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Vitamin D metabolites may be protective against prostate cancer (PCa). We conducted a cross-sectional analysis to evaluate associations between in vivo vitamin D status, genetic ancestry, and degree of apoptosis using prostatic epithelial terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining.Benign and tumor epithelial punch biopsies of participants with clinically localized PCa underwent indirect TUNEL staining. Serum levels of 25 hydroxyvitamin D [25(OH)D] and 1,25 dihydroxyvitamin D were assessed immediately before radical prostatectomy; levels of prostatic 25(OH)D were obtained from the specimen once the prostate was extracted. Ancestry informative markers were used to estimate the percentage of genetic West African, Native American, and European ancestry.One hundred twenty-one newly diagnosed men, age 40-79, were enrolled between 2013 and 2018. Serum 25(OH)D correlated positively with both tumor (ρ = 0.17, p = 0.03), and benign (ρ = 0.16, p = 0.04) prostatic epithelial TUNEL staining. Similarly, prostatic 25(OH)D correlated positively with both tumor (ρ = 0.31, p 0.001) and benign (ρ = 0.20, p = 0.03) epithelial TUNEL staining. Only Native American ancestry was positively correlated with tumor (ρ = 0.22, p = 0.05) and benign (ρ = 0.27, p = 0.02) TUNEL staining. In multivariate regression models, increasing quartiles of prostatic 25(OH)D (β = 0.25, p = 0.04) and Native American ancestry (β = 0.327, p = 0.004) were independently associated with tumor TUNEL staining.Physiologic serum and prostatic 25(OH)D levels and Native American ancestry are positively associated with the degree of apoptosis in tumor and benign prostatic epithelium in clinically localized PCa. Vitamin D may have secondary chemoprevention benefits in preventing PCa progression in localized disease.

PDF file, 117K, -Log10 P-value plot of genotyped SNPs in IL-16 (±250kb) region in Washington, D.C. AA discovery samples.

Background: HIV-infected (HIV+) men face cancer treatment disparities that impact outcome. Prostate cancer treatment and treatment appropriateness in HIV+ men are unknown.Methods: We used electronic chart review to conduct a retrospective cohort study of 43 HIV+ cases with prostate cancer and 86 age- and race-matched HIV-uninfected (HIV−) controls with prostate cancer, ages 40 to 79 years, from 2001 to 2012. We defined treatment appropriateness using National Comprehensive Cancer Network guidelines and the Charlson comorbidity index (CCI) to estimate life expectancy.Results: Median age was 59.5 years at prostate cancer diagnosis. Median CD4+ T-cell count was 459.5 cells/mm3, 95.3% received antiretroviral therapy, and 87.1% were virally suppressed. Radical prostatectomy was the primary treatment for 39.5% of HIV+ and 71.0% of HIV− men (P = 0.004). Only 16.3% of HIV+ versus 57.0% of HIV− men received open radical prostatectomy (P < 0.001). HIV+ men received more radiotherapy (25.6% vs. 16.3%, P = 0.13). HIV was negatively associated with open radical prostatectomy (OR = 0.03, P = 0.007), adjusting for insurance and CCI. No men were undertreated. Fewer HIV+ men received appropriate treatment (89.2% vs. 100%, P = 0.003), due to four overtreated HIV+ men. Excluding AIDS from the CCI still resulted in fewer HIV+ men receiving appropriate treatment (94.6% vs. 100%, P = 0.03).Conclusion: Prostate cancer in HIV+ men is largely appropriately treated. Under- or overtreatment may occur from difficulties in life expectancy estimation. HIV+ men may receive more radiotherapy and fewer radical prostatectomies, specifically open radical prostatectomies.Impact: Research on HIV/AIDS survival indices and etiologies and outcomes of this prostate cancer treatment disparity in HIV+ men are needed. Cancer Epidemiol Biomarkers Prev; 23(10); 2009–18. ©2014 AACR.

PDF file, 114K, LD plots of the 11 SNPs in 1000 genome European population.

PDF file, 98K, Fine-mapping of IL16 gene and prostate cancer risk in African Americans.

Background: Prostate cancer is the most common type of cancer among men in the United States, and its incidence and mortality rates are disproportionate among ethnic groups. Although genome-wide association studies of European descents have identified candidate loci associated with prostate cancer risk, including a variant in IL16, replication studies in African Americans (AA) have been inconsistent. Here we explore single-nucleotide polymorphism (SNP) variation in IL16 in AAs and test for association with prostate cancer.Methods: Association tests were conducted for 2,257 genotyped and imputed SNPs spanning IL16 in 605 AA prostate cancer cases and controls from Washington, D.C. Eleven of them were also genotyped in a replication population of 1,093 AAs from Chicago. We tested for allelic association adjusting for age, global and local West African ancestry.Results: Analyses of genotyped and imputed SNPs revealed that a cluster of IL16 SNPs were significantly associated with prostate cancer risk. The strongest association was found at rs7175701 (P = 9.8 × 10−8). In the Chicago population, another SNP (rs11556218) was associated with prostate cancer risk (P = 0.01). In the pooled analysis, we identified three independent loci within IL16 that were associated with prostate cancer risk. SNP expression quantitative trait loci analyses revealed that rs7175701 is predicted to influence the expression of IL16 and other cancer-related genes.Conclusion: Our study provides evidence that IL16 polymorphisms play a role in prostate cancer susceptibility among AAs.Impact: Our findings are significant given that there has been limited focus on the role of IL16 genetic polymorphisms on prostate cancer risk in AAs. Cancer Epidemiol Biomarkers Prev; 21(11); 2059–68. ©2012 AACR.

PDF file, 204K, LD plot of the top 30 genotyped and imputed SNPs generated with 1000 Genomes YRI genotype data.

PDF file, 122K, -log10 P-value plot of association tests after imputation masking 24 genotyped SNPs. In this analysis, rs7175701 was masked and imputed yet remained the most significant SNP.

