Racial Disparities In Prostate Cancer Research Articles

Racial disparities in prostate cancer in the UK and the USA: similarities, differences and steps forwards.

In the USA, Black men are approximatelytwice as likely to be diagnosed with and to die of prostate cancer than white men. In the UK, despite Black men having vastly different ancestral contexts and health-care systems from Black men in the USA, the lifetime risk of being diagnosed with prostate cancer is two-to-three times higher among Black British men than among white British men and Black British men are twice as likely to die of prostate cancer as white British men. Examination of racial disparities in prostate cancer in the USA and UK highlights systemic, socio-economic and sociocultural factors that might contribute to these differences. Variation by ancestry could affect incidence and tumour genomics. Disparities in incidence might alsobe affected by screening guidelines and access to and uptake of screening. Disparities in treatment access, continuity of care and outcomes could contribute to survival differences. In both localized and metastatic settings, equal access could diminish the observed disparities in both the USA and the UK. An understanding of behavioural medicine, especially an appreciation of cultural beliefs about illness and treatment, could inform and improve the ways in which health systems can engage withand deliver care to patients in minoritized groups affected by prostate cancer. Methods of promotingequity include targeting systemic barriers including systemic racism,proportional recruitment of patients into clinical trials, diversifying the health-care workforce and facilitating care informed by cultural humility.Actively engaging patients and communities in research and intervention might enable the translation of research into increasingly equitable care for patients with prostate cancer in the UK, the USAand globally.

Nutrient Intakes in Prostate Cancer Survivors in the United States: A Nationally Representative Study

There are currently more than 3.3 million prostate cancer (PC) survivors in the United States. Conformance with national dietary guidelines and a good diet quality may lower the risk for Gleason grade progression in PC patients. Assessing the nutritional status of PC survivors is thus of paramount importance from a public health nutrition perspective. We used 24-h dietary recall data from the National Health and Nutrition Examination Surveys (NHANES) to systematically estimate nutrient intakes in n = 360 PC survivors (which may be extrapolated to represent n = 1,841,030 PC survivors) aged 70.69 years on average, and contrasted the results to the daily nutritional goals (DNG) in the 2020–2025 Dietary Guidelines for Americans (DGA). Diet quality in PC survivors was found to be generally poor, and the DNG as specified in the DGA were not met for many micronutrients, including calcium, magnesium and potassium. PC survivors had an insufficient intake of many vitamins (including vitamins A, C, D and E), and did not meet the intake recommendations for dietary fiber. Racial disparities in PC were reflected in the lower overall DQ in Non-Hispanic Black participants. Our results reiterate the need for nutritional assessment and counseling to improve DQ in PC patients.

Abstract A039: Joint roles of proteomics and neighborhood-level social determinants of metastatic prostate cancer

