Risk Of Lethal Prostate Cancer Research Articles

Abstract 2207: Fiber intake and risk of lethal prostate cancer among men at increased genetic risk

Abstract Introduction High fiber intake from grains may lower advanced prostate cancer risk by enhancing insulin sensitivity, lowering insulin-like growth factor 1 and systemic inflammation. Whether a high-fiber diet can lower risk of metastatic disease and prostate cancer death in men at high genetic risk is unclear. Methods Using a new 400-SNP polygenic risk score (PRS) for prostate cancer, we quantified the genetic risk of 10,269 men with available genotype data in the Health Professionals Follow-up Study, followed between 1993 and 2019. Men in the top 50-100% PRS category were considered high-risk and included for analysis. Total fiber intake and different sources (cereal, fruits, vegetables) were assessed by validated food frequency questionnaires. Overall and lethal prostate cancer (metastatic disease/prostate cancer death) were analyzed using Cox proportional hazards models estimating hazard ratios (HRs) and 95% confidence intervals (CIs). Results During 26 years of follow-up, we recorded 1,494 overall and 174 lethal prostate cancer events in the high genetic risk group. As expected, no associations were observed fiber intake with risk of overall prostate cancer. For lethal prostate cancer, the results varied according to the source of fiber. Higher cereal fiber intake was associated with a lower risk of lethal prostate cancer (per 3 g/d higher intake: 0.81 [0.68, 0.97], P-trend=0.02). We further observed a higher disease risk among men with higher fruit fiber intake (per 3g/d higher intake: 1.18 [1.02, 1.36], P-trend=0.03). The associations remained similar when mutually adjusted for each fiber type. No associations were observed for total or vegetable fiber intake. Conclusion In this analysis of men at high prostate cancer genetic risk, we observed that higher cereal fiber intake was associated with lower lethal prostate cancer risk, whereas higher fruit fiber intake showed an opposite trend. Further studies in different populations and investigations into the underlying mechanisms are needed. Fiber intake with risk of overall and lethal prostate cancer among men at high genetic risk. Fiber type Overall prostate cancer: No.event/PY Overall prostate cancer: HR (95% CI) Lethal prostate cancer: No.event/PY Lethal prostate cancer: HR (95% CI) All fiber, g/d T1, median=15.8 490/66047 ref. 42/73826 ref. T2, median=21.8 484/62237 0.96 (0.83-1.11) 61/69849 1.16 (0.77-1.75) T3, median=29.9 520/67374 1.02 (0.86-1.21) 71/75242 1.24 (0.75-2.05) Per 3 g/d 0.98 (0.96-1.01) 1.00 (0.92-1.08) P for trend 0.27 0.93 Cereal fiber, g/d T1, median=4.6 491/63911 ref. 49/72367 ref. T2, median=6.7 512/66251 1.04 (0.91-1.20) 76/73384 1.30 (0.90-1.87) T3, median=9.4 491/65496 0.92 (0.80-1.06) 49/73166 0.75 (0.50-1.12) Per 3 g/d 0.96 (0.90-1.01) 0.81 (0.68-0.97) P for trend 0.14 0.02 Fruit fiber, g/d T1, median=2.5 471/66306 ref. 33/74056 ref. T2, median=4.5 514/63268 1.06 (0.92-1.22) 51/70430 1.21 (0.76-1.91) T3, median=7.2 509/66085 1.00 (0.86-1.16) 90/74431 1.84 (1.18-2.87) Per 3 g/d 0.97 (0.91-1.03) 1.18 (1.02-1.36) P for trend 0.34 0.03 Vegetable fiber, g/d T1, median=4.8 481/64139 ref. 51/71594 ref. T2, median=6.9 505/64938 1.04 (0.91-1.20) 66/72291 1.22 (0.84-1.78) T3, median=9.6 508/66581 1.04 (0.90-1.20) 57/75031 0.98 (0.65-1.45) Per 3 g/d 0.99 (0.93-1.05) 0.97 (0.82-1.15) P for trend 0.72 0.74 Citation Format: Yiwen Zhang, Konrad H. Stopsack, Lorelei A. Mucci, Edward Giovannucci, Anna Plym. Fiber intake and risk of lethal prostate cancer among men at increased genetic risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2207.

Multivitamin use after diagnosis and prostate cancer survival among men with nonmetastatic prostate cancer.

Multivitamin use is common among cancer patients. Whether post-diagnostic multivitamin supplementation is beneficial for prostate cancer survival is largely unknown, and some evidence even suggests potential harm. We prospectively assessed post-diagnostic multivitamin use in relation to prostate cancer survival among 4756 men with nonmetastatic prostate cancer at diagnosis in the Health Professionals Follow-up Study (1986-2016). Cox regression models were used to evaluate the association between post-diagnostic multivitamin use and frequency and risk of lethal prostate cancer (distant metastases or prostate cancer-specific death) and all-cause mortality. We observed 438 lethal prostate cancer and 2609 deaths during a median follow-up of 11 years. Compared to non-users, post-diagnostic multivitamin use was not associated with risk of lethal prostate cancer (HR [95% CI], 0.98 [0.74-1.30]) or all-cause mortality (1.00 [0.88-1.12]), after adjustment for potential confounders. Similarly, null associations were observed across various categories of use frequency. Compared to non-users, men who used multivitamins regularly (6-9 tablets/week) after cancer diagnosis had similar risk of lethal prostate cancer (0.96 [0.72-1.28]) and all-cause mortality (0.99 [0.88-1.12]). We found no evidence that post-diagnostic multivitamin use among men with nonmetastatic prostate cancer was associated with better or worse survival in a well-nourished population.

