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Gleason score, a measure of prostate tumor differentiation, is the strongest predictor of lethal prostate cancer at the time of diagnosis. Metabolomic profiling of tumor and of patient serum could identify biomarkers of aggressive disease and lead to the development of a less-invasive assay to perform active surveillance monitoring. Metabolomic profiling of prostate tissue and serum samples was performed. Metabolite levels and metabolite sets were compared across Gleason scores. Machine learning algorithms were trained and tuned to predict transformation or differentiation status from metabolite data. A total of 135 metabolites were significantly different (Padjusted < 0.05) in tumor versus normal tissue, and pathway analysis identified one sugar metabolism pathway (Padjusted = 0.03). Machine learning identified profiles that predicted tumor versus normal tissue (AUC of 0.82 ± 0.08). In tumor tissue, 25 metabolites were associated with Gleason score (unadjusted P < 0.05), 4 increased in high grade while the remainder were enriched in low grade. While pyroglutamine and 1,5-anhydroglucitol were correlated (0.73 and 0.72, respectively) between tissue and serum from the same patient, no metabolites were consistently associated with Gleason score in serum. Previously reported as well as novel metabolites with differing abundance were identified across tumor tissue. However, a “metabolite signature” for Gleason score was not obtained. This may be due to study design and analytic challenges that future studies should consider. Implications: Metabolic profiling can distinguish benign and neoplastic tissues. A novel unsupervised machine learning method can be utilized to achieve this distinction.

We previously observed a positive association between seropositivity for the parasite Trichomonas vaginalis and risk of clinically significant prostate cancer at diagnosis. Here, we examined whether T. vaginalis seropositivity was associated with increased prostate cancer-specific or all-cause mortality among prostate cancer patients. We studied 736 men with prostate cancer from the Physicians' Health Study (PHS) and 749 men with prostate cancer from the Health Professionals Follow-Up Study (HPFS). We used Cox proportional hazards regression models to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of the association between T. vaginalis serostatus and progression to death from prostate cancer and from all causes. In PHS, 423 men died of any cause during a median follow-up of 13.8 years from the date of cancer diagnosis, among whom 131 died of prostate cancer. In HPFS, there were 287 deaths, including 77 deaths from prostate cancer, during a median follow-up of 12.8 years. We found no association between T. vaginalis serostatus and either prostate cancer mortality or all-cause mortality in either the PHS or HPFS. While previous studies suggest a possible role for T. vaginalis in the development of clinically significant prostate cancer, our findings do not support the hypothesis that T. vaginalis serostatus is associated with mortality among prostate cancer patients.

Purpose: Breast and prostate cancer co-occur in families, and women with a family history of prostate cancer are at increased breast cancer risk. Prostate cancer is among the most heritable cancers, but few studies have investigated its association with familial breast cancer. The objective of this study is to investigate the extent to which familial breast or prostate cancer in first-degree relatives increases prostate cancer risk. Experimental Design: A prospective study of 37,002 U.S. men in the Health Professionals Follow-up Study. During the 16-year follow-up to 2012, 4,208 total and 344 lethal cases were diagnosed. Using cause-specific hazards regression, we estimated the multivariable HRs and 95% confidence intervals (CI) for associations between familial breast or prostate cancer and total and lethal prostate cancer. Results: Those with familial breast cancer had a 21% greater risk of prostate cancer overall (95% CI, 1.10–1.34), and a 34% greater risk of lethal disease (HR 1.34; 95% CI, 0.96–1.89). Family history of prostate cancer alone was associated with a 68% increased risk of total disease (95% CI, 1.53–1.83) and a 72% increased risk of lethal disease (95% CI, 1.25–2.38). Men with a family history of both cancers were also at elevated risk. Conclusions: Our study found that men with a family history of breast or prostate cancer had elevated prostate cancer risks, including risk of lethal disease. These findings have translational relevance for cancer risk prediction in men.

