This observational signal, backed by numerous preclinical studies showing metformin’s anti-tumor effects across subtypes, motivated the MA.32 trial—a phase III, randomized, double-blind, placebo-controlled study conducted from August 2010 to March 2013 in Canada, Switzerland, the US, and the UK; the study involved 3649 non-diabetic, high-risk operable breast cancer patients (stratified by hormone receptor status, HER2 status, BMI, and chemotherapy) that received either 850 mg metformin or placebo twice daily for five years. This evidence concerns the gene NR4A1 and breast carcinoma.