Post-diagnostic health behaviour scores in relation to fatal prostate cancer.

BACKGROUND: Individual health behaviours have been associated with fatal prostate cancer (PCa). Their combined association with fatal PCa after diagnosis is unknown. METHODS: This prospective cohort included 4518 men diagnosed with nonmetastatic PCa from the Health Professionals Follow-up Study. Exposures included a three-factor score integrating post-diagnostic fatal PCa risk factors ("2021 PCa Behaviour Score"), six-factor score integrating incident aggressive PCa risk factors ("2015 PCa Behaviour Score"), and two scores integrating recommendations for cancer prevention and survival, respectively. Multivariable Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for fatal PCa. RESULTS: Over a median 10.2 years, we observed 219 PCa deaths. Each additional point of one of the PCa-specific health behaviour scores (2015 PCa Behaviour Score) was associated with a 19% reduced fatal PCa risk (HR: 0.81, 95%CI: 0.68-0.97). The 2021 PCa Behaviour Score and scores integrating national recommendations were not associated with fatal PCa. CONCLUSIONS: While a PCa-specific health behaviour score was associated with a reduced risk of fatal PCa, we did not otherwise observe strong evidence of associations between post-diagnostic scores and fatal PCa. Avoiding tobacco, healthy body size, and physical activity may decrease PCa death risk, but further research is needed to inform cancer survivorship recommendations.

Racial Disparities in Prostate Cancer: Evaluation of Diet, Lifestyle, Family History, and Screening Patterns.

BACKGROUND: Racial disparities in prostate cancer incidence and mortality rates are considerable. We previously found in the Health Professionals Follow-up Study (HPFS) that African-American men had an 80% higher prostate cancer risk than White men. With 21 additional years of follow-up and four-fold increase in cases, we undertook a contemporary analysis of racial differences in prostate cancer incidence and mortality in HPFS. METHODS: For 47,679 men, we estimated HRs and 95% confidence intervals (CI) for the association between race and risk of prostate cancer through 2016 using Cox proportional hazards regression. Multivariable models (mHR) were adjusted for lifestyle, diet, family history, and PSA screening collected on biennial questionnaires. RESULTS: 6,909 prostate cancer cases were diagnosed in White, 89 in African-American, and 90 in Asian-American men. African-Americans had higher prostate cancer incidence (mHR = 1.31; 95% CI, 1.06-1.62) and mortality (mHR = 1.67; 95% CI, 1.00-2.78), and lower PSA screening prevalence than White men. The excess risk was greater in the pre-PSA screening era (HR = 1.68; 95% CI, 1.14-2.48) than the PSA screening era (HR = 1.20; 95% CI, 0.93-1.56). Asian-Americans had lower prostate cancer risk (mHR = 0.74; 95% CI, 0.60-0.92), but similar risk of fatal disease compared with white men. CONCLUSIONS: Racial differences in prostate cancer incidence and mortality in HPFS are not fully explained by differences in lifestyle, diet, family history, or PSA screening. IMPACT: Additional research is necessary to address the disproportionately higher rates of prostate cancer in African-American men.

5-Alpha Reductase Inhibitors and Prostate Cancer Mortality among Men with Regular Access to Screening and Health Care.

BACKGROUND: How 5-alpha reductase inhibitor (5-ARI) use influences prostate cancer mortality is unclear. The objective of this study was to determine whether men taking 5-ARIs with regular health care access have increased prostate cancer mortality. METHODS: We undertook two analyses in the Health Professionals Follow-up Study examining 5-ARI use, determined by biennial questionnaires, and prostate cancer. A cohort analysis followed 38,037 cancer-free men for prostate cancer incidence from 1996 through January 2017 and mortality through January 2019. A case-only analysis followed 4,383 men with localized/locally advanced prostate cancer for mortality over a similar period. HRs and 95% confidence intervals (CI) were calculated for prostate cancer incidence and mortality. RESULTS: Men using 5-ARIs underwent more PSA testing, prostate exams and biopsies. Over 20 years of follow-up, 509 men developed lethal disease (metastases or prostate cancer death). Among men initially free from prostate cancer, 5-ARI use was not associated with developing lethal disease [HR, 1.02; 95% confidence interval (CI), 0.71-1.46], but was associated with reduced rates of overall and localized disease (HR, 0.71; 0.60-0.83). Among men diagnosed with prostate cancer, there was no association between 5-ARI use and cancer-specific (HR, 0.78; 95% CI, 0.48-1.27) or overall survival (HR, 0.88; 95% CI, 0.72-1.07). CONCLUSIONS: Men using 5-ARIs were less likely to be diagnosed with low-risk prostate cancer, without increasing long-term risk of lethal prostate cancer or cancer-specific death after diagnosis. IMPACT: Our results provide evidence that 5-ARI use is safe with respect to prostate cancer mortality in the context of regular health care access. See related commentary by Hamilton, p. 1259.

