The Effect of Metformin vs Placebo on Sex Hormones in Canadian Cancer Trials Group MA.32.

Abstract

BACKGROUND:

Metformin has been associated with lower breast cancer (BC) risk and improved outcomes in observational studies. Multiple biologic mechanisms have been proposed, including a recent report of altered sex hormones. We evaluated the effect of metformin on sex hormones in MA.32, a phase III trial of nondiabetic BC subjects who were randomly assigned to metformin or placebo.

METHODS:

We studied the subgroup of postmenopausal hormone receptor-negative BC subjects not receiving endocrine treatment who provided fasting blood at baseline and at 6 months after being randomly assigned. Sex hormone-binding globulin, bioavailable testosterone, and estradiol levels were assayed using electrochemiluminescence immunoassay. Change from baseline to 6 months between study arms was compared using Wilcoxon sum rank tests and regression models.

RESULTS:

312 women were eligible (141 metformin vs 171 placebo); the majority of subjects in each arm had T1/2, N0, HER2-negative BC and had received (neo)adjuvant chemotherapy. Mean age was 58.1 (SD=6.9) vs 57.5 (SD=7.9) years, mean body mass index (BMI) was 27.3 (SD=5.5) vs 28.9 (SD=6.4) kg/m2 for metformin vs placebo, respectively. Median estradiol decreased between baseline and 6 months on metformin vs placebo (-5.7 vs 0 pmol/L; P < .001) in univariable analysis and after controlling for baseline BMI and BMI change (P < .001). There was no change in sex hormone-binding globulin or bioavailable testosterone.

CONCLUSION:

Metformin lowered estradiol levels, independent of BMI. This observation suggests a new metformin effect that has potential relevance to estrogen sensitive cancers.

• Authors: Isabel Pimentel, Bingshu E Chen, Ana Elisa Lohmann, Marguerite Ennis, Jennifer Ligibel, Lois Shepherd, Dawn L Hershman, Timothy Whelan, Vuk Stambolic, Ingrid Mayer, Timothy Hobday, Julie Lemieux, Alastair Thompson, Priya Rastogi, Karen Gelmon, Daniel Rea, Manuela Rabaglio, Susan Ellard, Mihaela Mates, Philippe Bedard, Lacey Pitre, Theodore Vandenberg, Ryan J O Dowling, Wendy Parulekar, Pamela J Goodwin
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 113 Issue 2 Pg. 192-198 (02 01 2021) ISSN: 1460-2105 [Electronic] United States
• PMID: 33527137 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Gonadal Steroid Hormones
• Testosterone
• Estradiol
• Metformin
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Body Mass Index
• Breast Neoplasms (drug therapy, genetics, pathology)
• Estradiol (genetics)
• Female
• Gonadal Steroid Hormones (antagonists & inhibitors, genetics)
• Humans
• Metformin (administration & dosage)
• Middle Aged
• Receptor, ErbB-2 (genetics)
• Testosterone (antagonists & inhibitors, genetics)