Abstract Introduction: Striking racial disparities in prostate cancer (PCa) outcomes among American Black men warrant significant efforts to identify early predictors of lethal PCa, to avoid over- treatment of clinically favorable disease with minimal risk of progression. Building on prior work, this study examined independent and joint roles of proteomic markers and social determinants of health (SDOHs) in predicting prostate disease aggressiveness in a racially diverse cohort of men undergoing prostate biopsy. Methodology: A retrospective cohort of 300 men biopsied for prostate cancer was assembled at University Hospitals (UH) Seidman Cancer Center in Cleveland, Ohio between January 1, 2005-May 2022. An extensive medical chart review was performed to identify Black and White men undergoing transrectal ultrasound- guided biopsy that resulted in: (i) a negative biopsy in patients with a history of 1+ prior negative biopsy and no PCa history (“NEG”); (ii) a biopsy-detected PCa of Gleason sum 6 (“GL6”); and (iii) biopsy-detected PCa with nodal and/or distant metastases at initial cancer detection (“METS”). Prostate biopsy tissues were obtained on each patient, balancing 100 men per biopsy group, and balanced on race (1:1) within each biopsy group. Informed by findings from an untargeted analysis of the entire proteome of 60 patients (“Discovery cohort”), we conducted a targeted proteomics analysis of 16 protein markers generated from prostate biopsy tissue, using mass spectrometry, on n=240 patients (“Verification cohort”). Chi-square testing and Analysis of Variance (ANOVA) were used to assess associations between protein expression, neighborhood-level SDOHs, and biopsy group. Race-stratified analyses were performed to examine statistical interactions between study associations. Principal components (PC) analysis was used to identify protein markers that predicted the greatest variance in biopsy group. Multivariable logistic regression (MLR) was used to predict METS (vs. NEG and GL6, combined), as a function of PC-selected protein markers and census block-group level area deprivation index (ADI). Bonferroni correction was used to establish the threshold for the decision rule of statistical significance (alpha error 0.05/16 markers: p< 0.0031). Results: Median patient age was 68 years. Protein expression distributions were transformed into quintiles due to non-normality. Of 16 protein markers, 14 were significantly correlated with biopsy group, including PARP 1 and TGFB1, for which METS patients had the highest expression. ADI was strongly correlated with race but not protein expression. ADI was significantly higher in METS patients, followed by GL6 and lowest in NEG group; however no associations were seen for ADI with protein expression. Eight proteins were found to predict METS in PC and MLR analysis. Conclusions: These data support use of proteomics markers to predict a metastatic versus non-metastatic biopsy result. Next steps include deep exploration of proteome findings generated in the Discovery cohort, such as biological pathways. Citation Format: Jennifer Cullen, Tao Liu, Holly Hartman, Fangzhou Liu, Anood Alfahmy, Rini Ghosh, Ayesha Shafi, Julia Payne, Randy Vince, Lee Ponsky, Gregory MacLennan. Joint roles of proteomics and neighborhood-level social determinants of metastatic prostate cancer [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A039.

Abstract C117: Integrative multi-omics profiling in patients of African descent diagnosed with prostate cancer reveals distinct tumor-promoting immunosuppressive niches at a single-cell level and spatial resolution

Abstract In the United States and globally, prostate cancer (PCa) mortality rates are the highest among men of African descent. 24% of the disparities in PCa remains even when controlled for access to care and stage at presentation. Moreover, the tumor microenvironment plays an essential role in tumor progression, aggressiveness, therapeutic response, and patient outcomes. Additionally, the association of the genomic findings with patient ancestry and other characteristics, such as tumor biology and transcriptomic alterations, remains poorly understood. Here, we performed a multi-Omics approach (N=447) to unravel the complexity of tumor heterogeneity and understand disease progression & distinct tumor biology influenced by genetic ancestry. We performed Whole Exome (Normal/tumor paired) Sequencing matched with Methyl Seq and Whole transcriptomic Sequencing for three datasets of our African, African American Men (AAM), and European Men (EAM). Additionally, we ran Spatial NanoString high-plex GeoMx-DSP for a total of 118 treatment-naive PCa patients (around 500 ROIs). Simultaneously, we added matched whole transcriptome Sequencing for these patients. The cohort comprised 87 AAM, 3 unknown, and 28 EAM self-reported individuals. To verify the self-reported race, the genomic ancestry was qualified using genotype and Admixture analysis. To further validate differentially expressed genes at the protein level, we performed multi-plex histological staining of 40 markers to determine the spatial resolution and neighborhood clustering within the tumor and the microenvironment. In parallel, we performed scMultiOmics sequencing (scRNA & scATAC-Seq) at a single-cell resolution (6000 cells/sample at 25K reads per cell) from an additional 12 patients (9 AAM & 3 EAM). We reconstructed a 3D model of the distinct tumor microenvironment at subcellular resolution using serially sectioned hematoxylin and eosin- stained tissue sections (CODA technology). Our results demonstrate that patients who self-report as AAM or Nigerian are assigned to high African (> 70%) Ancestry with either Yoruba (Nigeria) and/or Bantu subpopulation in the Sub-Saharan area. Additionally, high African Ancestry patients are diagnosed at a younger age and show advanced pathology stages compared to patients with European Ancestry. AAM of Yoruba descent expresses significantly higher immune-inflammatory signatures (STAT/IFNG-signaling pathway) compared to the Nigerian-Yoruba subpopulation. Our scRNA-Seq analysis shows that AAM has suppressive myeloid cells infiltrate within the tumor cells. The infiltrations of these cells change with age, Gleason Grade, and pathology stage. Moreover, AAM-tumor cells (scATAC-Seq) have increased open Chromatin accessibility with STAT motifs enrichment (p-value;0.0001), which could be the driver regulators of the immune-suppressive signature as well as influence the upregulation of STAT/IFNG signature within African Ancestry patients. Our study provides new insight into how genetic ancestry impacts immune signatures in AAM/African and contributes to PCa racial disparities. Citation Format: Isra Elhussin, Ezra Baraban1, Ashley Kiemen, Tamara L Lotan, Cathy Handy Marshall, Emmanuel Antonarakis, Moray J Campbell, Melissa Davis, Michael Dixon, Isaac Kim, Stefan Ambs, Rick Kittles, Adam B Murphy, Clayton Yates. Integrative multi-omics profiling in patients of African descent diagnosed with prostate cancer reveals distinct tumor-promoting immunosuppressive niches at a single-cell level and spatial resolution [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C117.