Healthy dietary patterns and risk of prostate cancer in men at high genetic risk.

Prostate cancer has high heritability. Healthy lifestyle has been associated with lower lethal prostate cancer risk among men at increased genetic susceptibility, but the role of healthy dietary patterns remains unknown. We prospectively followed 10,269 genotyped men in the Health Professionals Follow-up Study (1993-2019). Genetic risk was quantified using an established polygenic risk score (PRS). Five dietary patterns were investigated: healthy eating index, Mediterranean, diabetes risk-reducing, hyperinsulinemic and inflammatory diet. Overall and lethal prostate cancer rates (metastatic disease/prostate cancer-specific death) were analyzed using multivariable Cox proportional hazards models. During 26 years of follow-up, 2133 overall and 253 lethal prostate cancer events were documented. In the highest PRS quartile, higher adherence to a diabetes risk-reducing diet was associated with lower rates of overall (top vs. bottom quintile HR [95% CI], 0.74 [0.58-0.94]) and lethal prostate cancer (0.43 [0.21-0.88]). A low insulinemic diet was associated with similar lower rates (overall, 0.76 [0.60-0.95]; lethal, 0.46 [0.23-0.94]). Other dietary patterns showed weaker, but similar associations. In the highest PRS quartile, men with healthy lifestyles based on body weight, physical activity, and low insulinemic diet had a substantially lower rate (0.26 [0.13-0.49]) of lethal prostate cancer compared with men with unhealthy lifestyles, translating to a lifetime risk of 3.4% (95% CI, 2.3%-5.0%) among those with healthy lifestyles and 9.5% (5.3%-16.7%) among those with unhealthy lifestyles. Our findings indicate that lifestyle modifications lowering insulin resistance and chronic hyperinsulinemia could be relevant in preventing aggressive prostate cancer among men genetically predisposed to prostate cancer.

Association of neighborhood gentrification with prostate cancer and immune markers in African American and European American men.

Prior studies showed that neighborhood deprivation increases the risk of lethal prostate cancer. However, the role of neighborhood gentrification in prostate cancer development and outcome remains poorly understood. We examined the relationships of gentrification with prostate cancer and serum proteome-defined inflammation and immune function in a diverse cohort. The case-control study included 769 cases [405 African American (AA), 364 European American (EA) men] and 1023 controls (479 AA and 544 EA), with 219 all-cause and 59 prostate cancer-specific deaths among cases. Geocodes were linked to a neighborhood gentrification index (NGI) derived from US Census data. Cox and logistic regression, and MANOVA, were used to determine associations between NGI, as continuous or quintiles (Q), and outcomes. Adjusting for individual socioeconomic status (SES), continuous NGI was positively associated with prostate cancer among all men (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.01-1.14). AA and low-income men experienced the highest odds of prostate cancer when residing in tracts with moderate gentrification, whereas EA men experienced reduced odds of regional/metastatic cancer with increased gentrification in SES-adjusted analyses. Continuous NGI also associated with mortality among men presenting with localized disease and low-income men in SES-adjusted Cox regression analyses. NGI was not associated with serum proteome-defined chemotaxis, inflammation, and tumor immunity suppression. Findings show that neighborhood gentrification associates with prostate cancer and mortality in this diverse population albeit associations were heterogenous within subgroups. The observations suggest that changing neighborhood socioeconomic environments may affect prostate cancer risk and outcome, likely through multifactorial mechanisms.

Gut Microbiome and Risk of Lethal Prostate Cancer: Beyond the Boundaries

The gut microbiome is critical in balancing human health and in influencing the risk of several chronic diseases, including cancer [...]

Abstract B088: Association of neighborhood gentrification with prostate cancer in African American and European American men

