Prediagnostic plasma C-peptide levels and prostate cancer incidence and survival.

A204

Abstract Background: Obesity has been linked to prostate cancer mortality and poor prognosis, in which hyperinsulinemia or insulin resistance may play a role. However, prospective studies on insulin or related biomarkers are sparse and inconsistent and have not evaluated the association with prostate cancer severity or lethal outcome. We assessed the association of C-peptide (a marker of insulin secretion) and insulin-like-growth factor binding protein (IGFBP)-1 (low levels indicate insulin resistance) with prostate cancer risk and survival. Methods: The study is nested in the Physicians' Health Study. In 1982, 14,916 US male physicians, aged 40-84, provided blood samples at baseline. After excluding men with diabetes, 694 cases and 667 age- and smoking-matched controls had sufficient plasma for C-peptide and IGFBP-1 measurements. BMI was calculated from baseline weight and height (kg/m²). We used the conditional logistic regression model controlling for fasting status for the nested case-control analysis, and the Cox proportional hazard model controlling for age and fasting status for the survival analysis. Results: Among controls, plasma C-peptide levels were positively correlated with age (spearman correlation r=0.20) and BMI (r=0.26). IGFBP-1 was inversely correlated with C-peptide (r=-0.36) and BMI (r=-0.27) but not with age. In the nested case-control analysis, C-peptide levels were not associated with risk of prostate cancer, neither by tumor grade nor by clinical stage. In the survival analysis among the 694 prostate cancer cases (100 died of this cancer by the end of 2005), we observed a significant positive association between prediagnostic C-peptide levels and risk of dying from prostate cancer; the hazard ratios (HR)s (95% confidence interval, CI) for quartiles 1-4 of C-peptide were: 1.0 (ref), 1.9 (1.1-3.5), 1.3 (0.7-2.4), 2.7 (1.4-5.2), P_trend=0.05. The association persisted after further controlling for BMI, tumor grade, and clinical stage; the correspondent HRs were: 1.0 (ref), 1.2 (0.7-2.3), 1.2 (0.6-2.3), and 2.2 (1.1-4.3), P_trend=0.04. BMI significantly modified the association such that the positive trend was significant among overweight men (BMI≥25 kg/m², P_trend=0.01) but not among normal weight men (BMI<25 kg/m², P_trend=0.46). Overweight men with C-peptide in the highest quartile were four times likely to die of prostate cancer after diagnosis (HR=4.3, 2.0-9.3; P_ineraction=0.01) compared to normal weight men with C-peptide in the lowest quartile. IGFBP-1 was not associated with prostate cancer risk or death. Conclusion: Prediagnostic C-peptide levels were not associated with risk of incident prostate cancer. However, our survival data suggest that elevated C-peptide levels many years before cancer diagnosis predispose men, especially overweight men, to fatal prostate cancer, independent of age, tumor grade, and clinical stage at diagnosis.