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.