Abstract Abstract Background: Prior studies showed that neighborhood deprivation increases the risk of lethal prostate cancer. However, the role of neighborhood gentrification in prostate cancer development and outcome remains poorly understood. We examined the relationships of gentrification with prostate cancer in a diverse cohort. Methods: This case-control study included 769 cases [405 African American (AA), 364 European American (EA) men] and 1023 controls (479 AA, 544 EA), with 219 all-cause and 59 prostate cancer-specific deaths among cases. Geocodes were linked to a neighborhood gentrification index (NGI) derived from US Census data. Cox and logistic regression were used to determine associations between NGI, as continuous or quintiles (Q), and outcomes. Results: Adjusting for individual socioeconomic status (SES), continuous NGI was associated with prostate cancer among all men (odds ratio (OR) 1.07, 95%CI 1.01-1.14). AA experienced the highest odds of prostate cancer when residing in tracts with moderate gentrification (Q3 OR 1.79, 95%CI 1.11-2.88). However, EA men experienced a reduced risk of regional/metastatic cancer (risk ratio 0.62, 95%CI 0.40-0.97) with increased gentrification, adjusting for SES. Continuous NGI was associated with mortality among men presenting with localized disease (all-cause HR 1.10, 95%CI 1.01-1.20; disease-specific SHR 1.16, 95%CI: 1.01-1.33). Conclusions: Findings show that neighborhood gentrification modestly associates with prostate cancer and mortality in this diverse population. They suggest that changing neighborhood socioeconomic environments may affect prostate cancer risk and outcome, likely through multifactorial mechanisms. Citation Format: Catherine M. Pichardo, Adaora Ezeani, Margaret Pichardo, Tanya Agurs-Collins, Tiffany M. Powell-Wiley, Brid Ryan, Tsion Minas, Maeve Bailey-Whyte, Wei Tang, Tiffany H. Dorsey, William Wooten, Christopher A. Loffredo. Association of neighborhood gentrification with prostate cancer in African American and European American men [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B088.

Hyperinsulinemia and risk of lethal prostate cancer.

e17008 Background: Epidemiologic studies have found that insulin-like growth factor (IGF)-1 causally increases prostate cancer incidence and mortality, but the effect of insulin is less clear. IGF-1 and insulin act as mitogens by binding non-selectively to their receptors. To this end, this study tests the hypothesis that high circulating insulin increases risk for lethal (fatal or metastatic) prostate cancer among men with non-metastatic prostate cancer. Methods: The study population was drawn from two U.S.-based longitudinal cohorts: the Health Professionals Follow-Up Study (HPFS) of 51,529 health professionals and the Physicians’ Health Study (PHS) of 29,067 physicians. Pre-diagnostic plasma concentration of C-peptide was used as a proxy for insulin and measured on blood collected in 1993-1995 (HPFS) or 1982 (PHS) and stratified into quartiles for analysis. The empiric lifestyle index (based on body mass index (BMI), physical activity, and diet) for hyperinsulinemia (ELIH) was calculated from questionnaire data. Covariates of interest (age and fasting status at blood draw, BMI, height, clinical stage, and tumor grade) were attained from questionnaires and medical records. We followed patients for development of metastasis or death (lethal) through 2019 (HPFS) and 2015 (PHS). SAS 9.4 and R Studio were used for analyses. Chi-squared tests and Mann Whitney U tests were used to compare differences between groups, and Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% CI. Results: The sample included 2,812 men with 353 lethal prostate cancer events and a mean follow-up of 164 months from diagnosis to death. The mean time from blood draw to cancer diagnosis was 8.1 years. Compared to men with non-lethal prostate cancer, those with lethal disease had significantly more severe clinical grade and stage at diagnosis, higher BMI (25.1 vs 24.6), older age at blood draw (64.5 vs 61.9 years), and higher ELIH index. There were no differences by other covariates. There was no association between pre-diagnostic c-peptide levels and cancer-specific survival in a multivariable model that included clinical stage and grade (HR, 95% CI for high vs. low quartiles: 1.17, 0.83, 1.67). High ELIH was positively associated with risk of lethal prostate cancer (HR, 95% CI: 2.41, 1.36, 4.28), even when controlling for C-peptide (HR, 95% CI: 2.18, 1.20, 3.96). Conclusions: C-peptide levels measured prior to cancer diagnosis were not associated with increased mortality from prostate cancer. Higher ELIH was associated with increased risk of lethal prostate cancer among those diagnosed with prostate cancer, which could be partly mediated by hyperinsulinemia, but other dietary, physical activity, or BMI mechanisms could contribute.

Racial Disparities in Prostate Cancer Mortality Rates Partially Explained By Differences in Dietary and Lifestyle Factors

Introduction: Black individuals have 2.1 times higher prostate cancer mortality rates than White individuals in the United States. Several dietary and lifestyle factors may influence the risk of lethal prostate cancer. This study evaluated to what extent differences in the prevalence of these modifiable risk factors by race could explain racial disparities in prostate cancer mortality. Methods: We compared the prevalence of seven potentially modifiable risk factors for lethal prostate cancer among Black and White individuals, using the National Health and Nutrition Examination Study at two time points (1988–1994; 2017–2018). Relative risks for lethal prostate cancer were estimated in the Health Professionals Follow-up Study. We calculated the population attributable fraction (PAF) for each factor by self-identified race, defined as the reduction in mortality that would be achieved if the population had been entirely unexposed, compared with the current exposure pattern. We also calculated the difference in the PAF between Black and White individuals, assuming causality of risk factors and no multiplicative effect measure modification by race. Results: Based on data from NHANES III (1988–1994), the largest prevalence differences between Black and White individuals were for vitamin D deficiency, current smoking, and coffee, respectively. Elimination of these risk factors among Black individuals could have led to a larger reduction in lethal prostate cancer in comparison to eliminating these same risk factors among White individuals. Given the prevalence of these risk factors in 2017–2018, current interventions on vitamin D deficiency, current smoking, and coffee could influence future PAF differences for lethal prostate cancer mortality among Black individuals compared to White individuals. Conclusions: Differences in the prevalence of some modifiable lifestyle and dietary factors are potentially responsible for a portion of the racial disparity in prostate cancer mortality.

