(2016). A meta-analysis of individual participant data reveals an association between circulating levels of IGF-I and prostate risk.

the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group Abstract The role of insulin-like growth factors (IGFs) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the odds ratios (ORs) for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (Ptrend all ≤ 0.005), and IGFBP-1 was weakly inversely associated with risk (Ptrend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (Pheterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, Pheterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval=1.16-1.43) for IGF-I, 0.81 (0.68-0.96) for IGFBP-1, and 1.25 (1.12-1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development. of IGF-I with risk by increasing age at diagnosis; with a stronger association for men diagnosed the 60 years 80 percentile in IGF-I = 1.80, 1.34-2.42, P heterogeneity/trend by age 0.05/0.04, We also assessed overall risk for prostate cancer in relation to deciles of IGF-I and IGFBP-3 concentrations for the prospective studies: results were consistent with a linear trend for both analytes ( P trend <0.001 for both, Supplementary Table S6). The risk in the highest versus lowest decile was 1.43 (1.24-1.65) for IGF-I and 1.39 (1.19-1.63) for IGFBP-3. The results of this large collaborative analysis of individual participant data confirm moderate positive associations between prediagnostic circulating concentrations of IGF-I and prostate cancer risk. However, there was evidence of heterogeneity in the association between prospective and cross-sectional studies and, when ProtecT was excluded, men with high IGF-I concentrations had a 29% higher risk compared to those with low concentrations. These analyses include nearly all (>98%) of the published worldwide prospective data on IGFs and prostate cancer risk. The results from one small nested case-control study of IGF-I and IGFBP-3 in relation to prostate cancer risk (96 cases and 416 matched controls, OR for IGF-I = 1.26, 95% CI 0.66-2.41; OR for IGFBP-3 = 1.35, 0.15-6.59), which were unavailable for this re-analysis are compatible with our findings and their inclusion would not have materially altered our summary relative risk estimates (25). The large numbers of cases and corresponding matched controls make it possible not only to estimate prostate cancer risk associated with IGFs with greater precision but also to examine risks at extremes of the distribution. Results from an analysis of risk in relation to deciles of IGF-I and IGFBP-3 provide no suggestion that the association is anything but linear. In the prospective studies, risk for prostate cancer was approximately 40% higher in men with IGF-I or IGFBP-3 concentrations in the highest tenth of the distribution than in men with concentrations in the lowest tenth. IGF-2 concentration in the ProtecT study (2) and the identification of a common prostate cancer susceptibility allele in the region of the IGF-II gene (36). Based on over 5000 cases, our findings suggest a moderate association of IGF-II with prostate cancer risk but interpretation of these findings is difficult because of the heterogeneity in the association between individual studies. Our findings also suggest that raised IGF-II levels may be associated with an increased risk of PSA-screen detected disease, with the strongest associations being observed among men who had a high PSA at baseline, who were diagnosed with low-intermediate grade disease and who were diagnosed after the introduction of