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. 2013 Oct;22(10):1786-96.
doi: 10.1158/1055-9965.EPI-13-0375.

Plasma C-peptide, mammographic breast density, and risk of invasive breast cancer

Thomas P Ahern  1 , Susan E Hankinson, Walter C Willett, Michael N Pollak, A Heather Eliassen, Rulla M Tamimi
Affiliations

Plasma C-peptide, mammographic breast density, and risk of invasive breast cancer

Thomas P Ahern et al. Cancer Epidemiol Biomarkers Prev. 2013 Oct.

Abstract

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.

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Figures

Figure 1
Figure 1
Directed acyclic graph depicting the hypothesized relationship between variables relevant to the estimation of associations between c-peptide levels, mammographic density measurements, and risk of invasive breast carcinoma.
Figure 2
Figure 2
Confidence interval functions depicting heterogeneity of associations between c-peptide level and breast cancer incidence (4th quartile compared with the 1st quartile) according to menopausal status at breast cancer diagnosis, hormone therapy (PMH) status, and estrogen receptor status of the primary tumor
See this image and copyright information in PMC

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