PDF file, 93K, Assessment of imputation accuracy and results of imputation.

PDF file, 125K, -log10 P-value plot of association tests using genotyped and imputed SNPs from MACH and HapMap data analysis showing that the same three SNPs have the strongest association.

PDF file, 93K, Distribution of percent global West African Ancestry estimates in the discovery and replication cases (mean global WAA in discovery cases = 81.2%, mean global WAA in replication cases = 79.1 %; T-test P=0.342).

Supplemental Table 1: National Comprehensive Cancer Network guidelines for risk-appropriate therapy for prostate cancer. We have described appropriate treatments for low, intermediate, high, and very high risk categories, along with metastatic disease.

Background: Genetic factors play an important role in prostate cancer (PCa) susceptibility.Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry.Design, setting, and participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry.Outcome measurements and statistical analysis: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness.Results and limitations: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10-4).Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry.Patient summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.

Objective To compare Prostate Health Index (PHI) and prostate‐specific antigen (PSA) density as secondary tests after multiparametric magnetic resonance imaging (mpMRI) in improving the detection accuracy of Gleason grade group (GG) 2‐5 prostate cancer (PCa) and in decreasing unnecessary biopsies in a multiethnic biopsy‐naïve population. Methods From February 2017 to February 2020, we recruited consecutive biopsy‐naïve men in participating urology clinics for elevated PSA levels. They all had a PHI score, mpMRI, and prostate biopsy. Experienced genitourinary radiologists read all mpMRI studies based on PIRADS version 2.0. Logistic regression models were used to generate receiver operating characteristic curves. Models were tested for effect modification between Race (Black vs White) and both PHI and PSA density, and Race and PIRADS to determine if race impacted their prediction accuracy. Sensitivity, specificity, and predictive values of PHI and PSA density thresholds were calculated by PIRADS scores. The primary outcome was GG2‐5 PCa, that is, Gleason score ≥3 + 4. Results The study included 143 men, of which 65 (45.5%) were self‐reported Black. Median age was 62.0 years and 55 men (38.4%) had GG2‐5 PCa. Overall, 18.1% had PIRADS 1‐2, 32.9% had PIRADS 3, and 49.0% had PIRADS 4‐5. For the binary logistic regressions, the interactions between PIRADS and Race (P = .08), Log (PHI) and Race (P = .17), and Log (PSA density) and Race (P = .42) were not statistically significant. Within PIRADS 3 lesions, a PHI ≥49 prevented unnecessary biopsies in 55% of men and missed no GG2‐5 PCa, yielding a negative predictive value of 100%. There was no reliable PHI or PSA density threshold to avoid PCa biopsies in PIRADS 1‐2 or 4‐5. Conclusions PHI and PSA density can be used after mpMRI to improve the detection of GG2‐5 PCa in a biopsy‐naïve cohort. PHI may be superior to PSA density in PIRADS 3 lesions by avoiding 55% of unnecessary biopsies. Using both PHI and PSA density in series may further increase specificity and lead to fewer unnecessary biopsies, but further larger studies are warranted to determine the optimal threshold of each biomarker.

PURPOSE The Genomic Prostate Score (GPS), performed on biopsy tissue, predicts adverse outcome in prostate cancer (PCa) and has shown promise for improving patient selection for active surveillance (AS). However, its impact on treatment choice in high-risk populations of African Americans is largely unknown and, in general, the effect of the GPS on this difficult decision has not been evaluated in randomized trials. METHODS Two hundred men with National Comprehensive Cancer Network very low to low-intermediate PCa from three Chicago hospitals (70% Black, 16% college graduates) were randomly assigned at diagnosis to standard counseling with or without a 12-gene GPS assay. The primary end point was treatment choice at a second postdiagnosis visit. The proportion of patients choosing AS was compared, and multivariable modeling was used to estimate the effects of various factors on AS acceptance. RESULTS AS acceptance was high overall, although marginally lower in the intervention group (77% v 88%; P = .067), and lower still when men with inadequate specimens were excluded ( P = .029). Men with lower health literacy who received a GPS were seven-fold less likely to choose AS compared with controls, whereas no difference was seen in men with higher health literacy ( Pinteraction = .022). Among men with low-intermediate risk, 69% had GPS values consistent with unfavorable intermediate or high-risk cancer. AS choice was also independently associated with a family history of PCa and having health insurance. CONCLUSION In contrast to other studies, the net effect of the GPS was to move patients away from AS, primarily among men with low health literacy. These findings have implications for our understanding of how prognostic molecular assays that generate probabilities of poor outcome can affect treatment decisions in diverse clinical populations.

Background and objectives Prostate cancer is the most commonly diagnosed cancer in Nigerian men despite the lack of PSA based screening. Current prevalence estimates in Nigeria are based on cancer registry data obtained primarily from hospital admissions and therefore not truly reflective of prostate cancer incidence. Prior autopsy series did not adhere to modern pathologic quality practices. The aim of this study was to explore the prevalence of asymptomatic prostate cancer among Nigerian men at the time of autopsy. Methods Prostates were collected at autopsy at the Universities of Lagos and Calabar Teaching Hospitals from men aged more than 40 who died from causes other than prostate cancer. Thirty-nine prostates from Nigerian men autopsied in 2017 to 2018 were formalin-fixed, weighed, and sliced at 4 mm intervals. Haematoxylin and eosin-stained paraffin sections were prepared from these slices. Presence and Gleason grade of prostatic adenocarcinomas and presence of high-grade prostatic intraepithelial neoplasia (HGPIN) were recorded. Results Mean age of cases was 55 ± 11 years and mean prostatic weight was 23.0 ± 10.9 g. The crude prevalence of HGPIN was 20.6%. Overall crude prevalence of prostate cancer was 8.8% (n = 34), increasing from 8.3% for men aged 40-59 (n = 23) to 10.0% for men ≥60 years old (n = 10). Two tumors were small and had Gleason Grade 3 + 3 or 3 + 4, and one large stage T3 tumor with Gleason Grade 4 + 3 disease and neuroendocrine appearance was found in a 54-year-old man. Conclusions The 8.8% prevalence of subclinical prostate cancer at autopsy was similar to previously reported Nigerian studies with more limited tissue sampling (6.7%-10%), but considerably lower than estimates in other populations, including African Americans. Our findings suggest that latent, clinically asymptomatic prostate cancer is less frequent in Nigerians than in African Americans, despite shared genetic ancestry. Future studies with increased sample size are warranted to provide insight in the natural history and true prevalence of prostate cancer in West Africa.

