Breast Cancer Res Treat (2007) 105:67–74 Fig. 1 Changes in inhibitor- responsive genes after treatment with letrozole, anastrozole, or tamoxifen. The Venn diagrams show the numbers of genes responsive to individual inhibitors in hormone-regulated genes. Reprinted from [26], with permission from the American Association for Cancer Research Institute Common Terminology Criteria for Adverse Events v3.0), and adequate hematologic, hepatic, and renal function. Patients with T4 tumors, metastatic disease, contralat- eral 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 Eligible patients are randomized to receive either letrozole 2.5 mg or anastrozole 1 mg daily for up to 5 years (see Fig. 2). The date of randomization must be no more than 12 weeks from completion of surgery or 4 weeks after completion of adjuvant chemotherapy. Treatment assign- ments are balanced based on the number of lymph nodes (1–3, 4–9, 10+) and HER2 status (positive, negative, or unknown). Treatment will commence within 30 days of randomization and following the completion of standard chemotherapy (if given) and concurrently with radiother- apy (if given). Patients receive treatment with the allocated AI for up to 5 years or until disease recurrence/relapse. Recurrence and survival will be assessed every 12 months. 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 contra- lateral breast; or death from any cause. 71 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 contra- lateral 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 recommen- dations to a Trial Steering Committee chaired by Dr. Kathy Fig. 2 FACE randomized trial design 123