Effect of metformin versus placebo on metabolic factors in the MA.32 randomized breast cancer trial

Research output: Contribution to journalArticlepeer-review


  • Pamela J Goodwin
  • Ryan J O Dowling
  • Marguerite Ennis
  • Bingshu E Chen
  • Wendy R Parulekar
  • Lois E Shepherd
  • Margot J Burnell
  • Rachel Vander Meer
  • Andrea Molckovsky
  • Anagha Gurjal
  • Karen A Gelmon
  • Jennifer A Ligibel
  • Dawn L Hershman
  • Ingrid A Mayer
  • Timothy J Whelan
  • Timothy J Hobday
  • Priya Rastogi
  • Manuela Rabaglio-Poretti
  • Julie Lemieux
  • Alastair M Thompson
  • Vuk Stambolic

Colleges, School and Institutes

External organisations

  • Hoffman-La Roche Limited
  • Queen's University
  • Saint John Regional Hospital
  • Department of Oncology
  • Department of Medical Oncology
  • British Columbia Cancer Agency
  • Dana-Farber Cancer Institute
  • Columbia University Irving Medical Center/New York-Presbyterian Hospital
  • Vanderbilt University
  • McMaster University
  • Mayo Clinic
  • University of Pittsburgh
  • Bern University Hospital and University of Bern
  • Université Laval
  • Baylor College of Medicine
  • University Health Network
  • University of Toronto
  • University of British Columbia
  • University of Calgary


Metformin may exert anticancer effects through indirect (mediated by metabolic changes) or direct mechanisms. The goal was to examine metformin impact on metabolic factors in non-diabetic subjects and determine whether this impact varies by baseline BMI, insulin, and rs11212617 SNP in CCTG MA.32, a double-blind placebo-controlled randomized adjuvant breast cancer (BC) trial. 3649 subjects with T1-3, N0-3, M0 BC were randomized; pretreatment and 6-month on-treatment fasting plasma was centrally assayed for insulin, leptin, highly sensitive C-reactive protein (hsCRP). Glucose was measured locally and homeostasis model assessment (HOMA) calculated. Genomic DNA was analyzed for the rs11212617 SNP. Absolute and relative change of metabolic factors (metformin versus placebo) were compared using Wilcoxon rank and t-tests. Regression models were adjusted for baseline differences and assessed interactions with baseline BMI, insulin, and the SNP. Mean age was 52 years. The majority had T2/3, node positive, hormone receptor positive, HER2 negative BC treated with (neo)adjuvant chemotherapy and hormone therapy. Median baseline body mass index (BMI) was 27.4 kg/m2 (metformin) and 27.3 kg/m2 (placebo). Median weight change was -1.4 kg (metformin) vs +0.5 kg (placebo). Significant improvements were seen in all metabolic factors, with 6 month standardized ratios (metformin/placebo) of 0.85 (insulin), 0.83 (HOMA), 0.80 (leptin), and 0.84 (hsCRP), with no qualitative interactions with baseline BMI or insulin. Changes did not differ by rs11212617 allele. Metformin (vs placebo) led to significant improvements in weight and metabolic factors; these changes did not differ by rs11212617 allele status.

Bibliographic note

Funding Information: This work was supported by the Canadian Cancer Society Research Institute (#021039); National Cancer Institute (US) (#CA077202, CA180868, CA180822); The Breast Cancer Research Foundation (New York); Canadian Breast Cancer Foundation – Ontario Region, Ontario Institute for Cancer Research (#10NOV-467); Canadian Institutes of Health Research (#162296); Apotex Canada (in kind donation of placebo and metformin); and Hold’em for Life Charity. The study sponsors had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. Publisher Copyright: © 2021, The Author(s).


Original languageEnglish
Article number74
Number of pages8
JournalBreast Cancer
Issue number1
Early online date8 Jun 2021
Publication statusE-pub ahead of print - 8 Jun 2021