PURPOSE: The Prostate Health Index is validated for prostate cancer detection but has not been well validated for Gleason grade group 2-5 prostate cancer detection in Black men. We hypothesize that the Prostate Health Index has greater accuracy than prostate specific antigen for detection of Gleason grade group 2-5 prostate cancer. We estimated probability of overall and Gleason grade group 2-5 prostate cancer across previously established Prostate Health Index ranges and identified Prostate Health Index cutoffs that maximize specificity for Gleason grade group 2-5 prostate cancer with sensitivity >90%. MATERIALS AND METHODS: We recruited a “cancer-free” Black control cohort (135 patients) and a cohort of biopsy naïve Black men (158) biopsied for elevated prostate specific antigen. Descriptive statistics compared the prostate cancer cases and controls and the frequency of Gleason grade group 2-5 prostate cancer across Prostate Health Index scores. Receiver operating characteristics compared the discrimination of prostate specific antigen, Prostate Health Index and other prostate specific antigen related biomarkers. Sensitivity and specificity for Gleason grade group 2-5 prostate cancer detection were assessed at prostate specific antigen and Prostate Health Index thresholds alone and in series. RESULTS: Of biopsied subjects 32.9% had Gleason grade group 2-5 prostate cancer. In Blacks with prostate specific antigen from 4.0–10.0 ng/ml, Prostate Health Index and prostate specific antigen had similar discrimination for Gleason grade group 2-5 prostate cancer (0.63 vs 0.57, p=0.27). In Blacks with prostate specific antigen ≤10.0, a threshold of prostate specific antigen ≥4.0 had 90.4% sensitivity for Gleason grade group 2-5 prostate cancer; a threshold of prostate specific antigen ≥4.0 with Prostate Health Index ≥35.0 in series avoided unnecessary biopsy in 33.0% of men but missed 17.3% of Gleason grade group 2-5 prostate cancer. Prostate specific antigen ≥4.0 with Prostate Health Index ≥28.0 in series spared biopsy in 17.9%, while maintaining 90.4% sensitivity of Gleason grade group 2-5 prostate cancer. CONCLUSIONS: The Prostate Health Index has moderate accuracy in detecting Gleason grade group 2-5 prostate cancer in Blacks, but Prostate Health Index ≥28.0 can be safely used to avoid some unnecessary biopsies in Blacks.

Vitamin D is a steroid hormone that confers anti-proliferative and anti-inflammatory properties in prostate cells. Vitamin D deficiency is associated with advanced prostate cancer (PCa) stage, grade, and increased mortality. Since AA men are more likely to be vitamin D deficient compared to EA men, elucidating the pleiotropic effects of vitamin D may provide additional drug targets to mitigate disparate outcomes for AA men with PCa. Total RNA sequencing (RNAseq) was performed on an AA prostate cell line, RC-77N/E, derived from non-malignant epithelial tissue obtained from a PCa patient. We compared untreated RC-77N/E cells with RC-77N/E cells treated with 10 nM of vitamin D3 metabolite, 1α,25(OH)2D3 at 24h. Bioinformatic analysis, public cohort data mining, and RT-qPCR was performed to filter and validate selected statistically significant differentially expressed genes from RNAseq analysis. Our comparison of 1α,25(OH)2D3 treated versus untreated control RC-77N/E cell replicates revealed, 1601 significantly differentially expressed genes (DEGs) (FDR p < 0.05). Ingenuity Pathway Analysis software was used to conduct pathway enrichment analysis, which predicted repression of signaling pathways involved in actin cytoskeleton organization, epithelial-mesenchymal transitioning, adherens junction pathway, and RhoA pathway signaling with high enrichment z-score and statistically significant p-value. We additionally report predicted repression of PCa cell viability, invasion, cell proliferation and organismal death, for disease and function. We prioritized differentially expressed genes by identifying genes with 1) vitamin D response elements (VDREs) and 2) predicted poor prognosis, by performing overall survival analyses using The Cancer Genome Atlas (TCGA) Prostate Adenocarcinoma (PRAD) Cohort. We identified ANLN (Anillin) and ECT2 (Epithelial Cell Transforming 2), which were further validated using an AA tumor/benign contralateral matched clinical cohort, and a public cohort study using a non-malignant European prostate cell line, RWPE1. Our data suggest 1α,25(OH)2D3 significantly downregulates ANLN and ECT2 (FDR p < 0.05) in the RC-77N/E cell line, where survival analyses in the TCGA PRAD cohort show low expression of both ANLN and ECT2 are associated with significantly better overall survival outcome (p < 0.05). In our clinical cohort validations, both ANLN and ECT2 also show significantly decreased expression in non-malignant compared to tumor (p < 0.05). In conclusion, our study provides more insight of vitamin D3 regulation of PCa biomarkers and their potential roles in AA prostate cancer prevention, adjuvant treatment, as well as improving cancer survivor outcome Citation Format: Jabril R. Johnson, Rachel N. Martini, Yate Yuan-Ching, Leanne Woods-Burnham, Mya Walker, Greisha L. Ortiz-Hernandez, Dorothy Galloway, Melissa B. Davis, Sean K. Kimbro, Adam B. Murphy, Rick A. Kittles. 1,25-dihydroxyvitamin D3-mediated suppression of genes associated with cell cycle regulation and actin organization in a non-malignant African American prostate cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3509.

