OBJECTIVES

Metformin has demonstrated a chemoprotective effect in breast cancer; however, the effect of cumulative exposure to metformin and the risk of HR+/HER2- subtype needs further investigation. This study assesses the risk of HR+/HER2- breast cancer with metformin-use in a dose- and intensity-dependent manner in postmenopausal women with type-2 diabetes mellitus (T2DM).

METHODS

A case-control study was performed using the Surveillance, Epidemiology, and End Results-Medicare data (2008-2015). The cohort entry date was the date of incident T2DM diagnosis. Cases were those diagnosed with HR+/HER2- breast cancer as their first/only cancer after cohort entry. Each case was matched to up to 4 non-cancer T2DM controls on age at cohort entry and duration of T2DM. Cumulative dose and average intensity of metformin were measured during the 1-year lookback period before the event date. 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. Intensity (mg/day) was categorized as: 0, 1-500, and >500. Demographic variables were measured at cohort entry, and clinical variables (diabetes severity, metabolic syndrome, comedications, health status) were measured during the lookback period. Conditional logistic regression was used to assess the risk of HR+/HER2- breast cancer with metformin-use.

RESULTS

The study included 690 cases and 2,747 controls. The median duration of T2DM was 1,178 days in controls and 1,180 days in cases. In the adjusted analysis, higher-level categories: 4 (OR=0.72, 95% CI:0.55 to 0.95, p=0.02), and 5 (OR=0.60, 95% CI:0.42 to 0.85, p<0.01) of cumulative dose 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 to 0.82, p<0.01) compared to the 0 mg/day group.

CONCLUSIONS

This novel study shows reduced risk of HR+/HER2- breast cancer with increasing exposure to metformin, adding to the evidence supporting metformin’s chemoprotective effect.