Abstract OT2-2-04: A phase III randomized, placebo-controlled clinical trial evaluating the use of adjuvant endocrine therapy +/− one year of everolimus in patients with high-risk, hormone receptor- (HR) positive and HER2-negative breast cancer: SWOG/NSABP S1207.

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Abstract BACKGROUND: Abnormalities of the PI3kinase/AKT/mTOR signaling network are some of the most common molecular anomalies in breast cancer. This pathway has been associated with resistance to endocrine therapies among HR-positive breast tumors. Everolimus, an mTOR-inhibitor, has been shown to increase the biological activity of aromatase inhibitors. In the metastatic setting, everolimus in combination with tamoxifen or exemestane increased the progression-free survival in patients previously treated with endocrine therapy. S1207 proposes to evaluate the role of everolimus used in combination with endocrine therapy in the adjuvant setting. SPECIFIC AIMS/TRIAL DESIGN: S1207 is a SWOG/NSABP randomized phase III double-blind, placebo-controlled clinical trial. The primary objective of the study is to assess whether the addition of one year of everolimus to standard adjuvant endocrine therapy improves invasive disease-free survival (DFS) among patients with high risk HR-positive breast cancer. Secondary objectives include overall survival, distant recurrence-free survival, safety, adherence and quality of life. Submission of tissue specimens/blood samples is required for translational studies. Patients will be randomized to receive standard adjuvant endocrine therapy (selected by treating physician) in combination with one year of everolimus (10 mg PO daily) or standard adjuvant endocrine therapy in combination with one year of matched placebo. ELIGIBILITY CRITERIA: Patients with histologically confirmed invasive breast cancer HER2-negative and HR-positive with high risk features including: 1) node-negative disease with tumors ≥2cm and a recurrence score (RS) >25; 2) 1–3 positive nodes and RS >25; 3) patients with ≥4 positive lymph nodes regardless of RS. Patients with ≥4 positive lymph nodes after completing neoadjuvant chemotherapy are also eligible. All patients must have completed surgery, adjuvant/neoadjuvant chemotherapy, and radiation therapy (if indicated) before registration. Prior exposure to mTOR inhibitors is not allowed. STATISTICAL METHODS/TARGET ACCRUAL: This is a parallel randomization design with equal allocation to the two treatment groups (everolimus and placebo). Randomization is stratified by 4 risk groups. All analyses are intent-to-treat by randomized assignment of eligible patients. The study plans to randomize 3,500 patients over a 3.5-year accrual period with the primary analysis conducted 3 years after the last patient is randomized. The study has 90% power (with 2-sided α=0.05) to detect an effective hazard ratio of 0.75 for everolimus versus placebo, corresponding to a gain in DFS of approximately 4.3% at 5 years. All patients will be followed for 10 years to assess overall survival and late adverse events. The expected trial duration from activation to reporting of DFS is about 7 years. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-2-04.