Association of plant-based diet index with prostate cancer risk.

BACKGROUND: Plant-based diets are associated with multiple health benefits and a favorable environmental impact. For prostate cancer, previous studies suggest a beneficial role of specific plant-based foods (e.g., tomatoes) and a potentially harmful role of specific animal-based foods (e.g., meat, dairy). However, less is known about plant-based dietary patterns. OBJECTIVES: We sought to examine the relation between plant-based diet indices and prostate cancer risk, including clinically relevant disease. METHODS: This was a prospective cohort study including 47,239 men in the Health Professionals Follow-Up Study (1986-2014). Overall and healthful plant-based diet indices were calculated from FFQs. Cox proportional hazards models were used to estimate HRs and 95% CIs to examine the risk of incident prostate cancer (total and by clinical category), among men ages <65 and ≥65 y. RESULTS: Of the 47,239 men, 6655 men were diagnosed with prostate cancer over follow-up, including 515 with advanced-stage disease at diagnosis, 956 with lethal disease (metastasis or death), and 806 prostate cancer deaths. Greater overall plant-based consumption was associated with a significantly lower risk of fatal prostate cancer (HR: 0.81; 95% CI: 0.64, 1.01; P-trend = 0.04). In men aged <65, a higher plant-based diet index was associated with a lower risk of advanced, lethal, and fatal prostate cancer. Moreover, greater consumption of a healthful plant-based diet was associated with lower risks of total (HR: 0.84; 95% CI: 0.73, 0.98; P-trend = 0.046) and lethal prostate cancer (HR: 0.56; 95% CI: 0.34, 0.94; P-trend = 0.03) at age <65. There were no associations between overall or healthful plant-based diet indices with prostate cancer among men ≥65 y. Fewer than 1% of participants followed a strict vegetarian or vegan diet. CONCLUSIONS: This prospective study provides supportive evidence that greater consumption of healthful plant-based foods is associated with a lower risk of aggressive forms of prostate cancer, with stronger benefit among men aged <65 y.

Association of Prediagnostic Blood Metabolomics with Prostate Cancer Defined by ERG or PTEN Molecular Subtypes.

BACKGROUND: The TMPRSS2:ERG gene fusion and PTEN loss are two of the most common somatic molecular alterations in prostate cancer. Here, we investigated the association of prediagnostic-circulating metabolomics and prostate cancer defined by ERG or PTEN status to improve understanding of these etiologically distinct molecular prostate cancer subtypes. METHODS: The study was performed among 277 prostate cancer cases with ERG status, 211 with PTEN status, and 294 controls nested in the Health Professionals Follow-up Study (HPFS) and the Physicians' Health Study (PHS). We profiled 223 polar and non-polar metabolites using LC-MS in prediagnostic plasma specimens. We applied enrichment analysis and multinomial logistic regression models to identify biological metabolite classes and individual metabolites associated with prostate cancer defined by ERG or PTEN status. RESULTS: Compared with noncancer controls, sphingomyelin (P: 0.01), ceramide (P: 0.04), and phosphatidylethanolamine (P: 0.03) circulating levels were enriched among ERG-positive prostate cancer cases. Sphingomyelins (P: 0.02), ceramides (P: 0.005), and amino acids (P: 0.02) were enriched among tumors exhibiting PTEN-loss; unsaturated diacylglycerols (P: 0.003) were enriched among PTEN-intact cases; and unsaturated triacylglycerols were enriched among both PTEN-loss (P: 0.001) and PTEN-intact (P: 0.0001) cases. Although several individual metabolites identified in the above categories were nominally associated with ERG or PTEN-defined prostate cancer, none remained significant after accounting for multiple testing. CONCLUSIONS: The molecular process of prostate carcinogenesis may be distinct for men with different metabolomic profiles. IMPACT: These novel findings provide insights into the metabolic environment for the development of prostate cancer.