Background: Although there are considerable racial and ethnic disparities in prostate cancer incidence and mortality in the United States and globally, clinical trials often do not reflect disease incidence across racial and ethnic subgroups. This study aims to comprehensively review the reporting of race and ethnicity data and the representation of race and ethnicity across prostate cancer treatment-, prevention-, and screening-based clinical trials. Methods: Seventy-two global phase III and IV prevention, screening, and treatment prostate cancer clinical trials with enrollment start dates between 1987 and 2016 were analyzed in this study, representing a total of 893,378 individual trial participants. Availability and representation of race and ethnicity data by trial funding type, temporal changes in the racial/ethnic diversity of participants, and geographic representation of countries were assessed. Results: Of the 72 trials analyzed, 59 (81.9%) had available race data, and 11 (15.3%) of these trials additionally reported ethnicity. Of the trials reporting data, participants were overwhelmingly white men (with the highest proportion in U.S. nonpublicly funded trials), comprising over 96% of the study population. The proportion of white participants in prostate cancer clinical trials has remained at over 80% since 1990. Geographically, Africa and the Caribbean were particularly underrepresented with only 3% of countries included. Conclusions: Trial participants continue to be majority white despite the known racial disparities in prostate cancer clinical outcomes. Impact: Current and future trials must use novel recruitment strategies to ensure enrollment of underrepresented men. Targeting the inclusion of African and Caribbean medical centers is crucial to achieve equity in representation.

Purpose: Gleason score strongly predicts prostate cancer mortality; however, scoring varies among pathologists, and many men are diagnosed with intermediate-risk Gleason score 7. We previously developed a 157-gene signature for Gleason score using a limited gene panel. Using a new whole-transcriptome expression dataset, we verified the previous signature's performance and developed a new Gleason signature to improve lethal outcome prediction among men with Gleason score 7. Experimental Design: We generated mRNA expression data from prostate tumor tissue from men in the Physicians' Health Study and Health Professionals Follow-Up Study (N = 404) using the Affymetrix Human Gene 1.0 ST microarray. The Prediction Analysis for Microarrays method was used to develop a signature to distinguish high (≥8) versus low (≤6) Gleason score. We evaluated the signature's ability to improve prediction of lethality among men with Gleason score 7, adjusting for 3 + 4/4 + 3 status, by quantifying the area under the receiver operating characteristic (ROC) curve (AUC). Results: We identified a 30-gene signature that best distinguished Gleason score ≤6 from ≥8. The AUC to predict lethal disease among Gleason score 7 men was 0.76 [95% confidence interval (CI), 0.67–0.84] compared with 0.68 (95% CI, 0.59–0.76) using 3 + 4/4 + 3 status alone (P = 0.0001). This signature was a nonsignificant (P = 0.09) improvement over our previous signature (AUC = 0.72). Conclusions: Our new 30-gene signature improved prediction of lethality among men with Gleason score 7. This signature can potentially become a useful prognostic tool for physicians to improve treatment decision making. Clin Cancer Res; 23(1); 81–87. ©2016 AACR. See related commentary by Yin et al., p. 6

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.

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.

To review and summarize evidence on the role of diet and lifestyle factors and prostate cancer progression, with a specific focus on habits after diagnosis and the risk of subsequent disease recurrence, progression, or death.Given the well-documented heterogeneity of prostate cancer and the long survivorship of the majority of diagnoses, our goal was to summarize and describe modifiable risk factors for clinically relevant prostate cancer. We focused where possible on epidemiologic studies of post-diagnostic habits and prostate cancer progression, defined as recurrence (e.g., PSA risk, secondary treatment), metastasis, or death. Where data were limited, we also describe evidence on risk factors and indicators of prostate cancer aggressiveness at diagnosis.A variety of dietary and lifestyle factors appear to affect prostate cancer progression. Several generally widely recommended lifestyle factors such as not smoking, maintaining a healthy body weight, and regular vigorous physical exercise also appear to affect prostate cancer progression. Several dietary factors, such as tomato sauce/lycopene, cruciferous vegetables, healthy sources of vegetable fats, and coffee, may also have a role in reducing risk of prostate cancer progression.Diet and lifestyle factors, in particular exercise and smoking cessation, may reduce the risk of prostate cancer progression and death. These promising findings warrant further investigation, as their overall impact might be large.

