Plasma C-Peptide, Mammographic Breast Density, and Risk of Invasive Breast Cancer

Background: Insulin may promote breast cancer directly by stimulating the insulin receptor or indirectly by increasing the plasma concentration of active sex hormones. The association between insulin and breast density, a strong breast cancer risk factor, has not been thoroughly studied. We measured associations between c-peptide (a molar marker of insulin secretion), breast cancer risk, and breast density measurements in case-control studies nested within the Nurses' Health Study and Nurses' Health Study II cohorts. Methods: Breast cancer associations were estimated with multivariate logistic regression models and then pooled across cohorts (total n = 1,084 cases and 1,785 controls). Mammographic density associations (percent dense area, dense area, and nondense area) were estimated as the difference in least-square means of the density parameters between quartiles of c-peptide concentration in all breast cancer controls with available screening mammography films (n = 1,469). Results: After adjustment for adiposity, c-peptide was not associated with any measure of breast density. However, c-peptide was associated with an approximately 50% increased risk of invasive breast cancer [ top vs. bottom quartile, adjusted OR = 1.5, 95% confidence interval (CI), 1.1-2.0] that was robust to adjustment for plasma-free estradiol and sex hormone-binding globulin. The association was stronger for ER-negative disease (adjusted OR = 2.0; 95% CI, 1.2-3.6). Conclusions: Our data suggest a positive association between hyperinsulinemia and breast cancer risk that occurs through nonestrogenic mechanisms, and that is not mediated by breast density. Impact: Primary prevention of breast cancer in women with hyperinsulinemia may be possible by targeting insulin signaling pathways. (C) 2013 AACR.