International audience; Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age

Objective To validate the 17-gene Oncotype DX Genomic Prostate Score (GPS) as a predictor of adverse pathology (AP) in African American (AA) men and to assess the distribution of GPS in AA and European American (EA) men with localized prostate cancer. Methods The study populations were derived from 2 multi-institutional observational studies. Between February 2009 and September 2014, AA and EA men who elected immediate radical prostatectomy after a ≥10-core transrectal ultrasound biopsy were included in the study. Logistic regressions, area under the receiver operating characteristics curves (AUC), calibration curves, and predictive values were used to compare the accuracy of GPS. AP was defined as primary Gleason grade 4, presence of any Gleason pattern 5, and/or non-organ-confined disease (≥pT3aN0M0) at radical prostatectomy. Results Overall, 96 AA and 76 EA men were selected and 46 (26.7%) had AP. GPS result was a significant predictor of AP (odds ratio per 20 GPS units [OR/20 units] in AA: 4.58; 95% confidence interval (CI) 1.8-11.5, P = .001; and EA: 4.88; 95% CI 1.8-13.5, P = .002). On multivariate analysis, there was no significant interaction between GPS and race (P >.10). GPS remained significant in models adjusted for either National Comprehensive Cancer Network (NCCN) risk group or Cancer of the Prostate Risk Assessment (CAPRA) score. In race-stratified models, area under the receiver operating characteristics curves for GPS/20 units was 0.69 for AAs vs 0.74 for EAs (P = .79). The GPS distributions were not statistically different by race (all P >.05). Conclusion In this clinical validation study, the Oncotype DX GPS is an independent predictor of AP at prostatectomy in AA and EA men with similar predictive accuracy and distributions.

Background: Black men are more likely than Non-Hispanic White (NHW) men to be diagnosed with high-risk prostate cancer. We examined the extent to which social factors were associated with differences in prostate cancer risk profiles between Black men and NHW men [using a modification to the original D'Amico risk groups based on prostate specific antigen (PSA), Gleason score (GS), and TNM stage (stage)], based on individual and combined clinicopathologic characteristics. Methods: We conducted a cross-sectional population-based study of 23,555 Black men and 146,889 NHW men diagnosed with prostate cancer in the California Cancer Registry from 2004 to 2017. We conducted multivariable logistic regression to examine the association of year of diagnosis, block group-level neighborhood socioeconomic status (nSES), marital status, and insurance type on differences in prostate cancer risk profiles between Black and NHW men. Results: High PSA (>20 ng/mL), GS, stage, individually and combined prostate cancer risk profiles were more common among Black men versus NHW men. In fully adjusted models, relative to NHW men, we observed a persistent 67% increased odds of high PSA among Black men. nSES was the factor most strongly associated with racial disparity in high PSA, accounting for 25% of the difference. Marital status was the factor that was second most associated with a racial disparity. Conclusions: nSES was the factor most strongly associated with racial disparities in high PSA prostate cancer. Impact: The influence of nSES on racial disparities in PSA, GS, stage, and prostate cancer risk profiles warrants further consideration.

There is evidence that vitamin D metabolites such as 25 hydroxyvitamin D [25(OH)D], may be protective against prostate cancer (PCa). Vitamin D and its analogs are hypothesized to have pro-apoptotic effects in multiple cell lines. Blacks have higher rates of vitamin D deficiency, higher tumor progression rates 1,2, and higher apoptosis rates3 compared to Whites. West African ancestry (WAA) may confound this relationship if it is associated with both vitamin D status and apoptosis rates. Our objective is to assess for independent associations between in vivo vitamin D status, genetic ancestry, and degree of apoptosis using prostatic epithelial Terminal deoxynucleotide transferase dUTP Nick End Labeling (TUNEL) staining. Radical prostatectomy specimens of men with clinically localized PCa were stained for TUNEL. Prostatic and serum levels of 25(OH)D and serum levels of 1,25 hydroxyvitamin D were assessed at the time of surgery. Ancestry informative markers were used to estimate the percentage of genetic West African, Native American, and European ancestry. Continuous variables were compared using medians tests across three groups of vitamin D status. Categorical variables were compared using the Chi-Squared test. Correlations between the degree of TUNEL staining and vitamin D metabolites were assessed using Spearman correlations. Linear regressions were used to access the bivariant associations between tumor and benign epithelial TUNEL staining with quartiles of ancestry, and serum and prostatic vitamin D metabolite levels. Multivariate linear regressions for the percentage of benign and tumor TUNEL staining were used to test the independent associations of vitamin D metabolites and genetic ancestry. Overall, 121 men, age 40-79, who underwent radical prostatectomy were enrolled between 2013-2018. Serum 25(OH)D correlated positively with both tumor (ρ = 0.17, p = 0.03), and benign (ρ = 0.16, p = 0.04) prostatic epithelial TUNEL staining. Similarly, prostatic 25(OH)D correlated positively with both tumor (ρ = 0.31, p < 0.001) and benign (ρ = 0.20, p = 0.03) prostatic tissue TUNEL staining. Relative to West African ancestry, Native American ancestry was more strongly positively correlated with tumor (ρ = 0.22, p = 0.05) and benign (ρ = 0.27, p= 0.02) TUNEL staining. In multivariate regression models, increasing quartiles of prostatic 25(OH)D (β = 0.25, p = 0.04) and Native American ancestry (β = 0.327, p = 0.004) were significant predictors of tumor TUNEL staining. Physiologic levels of serum and prostatic 25(OH)D and percentage of Native American ancestry are positively associated with the degree of apoptosis in tumor and benign prostatic epithelium from men with clinically localized PCa. Vitamin D may have secondary chemoprevention benefits in preventing PCa progression in localized disease. Citation Format: Cordero L. McCall, James Stinson, Ryan W. Dobbs, Neil Mistry, Adrian Rosenberg, Oluwarotimi Nettey, Pooja Sharma, Michael Dixon, Jamila Sweis, Virgilia Macias, Roohollah Sharifi, Rick A. Kittles, Andre Kajdacsy Balla, Adam B. Murphy. Genetic ancestry and vitamin D may predict degree of prostatic apoptosis in prostate tumor and benign epithelium among men undergoing radical prostatectomy [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A079.

