Background: Metabolic unbalanced conditions, which can include the presence of metabolic syndrome, weight gain, central obesity, elevated serum insulin and glucose levels, and insulin resistance, have been strongly associated with breast cancer (BC) recurrence and worse outcomes after treatment. Preclinical and clinical studies have demonstrated the efficacy of metformin, the oral insulin-sensitizing drug most widely prescribed for the treatment of type 2 diabetes, to inhibit the growth of BC cells. In particular, a recent pre-surgical clinical study has shown the efficacy of 4 weeks of metformin to reduce Ki-67 (now fully considered a standard surrogate biomarker to test the activity of candidate drugs) in BC cells specifically in metabolic unbalanced subjects.
Hypothesis: We think that this commonly used and cheap oral anti-diabetic drug, given for 1 year, may decrease epithelial cells proliferation also in healthy, metabolic unbalanced BC survivors. Moreover it may favorably modulate various translational risk factors related to the target tissue and the host characteristics. Thus we hypothesize that these effects may induce a possible reduction of early and late BC recurrence/second primary.
Study design: We propose a randomized, placebo-controlled, phase II study (1 year of accrual, 1 year of treatment, and 1 year of follow-up and analysis of results) with metformin/placebo in 236 pre- and postmenopausal (aged 18-70), metabolic unbalanced (BMI >25 Kg/m2) BC survivors at higher risk for recurrence. We will randomize non-diabetic patients with prior triple negative BC (TNBC), or estrogen receptor (ER) negative progesterone receptor (PgR) negative HER2 positive BC, or Luminal B HER2 positive BC at the end of standard adjuvant therapies (no later than 2 years from the cessation). The Primary Endpoint is the effect of treatment on the change of Ki-67 in contralateral unaffected breast biopsies after 12 months of treatment. Secondary Endpoints are the effects of metformin on a series of circulating and molecular biomarkers, the validation of metformin anticancer-action pathways, and various transcriptomics, epigenomics and metabolomics analyses. Safety and toxicity of the treatment will be additional endpoints.The joint effort of our research consortium will contribute to better elucidate the clinical and molecular effects of metformin and to confirm its role in tertiary prevention of high risk patients.