Effect of metformin and lifestyle intervention on adipokines and hormones in breast cancer survivors: a pooled analysis from two randomized controlled trials

Purpose We investigated the effect of metformin and lifestyle intervention on metabolic, inflammatory, and steroid biomarkers of breast cancer (BC) recurrence risk in two intervention trials among BC survivors with overweight or obesity. Methods Baseline and follow-up serum samples collected during the two trials were analyzed and data pooled. The USA trial (Reach for Health) included postmenopausal BC survivors (n = 333) randomly assigned to 6-month metformin vs placebo and lifestyle intervention (LSI) vs control (2 × 2 factorial design). The Italian trial (MetBreCS) included BC survivors (n = 40) randomized to 12-month metformin vs placebo. Insulin resistance (HOMA-IR), adipokines, cytokines, and steroids were measured. Results Metformin compared to placebo showed a favorable decrease in leptin (− 8.8 vs − 3.5 ng/mL; p < 0.01) and HOMA-IR (− 0.48 vs − 0.25; p = 0.03), and an increase in SHBG (2.80 vs 1.45 nmol/L; p < 0.01). Excluding women taking aromatase inhibitors, metformin (n = 84) compared to placebo (n = 99) decreased estradiol (− 4 vs 0 pmol/L; p < 0.01), estrone (− 8 vs 2 pmol/L; p < 0.01) and testosterone (− 0.1 vs 0 nmol/L-; p = 0.02). LSI favorably affected adiponectin (0.45 vs − 0.06 ug/mL; p < 0.01), leptin (− 10.5 vs − 4.4 ng/mL; p < 0.01), HOMA-IR (− 0.6 vs 0.2; p = 0.03), and SHBG (2.7 vs 1.1 nMol/L; p = 0.04) compared to controls. The strongest impact was observed combining metformin with LSI on adipokines, CRP, SHBG, and estrogens. Conclusions Supportive healthy lifestyle programs combined with metformin to achieve maximal risk reduction among BC cancer survivors are recommended, especially for those with obesity in menopause.