West African Genetic Ancestry, Neighborhood Deprivation, and Prostate Cancer

Racial disparities in prostate cancer are likely the result of complex relationships between both socioeconomic and environmental factors captured by the neighborhood environment and genetic factors, including West African genetic ancestry. However, few studies have examined the combined role of neighborhood environment and genetic ancestry in developing lethal prostate cancer. To examine the interactions between West African genetic ancestry and neighborhood deprivation in modifying prostate cancer risk and mortality. This case-control study was conducted in the Greater Baltimore area. Participants included men of African and European descent (617 cases with prostate cancer, 852 controls without prostate cancer) enrolled between January 2005 and January 2016. Follow-up was performed through December 31, 2020, using the National Death Index. Analysis was conducted from August 2023 to January 2024. Included exposures were West African genetic ancestry, derived from large-scale genotyping, and neighborhood deprivation, defined using 2000 census-tract-level Neighborhood Deprivation Index (NDI) score. Outcomes of interest were prostate cancer and all-cause mortality. Among a total of 1469 participants (mean [SD] age, 64.96 [7.95] years), there were 736 self-identified Black and 733 White men, and the mean (range) proportion of West African genetic ancestry was 0.27 (0.04-0.84) among participants residing in areas with low levels of deprivation and 0.48 (0.07-0.83) among participants residing in areas with high levels of deprivation. Multivariable logistic regression analysis revealed a significant multiplicative interaction of West African genetic ancestry and neighborhood deprivation with the odds of a prostate cancer diagnosis (P for interaction = .02). Among individuals living in neighborhoods with high NDI scores, West African genetic ancestry was associated with increased odds of a prostate cancer diagnosis (age-adjusted odds ratio [OR], 1.98; 95% CI, 1.23-3.19). In contrast, West African genetic ancestry was associated with reduced odds of this diagnosis among individuals residing in areas with medium to low levels of deprivation (age-adjusted OR, 0.22; 95% CI, 0.11-0.44). There was no significant multiplicative interaction between West African genetic ancestry and neighborhood deprivation for all-cause mortality (P for interaction = .44). The positive association of neighborhood deprivation with prostate cancer was independent of West African genetic ancestry (age- and West African ancestry-adjusted OR, 1,70; 95% CI, 1.50-1.94). This case-control study of men with West African and European ancestry found that West African genetic ancestry was associated with increased odds of prostate cancer among males who resided in neighborhoods with high deprivation but lower odds in more affluent neighborhoods. Thus, neighborhood environments may play a critical role in defining how genetic ancestry modulates prostate cancer risk.

Kataegis associated mutational processes linked to adverse prostate cancer presentation in African men.