Background: Epidemiologic studies and secondary analyses of randomized trials supported the hypothesis that selenium and vitamin E lower prostate cancer risk. However, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed no benefit of either supplement. Genetic variants involved in selenium or vitamin E metabolism or transport may underlie the complex associations of selenium and vitamin E. Methods: We undertook a case–cohort study of SELECT participants randomized to placebo, selenium, or vitamin E. The subcohort included 1,434 men; our primary outcome was high-grade prostate cancer (N = 278 cases, Gleason 7 or higher cancer). We used weighted Cox regression to examine the association between SNPs and high-grade prostate cancer risk. To assess effect modification, we created interaction terms between randomization arm and genotype and calculated log likelihood statistics. Results: We noted statistically significant (P < 0.05) interactions between selenium assignment, SNPs in CAT, SOD2, PRDX6, SOD3, and TXNRD2, and high-grade prostate cancer risk. Statistically significant SNPs that modified the association of vitamin E assignment and high-grade prostate cancer included SEC14L2, SOD1, and TTPA. In the placebo arm, several SNPs, hypothesized to interact with supplement assignment and risk of high-grade prostate cancer, were also directly associated with outcome. Conclusion: Variants in selenium and vitamin E metabolism/transport genes may influence risk of overall and high-grade prostate cancer, and may modify an individual man's response to vitamin E or selenium supplementation with regards to these risks. Impact: The effect of selenium or vitamin E supplementation on high-grade prostate cancer risk may vary by genotype. Cancer Epidemiol Biomarkers Prev; 25(7); 1050–8. ©2016 AACR.

Circulating insulin-like growth factor-1 (IGF-1) is consistently associated with prostate cancer risk. IGF-1 binds to IGF-1 receptor (IGF1R) and insulin receptor (IR), activating cancer hallmark pathways. Experimental evidence suggests that TMPRSS2:ERG may interact with IGF/insulin signaling to influence progression. We investigated IGF1R and IR expression and its association with lethal prostate cancer among 769 men. Protein expression of IGF1R, IR and ERG (i.e. a surrogate of ERG fusion genes) were assayed by immunohistochemistry. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI) adjusted for clinical characteristics. Among patients, 29% had strong tumor IGF1R expression and 10% had strong IR expression. During a mean follow-up of 13.2 years through 2012, 80 men (11%) developed lethal disease. Tumors with strong IGF1R or IR expression showed increased cell proliferation, decreased apoptosis and a higher prevalence of ERG. In multivariable models, strong IGF1R was associated with a borderline increased risk of lethal prostate cancer (HR 1.7; 95% CI 0.9-3.1). The association appeared greater in ERG-positive tumors (HR 2.8; 95% CI 0.9-8.4) than in ERG-negative tumors (HR 1.3; 95% CI 0.6-3.0, p-heterogeneity 0.08). There was no association between IR and lethal prostate cancer (HR 0.8; 95% CI 0.4-1.9). These results suggest that tumor IGF1R expression may play a role in prostate cancer progression to a lethal phenotype and that ERG-positive tumors may be more sensitive to IGF signaling. These data may improve our understanding of IGF signaling in prostate cancer and suggest therapeutic options for disease subtypes.

INTRODUCTION AND OBJECTIVES: There is increasing evidence that a baseline PSA during mid-life can predict future development of lethal prostate cancer. We determined baseline PSA levels for US men aged 40 to 60 years in a nationally representative cohort and studied the influence of race, BMI, and waist circumference on median PSA levels among men without diagnosed prostate cancer. METHODS: We leveraged data from the National Health and Nutrition Examination Survey (NHANES), a set of studies that gathers lifestyle and nutrition information, and includes in person clinical assessments and biomarker measures. The study was nested among men with PSA measured between 2001-2010. Those with current infection or prostate inflammation, rectal exam in the past week, prostate biopsy or cystoscopy in the past month, or with a history of prostate cancer were excluded from PSA testing. We constructed a multivariable linear regression model to determine associations between age, body mass index (BMI), waist circumference, race, and log-transformed total PSA. RESULTS: There were 3,972 men aged 40 to 60 with PSA measured, of whom 49% were white, 20% black and 19% MexicanAmerican. Median total PSA levels by race, BMI and waist circumference are outlined in the table. In multivariable models, older age was positively associated with PSA levels. Moreover, PSA levels were higher among men of African-American and Mexican-American ancestry, compared to non-Hispanic white ancestry. In contrast, men with higher BMI or greater waist circumference had lower total PSA levels, adjusting for age and race. CONCLUSIONS: This study is among the first to report racial differences in PSA levels among men in midlife, and showing higher levels among African-American, and Mexican-American men. Conversely, BMI and waist circumference were inversely associated with PSA levels, and these associations were independent of race or age.

