As reported in JAMA by Pamela J. Goodwin, MD, MSc, FRCPC, FASCO, the phase III MA.32 trial showed no invasive disease–free survival benefit with metformin vs placebo in patients without diabetes receiving standard therapy for high-risk nonmetastatic breast cancer.

Pamela J. Goodwin, MD, MSc, FRCPC, FASCO

Study Details

In the double-blind trial, 3,649 patients from sites in Canada, Switzerland, the United States, and the United Kingdom were randomly assigned between August 2010 and March 2013 to receive metformin at 850 mg twice daily (n = 1,824) or placebo (n = 1,825) for 5 years. Patients were followed through October 2020.

A total of 1,268 patients in the metformin group and 1,265 in the placebo group had estrogen receptor– or progesterone receptor–positive disease (hormone receptor [HR]-positive); 556 and 560 had ER- and PR-negative disease (HR-negative). The primary outcome measure was invasive disease–free survival among HR-positive patients.

Invasive Disease–Free Survival

After the second interim analysis, futility was declared for the comparison of HR-negative patients, with the primary analysis thus being conducted among HR-positive patients.

Median duration of follow-up in the HR-positive group was 96.2 months (range = 0.2–121 months). The incidence rates for invasive disease–free survival events per 100 patient-years were 2.78 in the metformin group vs 2.74 in the placebo group (hazard ratio [HR] = 1.01, 95% confidence interval [CI] = 0.84–1.21, P = .93). The incidence rates for death per 100 patient- years were 1.46 vs 1.32 (HR = 1.10, 95% CI = 0.86–1.41, P = .47).

Median follow-up in the HR-negative group was 94.1 months (range = 0.03–121.0 months). Incidence rates per 100 patient-years were 3.58 vs 3.60 for invasive disease–free survival events (HR = 1.01, 95% CI = 0.79–1.30, P = .92) and 1.91 vs 2.15 for death (HR = 0.89, 95% CI = 0.64–1.23, P = .46).

In an exploratory analysis among 314 patients in the metformin group and 306 in the placebo group with HER2-positive disease, incidence rates per 100 patient-years were 1.93 vs 3.05 for invasive disease–free survival events (HR = 0.64, 95% CI = 0.43–0.95, P = .03) and 0.78 vs 1.43 for death (HR = 0.54, 95% CI = 0.30–0.98, P = .04). Benefit of metformin in both outcomes was observed in patients with rs11212617 CC or AC genotype but not in those with AA genotype.  No significant differences in either outcome were observed among patients with HER2-negative disease.

Adverse Events

Grade ≥ 3 nonhematologic adverse events occurred in 21.5% of patients in the metformin group vs 17.5% of the placebo group (P = .003). The most common in the metformin group were hypertension (2.4% vs 1.9% in placebo group), diarrhea (1.9% vs 7.0%), and irregular menses (1.5% vs 1.4%).

The investigators concluded, “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.”

Dr. Goodwin, of the University of Toronto and Mount Sinai Hospital, is the corresponding author for the JAMA article.

Disclosure: The study was supported by the Canadian Cancer Society Research Institute, U.S. National Cancer Institute, Breast Cancer Research Foundation, and others. For full disclosures of the study authors, visit jamanetwork.com.