Re: WHO Classification of Tumours, 5th Edition, Volume 8: Urinary and Male Genital Tumours

Prostate-specific antigen (PSA) levels in midlife are strongly associated with the long-term risk of lethal prostate cancer in cohorts not subject to screening. This is the first study evaluating the association between PSA levels drawn as part of routine medical care in the Norwegian population and prostate cancer incidence and mortality.To determine the association between midlife PSA levels <4.0 ng/ml, drawn as part of routine medical care, and long-term risk of prostate cancer death.The Norwegian Prostate Cancer Consortium collected >8 million PSA results from >1 million Norwegian males ≥40 yr of age. We studied 176 099 men (predefined age strata: 40–54 and 55–69 yr) without a prior prostate cancer diagnosis who had a nonelevated baseline PSA level (<4.0 ng/ml) between January 1, 1995 and December 31, 2005.Baseline PSA.We assessed the 16-yr risk of prostate cancer mortality. We calculated the discrimination (C-index) between predefined PSA strata (<0.5, 0.5–0.9, 1.0–1.9, 2.0–2.9, and 3.0–3.9 ng/ml) and subsequent prostate cancer death. Survival curves were plotted using the Kaplan-Meier method.The median follow-up time of men who did not get prostate cancer was 17.9 yr. Overall, 84% of men had a baseline PSA level of <2.0 ng/ml and 1346 men died from prostate cancer, with 712 deaths (53%) occurring in the 16% of men with the highest baseline PSA of 2.0–3.9 ng/ml. Baseline PSA levels were associated with prostate cancer mortality (C-index 0.72 for both age groups, 40–54 and 55–69 yr). The fact that the reason for any given PSA measurement remains unknown represents a limitation.We replicated prior studies that baseline PSA at age 40–69 yr can be used to stratify a man's risk of dying from prostate cancer within the next 15–20 yr.A prostate-specific antigen level obtained as part of routine medical care is strongly associated with a man’s risk of dying from prostate cancer in the next two decades.

Baseline Serum Prostate-specific Antigen Value Predicts the Risk of Subsequent Prostate Cancer Death—Results from the Norwegian Prostate Cancer Consortium

Background and objectiveProstate-specific antigen (PSA) levels in midlife are strongly associated with the long-term risk of lethal prostate cancer in cohorts not subject to screening. This is the first study evaluating the association between PSA levels drawn as part of routine medical care in the Norwegian population and prostate cancer incidence and mortality. The objective of the study was to determine the association between midlife PSA levels <4.0 ng/ml, drawn aspart of routine medical care, and long-term risk of prostate cancer death. MethodsThe Norwegian Prostate Cancer Consortium collected >8 million PSA results from >1 million Norwegian males (more than or equal to) 40 yr of age. We studied 176 099 men (predefined age strata: 40–54 and 55–69 yr) without a prior prostate cancer diagnosis who had a nonelevated baseline PSA level (<4.0 ng/ml) between January 1,1995 and December 31, 2005. We assessed the 16-yr risk of prostate cancer mortality. We calculated the discrimination (C-index) between predefined PSA strata (<0.5, 0.5–0.9, 1.0–1.9, 2.0–2.9, and 3.0–3.9 ng/ml) and subsequent prostate cancer death. Survival curves were plotted using the Kaplan-Meier method. Key findings and limitationsThe median follow-up time of men who did not get prostate cancer was 17.9 yr. Overall, 84% of men had a baseline PSA level of <2.0 ng/ml and 1346 men died from prostate cancer, with 712 deaths (53%) occurring in the 16% of men with the highest baseline PSA of 2.0–3.9 ng/ml. Baseline PSA levels were associated with prostate cancer mortality (C-index 0.72 for both age groups, 40–54 and 55–69 yr). The fact that the reason for any given PSA measurement remains unknown represents a limitation. Conclusions and clinical implicationsWe replicated prior studies that baseline PSA at age 40–69 yr can be used to stratify a man’s risk of dying from prostate cancer within the next 15–20 yr. Patient summaryA prostate-specific antigen level obtained as part of routine medical care is strongly associated with a man’s risk of dying from prostate cancer in the next two decades.

