Temporal Trends and Risk Factors for Aggressive and Fatal Prostate Cancer

Purpose: Prostate cancer is one of the most frequently diagnosed cancers worldwide, and a leading cause of morbidity and mortality in men. The introduction of the prostate-specific antigen (PSA) test has resulted in a majority of diagnosed prostate cancers being indolent or asymptomatic, resulting in significant over-treatment. Consequently, a fundamental issue is to identify potentially aggressive or fatal disease at an early stage. The overall purpose of this research was to delineate the etiology and temporal trends of aggressive and fatal prostate cancer by using innovative epidemiologic methodology.;Methods: We conducted the following three epidemiologic investigations: 1) we examined temporal trends in fatal and non-fatal prostate cancer incidence rates in the United States since 1975 using age-period-cohort models; 2) we evaluated whether age-specific body weight, weight change and body mass index (BMI) trajectories across the adult life course were associated with total, aggressive and/or fatal prostate cancer using Cox proportional-hazards regression models with age as the time metric to estimate Hazard ratios (HRs) and 95% confidence intervals (CIs); and 3) we assessed whether genetic polymorphisms modified the association between sex steroid hormonal balance and aggressive prostate cancer using conditional logistic regression models to estimate odds ratios (ORs) and 95% CIs, and conducted tests for synergistic and multiplicative interactions.;Results: In the age-period cohort analysis, fatal prostate cancer accounted for 17% (n = 51,680) of cases and incidence increased 1% per year prior to 1992, subsequently declined by 15% per year during the following 3 years, and further declined by 5% per year from 1995--2002. In contrast, non-fatal rates exhibited a pattern similar to, but more pronounced than, overall prostate cancer. Age-specific incidence rates of fatal disease decreased over 2% per year among older men, yet increased up to 1% per year among younger men. Fatal disease rates were more than 2 fold higher in black men compared with white men in every period and cohort examined, a racial disparity that increased to 3--6 fold among younger men.;In the analysis of weight change in the PLCO, body weight and body mass index (BMI) at all ages were associated with increased risks of fatal prostate cancer (HRs, 1.1 to 1.3 per 5 unit increase). Fatal prostate cancer risk was positively associated with higher maximum attained weight (HRQ4 vs Q1 = 1.64; CI = 1.12 to 2.39). In the five distinct BMI trajectories identified, fatal prostate cancer risk was increased in men who were normal weight (HR = 1.92; CI = 1.18 to 3.13) or overweight (HR = 2.93; CI = 1.58 to 5.46) at age 20 and developed obesity by baseline. Body size was not associated with aggressive prostate cancer, and modest inverse associations were seen for total and nonaggressive prostate cancer.;In the gene-environmental interaction analysis, risk of aggressive prostate cancer was inversely associated with the estradiol:testosterone ratio (OR 4th quartile vs. 1st = 0.29; 95% CI = 0.12 to 0.70). Of 17 prostate cancer susceptibility variants examined, two were marginally associated with aggressive disease; rs10993994 within 10q11.23 (OR = 1.35; CI = 0.98 to 1.86) and rs4430796 within 17q12 (OR = 1.72; CI = 1.00 to 2.99), the latter of which modified (Peffect modification = 0.04) the protective effect of higher estradiol:testosterone ratios on aggressive disease and displayed tentative evidence of synergistic interaction (Padditive = 0.03). Of the 9 deleterious/functional SNPs examined, the highest functionally-scored variant for deleteriousness---rs4148301 near UGT2A2 (OR = 1.72; 95% CI = 1.02 to 2.90)---was positively associated with aggressive disease. None of the predicted deleterious or functional SNPs modified the association between estradiol:testosterone ratio and aggressive prostate cancer. All associations were not significant after correction for multiple testing.;Conclusion: These analyses collectively suggest while fatal prostate cancer incidence has been declining in the US, there remains a lack of a decline in fatal disease among younger men and a persistent black-to-white racial disparity. Furthermore, risk factors such as substantial weight change that results in obesity may increase the risk of fatal disease, while genetics variants may modify the protective associations between higher ratios of estradiol:testosterone and aggressive disease. Larger studies that focus on aggressive and fatal disease are needed to confirm our results and aid in understanding these relationships.