Metformin impact on breast cancer: a systematic review

Background: Metformin, a widely used drug for diabetes treatment, has shown promising anticancer effects in preclinical studies and observational data for breast cancer (BC). This systematic review evaluates the available evidence on the association between metformin use and key clinical outcomes in BC patients. Objective: To assess the impact of metformin as an adjunct to standard of care (SOC) on overall survival (OS), progression-free survival (PFS), and pathological complete response (pCR) in breast cancer patients, following PRISMA 2020 guidelines. Methods: A comprehensive literature search was conducted in PubMed and Google Scholar up to October 30, 2025, including randomized controlled trials (RCTs) and observational studies. Eligible studies reported at least one primary (OS) or secondary (PFS, pCR) outcome. Risk of bias was assessed using RoB2 for RCTs and ROBINS-I for observational studies. Results were synthesized narratively due to heterogeneity. Results: Included studies comprised of13 RCTs and 6 observational studies. In patients without diabetes, RCTs consistently showed no significant improvement in OS, PFS, or pCR with the addition of metformin. Observational studies, primarily in patients with diabetes, frequently reported better OS (HR ranging across studies from 0.75 to 0.82 in HR+ subgroups) and higher pCR rates, though they are prone to biases like immortal time bias and confounding. Benefits appeared more pronounced in patients with diabetes or insulin-resistant patients, particularly HR+ (Hormone Receptor positive) subtypes, but were inconsistent in -patients without diabetes or triple-negative BC. Conclusion: Current evidence does not support routine addition of metformin to standard BC therapy, especially in patients without diabetes. Potential benefits may exist in patientswith diabetesand metabolic abnormalities or specific subtypes (e.g., HR+), likely through its insulin-sensitizing effects. Larger, biomarker-stratified RCTs are needed to clarify subgroups that may benefit from metformin repurposing.