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

Author:

Pimentel Isabel1ORCID,Chen Bingshu E2ORCID,Lohmann Ana Elisa3,Ennis Marguerite4ORCID,Ligibel Jennifer5,Shepherd Lois6,Hershman Dawn L7ORCID,Whelan Timothy8,Stambolic Vuk9ORCID,Mayer Ingrid10,Hobday Timothy11,Lemieux Julie12,Thompson Alastair13,Rastogi Priya14,Gelmon Karen15ORCID,Rea Daniel16,Rabaglio Manuela17,Ellard Susan18ORCID,Mates Mihaela19ORCID,Bedard Philippe9ORCID,Pitre Lacey20ORCID,Vandenberg Theodore21ORCID,Dowling Ryan J O9ORCID,Parulekar Wendy22,Goodwin Pamela J23

Affiliation:

1. Vall d`Hebron Institute of Oncology (VHIO), Barcelona, Spain

2. Canadian Cancer Trials Group, Queen’s University–Cancer Research Institute, Kingston, ON, Canada

3. University of Western Ontario, London, ON, Canada

4. Applied Statistician, Markham, ON, Canada

5. Dana-Farber Cancer Institute, Boston, MA, USA

6. Canadian Cancer Trials Group, Queen’s University–Cancer Research Institute, Kingston, ON, Canada

7. Herbert Irving Cancer Center, Columbia University, New York, NY, USA

8. Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, ON, Canada

9. University Health Network, Princess Margaret Hospital, Toronto, ON, Canada

10. Vanderbilt University, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA

11. Mayo Clinic, Rochester, MN, USA

12. CHA-Hopital Du St-Sacrement, Hopital Enfant Jesus Site, Quebec City, Canada

13. Baylor College of Medicine, Houston, TX, USA

14. National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA, USA

15. BCCA–Vancouver Cancer Centre, Vancouver, BC, Canada

16. Institute of Cancer Research, Clinical Trials and Statistics Unit, Sutton, UK

17. IBCSG Coordinating Centre, Bern, Switzerland

18. BCCA-Cancer Centre for the Southern Interior, Kelowna, BC, Canada

19. Cancer Centre of Southeastern Ontario, Kingston, ON, Canada

20. Health Sciences North, Sudbury, ON, Canada

21. London Regional Cancer Program, London, ON, Canada

22. Canadian Cancer Trials Group , Queen’s University–Cancer Research  Institute, Kingston, ON, Canada

23. Lunenfeld Tanenbaum Research Institute at Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada

Abstract

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.

Funder

Canadian Cancer Society Research Institute

National Cancer Institute

Breast Cancer Research Foundation

Canadian Breast Cancer Foundation

Hold’Em for Life, and Apotex Canada

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Oncology

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