Statin Therapy in Early Breast Cancer: The MASTER Trial; A Randomized Phase III, Placebo-Controlled Comparison of Standard (Neo)Adjuvant Therapy Plus Atorvastatin versus Standard (Neo)Adjuvant Therapy Plus Placebo.

Purpose: Statin use has been consistently associated with improved clinical outcomes (especially recurrence) in breast cancer in multiple observational studies backed by compelling preclinical evidence. The strength of this evidence warrants a clinical trial to test the efficacy of statin exposure on breast cancer recurrence. Patients and Methods: The double-blind, phase III, randomized, placebo-controlled MASTER (MAmmary cancer STatins in ER positive breast cancer) trial includes women diagnosed with early-stage, estrogen receptor-positive (ER+) breast cancer who are candidates for systemic (neo)adjuvant therapy. Enrolled patients are given standard (neo)adjuvant therapy and additionally randomized to either atorvastatin (80 mg/day) or placebo for two years. The trial's primary outcome is invasive disease-free survival (IDFS), with a target accrual of 3360 patients in total to achieve 80% power (two-sided alpha=0.05) to detect a 25% reduction in the risk of an IDFS event comparing the statin and placebo arms. At 3-, 6-, 12-, and 24-month follow-up time points, patients will have blood drawn for biomarker studies, answer patient-reported outcome (PRO) questionnaires, and control for adverse events. Subsequently, patients will receive annual PRO-criteria for Adverse Events (CTCAE) questionnaires until the completion of their 10 years of follow-up. Secondary endpoints include additional clinical endpoints; pathological response (neo-adjuvant treated patients), recurrence-free survival, distant-recurrence-free interval, overall survival and cardiac death-free interval, co-morbidity, and health-related quality-of-life measured by PRO-CTCAE questionnaires during and beyond study medication. Translational endpoints are evaluated in collected blood- and tumor samples. Discussion: If a protective effect of statins on breast cancer recurrence is supported by evidence from the MASTER trial, then the indications for a safe, well-tolerated, and inexpensive treatment can be expanded towards improved clinical outcomes for breast cancer patients.