Relationship between diabetes and diabetes medications and risk of different molecular subtypes of breast cancer

Background: Type II diabetes and certain diabetes treatments have been observed to impact breast cancer risk. However, their associations with different breast cancer molecular subtype defined by estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor-2 (HER2) status is unclear. Methods: We conducted a retrospective multi-center population-based case-case study consisting of 4,557 breast cancer cases to evaluate the impact of type II diabetes and diabetes medications on the risk of different breast cancer molecular subtypes (ER+/HER2-, ER+/HER2+, triple negative (TN, ER-/PR-/HER2-) and HER2-overexpressing (H2E, ER-/PR-/HER2+)). Using ER+/HER2- cases as the reference group, we estimated odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for each subtype using polytomous logistic regression. Results: Compared to those without a diabetes history, women with type II diabetes had a 38% (95% CI: 1.01-1.89) increased odds of TN breast cancer. Current and longer-term recent metformin use (13-24 months of treatment within the 24-month period prior to breast cancer diagnosis) were associated with elevated odds of TN breast cancer (OR=1.54; 95% CI: 1.07-2.22 and OR=1.80; 95% CI: 1.13-2.85, respectively). Conclusions: The odds of having a TN rather than ER+/HER2- breast cancer is greater for women with type II diabetes, and particularly for those who were users of metformin. This finding is supported by some preclinical data suggesting that diabetes may be more strongly associated with risk of TN disease. Impact: Our study provides novel evidence regarding potential differential effects of type II diabetes and metformin use on risk of different molecular subtypes of breast cancer.