For a study, researchers sought to determine if giving adjuvant metformin (vs. placebo) to patients with breast cancer who do not have diabetes improved outcomes. MA.32, a phase 3 randomized, placebo-controlled, double-blind trial conducted in Canada, Switzerland, the United States, and the United Kingdom, enrolled 3,649 patients with high-risk nonmetastatic breast cancer receiving standard therapy between August 2010 and March 2013, with a follow-up period ending in October 2020. Patients were randomized to 850 mg of oral metformin twice a day (n=1,824) or oral placebo twice a day (n=1,825) for 5 years (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=1,824) or oral placebo twice a day (n=1,825) for 5 years. In hormone receptor-positive breast cancer, the primary endpoint was invasive disease-free survival. Overall survival, distant relapse-free survival, and breast cancer-free interval were among the eight secondary endpoints studied.
All (100%) of the 3,649 randomized patients (mean age, 52.4 years; 3,643 women [99.8%]) were included in the analysis. After a second interim analysis revealed that individuals with ER/PgR were futile, the primary study was performed on 2,533 ER/PgR+ patients. In the ER/PgR+ group, the median period of follow-up was 96.2 months (range, 0.2-121 months). Invasive disease-free survival events occurred in 465 ER/PgR+ individuals. In the metformin group, the incidence rate of invasive disease-free survival events was 2.78 per 100 patient years compared to 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 rate of death was 1.46 per 100 patient-years compared to 1.32 per 100 patient-years in the placebo group (HR, 1.10; 95% CI, 0.86-1. Following patients with ER/PgR for a median of 94.1 months, the incidence of invasive disease-free survival events was 3.58 versus 3.60 per 100 patient-years (HR, 1.01; 95% CI, 0.79-1.30; P=.92). There were no statistically significant changes in any of the three secondary outcomes studied in the ER/PgR+ group. Grade 3 nonhematological toxic events occurred more often in metformin patients than in placebo patients (21.5% versus 17.5%, P=.003). In the metformin vs. placebo groups, the most prevalent grade 3 or higher adverse events were hypertension (2.4% vs. 1.9%), irregular menstruation (1.5% vs. 1.4%), and diarrhea (1.9% vs 7.0%). The addition of metformin versus placebo to conventional breast cancer treatment did not substantially increase invasive disease-free survival in patients with high-risk operable breast cancer who did not have diabetes.