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

Pimentel, Isabel; Chen, Bingshu E; Lohmann, Ana Elisa; Ennis, Marguerite; Ligibel, Jennifer; Shepherd, Lois; Hershman, Dawn L; Whelan, Timothy; Stambolic, Vuk; Mayer, Ingrid; Hobday, Timothy; Lemieux, Julie; Thompson, Alastair; Rastogi, Priya; Gelmon, Karen; Rea, Daniel; Rabaglio, Manuela; Ellard, Susan; Mates, Mihaela; Bedard, Philippe; ... (2020). The effect of metformin vs placebo on sex hormones in CCTG MA.32. Journal of the National Cancer Institute, 113(2), pp. 192-198. Oxford University Press 10.1093/jnci/djaa082

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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.

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