Abstract PS4-08-11: Standardized Definitions for Efficacy End Points (STEEP, STEEP2) in the CCTG MA.32 randomized breast cancer trial of metformin versus placebo: Implications of the type of recurrence and new non-breast cancer primary on outcome ass

Abstract Background: STEEP criteria were developed to standardize interpretation of adjuvant breast cancer (BC) clinical trial outcomes. Invasive disease-free survival (IDFS), defined as time from randomization to the earliest occurrence of invasive local, regional, or distant recurrence, new primary invasive cancers (breast or non-breast), and death due to any cause, was initially recommended as a preferred optimal outcome in STEEP (Hudis JCO 2007). Non-breast primary cancers were excluded in Invasive BC-Free Survival (IBCFS) in STEEP 2 (Tolaney JCO 2021). We examine these STEEP outcomes, as well as Distant Recurrence-Free Survival (DRFS), BC Specific Survival (BCSS) and Overall Survival (OS) in CCTG MA.32. Methods: MA.32 (NCT01101438) evaluated the efficacy of metformin versus placebo among 3,649 non-diabetic women with high-risk early BC enrolled between 2010 and 2013. The previously reported analysis of the primary outcome measure (IDFS) and OS showed no metformin benefit on hormone receptor positive or negative BC (any HER2) but suggested a beneficial effect in HER2+ BC (Goodwin JAMA 2022). We summarized individual components of IDFS across BC subtypes- luminal (ER/PR+, HER2-), triple negative (TN; ER/PR/HER2-), HER2+ (any ER/PR) and analyzed treatment effect (metformin versus placebo) on IDFS, IBCFS, DRFS, BCSS and OS to determine whether conclusions regarding treatment efficacy differed by endpoint selection. Statistical methods included Cox regression models and log rank tests. All analyses were two-sided and statistical significance was defined at the p=0.05 level. Results: In the overall population, 710 patients experienced an invasive cancer event; 127 (17.9%) of these events were local/regional. The majority of events were distant recurrences (luminal 55.8%, TN 47.5%, HER2+ 54.5%) and a minority were new non-breast primary cancers (luminal 20.4%, TN 15.2%, HER2+ 20.2%). Within each BC subtype, there was little variation in the hazard ratios (HRs) comparing metformin to placebo and no difference in statistical significance across outcomes (IDFS, IBCFS, DRFS, BSCC, OS). The types of events and HRs for efficacy endpoints of interest are summarized by subtype in the Table. Conclusions: MA.32 enrolled patients with high risk breast cancer, resulting in a predominance of distant breast cancer recurrences. All endpoints provided similar information regarding metformin efficacy across BC subtypes regardless of whether metformin was ineffective (luminal, TN) or showed potential efficacy in an exploratory analysis (HER2+) in this trial where most events were distant recurrences. Citation Format: K. J. Jerzak, W. R. Parulekar, B. E. Chen, A. E. Lohmann, P. J. Goodwin. Standardized Definitions for Efficacy End Points (STEEP, STEEP2) in the CCTG MA.32 randomized breast cancer trial of metformin versus placebo: Implications of the type of recurrence and new non-breast cancer primary on outcome assessment [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-08-11.