Effect of metformin vs placebo on invasive disease-free survival in patients with breast cancer: the MA.32 randomized clinical trial

Pamela J Goodwin, Bingshu E Chen, Karen A Gelmon, Timothy J Whelan, Marguerite Ennis, Julie Lemieux, Jennifer A Ligibel, Dawn L Hershman, Ingrid A Mayer, Timothy J Hobday, Judith M Bliss, Priya Rastogi, Manuela Rabaglio-Poretti, Som D Mukherjee, John R Mackey, Vandana G Abramson, Conrad Oja, Robert Wesolowski, Alastair M Thompson, Daniel ReaPaul M Stos, Lois E Shepherd, Vuk Stambolic, Wendy R Parulekar

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1963-1973
Number of pages11
JournalJAMA The Journal of the American Medical Association
Issue number20
Publication statusPublished - 24 May 2022

Bibliographical note

Funding Information:
Funding/Support: This work was supported by grants 021039 from the Canadian Cancer Society Research Institute; CA077202, CA180868, and CA180822 from the US National Cancer Institute; the Breast Cancer Research Foundation; Canadian Breast Cancer Foundation–Ontario Region; 10NOV-467 from the Ontario Institute for Cancer Research; 02689-08-2010 from the Stiftung Krebsforschung Schweiz KFS; Cancer Research UK; Apotex Canada (in kind donation of placebo and reported grants from CCTG per case funding during the conduct of the study. Dr Whelan reported nonfinancial support from Exact Sciences Genomic Health Research support outside the submitted work. Dr Ennis reported serving as a consultant for Mount Sinai Hospital during and outside the conduct of the study. Dr Lemieux reported serving as a consultant to Pfizer, Gilead, Astra Zeneca, Eli Lilly, and Novartis outside the submitted work. Dr Mayer reported serving on the advisory boards of AstraZeneca, Novartis, Pfizer, Genentech, Lilly, GSK, Puma, AbbVie, Immunomedics, Macrogenics, SeaGen, Cyclacell, and Blueprint outside the submitted work; being employed by AstraZeneca since December 2, 2021; and receiving grants from Genentech and Pfizer. Dr Bliss reported receiving grants to ICR-CTSU from AstraZeneca, Merck Sharp & Dohme, Puma Biotechnology, Pfizer, Roche, Novartis (previously GlaxoSmithKline), Eli Lilly, Janssen-Cilag, Clovis Oncology, and Cancer Research UK; and nonfinancial support from the National Institute for Health Research (NIHR). Dr Rastogi reported receiving travel expenses from Genentech, Roche, Lilly, and AstraZeneca outside the submitted work. Dr Abramson reported serving on the advisory boards of Eisai, Daiichi Sankyo, and Mersana Therapeutics and receiving grants from Lilly. Dr Rea reported receiving grants from Roche, Celgene, Biotheranostics, and RNA Diagnostics and personal fees from Novartis, AstraZeneca, Pfizer, Lilly, and Roche outside the submitted work. Dr Shepherd reported receiving grants from the Breast Cancer Research Foundation and support for correlatives and drug distribution during the conduct of the study. No other disclosures were reported.

Publisher Copyright:
© 2022 American Medical Association. All rights reserved.


  • Antineoplastic Combined Chemotherapy Protocols/therapeutic use
  • Breast Neoplasms/pathology
  • Diabetes Mellitus, Type 2/drug therapy
  • Disease-Free Survival
  • Double-Blind Method
  • Female
  • Humans
  • Metformin/adverse effects
  • Middle Aged
  • Neoplasm Recurrence, Local/drug therapy
  • Receptor, ErbB-2/metabolism
  • Receptors, Estrogen


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