The effect of metformin vs placebo on sex hormones in CCTG MA.32.

BACKGROUND Metformin has been associated with lower breast cancer risk and improved outcomes in observational studies. Multiple biologic mechanisms have been proposed, including a recent report of altered sex hormones (SHs). We evaluated the effect of metformin on SHs in MA.32, a phase III trial of nondiabetic BC subjects randomized to metformin or placebo. METHODS We studied the subgroup of post-menopausal hormone receptor negative BC subjects not receiving endocrine treatment who provided fasting blood at baseline and at 6 months after randomization. Sex hormone binding globulin (SHBG), bioavailable testosterone (BT) and estradiol levels were assayed using ECLIA (electrochemiluminescense 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 ± SD was 58.1±6.9 vs 57.5±7.9 years, mean BMI was 27.3±5.2 vs 28.9±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 < 0.001) in univariable analysis and after controlling for baseline BMI and BMI change (p < 0.001). There was no change in SHBG or BT. CONCLUSION Metformin lowered estradiol levels, independent of BMI. This observation suggests a new metformin effect that has potential relevance to estrogen sensitive cancers.