Gene Expression Pathways in Prostate Tissue Associated with Vigorous Physical Activity in Prostate Cancer.

BACKGROUND: Men engaged in high physical activity have lower risks of advanced and fatal prostate cancer. Mechanisms underlying this association are not well understood but may include systemic and tumor-specific effects. We investigated potential mechanisms linking physical activity and gene expression in prostate tissue from men with prostate cancer. METHODS: We included a subset of 118 men in the Health Professionals Follow-up Study diagnosed with prostate cancer between 1986 and 2005 with whole-transcriptome gene expression profiling on tumor and adjacent normal prostate tissue and physical activity data. Long-term vigorous physical activity was self-reported as the average time spent engaged in various forms of recreational physical activity at baseline and biennially until prostate cancer diagnosis. Gene set enrichment analysis was performed among KEGG and Hallmark gene sets to identify pathways with differential expression based on vigorous physical activity. RESULTS: In adjacent normal tissue, we identified 25 KEGG gene sets enriched (downregulated) in the highest compared with lowest quintile of vigorous physical activity at an FDR <0.10, including a number of cancer- and immune-related pathways. Although no gene sets reached statistical significance in tumor tissue, top gene sets differentially expressed included TGF beta, apoptosis, and p53 signaling pathways. CONCLUSIONS: These findings suggest that physical activity may influence the tumor microenvironment. Future studies are needed to confirm these findings and further investigate potential mechanisms linking physical activity to lethal prostate cancer. IMPACT: Identification of gene expression alterations in the prostate associated with physical activity can improve our understanding of prostate cancer etiology.

Insulinemic and Inflammatory Dietary Patterns and Risk of Prostate Cancer.

BACKGROUND: Hyperinsulinemia and inflammation are inter-related pathways that link diet with the risk of several chronic diseases. Evidence suggests that these pathways may also increase prostate cancer risk. OBJECTIVE: To determine whether hyperinsulinemic diet and inflammatory diet are associated with prostate cancer incidence and mortality. DESIGN, SETTING, AND PARTICIPANTS: We prospectively followed 41 209 men in the Health Professionals Follow-up Study (1986-2014). Scores for two validated dietary patterns were calculated from food frequency questionnaires at baseline and updated every 4 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Total, advanced, and lethal prostate cancer outcomes were assessed. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were determined for associations between two empirical hypothesis-oriented dietary patterns-empirical dietary index for hyperinsulinemia and empirical dietary inflammatory pattern-and prostate cancer risk estimated using Cox proportional hazard regression. RESULTS AND LIMITATIONS: During 28 yr of follow-up, 5929 incident cases of total prostate cancer, including 1019 advanced and 667 fatal, were documented. In multivariable-adjusted models, there was a 7% higher risk of advanced prostate cancer (HR: 1.07; 95% CI: 1.01-1.15) and a 9% higher risk of fatal prostate cancer (HR: 1.09; 95% CI: 1.00-1.18) per standard deviation (SD) increase in the hyperinsulinemic diet. When stratified by age, the hyperinsulinemic diet was associated with only earlier-onset aggressive prostate cancer (men under 65 yr), with per SD HRs of 1.20 (95% CI: 1.06-1.35) for advanced, 1.22 (1.04-1.42) for fatal, and 1.20 (1.04-1.38) for lethal. The inflammatory diet was not associated with prostate cancer risk in the overall study population, but was associated with earlier-onset lethal prostate cancer (per SD increase HR: 1.16; 95% CI: 1.00-1.35). CONCLUSIONS: Hyperinsulinemia and inflammation may be potential mechanisms linking dietary patterns with the risk of aggressive prostate cancer, particularly earlier-onset disease. PATIENT SUMMARY: Avoiding inflammatory and hyperinsulinemic dietary patterns may be beneficial for the prevention of clinically relevant prostate cancer, especially among younger men.

Racial and Ethnic Variation in PSA Testing and Prostate Cancer Incidence Following the 2012 USPSTF Recommendation.