MP44-15 THE VALUE OF PROSTATE-SPECIFIC ANTIGEN DENSITY IN LONG-TERM PROSTATE CANCER-MORTALITY RISK PREDICTION

You have accessJournal of UrologyCME1 Apr 2023MP44-15 THE VALUE OF PROSTATE-SPECIFIC ANTIGEN DENSITY IN LONG-TERM PROSTATE CANCER-MORTALITY RISK PREDICTION Sara Yousef Yacoub, Per-Olof Lundgren, Anders Kjellman, and Ove Gustafsson Sara Yousef YacoubSara Yousef Yacoub More articles by this author , Per-Olof LundgrenPer-Olof Lundgren More articles by this author , Anders KjellmanAnders Kjellman More articles by this author , and Ove GustafssonOve Gustafsson More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003290.15AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: PSA density (PSAD) is used to distinguish elevated serum levels of PSA due to benign prostatic hyperplasia (BPH) from high serum levels caused by malignant disease. Several studies have demonstrated an association between high PSAD and risk for both biochemical recurrences after treatment with curative intent, as well as the risk for upstaging after prostatectomy after an initial strategy of active monitoring. In this study, our objective was to examine whether a baseline metric of PSAD is associated with prostate cancer-specific mortality after thirty years of follow-up. METHODS: In the late nineteen eighties, 2400 men between the ages of 55 and 70 were randomly sampled from a background population of about 27 000 men in the same age group living in a defined part of Stockholm, Sweden. 1779 men accepted the invitation for the study. The sampled cohort was invited to undergo screening for prostate cancer with a PSA test, digital rectal exam, and ultrasound of the prostate. PSAD was calculated for each patient. Outcomes, ie prostate cancer-specific mortality were extracted from the Swedish national cause of death registry. Hazard ratios for cancer-specific deaths were estimated using a Cox proportional hazard regression model. The area under the receiver operating curve (AUC) was determined using conditional logistic regression for men with a baseline PSA of 3.0 or more. RESULTS: PSAD was available for 1748 men. Median PSAD was 0.095 ng/mL/cm3 (IQR 0.073-0.14). The age-adjusted hazard ratio for lethal prostate cancer in the cohort of men with PSA>3.0 ng/mL was 3.5 (95% CI 2.5-4.9) per unit increase in PSAD. 463 men had a PSA of 3.0 ng/mL or more; in this cohort, there were 50 deaths attributed to prostate cancer. All 50 men who died from prostate cancer had a PSAD above the median at baseline. A model including PSAD, palpation, and ultrasound findings could distinguish lethal prostate cancer from non-cases at 30 years of follow-up with an AUC of 0.78. CONCLUSIONS: Several risk stratification models or tools have been evaluated to predict high-grade prostate cancer. If the endpoint of high-grade cancer is substituted with cancer-specific mortality a simple measure of PSA density performs similarly. For men with PSA in the gray area, PSAD predicts the lifelong risk for lethal prostate cancer. Limitations to this study include the lack of clinical data during follow-up, e.g not all nonlethal cancers are indolent which should be acknowledged when interpreting the results. Source of Funding: Grafströms foundation for urological research © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e617 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sara Yousef Yacoub More articles by this author Per-Olof Lundgren More articles by this author Anders Kjellman More articles by this author Ove Gustafsson More articles by this author Expand All Advertisement PDF downloadLoading ...

Abstract P011: Clonal hematopoiesis and risk of lethal prostate cancer: a prospective cohort study with long-term follow-up

Abstract Background: Clonal hematopoiesis (CH), the presence of acquired mutations in leukemia driver genes, promotes systemic inflammation and is common among aging men. Prostate cancer, a subset of which is lethal, also develops in aging men. We hypothesized that CH contributes to development of lethal prostate cancer. Methods: We conducted nested case-cohort studies for metastatic prostate cancer and prostate cancer-specific death (lethal prostate cancer) within the prospective Health Professionals Follow-up Study. First, we followed 1155 men free of prostate cancer and cardiovascular disease at blood draw (1993-1995) for development of lethal prostate cancer over up to 26 years. Second, we followed 532 men with incident non-metastatic prostate cancer for development of lethal prostate cancer. We sequenced blood DNA from 1488 participants for putative CH driver mutations in the 9 most common CH-defining genes with a custom targeted panel (VariantPlex, Invitae, Inc.) at ultra-high depth (mean, 18,000x), employing unique molecular identifiers for error correction. CH variant calling used a novel ensemble calling approach, ArCCH, validated with in-silico tumor dilutions and blinded technical replicates, which had high accuracy for variant allele frequencies (VAFs) as low as 0.1%. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) in proportional hazards regression with Prentice case-cohort weights. Results: In a random sample of 968 men initially free of prostate cancer and cardiovascular disease (median age at blood draw 60 years, interquartile range 52 to 67), 80% of men had CH at a variant allele frequency (VAF) of &amp;gt;0.1%, 15% had VAFs &amp;gt;2%, and 3% had VAFs &amp;gt;10%; 75% of men had variants in epigenetic modifier genes (DNMT3A, TET2, ASXL1), and 21% had variants in DNA repair genes (PPM1D, TP53, CHEK2). CH burden was strongly age-associated, with approximately one additional CH variant per decade of age at blood draw (mean difference 1.07 variants, 95% CI 0.93 to 1.21). Among men initially free from prostate cancer, after adjusting for age at blood draw, CH clones between 0.1% and 10% VAF were not related to lethal prostate cancer (206 events total; HR 0.93, 95% CI 0.49-1.76 for VAFs 2-10% vs. no variants detected at &amp;gt;0.1% VAF). Results for epigenetic modifiers and DNA repair genes were similar. While inconclusive, data were compatible with positive associations among younger men (&amp;lt; 65 years) or for VAFs &amp;gt;10%. Among men initially diagnosed with non-metastatic prostate cancer, results were similarly null for progression to lethal prostate cancer (164 events). Conclusions: This large prospective study with long-term follow-up suggests that low-level CH is unlikely a major contributor to and not well suited for early detection of lethal prostate cancer. Citation Format: Konrad H. Stopsack, Irenaeus C. Chan, Evelyn Schmidt, Alex Panchot, Samantha McNulty, Nicole A. Schreiber, Yiwen Zhang, Kathryn L. Penney, Michael F. Berger, Luis A. Diaz, Ross L. Levine, Kelly L. Bolton, Lorelei A. Mucci, Philip W. Kantoff. Clonal hematopoiesis and risk of lethal prostate cancer: a prospective cohort study with long-term follow-up. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P011.

