Cancer Antigen 15-3/Mucin 1 Levels in CCTG MA.32: A Breast Cancer Randomized Trial of Metformin vs Placebo.

Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, and Department of Medicine, University of Toronto, Toronto, ON, Canada. Hoffman-La Roche Limited, Mississauga, ON, Canada. Applied Statistician, Markham, ON, Canada. Canadian Cancer Trials Group, Queen's University, Kingston, ON, Canada. University of British Columbia, BC Cancer Agency, Vancouver, BC, Canada. McMaster University, Juravinski Cancer Centre, Hamilton, ON, Canada. Dana-Farber Cancer Institute, Boston, MA, USA. Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, NY, USA. Vanderbilt University, Nashville, TN, USA. Mayo Clinic, Rochester, MN, USA. NRG Oncology and University of Pittsburgh Medical Center, Pittsburgh, PA, USA. IBCSG and Department of Oncology, Bern University Hospital, University of Bern, Bern, Switzerland. CHU de Québec-Université Laval, Québec, QC, Canada. Baylor College of Medicine, Houston, TX, USA. Cancer Research UK Clinical Trials Unit (CRCTU), Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK. Department of Medical Biophysics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada and University of Toronto, Toronto, ON, Canada.

JNCI cancer spectrum. 2021;(5)
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Abstract

BACKGROUND Circulating levels of cancer antigen (CA) 15-3, a tumor marker and regulator of cellular metabolism, were reduced by metformin in a nonrandomized neoadjuvant study. We examined the effects of metformin (vs placebo) on CA 15-3 in participants of MA.32, a phase III randomized trial in early-stage breast cancer. METHODS A total of 3649 patients with T1-3, N0-3, M0 breast cancer were randomly assigned; pretreatment and 6-month on-treatment fasting plasma were centrally assayed for CA 15-3. Genomic DNA was analyzed for the rs11212617 single nucleotide polymorphism. Absolute and relative change of CA 15-3 (metformin vs placebo) were compared using Wilcoxon rank and t tests. Regression models adjusted for baseline differences and assessed key interactions. All statistical tests were 2-sided. RESULTS Mean (SD) age was 52.4 (10.0) years. The majority of patients had T2/3, node-positive, hormone receptor-positive, HER2-negative breast cancer treated with (neo)adjuvant chemotherapy and hormone therapy. Mean (SD) baseline CA 15-3 was 17.7 (7.6) and 18.0 (8.1 U/mL). At 6 months, CA 15-3 was statistically significantly reduced in metformin vs placebo arms (absolute geometric mean reduction in CA 15-3 = 7.7% vs 2.0%, P < .001; relative metformin: placebo level of CA 15-3 [adjusted for age, baseline body mass index, and baseline CA 15-3] = 0.94, 95% confidence interval = 0.92 to 0.96). This reduction was independent of tumor characteristics, perioperative systemic therapy, baseline body mass index, insulin, and the single nucleotide polymorphism status (all Ps > .11). CONCLUSIONS Our observation that metformin reduces CA 15-3 by approximately 6% was corroborated in a large placebo-controlled randomized trial. The clinical implications of this reduction in CA 15-3 will be explored in upcoming efficacy analyses of breast cancer outcomes in MA.32.

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MeSH terms : Metformin