BACKGROUND: The 2012 US Preventive Services Task Force recommendation against routine prostate-specific antigen (PSA) testing led to a decrease in prostate cancer screening, but the heterogeneity of its impact by race and ethnicity remains unclear. METHODS: The proportion of 40- to 74-year-old men who self-reported receiving a routine PSA test in the past year was estimated in the Behavioral Risk Factor Surveillance System (2012-2018). Odds ratios (ORs) of undergoing screening by race and ethnicity were estimated, adjusting for healthcare-related factors. Prostate cancer incidence rates and rate ratios (IRRs) by race and ethnicity were estimated using Surveillance, Epidemiology, and End Results registry data (2004-2017). RESULTS: PSA testing frequencies were 32.3% (95% confidence interval [CI] = 31.7% to 32.8%) among non-Hispanic White (NHW), 30.3% (95% CI = 28.3% to 32.3%) among non-Hispanic Black (NHB), 21.8% (95% CI = 19.9% to 23.7%) among Hispanic, and 17.7% (95% CI = 14.1% to 21.3%) among Asian and Pacific Islander men in 2012. The absolute screening frequency declined by 9.5% from 2012 to 2018, with a larger decline among NHB (11.6%) than NHW men (9.3%). The relative annual decrease was greater among NHB (OR = 0.86, 95% CI = 0.84 to 0.88) than NHW men (OR = 0.89, 95% CI = 0.89 to 0.90; Pheterogeneity = .005), driven by a larger decline among NHB men ages 40-54 years. The NHB to NHW IRR for total prostate cancer increased from 1.73 (95% CI = 1.69 to 1.76) in 2011 to 1.87 (95% CI = 1.83 to 1.92) in 2012 and has remained elevated, driven by differences in localized tumor incidence. Metastatic disease incidence is rising across all racial and ethnic groups. CONCLUSIONS: The frequency of prostate cancer screening varies by race and ethnicity, and there was a modestly steeper decline in PSA testing among younger NHB men relative to NHW men since 2012. The NHB to NHW IRR for localized prostate cancer modestly increased following 2012.

The association between neighborhood greenness and incidence of lethal prostate cancer: A prospective cohort study.

BACKGROUND: Growing evidence suggests that neighborhood contextual environment could influence risk factors and, therefore, incidence of lethal prostate cancer. We studied the association between neighborhood greenness and lethal prostate cancer incidence and assessed mediation by vigorous physical activity. METHODS: A total of 47,958 participants were followed in the Health Professionals Follow-up Study from 1986 to 2014. Neighborhood greenness exposure was estimated using normalized difference vegetation index (NDVI) with 1 km resolution, assigned to home or work addresses at start of follow-up. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were estimated using sequentially adjusted Cox models with individual and contextual prostate cancer risk factors as covariates. Analyses were compared among those whose addresses were constant over follow-up and stratified by population density and address type. RESULTS: We observed 898 cases over 1,054,743 person-years. An interquartile range increase in NDVI was associated with 5% lower rate of lethal prostate cancer (aHR = 0.95, 95% CI = 0.88, 1.03), with stronger associations in nonmovers (aHR = 0.92, 95% CI = 0.85, 1.01). Inverse associations were observed among men in high (aHR = 0.90, 95% CI = 0.82, 0.99) but not low (aHR = 1.11, 95% CI = 0.95, 1.29, P het = 0.086) population density areas, and those reporting from work (aHR = 0.87, 95% CI = 0.75, 1.01) but not home (aHR = 1.04, 95% CI = 0.91, 1.17, P het = 0.10) addresses. There was no evidence of mediation by vigorous physical activity. CONCLUSION: We report inverse associations between neighborhood greenness and lethal prostate cancer when restricting to nonmovers and in high population density areas. Replication could confirm findings and clarify mechanisms.

The association of diabetes with risk of prostate cancer defined by clinical and molecular features.