Post-diagnostic Zinc Supplement Use and Prostate Cancer Survival Among Men With Nonmetastatic Prostate Cancer.

Biological and experimental evidence support restoration of normal zinc levels in malignant prostate cells as a promising prostate cancer treatment, yet the influence of zinc supplementation after diagnosis on prostate cancer survival in a human population is unknown. We prospectively assessed post-diagnostic zinc supplementation in relation to prostate cancer survival among 5,788 men with nonmetastatic prostate cancer in the Health Professionals Follow-up Study (1986-2019). We used Cox regression models to estimate the multivariable hazard ratios and 95% confidence intervals of lethal prostate cancer (distant metastases or prostate cancer-specific death) and all-cause mortality according to post-diagnostic zinc supplement use and dosage. During a median follow-up of 11 years, we documented 527 lethal prostate cancer events and 3,198 all-cause deaths. Fifteen percent of men reported zinc supplement use post-diagnosis. Compared to nonusers, post-diagnostic zinc supplement use was associated suggestively with a lower risk of lethal prostate cancer (HR [95% CI], 0.82 [0.60-1.13]) and significantly with all-cause mortality (0.84 [0.74-0.96]). The inverse association was mostly observed among men who used post-diagnostic zinc supplements of 1-24 mg/d (lethal prostate cancer: 0.55 [0.32-0.96]; all-cause mortality: 0.77 [0.64-0.93]), while higher dosage did not show a lower risk. Post-diagnostic low-dose zinc supplement use among nonmetastatic prostate cancer patients was associated with lower risk of lethal prostate cancer and all-cause mortality. A potential benefit of low-dose post-diagnostic zinc supplement for prostate cancer survival merits further study.

Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program.

Genetic scores may provide an objective measure of prostate cancer risk and thus inform screening decisions. We evaluated whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with prostate cancer risk in a diverse population, including Black men, who have higher average risk of prostate cancer death but are often treated as a homogeneously high-risk group. This was a retrospective analysis of the Million Veteran Program, a national, population-based cohort study of US military veterans conducted 2011-2021. Cox proportional hazards analyses tested for association of genetic and other risk factors (including self-reported race and ethnicity and family history) with age at death from prostate cancer, age at diagnosis of metastatic (nodal or distant) prostate cancer, and age at diagnosis of any prostate cancer. A total of 590 750 male participants were included. Median age at last follow-up was 69 years. PHS290 was associated with fatal prostate cancer in the full cohort and for each racial and ethnic group (P < .001). Comparing men in the highest 20% of PHS290 with those in the lowest 20% (based on percentiles from an independent training cohort), the hazard ratio for fatal prostate cancer was 4.42 (95% confidence interval = 3.91 to 5.02). When accounting for guideline-recommended risk factors (family history, race, and ethnicity), PHS290 remained a strong independent predictor of any, metastatic, and fatal prostate cancer. PHS290 stratified US veterans of diverse ancestry for lifetime risk of prostate cancer, including metastatic and fatal cancer. Predicting genetic risk of lethal prostate cancer with PHS290 might inform individualized decisions about prostate cancer screening.