Kataegis, the focal hypermutation of single base substitutions (SBS) in tumour genomes, has received little attention with respect to prostate cancer (PCa) associated molecular and clinical features. Most notably, data is lacking with regards to this tumour evolutionary phenomenon and PCa racial disparities, with African men disproportionately impacted. Here through comparison between African (n = 109) and non-African (n = 79) whole genome sequenced treatment naïve primary tumours, using a single analytical workflow we assessed for shared and unique features of kataegis. Linking kataegis to aggressive presentation, structural variant burden and copy number loss, we attributed APOBEC3 activity through higher rates of SBS2 to high-risk African tumours. While kataegis positive African patients presented with elevated prostate specific antigen levels, their tumours showed evolutionary unique trajectories marked by increased subclonal and structural variant-independent kataegis. The potential to exacerbate tumour heterogeneity emphases the significance of continued exploration of biological behaviours and environmental exposures for African patients.

Racial disparity in prostate cancer: an outlook in genetic and molecular landscape.

Prostate cancer (PCa) incidence, morbidity, and mortality rates are significantly impacted by racial disparities. Despite innovative therapeutic approaches and advancements in prevention, men of African American (AA) ancestry are at a higher risk of developing PCa and have a more aggressive and metastatic form of the disease at the time of initial PCa diagnosis than other races. Research on PCa has underlined the biological and molecular basis of racial disparity and emphasized the genetic aspect as the fundamental component of racial inequality. Furthermore, the lower enrollment rate, limited access to national-level cancer facilities, and deferred treatment of AA men and other minorities are hurdles in improving the outcomes of PCa patients. This review provides the most up-to-date information on various biological and molecular contributing factors, such as the single nucleotide polymorphisms (SNPs), mutational spectrum, altered chromosomal loci, differential gene expression, transcriptome analysis, epigenetic factors, tumor microenvironment (TME), and immune modulation ofPCa racial disparities. This review also highlights future research avenues to explore the underlying biological factors contributing to PCa disparities, particularly in men of African ancestry.

Investigating MRI-Associated Biological Aspects of Racial Disparities in Prostate Cancer for African American and White Men.

Understanding the characteristics of multiparametric MRI (mpMRI) in patients from different racial/ethnic backgrounds is important for reducing the observed gaps in clinical outcomes. To investigate the diagnostic performance of mpMRI and quantitative MRI parameters of prostate cancer (PCa) in African American (AA) and matched White (W) men. Retrospective. One hundred twenty-nine patients (43 AA, 86 W) with histologically proven PCa who underwent mpMRI before radical prostatectomy. 3.0 T, T2-weighted turbo spin echo imaging, a single-shot spin-echo EPI sequence diffusion-weighted imaging, and a gradient echo sequence dynamic contrast-enhanced MRI with an ultrafast 3D spoiled gradient-echo sequence. The diagnostic performance of mpMRI in AA and W men was assessed using detection rates (DRs) and positive predictive values (PPVs) in zones defined by the PI-RADS v2.1 prostate sector map. Quantitative MRI parameters, including Ktrans and ve of clinically significant (cs) PCa (Gleason score ≥ 7) tumors were compared between AA and W sub-cohorts after matching age, prostate-specific antigen (PSA), and prostate volume. Weighted Pearson's chi-square and Mann-Whitney U tests with a statistically significant level of 0.05 were used to examine differences in DR and PPV and to compare parameters between AA and matched W men, respectively. A total number of 264 PCa lesions were identified in the study cohort. The PPVs in the peripheral zone (PZ) and posterior prostate of mpMRI for csPCa lesions were significantly higher in AA men than in matched W men (87.8% vs. 68.1% in PZ, and 89.3% vs. 69.6% in posterior prostate). The Ktrans of index csPCa lesions in AA men was significantly higher than in W men (0.25 ± 0.12 vs. 0.20 ± 0.08 min-1; P < 0.01). This study demonstrated race-related differences in the diagnostic performances and quantitative MRI measures of csPCa that were not reflected in age, PSA, and prostate volume. 3 TECHNICAL EFFICACY: Stage 2.