BACKGROUND: To prospectively examine the association between diabetes and risk of prostate cancer defined by clinical and molecular features. METHODS: A total of 49,392 men from the Health Professionals Follow-up Study (HPFS) were followed from 1986 to 2014. Data on self-reported diabetes were collected at baseline and updated biennially. Clinical features of prostate cancer included localised, advanced, lethal, low-grade, intermediate-grade, and high-grade. Molecular features included TMPRSS2: ERG and PTEN subtypes. Cox proportional hazards regression models were used to evaluate the association between diabetes and incidence of subtype-specific prostate cancer. RESULTS: During 28 years of follow-up, we documented 6733 incident prostate cancer cases. Relative to men free from diabetes, men with diabetes had lower risks of total (HR: 0.82, 95% CI: 0.75-0.90), localised (HR: 0.82, 95% CI: 0.74-0.92), low-and intermediate-grade prostate cancer (HR: 0.77, 95% CI: 0.66-0.90; HR: 0.77, 95% CI: 0.65-0.91, respectively). For molecular subtypes, the HRs for ERG-negative and ERG-positive cases were 0.63 (0.42-0.95) and 0.72 (0.46-1.12); and for PTEN-intact and PTEN-loss cases were 0.69 (0.48-0.98) and 0.52 (0.19-1.41), respectively. CONCLUSION: Besides providing advanced evidence for the inverse association between diabetes and prostate cancer, this study is the first to report associations between diabetes and ERG/PTEN defined prostate cancers.

Baldness and Risk of Prostate Cancer in the Health Professionals Follow-up Study.

BACKGROUND: The association between male pattern baldness and prostate cancer has been inconsistent. We prospectively investigated the association between baldness at age 45 and prostate cancer risk in the Health Professionals Follow-up Study (HPFS), focusing on clinical and molecular markers. METHODS: Baldness was self-reported on the 1992 questionnaire using the modified Norwood-Hamilton scale prior to diagnosis. We estimated HRs between baldness and prostate cancer risk among 36,760 men, with follow-up through 2014. We also investigated whether baldness was associated with prostate cancer defined by tumor protein expression of androgen receptor and the presence of the TMPRSS2:ERG fusion. RESULTS: During 22 years, 5,157 prostate cancer cases were identified. Fifty-six percent of the men had either frontal or vertex baldness. No significant associations were found between baldness and prostate cancer risk. Among men younger than 60 years, there was a statistically significant association between frontal and severe vertex baldness and overall prostate cancer (HR: 1.74; 95% confidence interval: 1.23-2.48). Baldness was not significantly associated with expression of molecular subtypes defined by AR and TMPRSS2:ERG IHC of prostate tumors. CONCLUSIONS: This study showed no association between baldness at age 45 and prostate cancer risk, overall or for clinical or molecular markers. The association between baldness and overall prostate cancer among younger men is intriguing, but caution is warranted when interpreting this finding. IMPACT: The null findings from this large cohort study, together with previous literature's inconclusive findings across baldness patterns, suggest that baldness is not a consistent biomarker for prostate cancer risk or progression.

A Metabolomics Analysis of Adiposity and Advanced Prostate Cancer Risk in the Health Professionals Follow-Up Study.

Obesity is associated with a higher risk of advanced prostate cancer, but men with the same body mass index (BMI) may differ in their underlying metabolic health. Using metabolomics data from nested case-control studies in the Health Professionals Follow-Up Study, we calculated Pearson correlations between 165 circulating metabolites and three adiposity measures (BMI, waist circumference, and derived fat mass from a validated prediction equation) to identify adiposity-associated metabolites. We used Lasso to further select metabolites for prediction models of adiposity measures, which we used to calculate metabolic scores representing metabolic obesity. In an independent set of 212 advanced prostate cancer cases (T3b/T4/N1/M1 or lethal during follow-up) and 212 controls, we used logistic regression to evaluate the associations between adiposity measures and metabolic scores with risk of advanced disease. All adiposity measures were associated with higher blood levels of carnitines (Pearson r range, 0.16 to 0.18) and lower levels of glutamine (r = -0.19) and glycine (r, -0.29 to -0.20), in addition to alterations in various lipids. No adiposity measure or metabolic score was associated with risk of advanced prostate cancer (e.g., odds ratio for a 5 kg/m2 increase in BMI 0.96 (95% CI: 0.73, 1.27) and BMI metabolic score 1.18 (95% CI: 0.57, 2.48)). BMI, waist circumference, and derived fat mass were associated with a broad range of metabolic alterations. Neither adiposity nor metabolic scores were associated with risk of advanced prostate cancer.

