Effect of Metformin vs Placebo on Invasive Disease-Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial

Abstract

Importance: Metformin, a biguanide commonly used to treat type 2 diabetes, has been associated with potential beneficial effects across breast cancer subtypes in observational and preclinical studies.

Objective: To determine whether the administration of adjuvant metformin (vs placebo) to patients with breast cancer without diabetes improves outcomes.

Design, setting, and participants: MA.32, a phase 3 randomized, placebo-controlled, double-blind trial, conducted in Canada, Switzerland, US, and UK, enrolled 3649 patients with high-risk nonmetastatic breast cancer receiving standard therapy between August 2010 and March 2013, with follow-up to October 2020.

Interventions: Patients were randomized (stratified for hormone receptor [estrogen receptor and/or progesterone receptor {ER/PgR}] status, positive vs negative; body mass index, ≤30 vs >30; human epidermal growth factor receptor 2 [ERBB2, formerly HER2 or HER2/neu], positive vs negative; and any vs no chemotherapy) to 850 mg of oral metformin twice a day (n = 1824) or oral placebo twice a day (n = 1825) for 5 years.

Main outcomes and measures: The primary outcome was invasive disease-free survival in hormone receptor-positive breast cancer. Of the 8 secondary outcomes, overall survival, distant relapse-free survival, and breast cancer-free interval were analyzed.

Results: Of the 3649 randomized patients (mean age, 52.4 years; 3643 women [99.8%]), all (100%) were included in analyses. After a second interim analysis, futility was declared for patients who were ER/PgR-, so the primary analysis was conducted for 2533 patients who were ER/PgR+. The median duration of follow-up in the ER/PgR+ group was 96.2 months (range, 0.2-121 months). Invasive disease-free survival events occurred in 465 patients who were ER/PgR+. The incidence rates for invasive disease-free survival events were 2.78 per 100 patient-years in the metformin group vs 2.74 per 100 patient-years in the placebo group (hazard ratio [HR], 1.01; 95% CI, 0.84-1.21; P = .93), and the incidence rates for death were 1.46 per 100 patient-years in the metformin group vs 1.32 per 100 patient-years in the placebo group (HR, 1.10; 95% CI, 0.86-1.41; P = .47). Among patients who were ER/PgR-, followed up for a median of 94.1 months, incidence of invasive disease-free survival events was 3.58 vs 3.60 per 100 patient-years, respectively (HR, 1.01; 95% CI, 0.79-1.30; P = .92). None of the 3 secondary outcomes analyzed in the ER/PgR+ group had statistically significant differences. Grade 3 nonhematological toxic events occurred more frequently in patients taking metformin than in patients taking placebo (21.5% vs 17.5%, respectively, P = .003). The most common grade 3 or higher adverse events in the metformin vs placebo groups were hypertension (2.4% vs 1.9%), irregular menses (1.5% vs 1.4%), and diarrhea (1.9% vs 7.0%).

Conclusions and relevance: Among patients with high-risk operable breast cancer without diabetes, the addition of metformin vs placebo to standard breast cancer treatment did not significantly improve invasive disease-free survival.

Trial registration: ClinicalTrials.gov Identifier: NCT01101438.

Figure 1.. Study Enrollment and Flow of Patients Without Diabetes With Estrogen Receptor and/or Progesterone Receptor Positive and Negative Breast Cancer Through the MA.32 Trial

^aInformation obtained in screening potential patients was not consistently collected across sites. ^bPatients were stratified by estrogen receptor and/or progesterone receptor (ER/PgR) status (positive vs negative), body mass index, calculated as weight in kilograms divided by height in meters squared, (<30 vs > 30), human epidermal growth factor receptor 2 (ERBB2, formerly HER2 or HER2/neu) status (positive vs negative), and chemotherapy (any vs none). ^cWe originally planned to include all randomized patients in the primary analysis. However, after the second interim analysis, futility was declared for ER/PgR− breast cancer (see the Methods section) causing the cessation of the study drug for these patients. The study was redesigned by an independent statistician for the primary analysis to be conducted for patients with HR+ breast cancer. ^dAdverse events or complications. ^eDisease-related events during active treatment.

Figure 2.. Effect of Metformin vs Placebo on Invasive Disease–Free Survival and Overall Survival

The median duration of follow-up was 96 months (IQR, 86-102) for treatment groups of patients with estrogen receptor and/or progesterone positive (ER/PgR+) breast cancer and was 94 months (IQR, 86-101) for both treatment groups of patients with ER/PgR− breast cancer. A, Invasive disease–free survival (events include breast cancer recurrence, new primary cancers, or death). B, Overall survival. C, Invasive disease–free survival (events include breast cancer recurrence, new primary cancers, or death). D, Overall survival.

Figure 3.. Exploratory Analysis of the Effect of Metformin vs Placebo on Invasive Disease-Free and Overall Survival in the Patients With ERBB2–Positive Breast Cancer

The median duration of follow-up was 96 months (IQR, 85-101) for both treatment groups of patients with human epidermal growth factor receptor 2 (ERBB2, formerly HER2 or HER2/neu). A, Invasive disease–free survival (events include breast cancer recurrence, new primary cancers, or death). B, Overall survival.