Introduction 1 2 3 4 ® ® 3 4 n n P P 3 5 P 5 6 n n 5 6 n P P P P 4 7 While both letrozole and anastrozole have been evaluated 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 8 9 Relative potency 10 11 50 50 12 13 13 Suppression of aromatization 14 15 P P P P 15 Breast cancer proliferation 16 16 17 Clinical activity 18 P P P 4 19 P 3 20 5 P P 3 5 21 22 23 4 3 5 P P 5 P 24 25 1 Table 1 25 Low risk  Steroid hormone receptors expression, node-negative, and all of the following features: pT ≤ 2 cm Grade 1 No peritumoral vascular invasion HER2/neu gene neither overexpressed nor amplified Age ≥35 years Intermediate risk Node-negative and at least one of the following features: pT > 2 cm Grade 2–3 Peritumoral vascular invasion HER2/neu gene either overexpressed or amplified Age < 35 years Node positive (1–3 involved nodes) and HER2/neu gene neither overexpressed nor amplified High risk Node positive (1–3 involved nodes) and HER2/neu gene either overexpressed or amplified Node-positive (4 or more involved nodes) HER2 pT Is one AI superior in early breast cancer? 26 1 26 Fig. 1 26  27 20 28 29 FACE trial design 30 27 Patients The trial is recruiting 4,000 patients from up to 250 international sites. Eligible patients are postmenopausal women with HR+ and lymph node-positive tumors who have recently undergone surgery for primary breast cancer (pathologic or clinical stage IIA, IIB, or IIIA). All patients must provide written informed consent. HR+ tumors are defined as tumors with any detectable ER or PgR expression by institutional standards. Patients who are PgR+ and ER− are eligible for the trial. Pathologic assessment of axillary lymph nodes is determined by sentinel node biopsy and/or axillary lymph node dissection. Patients are stratified according to the number of involved lymph nodes and HER2 tumor status. Adjuvant trastuzumab is permitted in patients with HER2+ tumors. Other inclusion criteria include World Health Organization performance status of 0 or 1, lipid panel (fasting total cholesterol and triglycerides) ≤ grade 1 (National Cancer Institute Common Terminology Criteria for Adverse Events v3.0), and adequate hematologic, hepatic, and renal function. Patients with T4 tumors, metastatic disease, contralateral breast cancer including ductal carcinoma in situ, or evidence of disease progression are excluded. Other exclusion criteria include prior neoadjuvant endocrine therapy; hormone replacement therapy (except intravaginal estradiol preparations) not stopped at least 4 weeks before randomization; adjuvant anti-estrogen therapy for > 1 month immediately following surgery, radiotherapy, and/or chemotherapy; breast cancer chemoprevention with anti-estrogens if < 18 months between stopping and diagnosis of breast cancer; and therapy with any hormonal agent, such as raloxifene, for management of osteoporosis. Randomized trial design and treatments 2 Fig. 2 FACE randomized trial design  Efficacy end points The primary end point is DFS, defined as the time from the date of randomization to the date of the first documentation of re-occurrence of invasive breast cancer in local, regional, or distant sites; new invasive breast cancer in the contralateral breast; or death from any cause. Secondary efficacy end points include OS, defined as the time from the date of randomization to date of death from any cause; breast cancer-free survival, defined as the time from date of randomization to the date of death due to breast cancer; time to development of distant metastases, defined as the time from date of randomization to the date of the first development of any recurrent or metastatic disease in sites other than the local mastectomy scar, the ipsilateral breast in case of breast conservation, or the contralateral breast; and time to development of contralateral breast cancer, defined as the time from date of randomization to the date of the first development of any disease in the contralateral breast. Although the FACE trial, co-chaired by Drs. Ian Smith and Joyce O’Shaughnessy, is an open-label trial, analysis of the data in a blinded fashion will make the data from this trial comparable with that obtained in a single-blinded trial. Both patients and their physicians will know which drug is being taken, but the analysis of the data will be conducted blinded to study treatment. The sponsor of the trial will not have access to the database, and all efficacy analyses will be conducted by an independent academic organization (the Instituto Nazionale Tumori, Milan, Italy), which will receive the data in a blinded manner. The data will be reviewed by an Independent Data Monitoring Committee, chaired by Professor Martine Piccart. The Independent Data Monitoring Committee will then make recommendations to a Trial Steering Committee chaired by Dr. Kathy Pritchard. The Independent Data Monitoring Committee will decide when the data will be released. The final analysis will be performed after the expected total number of DFS events have occurred. This is anticipated to be 7 years after the start of the study, following an accrual period of about 2 years and a minimum of 5 years of further follow-up. There are two planned interim analyses, scheduled to occur after one third and subsequently after two thirds of the maximum number of events have been observed. The interim analyses will be conducted after 320 and 639 events, respectively, have been recorded. In addition, analyses of secondary end points will be conducted at the interim time points. FACE is powered to detect a 3.5% absolute difference between the two treatment arms in DFS at 5 years. The 3.5% difference corresponds to a hazard ratio of 0.83 in favor of letrozole, corresponding to 5-year DFS values of 80.0% and 76.5% for letrozole and anastrozole, respectively. Safety end points General patient safety and drug tolerability will be evaluated. Adverse events are recorded at every visit and graded for severity using the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. A checklist of adverse events is used to solicit adverse event information from patients. Safety analyses specifically include cardiovascular events and bone fracture events. All patients are evaluated clinically for osteoporosis and fracture risks. Bone mineral density testing is recommended at least every 2 years for all patients during study therapy by dual X-ray absorptiometry, peripheral dual X-ray absorptiometry, or ultrasound densitometry. Osteoporosis may be managed as clinically indicated using calcium supplements, vitamin D, or bisphosphonates. Measurements of fasting serum lipids are obtained at 6 and 12 months and then annually thereafter for the duration of the study treatment. Other laboratory assessments include hematology and blood chemistry. Other head-to-head studies 31 32 26 33 35 *4/*4 wt/*4 35 36 37 Conclusions 3 4 9 25