Family history of prostate cancer and the incidence of ERG- and phosphatase and tensin homolog-defined prostate cancer.

Family history is among the strongest known risk factors for prostate cancer (PCa). Emerging data suggest molecular subtypes of PCa, including two somatic genetic aberrations: fusions of androgen-regulated promoters with ERG and, separately, phosphatase and tensin homolog (PTEN) loss. We examined associations between family history and incidence of these subtypes in 44,126 men from the prospective Health Professionals Follow-up Study. ERG and PTEN status were assessed by immunohistochemistry. Multivariable competing risks models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between self-reported family history of PCa and molecular subtypes of disease. Thirteen percent of men had a positive family history of PCa at baseline. During a median follow-up of 18.5 years, 5,511 PCa cases were diagnosed. Among them, 888 were assayed for ERG status (47% ERG-positive) and 715 were assayed for PTEN loss (14% PTEN null). Family history was more strongly associated with risk of ERG-negative (HR: 2.15; 95% CI: 1.71-2.70) than ERG-positive (HR: 1.49; 95% CI: 1.13-1.95) disease (pheterogeneity : 0.04). The strongest difference was among men with an affected father (HRERG-negative : 2.09; 95% CI: 1.64-2.66; HRERG-positive : 1.30; 95% CI: 0.96-1.76; pheterogeneity : 0.01). Family history of PCa was positively associated with both PTEN null (HR: 2.10; 95% CI: 1.26-3.49) and PTEN intact (HR: 1.72; 95% CI: 1.39-2.13) PCa (pheterogeneity : 0.47). Our results indicate that PCa family history may be positively associated with PCa in all ERG and PTEN subtypes, suggesting a role of genetic susceptibility in their development. It is possible that ERG-negative disease could be especially associated with positive family history.

The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 in a pooled analysis of 16,024 men from 22 studies.

Insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross-sectional associations of these exposures with circulating concentrations of IGFs (IGF-I and IGF-II) and IGFBPs (IGFBP-1, IGFBP-2 and IGFBP-3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22-89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGF-I, IGF-II and IGFBP-3. Higher body mass index was associated with lower concentrations of IGFBP-1 and IGFBP-2. Taller height was associated with higher concentrations of IGF-I and IGFBP-3 and lower concentrations of IGFBP-1. Smokers had higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGFBP-3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF-II and lower concentrations of IGF-I and IGFBP-2. African Americans had lower concentrations of IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 and Hispanics had lower IGF-I, IGF-II and IGFBP-3 than non-Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.

Guideline-Based Physical Activity and Survival Among US Men With Nonmetastatic Prostate Cancer.

The survival impact of adhering to current physical activity guidelines after prostate cancer diagnosis is unknown. We therefore emulated a target trial of guideline-based physical activity interventions and 10-year survival among US men with nonmetastatic prostate cancer. We used observational data on 2,299 men in the Health Professionals Follow-up Study who were diagnosed with nonmetastatic prostate cancer from 1998 to 2010 and were free of conditions that might have precluded participation at baseline (first postdiagnostic questionnaire). We estimated their survival under several guideline-based physical activity interventions starting at baseline and ending at the development of conditions limiting physical ability. We adjusted for baseline and time-varying risk factors for death using the parametric g-formula. Compared with the observed 15.4% mortality risk, the estimated 10-year risks of mortality were 13.0% (95% confidence interval (CI): 10.9, 15.4) and 11.1% (95% CI: 8.7, 14.1) for ≥1.25 hours/week and ≥2.5 hours/week of vigorous activity, respectively, and 13.9% (95% CI: 12.0, 16.0) and 12.6% (95% CI: 10.6, 14.7) for ≥2.5 hours/week and ≥5 hours/week of moderate activity, respectively. We estimated that these men would have experienced clinically meaningful reductions in mortality had they followed current physical activity recommendations until the development of conditions limiting physical ability. These findings may help guide clinical recommendations for prostate cancer patients and the design of future randomized trials.

A Prospective Study of the Association between Physical Activity and Risk of Prostate Cancer Defined by Clinical Features and TMPRSS2:ERG.