BACKGROUND The metabolism of normal prostate relies on glycolysis, with prostate cancer having reduced glycolysis and increased aerobic metabolism. Advanced glycation end products (AGEs) accumulate in tissues as a result of age and glycolytic rate. Differential AGE levels were recently observed in prostate cancer tissues. Herein we sought to quantify AGEs in benign and cancer prostate tissue in a diverse cohort of patients. METHODS Levels of the AGE Ne-(carboxylethyl)lysine (CML) were quantified by immunohistochemistry (IHC) in a tissue microarray which consisted of 3 cores from tumor and 2 cores from benign areas from 118 patients (87 African American and 31 European American). Ancestry informative markers for African Ancestry were available for 79 patients. Epithelial and stromal areas were quantified separately using an E-cadherin mask. CML levels were compared with clinical grade group and ancestry by mixed linear effect models. Age, prostate-specific antigen (PSA) levels, body mass index (BMI), and hemoglobin A1C were included as covariates. RESULTS CML levels were lower in areas of the tumor, for both epithelium and surrounding stroma, compared with benign, but did not significantly change with tumor grade group. Age, PSA levels, BMI, and hemoglobin A1C did not associate with CML levels. CML levels were inversely associated with the percentage of African Ancestry in all tissues. CONCLUSIONS The low CML levels in cancer may reflect the reduced glycolytic state of the tissue. The inverse relationship between African Ancestry and CML levels in both benign and cancer areas suggests a state of reduced glycolysis. It is yet to be determined whether altered glycolysis and CML levels are bystanders or drivers of carcinogenesis.

Men of African ancestry have demonstrated markedly higher rates of prostate cancer mortality than men of other races and ethnicities around the world. In fact, the highest rates of prostate cancer mortality worldwide are found in the Caribbean and Sub-Saharan West Africa, and among men of African descent in the USA. Addressing this inequity in prostate cancer care and outcomes requires a focused research approach that creates durable solutions to address the structural, social, environmental, and health factors that create racial disparities in care and outcomes.To introduce a conceptual model for evaluating racial inequities in prostate cancer care to facilitate the development of translational research studies and interventions.A collaborative review of literature relevant to racial inequities in prostate cancer care and outcomes was performed. Existing literature was used to highlight various components of the conceptual model to inform future research and interventions toward equitable care and outcomes.Racial inequities in prostate cancer outcomes are driven by a series of structural and social determinants of health that impact exposures, mediators, and outcomes. Social determinants of equity, such as laws/policies, economic systems, and structural racism, affect the inequitable access to environmental and neighborhood exposures, in addition to health care access. Although the incidence disparity remains problematic, various studies have demonstrated parity in outcomes when social and health factors, such as access to equitable care, are normalized. Few studies have tested interventions to reduce inequities in prostate cancer among Black men.Worldwide, men of African ancestry demonstrate worse outcomes in prostate cancer, a phenomenon driven largely by social factors that inform biologic, environmental, and health care risks. A conceptual model was presented that organizes the many factors that influence prostate cancer incidence and mortality. Within that framework, we must understand the current state of inequities in clinical prostate cancer practice, the optimal state of what equitable practice would be, and how achieving equity in prostate cancer care balances costs, benefits, and harms. More robust characterization of the sources of prostate cancer inequities should inform testing of ambitious and innovative interventions as we work toward equity in care and outcomes.Men of African ancestry demonstrate the highest rates of prostate cancer mortality, which may be reduced through social interventions. We present a framework for formalizing the identification of the drivers of prostate cancer inequities to facilitate the development of interventions and trials to eradicate them.

PURPOSE: To investigate the correlation between serum 25 hydroxyvitamin D, prostatic 25 hydroxyvitamin D, and serum 1,25 dihydroxyvitamin D, and their respective associations with prostatic tumor proliferation at the time of radical prostatectomy. METHODS: In this cross-sectional analysis of 119 men undergoing radical prostatectomy, serum from whole blood and expressed prostatic fluid was collected on the day of surgery. Tumor proliferation was measured in the dominant tumor on formalin-fixed prostatectomy tissues by immunohistochemical staining for Ki67 and quantified by Aperio imaging analysis. RESULTS: The sample included 88 African Americans (74%) and 31 (26%) European Americans. Serum and prostatic levels of 25 hydroxyvitamin D were correlated with each other (Spearman’s rho (ρ) = 0.27, p = 0.004), and there was also a correlation between serum 25 hydroxyvitamin D and 1,25 dihydroxyvitamin D (ρ = 0.34, p < 0.001). Serum and prostatic 25 hydroxyvitamin D levels were not correlated with Ki67 staining in tumor cells. Serum 1,25 dihydroxyvitamin D was inversely correlated with Ki67 staining in tumor cells (ρ = − 0.30, p = 0.002). On linear regression, serum 1,25 dihydroxyvitamin D was negatively associated with Ki67 staining in tumor cells (β = −0.46, 95% CI: −0.75, −0.04, p = 0.04). CONCLUSION: The correlation between physiologic serum levels of 25 hydroxyvitamin D with both prostatic 25 hydroxyvitamin D and serum 1,25 dihydroxyvitamin D suggests that serum levels are reasonable biomarkers of prostatic vitamin D status. Furthermore, serum 1,25 dihydroxyvitamin D has an inverse association with Ki67 staining in tumor cells at physiologic levels and may protect against tumor progression.