Shared Inherited Genetics of Benign Prostatic Hyperplasia and Prostate Cancer

BackgroundThe association between benign prostatic hyperplasia (BPH) and prostate cancer (PCa) remains controversial, largely due to a detection bias in traditional observational studies. ObjectiveTo assess the association between BPH and PCa using inherited single nucleotide polymorphisms (SNPs). Design, setting, and participantsThe participants were White men from the population-based UK Biobank (UKB). Outcome measurements and statistical analysisThe association between BPH and PCa was tested for (1) phenotypic correlation using chi-square, (2) genetic correlation (rg) based on genome-wide SNPs using linkage disequilibrium score regression, and (3) cross-disease genetic associations based on known risk-associated SNPs (15 for BPH and 239 for PCa), individually and cumulatively using genetic risk score (GRS). Results and limitationsAmong 214717 White men in the UKB, 24623 (11%) and 14311 (6.7%) had a diagnosis of BPH and PCa, respectively. Diagnoses of these two diseases were significantly correlated (χ2 = 1862.80, p < 0.001). A significant genetic correlation was found (rg = 0.16; 95% confidence interval 0.03–0.28, p = 0.01). In addition, significant cross-disease genetic associations for established risk-associated SNPs were also found. Among the 250 established genome-wide association study–significant SNPs of PCa or BPH, 49 were significantly associated with the risk of the other disease at p < 0.05, significantly more than expected by chance (N = 12, p < 0.001; χ2 test). Furthermore, significant cross-disease GRS associations were also found; GRSBPH was significantly associated with PCa risk (odds ratio [OR] = 1.26 [1.18–1.36], p < 0.001), and GRSPCa was significantly associated with BPH risk (OR = 1.03 [1.02–1.04], p < 0.001). Moreover, GRSBPH was significantly and inversely associated with lethal PCa risk in a PCa case-case analysis (OR = 0.58 [0.41–0.81], p = 0.002). Only White men were studied. ConclusionsBPH and PCa share common inherited genetics, which suggests that the phenotypic association of these two diseases in observational studies is not entirely caused by the detection bias. Patient summaryFor the first time, we found that benign prostatic hyperplasia and prostate cancer are genetically related. This finding may have implications in disease etiology and risk stratification.

Abstract 3354: A gene expression signature of high serum cholesterol and prostate cancer outcomes

Abstract Statin use is associated with reduced risk of lethal prostate cancer potentially through effects on serum cholesterol. Using data from a prospective study with measured serum cholesterol among men subsequently diagnosed with prostate cancer, we developed a tumour gene expression score to reflect the pre-diagnosis serum cholesterol environment these tumours developed in, and applied this score to a separate study to examine the relationship with prostate cancer-specific outcomes. We identified 127 men with prostate cancer in the prospective Health Professionals Follow-up Study, whose prostate tumors underwent whole genome gene expression profiling. Pre-diagnosis serum cholesterol was measured a median of 3.3 years (IQR 1.5-4.8 years) prior to cancer diagnosis. We excluded men using statins either at time of blood draw for serum cholesterol measurement or at cancer diagnosis. Using tumor biopsy whole genome transcriptomic data from 232 prostate cancer patients treated with radiotherapy in Northern Ireland (NI), we generated the serum cholesterol score by summing z-score-transformed expression for each gene. PTEN status was measured using a published 50-gene transcriptional signature. Both signatures were dichotomized using the median cut-point. Age-adjusted and multivariable Cox regression analysis was used to compute HRs and 95% CI for associations of the cholesterol gene score with biochemical recurrence and metastasis risk. We identified in HPFS a set of 30 genes associated with pre-diagnostic serum cholesterol with a fold change ≥4 which included PTEN. In the NI Cohort, tumors with above median cholesterol scores had higher expression of the PTEN-null signature (p&amp;lt;0.001). Increased serum cholesterol tumor score was associated with higher Gleason grade (p&amp;lt;0.001); this relationship was stronger in PTEN-null tumours relative to PTEN-intact. Over a median follow-up of 11 years, 68 men experienced biochemical recurrence, and 28 developed metastasis. In age-adjusted analysis, patients with high serum cholesterol score had increased risk of recurrence (HR 1.84; 95% CI 1.13-2.99) and metastasis (HR 1.98; 95% CI 0.91-4.29), though the latter was not statistically significant. Associations with recurrence and metastasis were attenuated following further adjustment for Gleason score (HR 1.65; 95% CI, 0.98-2.77 and HR 1.49; 95% CI 0.66-3.35, respectively). Men with increased tumor gene expression of a serum cholesterol score, derived to reflect tumor development within a high serum cholesterol environment, were more likely to be diagnosed with a PTEN-null prostate cancer. These men had more aggressive prostate cancer at diagnosis and increased risk of recurrence, particularly men with PTEN-null disease. Our results support recent findings showing a reduced risk of PTEN-null prostate cancer in statin users, and inform our understanding of the potential role of serum cholesterol in prostate cancer etiology. Citation Format: Sarah Jane Winter, Sophia R. Halliday, Travis A. Gerke, Lorelei Ann Mucci, Konrad H. Stopsack, Gillian Prue, Suneil Jain, Emma H. Allott. A gene expression signature of high serum cholesterol and prostate cancer outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3354.