Introduction: There are considerable differences in prostate cancer rates among white, black and Asian men, yet the underlying reasons for these differences are unknown. Our objectives were to study the association between race/ethnicity and prostate cancer risk, including aggressive cancer, accounting for differences in lifestyle factors and screening in a socioeconomically homogeneous population of US men. Materials and Methods: We conducted a prospective analysis using the Health Professionals Follow-up study (HPFS), a prospective cohort of 46,108 men that began in 1986 with follow-up through 2012. These men were followed-up through biennial questionnaires that collected lifestyle, medical history and demographic data. After 26 years of follow up, 6,072 new cases of prostate cancer were identified. We used Cox proportional hazards models to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the association between race/ethnicity and prostate cancer risk adjusting for potential confounders and PSA screening history. Results: At baseline in 1986, there were 44,795 Caucasian men, 470 black men and 834 Asian men. Black men had a significantly higher risk of overall prostate cancer (HR=1.38, 95% CI= 1.10 to 1.72) while Asian men had a lower risk (HR=0.73, 95% CI=0.58 to 0.92) compared to white men. These associations were independent of PSA testing history and family history. There was a suggestion of an increased risk of lethal and high-Gleason grade disease for both black (Lethal: HR=1.24, 95% CI= 0.68 to 2.28; High-grade: HR=1.12, 95% CI=0.58 to 2.18) and Asian men (Lethal: HR=1.29, 95% CI=0.75 to 2.23; High-grade: HR=1.43, 95% CI=0.86 to 2.37), compared to Caucasian men, despite the lower risk for overall prostate cancer among Asians. The positive associations with lethal cancer were even more striking in the era before PSA screening was common (before 1994). Conclusion: The increased incidence of prostate cancer overall among black men and reduced incidence in Asian men cannot be explained by differences in PSA testing, family history or other lifestyle factors. Citation Format: Nadine M. Hamieh, Sarah Markt, Sam Peisch, Edward Giovannucci, Kathryn Wilson, Lorelei Mucci. Does prostate cancer risk vary by race after accounting for lifestyle factors in the Health Professionals Follow-up Study. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B72.

Purpose: To assess the role of genetic and epidemiological risk factors in explaining racial disparities in prostate cancer incidence and mortality. Background: Black men are 1.6 times more likely to be diagnosed and 2.4 times more likely to die of prostate cancer than white men. An adequate explanation for these disparities remains elusive, as they have been shown to persist in equal care and equal access settings. Our group has previously shown associations between exposures of smoking, physical activity, body mass index (BMI) vitamin D level, coffee, lycopene, and genetic factors and risk of prostate cancer, particularly for lethal disease. We hypothesized that differences in the prevalence of these risk factors could explain a substantial proportion of the racial disparity in incident and lethal prostate cancer. Study Population: Our study utilized data on risk factor prevalence from the Health-Professionals Follow-Up Study (HPFS, N=51,529 men, 1986-2012) and the National Health and Nutrition Examination Study (NHANES III, 1988-1994), a nationally representative program of studies that gathers lifestyle and nutrition information. We used established relative risk estimates from the HPFS for the prostate cancer risk factors. Methods: To estimate the prostate cancer burden associated with these exposures, we calculated the population attributable fraction (PAF) for each risk factor by race. PAF can be defined as the reduction in incidence that would be achieved if the population had been entirely unexposed, compared with the current exposure pattern. We assumed that the risk ratio was the same among whites and blacks. To calculate the PAF, we used the prevalence of the exposure (risk factor) from the HPFS and NHANES III and crude and confounder-adjusted risk ratios from studies conducted in the HPFS cohort for each exposure and risk of lethal prostate cancer. We then calculated the difference in attributable risk between each race to estimate the reduction in lethal prostate cancer if black men had the same prevalence of risk factors as white men. Results: There were notable differences in risk factor prevalence by race. For example, black men had significantly lower levels of vitamin D, were less likely to drink coffee, and had a higher prevalence of obesity and smoking. The prevalence of several genetic loci for prostate cancer were also higher among black men. We estimated that if black men had the same prevalence of risk factors as white men, the percent reduction in prostate mortality was 18% for Vitamin D, 7% for obesity, 6% for genetic factors, 4% for coffee, 4% for current smoking, and 1% for lycopene. Conclusions: Certain lifestyle, dietary, and genetic factors are potentially responsible for a substantial proportion of the racial disparity in prostate cancer incidence and mortality. This important finding warrants further research and validation in additional cohorts, as our findings go beyond merely re-confirming that a racial disparity in prostate cancer persists: it suggests a strong underlying role for risk factors that could be addressed through prevention. The authors accept sole responsibility for all statements made in this abstract. Citation Format: Sam F. Peisch, Travis Gerke, Kathryn M. Wilson, Edward L. Giovannucci, Lisa B. Signorello, Lorelei A. Mucci. Racial disparities in prostate cancer: Estimating the role of diet, lifestyle, and genetic factors among African-American and Caucasian-American men. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A29.