Summary The fibromuscular stroma of the prostate regulates normal epithelial differentiation and contributes to carcinogenesis in vivo. We developed and characterized a human 3D prostate organoid co-culture model that incorporates prostate stroma. Primary prostate stromal cells increased organoid formation and directed organoid morphology into a branched acini structure similar to what is observed in vivo. Organoid branching occurred distal to physical contact with stromal cells, demonstrating non-random branching. Stroma-induced phenotypes were similar in all patients examined, yet they maintained inter-patient heterogeneity in the degree of response. Stromal cells expressed growth factors involved in epithelial differentiation, which was not observed in non-prostatic fibroblasts. Organoids derived from areas of prostate cancer maintained differential expression of alpha-methylacyl-CoA racemase and showed increased viability and passaging when co-cultured with stroma. The addition of stroma to epithelial cells in vitro improves the ability of organoids to recapitulate features of the tissue and enhances the viability of organoids., Graphical Abstract, Highlights • Co-culture with human primary prostate stroma improves epithelial organoid viability • Stromal cell contact in co-culture directs epithelial organoid branching • Prostate stromal cells express morphogenic factors unique from non-prostate fibroblasts • Co-culture with stroma maintains AMACR and increases survival of cancer derived-organoids, Bioengineering; Biological Sciences; Cell Biology; Tissue Engineering

Background African American men (AAM) are under-represented in prostate cancer (PCa) research despite known disparities. Screening with prostate-specific antigen (PSA) has low specificity for high-grade PCa leading to PCa over diagnosis. The Prostate Health Index (PHI) has higher specificity for lethal PCa but needs validation in AAM. Engaging AAM as citizen scientists (CSs) may improve participation of AAM in PCa research.Results and Lessons Learned: Eight CSs completed all training modules and 139 AAM were recruited. Challenges included equity in research leadership among multiple principal investigators (PIs) and coordinating CSs trainings. Conclusions Engaging AAM CSs can support engaging/recruiting AAM in PCa biomarker validation research. Equity among multiple stakeholders can be challenging, but proves beneficial in engaging AAM in research. Objectives Assess feasibility of mobilizing CSs to recruit AAM as controls for PHI PCa validation biomarker study. Methods We highlight social networks/assets of stakeholders, CSs curriculum development/implementation, and recruitment of healthy controls for PHI validation.

Prostate cancer (PCa) is the second most frequent malignancy in men worldwide. This disease is the cause of most cancer death among Puerto Rican men, representing 18.9% of overall cancer deaths. However, a patient outcome depends on the type of tumor, which can be indolent or aggressive. The indolent PCa is of slow tumor growth and favorable prognosis, whereas the aggressive form is of rapid tumor spread and high mortality. The discrimination between the indolent and aggressive forms of PCa has resulted in a significant problem of overtreating those patients with the indolent form of the disease. Thus, biomarkers that aid in the decision-making process regarding active surveillance in very low-, low-, and favorable intermediate-risk PCa face a large unmet need. For this purpose, we evaluate the expression of phospho-Rb S249 and epithelial to mesenchymal transition markers (E-cadherin, N-cadherin, B-catenin) to create a combination that can help distinguish between the indolent and aggressive forms of PCa. We hypothesize that the biomarkers E-cadherin, and B-catenin could be useful to identify indolence among PCa patients, whereas phospho-Rb S249 and N-cadherin could identify the aggressive form of the disease. As part of our methodology, we have conducted immunohistochemistry (N=182) against the expression of these biomarkers on PCa tumor microarrays (TMA’s). Correlation coefficient analyses were conducted to assess if the expression of these biomarkers could correlate with any of the patient’s clinical parameters (stage, grade, tumor size, lymph nodes metastasis, metastasis to distant sites, Gleason score, and Gleason grade). In addition, we created a linear regression analysis to determine if the combined proteins could precisely predict the staging, grade, or Gleason score of the patients. Results have shown that the combination of phospho-Rb S249, N-cadherin, E-cadherin, and B-catenin had a precision of 68% correctly predicting the staging of the patients, and adding the tumor size, lymph nodes metastasis, and metastasis to distant sites to the equation increased the prediction to a 96%. Additionally, we identified that E-cadherin and B-catenin negatively correlated with the tumor size, grade, stage, Gleason grade, and Gleason score of the patients. Whereas N-cadherin and phospho-Rb S249 positively correlate with the tumor size, stage, and Gleason grade. These results suggest that the expression of phospho-Rb S249, N-cadherin, E-cadherin, and B-catenin could be used as a potential tool to discriminate between the indolent and aggressive forms of PCa. This will contribute to enhancing the clinical decision of which patients should be treated or undergo active surveillance. Citation Format: Sheila M. Valle Cortes, Pedro Santiago Cardona, Carlos Diaz Osterman, Harold Saavedra, Shannalee R. Martinez, Gilberto Ruiz Deya, Jaileene Perez Morales, Adam B. Murphy. Phosphorylation of the retinoblastoma protein at Serine 249 and the cadherin switch as clinically informative biomarkers for the discrimination between indolent and aggressive forms of prostate cancer [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 6001.

