Reduction of Obesity Associated Breast Cancer Risk in a Phase II Clinical Trial of Metformin

Abstract

Current chemopreventive therapies for breast cancer have low uptake rates, effective only for ER-positive breast cancers and may have serious side effects. Accumulating research supports the potential of metformin for breast cancer prevention, with studies suggesting that metformin may only exert tumor suppressive effects in metabolic phenotypes of high adiposity and metabolic syndrome. We conducted a Phase II, double-blind, placebo-controlled clinical trial in overweight/obese premenopausal women with elements of metabolic syndrome to assess the safety and potential of metformin to modulate recognized and putative markers of breast cancer risk. After an intervention period of 12 months, the most commonly observed side-effects within our cohort were gastrointestinal. We observed high-compliance with agent intervention when assessed by pill counts, but lower compliance when quantifying the circulating metformin levels. Metformin intervention significantly reduced waist circumference and waist-to-hip ratio compared to the placebo group. We did not observe significant changes in breast density measurements and we did not observe favorable changes in the Insulin/IGF axis or adipokines compared to the placebo group. However, we observed significant decreases in leptin and the leptin-to-adiponectin ratio in the metformin arm longitudinally. Furthermore, limiting analysis to participants with detectable metformin in the blood serum resulted in favorable changes in insulin and the homeostatic model assessment of insulin resistance (HOMA-IR). Additionally, we observed a significant reduction in the neutrophil-to-lymphocyte ratio (NLR), a systemic inflammation marker, in the metformin group compared to the control group. Further investigations are needed to understand the cellular changes metformin may exert in the breast tissue.