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Background: Though obesity, measured by body mass index (BMI), is an established risk factor for several cancer sites, there is conflicting evidence on whether obesity increases prostate cancer risk or mortality and, if it does, whether it increases risk directly or indirectly by affecting prostate cancer screening efficacy., Methods: We examined associations between BMI and prostate cancer screening outcomes, incidence, and mortality in men randomly assigned to the intervention arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (n = 36 756) between 1993 and 2001. Participants received annual screening with the prostate-specific antigen test and digital rectal exam. Associations between baseline BMI and screening outcomes were assessed via multinomial logistic regression, and associations with prostate cancer incidence and mortality were assessed via Cox proportional hazards regression., Results: Individuals with higher BMI were less likely to screen positive via the prostate-specific antigen test and/or digital rectal exam and more likely to have an inadequate screen (all Ptrend < .01). Higher BMI was inversely associated with prostate cancer incidence (per 5 kg/m2 BMI increase: hazard ratio [HR] = 0.94, 95% confidence interval [CI] = 0.91 to 0.97), including incidence of early stage (HR = 0.94, 95% CI = 0.90 to 0.97) and advanced-stage (HR = 0.91, 95% CI = 0.82 to 1.02) disease, but positively associated with prostate cancer mortality (HR = 1.21, 95% CI = 1.06 to 1.37). The association with mortality was not modified by screening outcome (Pinteraction = .13)., Conclusions: Within this screened population, individuals with higher BMI had lower risk of prostate cancer diagnosis but higher risk of prostate cancer mortality. As higher BMI was not positively associated with advanced-stage prostate cancer risk, the increased mortality is unlikely to be due to delayed prostate cancer detection., (Published by Oxford University Press 2023.) more...

Background: Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer., Methods: Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium., Results: In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I., Conclusions: These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.) more...

Background: In the era of widespread prostate-specific antigen testing, it is important to focus etiologic research on the outcome of aggressive prostate cancer, but studies have defined this outcome differently. We aimed to develop an evidence-based consensus definition of aggressive prostate cancer using clinical features at diagnosis for etiologic epidemiologic research., Methods: Among prostate cancer cases diagnosed in 2007 in the National Cancer Institute's Surveillance, Epidemiology, and End Results-18 database with follow-up through 2017, we compared the performance of categorizations of aggressive prostate cancer in discriminating fatal prostate cancer within 10 years of diagnosis, placing the most emphasis on sensitivity and positive predictive value (PPV)., Results: In our case population (n = 55 900), 3073 men died of prostate cancer within 10 years. Among 12 definitions that included TNM staging and Gleason score, sensitivities ranged from 0.64 to 0.89 and PPVs ranged from 0.09 to 0.23. We propose defining aggressive prostate cancer as diagnosis of category T4 or N1 or M1 or Gleason score of 8 or greater prostate cancer, because this definition had one of the higher PPVs (0.23, 95% confidence interval = 0.22 to 0.24) and reasonable sensitivity (0.66, 95% confidence interval = 0.64 to 0.67) for prostate cancer death within 10 years. Results were similar across sensitivity analyses., Conclusions: We recommend that etiologic epidemiologic studies of prostate cancer report results for this definition of aggressive prostate cancer. We also recommend that studies separately report results for advanced category (T4 or N1 or M1), high-grade (Gleason score ≥8), and fatal prostate cancer. Use of this comprehensive set of endpoints will facilitate comparison of results from different studies and help elucidate prostate cancer etiology., (Published by Oxford University Press 2020.) more...