Dose-dependent Relation Between Metformin and the Risk of Hormone Receptor-positive, Her2-negative Breast Cancer Among Postmenopausal Women with Type-2 Diabetes

Purpose: Metformin has demonstrated a chemoprotective effect in breast cancer but there is limited evidence on the effect of cumulative exposure to metformin and the risk of hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR + /HER2-) breast cancer. This study assessed this risk with dose and intensity of metformin in postmenopausal women with type-2 diabetes mellitus (T2DM).

Methods: This nested case-control study used the Surveillance, Epidemiology, and End Results-Medicare data (2008-2015). Cohort entry was the date of incident T2DM diagnosis. Cases were those diagnosed with HR + /HER2- breast cancer (event date) as their first/only cancer. Non-cancer T2DM controls were matched using variable-ratio-matching. Cumulative dose and average intensity of metformin were measured during the 1-year lookback period. Dose(mg) was categorized as: (1)0, (2)0-30,000, (3)30,001-136,000, (4)136,001-293,000, and (5) > 293,000, and intensity(mg/day) as: 0, 1-500, and > 500. Covariates were conceptualized using the Andersen Behavioral Model. Conditional logistic regression was used to assess the risk of HR + /HER2- breast cancer with metformin-use.

Results: There were 690 cases and 2747 controls. The median duration of T2DM was 1178 days in controls and 1180 days in cases. Higher cumulative dose categories: 4 (adjusted odds ratio(aOR) = 0.72, 95% CI 0.55-0.95,p = 0.02), and 5 (OR = 0.60, 95% CI 0.42-0.85,p < 0.01) had significantly lower odds of HR + /HER2- breast cancer compared to category 0. The highest intensity category of metformin had 39% lower odds of HR + /HER2- breast cancer (OR = 0.61, 95% CI 0.46-0.82,p < 0.01) compared to the 0 mg/day group.

Conclusions: Higher metformin exposure was associated with reduced risk of HR + /HER2- breast cancer, adding to the evidence supporting metformin's chemoprotective effect.