 DFS events (16.9%) in the tamoxifen- only group (n = 2,459) [5, 6]. The ATAC trial, which compared anastrozole with tamoxifen for 5 years, did not have receptor positivity as a study requirement. After a median follow-up of 68 months (n = 6,186), anastrozole signiﬁcantly prolonged DFS (575 events with anastrozole vs. 651 events with tamoxifen; hazard ratio = 0.87, 95% CI 0.78, 0.97; P = 0.01) and time-to-recurrence (402 vs. 498 events; hazard ratio = 0.79, 95% CI 0.70, 0.90; P = 0.0005), and signiﬁcantly reduced the risk of developing distant metastases (324 vs. 375 events; hazard ratio = 0.86, CI 0.74, 0.99; P = 0.04) and contralateral breast cancers (35 vs. 59 events; 42% reduction, 95% CI 12, 62; P = 0.01) in the intent-to-treat (ITT) population [4]. However, neither the time to distant recurrence nor distant DFS (DDFS) were signiﬁcantly improved with anastrozole in the HR+ population [7]. While both letrozole and anastrozole have been evalu- ated extensively in early breast cancer, no head-to-head trial of these two AIs has been conducted in this setting. This report will focus on the design of the Femara versus Anastrozole Clinical Evaluation (FACE) trial, and describe how it will prospectively address potential efﬁcacy and safety differences between the two AIs. Rationale for head-to-head trial An American Society of Clinical Oncology technology assessment concluded that AIs should be included in the adjuvant treatment of postmenopausal women with HR+ breast cancer [8] but did not recommend one AI over another. The National Comprehensive Cancer Network has also recommended initial adjuvant therapy with an AI (speciﬁ- cally letrozole or anastrozole) as an alternative to tamoxifen [9]. Some evidence suggests that AIs may not be equivalent, even though they belong to the same pharmacologic class of agents; differences have been reported in terms of potency, suppression of aromatization, antitumor effects, and phar- macogenomics. However, whether or not one AI is superior in treating early breast cancer is not known. Relative potency Bhatnagar and colleagues compared the aromatase- inhibiting potency of letrozole and anastrozole in a variety of aromatase-containing cellular endocrine and tumor models [10, 11]. While letrozole and anastrozole were 123 Breast Cancer Res Treat (2007) 105:67–74 approximately equipotent in a cell-free aromatase system (human placental microsomes), letrozole was found to be more potent than anastrozole in inhibiting intracellular aromatase in intact rodent cells (50% inhibitory concen- tration [IC50] 20 vs. 600 nM, respectively), normal human adipose ﬁbroblasts (0.8 vs. 14 nM), and human cancer cell lines (MCF-7Ca 0.07 vs. 0.82 nM and JEG-3 0.07 vs. 0.99 nM). Miller and colleagues reported that letrozole and anastrozole were more potent than aminoglutethimide in vitro against tumor samples obtained from postmeno- pausal women with breast cancer, with letrozole demonstrating the lowest IC50 (2 nM, 8 nM, and 20 lM, respectively) [12]. Letrozole was compared with anas- trozole in vivo in athymic mice inoculated with MCF7 cells [13]. Tumor volumes increased to 145.9% in controls and decreased to 22.4% with letrozole 10 lg, and to 95.6% or 78.2% with anastrozole 10 or 60 lg, respectively. These results are consistent with a higher in vitro potency of le- trozole in cell-based assays [13]. Suppression of aromatization The effects of letrozole and anastrozole on suppression of total-body aromatization and plasma estrogen concentra- tions have been compared in patients with metastatic breast cancer [14, 15]. Levels of aromatase were detectable in 11 of 12 patients during treatment with anastrozole (mean percentage inhibition in the whole group, 97.3%) but in none of the 12 patients during treatment with letrozole ([ 99.1% suppression in all patients; Wilcoxon, P = 0.0022, comparing the two drug regimens). Suppres- sion of estrone and estrone sulfate was found to be signiﬁcantly greater during treatment with letrozole com- pared with anastrozole (P = 0.019 and P = 0.0037, respectively). Another study conducted in 54 postmeno- pausal women with invasive breast cancer showed that more complete inhibition of aromatase was achieved by 2.5 mg of letrozole than 1 mg of anastrozole, resulting in signiﬁcantly greater suppression of estradiol (P \ 0.0001) [15]. Thus, letrozole reduces estradiol levels to a greater degree than anastrozole, but it is not known whether this difference is clinically relevant. Breast cancer proliferation Biological changes in breast tumors occurring within 14 days of starting treatment may predict the efﬁcacy of different endocrine agents in the adjuvant setting and could prove to be useful surrogate markers to compare drug efﬁcacy [16]. A study of neoadjuvant endocrine therapy compared the effects of letrozole and anastrozole on the