A Healthy Lifestyle in Men at Increased Genetic Risk for Prostate Cancer

BackgroundProstate cancer is the most heritable cancer. There is a need to identify possible modifiable factors for men at an increased risk of prostate cancer due to genetic factors. ObjectiveTo examine whether men at an increased genetic risk of prostate cancer can offset their risk of disease or disease progression by adhering to a healthy lifestyle. Design, setting, and participantsWe prospectively followed 12 411 genotyped men in the Health Professionals Follow-up Study (1993–2019) and the Physicians’ Health Study (1983–2010). Genetic risk of prostate cancer was quantified using a polygenic risk score (PRS). A healthy lifestyle was defined by healthy weight, vigorous physical activity, not smoking, and a healthy diet. Outcome measurements and statistical analysisOverall and lethal prostate cancer events (metastatic disease/prostate cancer–specific death) were analyzed using time-to-event analyses estimating hazard ratios (HRs) and lifetime risks. Results and limitationsDuring 27 yr of follow-up, 3005 overall prostate cancer and 435 lethal prostate cancer events were observed. The PRS enabled risk stratification not only for overall prostate cancer, but also for lethal disease with a four-fold difference between men in the highest and lowest quartiles (HR, 4.32; 95% confidence interval [CI], 3.16–5.89). Among men in the highest PRS quartile, adhering to a healthy lifestyle was associated with a decreased rate of lethal prostate cancer (HR, 0.55; 95% CI, 0.36–0.86) compared with having an unhealthy lifestyle, translating to a lifetime risk of 1.6% (95% CI, 0.8–3.1%) among the healthy and 5.3% (95% CI, 3.6–7.8%) among the unhealthy. Adhering to a healthy lifestyle was not associated with a decreased risk of overall prostate cancer. ConclusionsOur findings suggest that a genetic predisposition for prostate cancer is not deterministic for a poor cancer outcome. Maintaining a healthy lifestyle may provide a way to offset the genetic risk of lethal prostate cancer. Patient summaryThis study examined whether the genetic risk of prostate cancer can be attenuated by a healthy lifestyle including a healthy weight, regular exercise, not smoking, and a healthy diet. We observed that adherence to a healthy lifestyle reduced the risk of metastatic disease and prostate cancer death among men at the highest genetic risk. We conclude that men at a high genetic risk of prostate cancer may benefit from adhering to a healthy lifestyle.

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

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. 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. 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). 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. 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.

Evaluating a polygenic hazard score to predict risk of developing metastatic or fatal prostate cancer in the multi-ancestry Million Veteran Program cohort.

155 Background: Early detection of prostate cancer to reduce mortality remains controversial because there is often also overdiagnosis of low-risk disease and unnecessary treatment. Genetic scores may provide an objective measure of a man’s risk of dying from prostate cancer and thus inform screening decisions. This might be especially useful in men of African ancestry, who have a higher average risk of prostate cancer death but are often treated as a homogeneous group. Our object was to determine whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with risk of metastatic or fatal prostate cancer in a racially and ethnically diverse population. Methods: We analyzed the Million Veteran Program (MVP), a multi-ancestry population of over 500,000 individuals participating in the VA healthcare system. Genotype data were used to calculate the genetic score, PHS290. Family history of prostate cancer (first-degree relative) and ancestry group (harmonized genetic ancestry and self-reported race/ethnicity: European, African, Hispanic, or Asian) were also studied. The primary outcome studied was age at death from prostate cancer. The key secondary outcome was age at diagnosis of prostate cancer metastases. Cox regression was used to test associations. Results: 513,997 MVP participants were included. Median age at last follow-up: 69 years. PHS290 was associated with age at death from prostate cancer in the full cohort and for each ancestry group ( p &lt;10-16). Comparing men in the highest 20% of PHS290 to those in the lowest 20%, the hazard ratio (HR80/20) for death from prostate cancer was 4.41 [95% CI: 3.9-5.02]. Corresponding hazard ratios for European, African, Hispanic, and Asian subsets were 4.26 [3.66-4.9], 2.4 [1.77-3.23], 4.72 [2.68-8.87], and 10.46 [2.01-101.0]. When accounting for family history and ancestry group, PHS290 remained a strong independent predictor of fatal prostate cancer (Table). PHS290 was also associated with metastasis. PHS290 was higher, on average, among men with African ancestry. Conclusions: PHS290 stratified US veterans of diverse ancestry for lifetime risk of metastatic or fatal prostate cancer. Predicting genetic risk of lethal prostate cancer with PHS290 might inform individualized decisions about prostate cancer screening.[Table: see text]

Clinical Management of Prostate Cancer in High-Risk Genetic Mutation Carriers.

Simple SummaryMen with certain genetic differences are at much higher risks of developing metastatic and lethal prostate cancer. With the recent introduction of a new class of medications specifically targeted to these gene repair pathways (PARP inhibitors), it is critical to review the state of the literature surrounding the management of men with prostate cancer who have these genetic differences. We review the existing literature to address common clinical questions pertaining to this population. There is an urgent need for further research regarding clinical management in these scenarios as patients are increasingly seeking out genetic testing and consulting healthcare professionals for guidance.Background: Prostate cancer is a leading cause of death. Approximately one in eight men who are diagnosed with prostate cancer will die of it. Since there is a large difference in mortality between low- and high-risk prostate cancers, it is critical to identify individuals who are at high-risk for disease progression and death. Germline genetic differences are increasingly recognized as contributing to risk of lethal prostate cancer. The objective of this paper is to review prostate cancer management options for men with high-risk germline mutations. Methods: We performed a review of the literature to identify articles regarding management of prostate cancer in individuals with high-risk germline genetic mutations. Results: We identified numerous publications regarding the management of prostate cancer among high-risk germline carriers, but the overall quality of the evidence is low. Conclusions: We performed a review of the literature and compiled clinical considerations for the management of individuals with high-risk germline mutations when they develop prostate cancer. The quality of the evidence is low, and there is an immediate need for further research and the development of consensus guidelines to guide clinical practice for these individuals.