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Original Investigation
May 24/31, 2022

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

Author Affiliations
  • 1Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  • 2Canadian Cancer Trials Group, Queen’s University, Kingston, Ontario, Canada
  • 3Department of Medicine, University of British Columbia, BC Cancer Agency, Vancouver, Canada
  • 4Department of Radiation Oncology, McMaster University, Juravinski Cancer Centre, Hamilton, Ontario, Canada
  • 5Applied Statistician, Markham, Ontario, Canada
  • 6Department of Hematology Research, CHU de Québec-Université Laval, Québec, Québec, Canada
  • 7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 8Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York
  • 9Department of Medicine, Vanderbilt University, Nashville, Tennessee
  • 10Department of Oncology, Mayo Clinic, Rochester, Minnesota
  • 11Division of Clinical Studies, ICR-CTSU, Institute of Cancer Research United Kingdom, London, United Kingdom
  • 12Department of Medicine, NRG Oncology and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
  • 13Department of Medical Oncology, IBCSG and Department of Oncology, Bern University Hospital, University of Bern, Berne, Switzerland
  • 14Department of Oncology, Juravinski Cancer Center, McMaster University, Hamilton, Ontario, Canada
  • 15Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Canada
  • 16Department of Internal Medicine, James Cancer Hospital, Ohio State Comprehensive Cancer Center, Columbus, Ohio
  • 17Department of Surgery, Baylor College of Medicine, Houston, Texas
  • 18School of Cancer and Genomic Science, Cancer Research UK Clinical Trials Unit (CRCTU), Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
  • 19Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
  • 20Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
JAMA. 2022;327(20):1963-1973. doi:10.1001/jama.2022.6147
Key Points

Question  Does the addition of metformin to standard breast cancer treatment improve invasive disease–free survival?

Findings  This randomized clinical trial included 3649 patients with high-risk operable breast cancer without diabetes. Treatment with metformin vs placebo resulted in a hazard ratio for an invasive disease–free survival event of 1.01; this was not statistically significant.

Meaning  Addition of metformin to standard breast cancer treatment did not significantly improve invasive disease–free survival.


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

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