Abstract OT1-02-01: A randomized, multicenter, double-blind, placebo-controlled comparison of standard (neo)adjuvant therapy plus placebo versus standard (neo)adjuvant therapy plus atorvastatin in patients with early stage breast cancer
Authors: Borgquist Signe , Jensen Maj-Britt , Ewertz Marianne , Jensen Anders Bonde , Ahern Thomas P. , Cronin-Fenton Deirdre , Christiansen Peer , Ejlertsen Bent 
Published: March 2020

Abstract
Background: Cholesterol-lowering medication (CLM), including statins, have received substantial scientific attention as cancer-inhibiting drugs. In a previous Danish study, a protective association between statin use and improved clinical breast cancer outcome was measured with high precision in a cohort of over 18,000 breast cancer patients. Most recently, a study nested in the Breast International Group 1-98 trial showed that the incidence of initiating CLM was higher among women taking letrozole, whereas cholesterol levels decreased over time among women taking tamoxifen, irrespective of CLM use. Initiation of CLM during endocrine therapy was associated with improved breast-cancer-free interval and distant-recurrence free interval. Given the compelling evidence supporting a protective effect of statins on breast cancer recurrence, calls for clinical trials have appeared in several prominent journals.
Trial Design: A prospective, two-armed, randomized (1:1), national, multicenter, double-blind, placebo-controlled study in early stage breast cancer patients. Eligibility criteria: Women with estrogen receptor positive breast cancer who are candidates for (neo)adjuvant systemic therapy OR have received ≤3 years of adjuvant endocrine therapy. Age &gt; 18 years. Performance status of ECOG ≤ 2. Prior to patient registration, written informed consent must be given according to Good Clinical Practice and national/local regulations.
Specific aims: The primary objective of this trial is to determine the clinical efficacy of (neo)adjuvant atorvastatin as measured by invasive disease-free survival (IDFS) among patients with primary breast cancer. A recurrence will be defined as any invasive breast cancer recurrence irrespective of localization. Secondary objectives include: recurrence-free survival, distant-recurrence-free interval including associations with first site of recurrence, overall survival and cardiac death-free interval as well as overall safety. Translational objectives include investigation of circulating markers and biomarkers in primary tumor tissue that predict response to (neo)adjuvant treatment with atorvastatin.
Statistical Methods: The intent-to-treat (ITT) population will be used in the primary analysis. Primary and secondary end points will be analyzed unadjusted by the Kaplan-Meier method and the stratified log-rank test, and with estimates of cumulative incidences using the Gray test for comparison for end points with competing events. Unadjusted hazard ratios [HR] will be estimated from the Cox proportional hazards regression model and the Fine-Gray sub-distribution hazards model to quantify the effect of treatment regimen. Multivariate models will be applied in the per-protocol population to exploratory analysis of interactions. Patients who receive any amount of study medication will be included in safety analyses.
Present accrual and target accrual: The trial will start recruiting in October 1, 2019. The target accrual is 3,360 patients.
Citation Format: Signe Borgquist, Maj-Britt Jensen, Marianne Ewertz, Anders Bonde Jensen, Thomas P. Ahern, Deirdre Cronin-Fenton, Peer Christiansen, Bent Ejlertsen. A randomized, multicenter, double-blind, placebo-controlled comparison of standard (neo)adjuvant therapy plus placebo versus standard (neo)adjuvant therapy plus atorvastatin in patients with early stage breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-02-01.