Isabel Pimentel1, Bingshu E Chen2, Ana Elisa Lohmann3, Marguerite Ennis4, Jennifer Ligibel5, Lois Shepherd6, Dawn L Hershman7, Timothy Whelan8, Vuk Stambolic9, Ingrid Mayer10, Timothy Hobday11, Julie Lemieux12, Alastair Thompson13, Priya Rastogi14, Karen Gelmon15, Daniel Rea16, Manuela Rabaglio17, Susan Ellard18, Mihaela Mates19, Philippe Bedard9, Lacey Pitre20, Theodore Vandenberg21, Ryan J O Dowling9, Wendy Parulekar22, Pamela J Goodwin23. 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
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.
RCT Entities:
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.
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