BACKGROUND: Growing evidence shows that clinical and molecular subtypes of prostate cancer (PCa) have specific risk factors. Observational studies suggest that physical activity may lower the risk of aggressive PCa. To our knowledge, the association between physical activity and PCa defined by TMPRSS2:ERG has not been evaluated. OBJECTIVE: To prospectively examine the association between physical activity and risk of PCa defined by clinical features and TMPRSS2:ERG. DESIGN, SETTING, AND PARTICIPANTS: We studied 49160 men aged 40-75 yr in the Health Professionals Follow-up Study from 1986 to 2012. Data was collected at baseline and every 2 yr with >90% follow-up. Total and vigorous physical activity were measured in metabolic equivalent of task (MET)-h/wk. OUTCOME MEASURES AND STATISTICAL ANALYSIS: Advanced PCa was defined as stage T3b, T4, N1, or M1 at diagnosis and lethal PCa as distant metastases or death due to disease over follow-up. Presence of TMPRSS2:ERG was estimated by immunohistochemistry of ERG protein expression. Cox proportional hazards models were used to obtain multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for incidence of subtype-specific PCa. RESULTS AND LIMITATIONS: During 26 yr of follow-up, 6411 developed PCa overall and 888 developed lethal disease. There were no significant associations between total physical activity and risk of PCa in the overall cohort. In multivariable-adjusted models, men in the highest quintile of vigorous activity had a significant 30% lower risk of advanced PCa (HR: 0.70, 95% CI: 0.53-0.92) and 25% lower risk of lethal PCa (HR: 0.75, 95% CI: 0.59-0.94) than men in the lowest quintile of vigorous activity. The association was independent of screening history. Vigorous activity was not associated with total PCa in the overall cohort but was inversely associated among highly screened men (top vs bottom quintile, HR: 0.83, 95% CI: 0.70-0.97). Of all cases, 945 were assayed for ERG (48% ERG-positive). Men with higher vigorous activity had a lower risk of ERG-positive PCa (top vs bottom quintile, HR: 0.71, 95% CI: 0.52-0.97). There was no significant association with the risk of ERG-negative disease (p heterogeneity=0.09). CONCLUSIONS: Our study confirms that vigorous physical activity is associated with lower risk of advanced and lethal PCa and provides novel evidence for a lower risk of TMPRSS2:ERG-positive disease. PATIENT SUMMARY: The identification of modifiable lifestyle factors for prevention of clinically important prostate cancer (PCa) is needed. In this report, we compared risk of PCa in men with different levels of physical activity. Men with higher vigorous activity had a lower risk of developing advanced and lethal PCa and PCa with the common TMPRSS2:ERG gene fusion.

A Prospective Study of Aspirin Use and Prostate Cancer Risk by TMPRSS2:ERG Status.

Background: In a case-control study, aspirin use was associated with a lower risk of a common prostate cancer molecular subtype, the TMPRSS2:ERG gene fusion. We sought to validate this finding in a prospective cohort.Methods: In the Health Professionals Follow-up Study, 49,395 men reported on aspirin use on biennial questionnaires and were followed for prostate cancer incidence over 23 years. TMPRSS2:ERG status was assessed by IHC for presence of ERG on archival tumor specimens for 912 patients with prostate cancer, of whom 48% were ERG-positive.Results: In multivariable models, we found no association between regular use of aspirin and risk of ERG-positive prostate cancer (HR, 1.02; 95% confidence interval, 0.85-1.23), nor any association with duration or frequency of aspirin use. In restricting to cases with either high Gleason grade or advanced stage disease, there remained no association with aspirin use.Conclusions: Data from this prospective study with repeated assessments of aspirin use do not support the hypothesis that aspirin use is associated with a lower risk of ERG-positive prostate cancer.Impact: Aspirin use is unlikely to lower the risk of this common molecular subtype of prostate cancer. However, there is emerging data supporting the role of other lifestyle and genetic factors underlying the development of the TMPRSS2:ERG fusion. Cancer Epidemiol Biomarkers Prev; 27(10); 1231-3. ©2018 AACR.

The Epidemiology of Prostate Cancer.