Objective To provide commentary on the disparities in access to clinical trials and precision oncology specific to Black men with Prostate Cancer (PCa) in the United States and lend a general framework to aid in closing these gaps. Materials and methods The ideas, commentaries and data presented in this narrative review were synthesized by utilizing qualitative and quantitative studies, reviews, and randomized control trials performed between 2010 and 2021. We searched PubMed using the key words "Medicaid", "Medicare", "clinical trials", "African Americans", "Black", "underrepresentation", "access", "Prostate Cancer", "minority recruitment", "racial disparities", "disparity", "genomics", "biomarkers", "diagnostic" "prognostic", "validation", "precision medicine", and "precision oncology" to identify important themes, trends and data described in the current review. Keywords were used alone and combination with both "AND" and "OR" terms. Results Black men with prostate cancer (PCa) in the United States have earlier onset of disease, present with more advanced stages, and worse prostate cancer-specific survival than their White counterparts. Potential causative factors vary from disparities in health care access to differences in tumor immunobiology and genomics along with disparate screening rates, management patterns and underrepresentation in clinical and translational research such as clinical trials and precision oncology. Conclusions To avoid increasing the racial disparity in PCa outcomes for Black men, we must increase inclusion of Black men into precision oncology and clinical trials, using multilevel change. Underrepresentation in clinical and translational research may potentiate poorly validated risk calculators and biomarkers, leading to poor treatment decisions in high-risk populations. Relevant actions include funding to include minority-serving institutions as recruitment sites, and inclusion of evidence based recruitment methods in funded research to increase Black representation in clinical trials and translational research.

In the version of this article originally published, the names of the equally contributing authors and jointly supervising authors were switched. The correct affiliations are: “These authors contributed equally: David V. Conti, Burcu F. Darst. These authors jointly supervised this work: David V. Conti, Rosalind A. Eeles, Zsofia Kote-Jarai, Christopher A. Haiman.” The error has been corrected in the HTML and PDF versions of the article.

International audience; Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

Introduction: Community Scientist (CS) programs — often referred to as Citizen Scientist programs — that facilitate direct engagement between scientific researchers and community members have emerged as effective strategies for building community trust in scientists and better informing research design and dissemination to address true community needs. While population health research has increasingly incorporated community stakeholders into the research continuum, basic and translational sciences struggle to do the same and may contribute to cancer disparities. We designed and implemented a virtual CS program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (LCC). We report barriers, facilitators, and lessons learned. Methods: Translational scientists (TSs) were recruited from among LCC investigators, and CSs were identified for participation from among LCC community networks. We sought to recruit a CS cohort representing LCC's catchment area and a TS cohort whose research focuses on cancers most impacting LCC catchment. CS program interactions included monthly meetings between two CSs and one TS wherein the CS-TS triad discuss TS research in lay terms and work together to co-create educational infographics suitable for dissemination to the catchment and LCC scientists. Virtual attendance was tracked and meeting recordings retroactively reviewed to identify and create product development. Results: Six CSs and three TSs agreed to participate in the CS program. The CS cohort includes cancer survivors, patient advocates, community organization leaders, a nurse, and an educator, while the TS cohort includes breast, prostate, and lung cancer researchers. Currently, 11 of 18 triad meetings have been completed, with attendance averaging 97%. Barriers to program implementation have included technological difficulties, restrictions on in-person meeting, scheduling conflicts, time limitation, and language barriers, while facilitators have included small group meetings to promote comfortable group-member contribution, presence of a trained facilitator, articulation of achievable meeting goals and mission for product creation, and clear assignment of team roles. Conclusion: The COVID-19 pandemic has illuminated pre-existing needs for improved connectivity between communities impacted by cancer disparities and cancer researchers. By identifying current barriers and facilitators to successful virtual CS program implementation, our findings can be used to guide development and implementation of similar programs at LCC and other cancer centers that are aimed at mitigating cancer health disparities. Citation Format: Will Dunne, Kai Holder, Kevin Wamala, Magdalena Nava, Laura Tom, Catherine O'Brian, Sharon Post, Carmen Velasquez, Candace Henley, Rosemarie Rogers, Joanne Glenn, Jose Lopez, Jorge Girotti, Qi Cao, Yanis Boumber, Deyu Fang, Tarneka Manning, Adam B. Murphy, Melissa A. Simon. Connecting cancer research and communities: Assessing barriers and facilitators to the implementation of a community scientist program [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-037.

Introduction and Objective: The low specificity of PSA in prostate cancer (PCa) screening has caused excessive biopsies and over-detection of PCa. The multi-parametric MRI (mpMRI) with its Prostate Imaging Reporting and Data Systems (PIRADS) score have emerged as an important tool to enhance detection of clinically significant PCa, i.e. Gleason grade group (GG) 2-5 PCa. Use of serum-based biomarkers, such as the Prostate Health Index (PHI), may be useful adjuncts to patients with lesions identified on mpMRI in detecting GG2-5 PCa and determining who would most benefit from a prostate biopsy. No study to date has investigated whether PHI improves accuracy of mpMRI in detecting GG2-5 PCa in biopsy-naïve men nor with adequate representation of Black men. The objective of this study was to determine the utility of PHI as a secondary reflex test to mpMRI in improving the accuracy for detecting GG2-5 PCa and improving specificity in a multi-ethnic biopsy-naïve population. Methods: From February 2017-2020, 143 men who were referred to participating urology clinics for elevated PSA levels were recruited into this prospective study and underwent both mpMRI and prostate biopsy. Enrolled men had to be between the ages of 40-79 years and prostate biopsy naïve to participate. Men with a history of a previous prostate cancer were excluded from the study. The mpMRI studies were blinded and read by two highly experienced genitourinary radiologists based on the standardized PIRADS criteria version 2.0. Logistic regression models were used to generate receiver operating characteristic curves. Models were tested for effect modification between Race and PHI and Race and PIRADS to determine if race impacted the prediction accuracy of either tool. The sensitivity, specificity, and predictive values of PHI thresholds were calculated by PIRADS scores. The primary outcome was GG2-5 PCa on biopsy, defined as any Gleason score ≥3+4. Results: The study included 143 men, of which 65 (45.5%) identified as Black. Median age was 62.0 years and 55 men (38.4%) had GG2-5 PCa. PIRADS risk groups were as follows: 18.1% PIRADS 1-2, 32.9% PIRADS 3, and 49.0% PIRADS 4-5. For the logistic regression models developed, the interactions between PIRADS and Race (p=0.08) and Log(PHI) and Race (p =0.17) variables were not statistically significant. A PHI score of ≥49 prevented unnecessary biopsies in 55% of men and missed zero cases of GG2-5 PCa, yielding a positive predictive value of 32.6% and negative predictive value of 100%. There was no reliable PHI threshold to exclude PCa biopsies in PIRADS 1-2 or 4-5. Conclusion: PHI and mpMRI of the prostate are independent predictors that aid in the detection of GG2-5 PCa in a Black enriched prostate biopsy cohort. PHI is particularly useful in men with equivocal PIRADS 3 lesions where a threshold of >49 safely avoids over 55% of unnecessary biopsies without missing GG2-5 PCa in our cohort. Citation Format: Samuel Carbunaru, Rilwan Babajide, Edward M. Schaeffer, Peter H. Gann, Adam B. Murphy. Predictive value of prostate health index (PHI) in multi-parametric MRI in an ethnically diverse cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2546.

BackgroundPredictive models that take race into account like the Prostate Cancer Prevention Trial Risk Calculator 2.0 (PCPT RC) and the new Prostate Biopsy Collaborative Group (PBCG) RC have been developed to equitably mitigate the overdiagnosis of prostate specific antigen (PSA) screening. Few studies have compared the performance of both calculators across racial groups.MethodsFrom 1485 prospectively recruited participants, 954 men were identified undergoing initial prostate biopsy for abnormal PSA or digital rectal examination in five Chicago hospitals between 2009 and 2014. Discrimination, calibration, and frequency of avoided biopsies were calculated to assess the performance of both risk calculators.ResultsOf 954 participants, 463 (48.5%) were Black, 355 (37.2%) were White, and 136 (14.2%) identified as Other. Biopsy results were as follows: 310 (32.5%) exhibited no cancer, 323 (33.9%) indolent prostate cancer, and 321 (33.6%) clinically significant prostate cancer (csPCa). Differences in area under the curve (AUC)s for the detection of csPCa between PCPT and PBCG were not statistically different across all racial groups. PBCG did not improve calibration plots in Blacks and Others, as it showed higher levels of overprediction at most risk thresholds. PCPT led to an increased number of avoidable biopsies in minorities compared to PBCG at the 30% threshold (68% vs. 28% of all patients) with roughly similar rates of missed csPCa (23% vs. 20%).ConclusionSignificant improvements were noticed in PBCG’s calibrations and net benefits in Whites compared to PCPT. Since PBCG’s improvements in Blacks are disputable and potentially biases a greater number of low risk Black and Other men towards unnecessary biopsies, PCPT may lead to better biopsy decisions in racial minority groups. Further comparisons of commonly used risk calculators across racial groups is warranted to minimize excessive biopsies and overdiagnosis in ethnic minorities.

Prostate cancer (PCa) disproportionately affects African American men. Early detection reduces risk of mortality. The United States Preventive Services Task Force (USPSTF) issued an updated recommendation statement on serum Prostate Specific Antigen (PSA)-based screening for PCa. Specifically, in 2012, the USPSTF recommended against PSA-based screening due to risk for overdiagnosis and overtreatment. However, the updated 2018 guidelines recommend consideration of screening for certain at risk men and revised the recommendation rating from “D” to “C.” This new guideline recommends providers to educate high-risk men on the benefits and harms of PSA-based PCa screening so that they can make an informed decision. The Affordable Care Act (ACA) includes provisions of service coverage for patient navigators who can help patients decide whether screening is appropriate, given potential risks and benefits, and training of health care providers in shared-decision regarding screening/treatment. These services can be utilized to support health care providers to better adhere to the new guideline. However, recommendations that are given a C rating or lower are not consistently reimbursed through many plans, including those offered through the ACA marketplace. The Society of Behavioral Medicine (SBM) supports the USPSTF guideline for the consideration of prostate cancer screening for high-risk men between the ages of 55 and 69. SBM encourages policymakers to include provisions for coverage of patient navigation services in the ACA to facilitate shared decision-making between providers and patients regarding screening.

Objectives Recent studies demonstrate vitamin D is inversely correlated with benign prostatic hyperplasia (BPH) and prostate cancer (PCa) incidence. We aim to clarify the associations of vitamin D with prostate volume. Methods This is an observational study investigating the associations of serum PSA, PSA Density (PSAD) and prostate volume with serum 25-hydroxyvitamin D (25-OH D) in PCa patients and men with negative biopsies seen in outpatient urology clinics in Chicago, IL. There were 571 men (40- to 79-years-old) with elevated PSA or abnormal digital rectal examination (DRE) with available prostate volume recorded from initial biopsy. The primary outcomes were the unadjusted associations of serum 25-hydroxyvitamin D deficiency with prostate volume. The secondary outcomes were the adjusted associations using linear and logistic regression analysis. Results On univariate analysis, serum 25-OH D < 20ng/ml inversely correlated with prostate volume among all men undergoing transrectal ultrasonography (p = 0.02), and this relationship remained significant for men with negative biopsy on stratified analysis. In adjusted models, controlling for age, serum PSA, 5-ARI use, obesity, and PCa diagnosis, prostate volume was inversely associated with vitamin D (p < 0.05) using serum vitamin D as a continuous and categorical variable. Logistic regression model also demonstrated an inverse association between vitamin D (continuous and categorical) and prostate volume ≥ 40 grams. Conclusion Serum 25-OH D levels are inversely associated with overall prostate volume and enlarged prostate gland (≥ 40 grams), especially in men with benign prostatic disease. Given the largely non-toxic effect of supplementation, consideration should be given to assessing vitamin D levels in men with benign prostatic disease in addition, to malignant prostatic disease.