Prostate cancer is a major cause of disease and mortality among men, and each year 1.6 million men are diagnosed with and 366,000 men die of prostate cancer. In this review, we discuss the state of evidence for specific genetic, lifestyle, and dietary factors associated with prostate cancer risk. Given the biological heterogeneity of this cancer, we focus on risk factors for advanced or fatal prostate cancer. First, we provide descriptive epidemiology statistics and patterns for prostate cancer incidence and mortality around the world. This includes discussion of the impact of prostate-specific antigen screening on prostate cancer epidemiology. Next, we summarize evidence for selected risk factors for which there is strong or probable evidence of an association: genetics, obesity and weight change, physical activity, smoking, lycopene and tomatoes, fish, vitamin D and calcium, and statins. Finally, we highlight future directions for prostate cancer epidemiology research.

Height, Obesity, and the Risk of TMPRSS2:ERG-Defined Prostate Cancer.

Background: The largest molecular subtype of primary prostate cancer is defined by the TMPRSS2:ERG gene fusion. Few studies, however, have investigated etiologic differences by TMPRSS2:ERG status. Because the fusion is hormone-regulated and a man's hormonal milieu varies by height and obesity status, we hypothesized that both may be differentially associated with risk of TMPRSS2:ERG-defined disease.Methods: Our study included 49,372 men from the prospective Health Professionals Follow-up Study. Participants reported height and weight at baseline in 1986 and updated weight biennially thereafter through 2009. Tumor ERG protein expression (a TMPRSS2:ERG marker) was immunohistochemically assessed. We used multivariable competing risks models to calculate HRs and 95% confidence intervals (CIs) for the risk of ERG-positive and ERG-negative prostate cancer.Results: During 23 years of follow-up, we identified 5,847 incident prostate cancers, among which 913 were ERG-assayed. Taller height was associated with an increased risk of ERG-positive disease only [per 5 inches HR 1.24; 95% confidence interval (CI), 1.03-1.50; Pheterogeneity = 0.07]. Higher body mass index (BMI) at baseline (per 5 kg/m2 HR 0.75; 95% CI, 0.61-0.91; Pheterogeneity = 0.02) and updated BMI over time (per 5 kg/m2 HR 0.86; 95% CI, 0.74-1.00; Pheterogeneity = 0.07) were associated with a reduced risk of ERG-positive disease only.Conclusions: Our results indicate that anthropometrics may be uniquely associated with TMPRSS2:ERG-positive prostate cancer; taller height may be associated with greater risk, whereas obesity may be associated with lower risk.Impact: Our study provides strong rationale for further investigations of other prostate cancer risk factors that may be distinctly associated with subtypes. Cancer Epidemiol Biomarkers Prev; 27(2); 193-200. ©2017 AACR.

A Walking Intervention Among Men With Prostate Cancer: A Pilot Study.

BACKGROUND: Men diagnosed with prostate cancer have increased risk for disease progression, cardiovascular events, and impairments in quality of life. This pilot study evaluated the feasibility of a randomized walking group intervention to improve quality of life, circulating biomarkers, and morbidity among men with newly diagnosed prostate cancer. METHODS: Men were recruited at Örebro University Hospital, Sweden, and randomized to an 11-week walking group intervention (n = 21) or usual care (n = 20). The intervention included weekly 1-hour walking group sessions and maintenance of 10,000 steps/day. Outcomes were changes in body composition, clinical factors, biomarkers of cardiovascular health, and quality of life between baseline and end of study. Analysis of covariance was used to compare outcomes in each group adjusted for baseline values. RESULTS: All 41 men randomized completed the 11-week trial. Men assigned to the intervention walked on average 10,644 steps/day, and 92% reported missing 2 or fewer sessions. Both groups experienced similar weight loss at 11 weeks. Men in the intervention had a significant adjusted mean change in high-density lipoprotein of 0.14 mmol/L (95% confidence interval [CI], 0.01-0.27; P = .04), and suggestive adjusted mean changes in low-density lipoprotein of -0.22 mmol/L (95% CI, -0.47 to 0.03; P = .08) and in systolic blood pressure of -8.5 mm Hg (95% CI, -21.2 to 4.2; P = .18), compared with the usual care group. CONCLUSIONS: A walking group intervention among men with recent diagnosis of prostate cancer is feasible and potentially effective in improving cardiovascular health. A larger randomized trial of longer duration is required to elucidate its potential for improvement in longer term outcomes.