PARP-ish: Gaps in Molecular Understanding and Clinical Trials Targeting PARP Exacerbate Racial Disparities in Prostate Cancer.

PARP is a nuclear enzyme with a major function in the DNA damage response. PARP inhibitors (PARPi) have been developed for treating tumors harboring homologous recombination repair defects that lead to a dependency on PARP. There are currently three PARPi approved for use in advanced prostate cancer, and several others are in clinical trials for this disease. Recent clinical trial results have reported differential efficacy based on the specific PARPi utilized as well as patient race. There is a racial disparity in prostate cancer, in which African American males are twice as likely to develop and die from the disease compared with European American males. Despite the disparity, there continues to be a lack of diversity in clinical trial cohorts for prostate cancer. In this review, PARP nuclear functions, inhibition, and clinical relevance are explored through the lens of racial differences. This review will touch on the biological variations that have been explored thus far between African American and European American males with prostate cancer to offer a rationale for investigating PARPi response in the context of race at both basic science and clinical development levels.

Abstract 7467: Multi-omics analysis reveals high chronic inflammation in African Americans compared to Native African Men with prostate cancer

Abstract Men of African descent have the highest prostate cancer (PCa) mortality rates in the United States and globally. Studies suggested that tumor subtypes or gene expression profiles had the greatest influence on overall racial/ethnic survival, accounting for 24% of the disparities in PCa and remains even when controlled for access to care and stage at presentation. Moreover, the tumor microenvironment plays an essential role in tumor progression, aggressiveness, therapeutic response, and patient outcomes. Additionally, the association of the genomic findings with patient ancestry and other characteristics, such as tumor biology and transcriptomic alterations, remains poorly understood. Here, we performed a multi-Omics approach (N=447) to unravel the complexity of tumor heterogeneity and understand disease progression &amp; distinct tumor biology influenced by genetic ancestry. We performed Whole Exome (Normal/tumor paired) Sequencing matched with Methyl Seq and Whole transcriptomic Sequencing for three datasets of our African, African American Men (AAM), and European Men (EAM). Additionally, we ran Spatial NanoString high-plex GeoMx-DSP at the protein and RNA levels for a total of 118 treatment-naive PCa patients (around 500 ROIs). Simultaneously, we added matched genome-wide Sequencing (whole transcriptome) for these patients. The cohort comprised 87 AAM, 3 unknown, and 28 EAM self-reported individuals. To verify the self-reported race, the genomic ancestry was qualified using genotype and Admixture analysis. To further validate differentially expressed genes at the protein level, we performed multi-plex histological staining of 40 markers to determine the spatial resolution and neighborhood clustering within the tumor and the microenvironment. In parallel, we performed scMultiOmics sequencing (scRNA &amp; scATAC-Seq) at a single-cell resolution (6000 cells/sample at 25K reads per cell) from an additional 12 patients (9 AAM &amp; 3 EAM). Our results demonstrate that patients who self-report as AAM or Nigerian are assigned to high African (&amp;gt; 70%) Ancestry with either Yoruba (Nigeria) and/or Bantu subpopulation in the Sub-Saharan area. Additionally, high African Ancestry patients are diagnosed at a younger age and show advanced pathology stages compared to patients with European Ancestry. AAM with Yoruba descent express significantly higher immune-inflammatory signatures (IFNG-signaling pathway) compared to the Nigerian-Yoruba subpopulation. Our scRNA-Seq analysis shows that AAM has myeloid cells that infiltrate within the tumor cells. The infiltrations of these cells change with age, Gleason Grade, and pathology stage. Our study provides new insight into how genetic ancestry impacts immune signatures in AAM/African and contributes to PCa racial disparities. Citation Format: Isra Elhussin, Ezra Baraban, Tamara L. Lotan, Cathy Handy Marshall, Emmanuel Antonarakis, Moray J. Campbell, Melissa Davis, Michael Dixon, Isaac Kim, Stefan Ambs, Rick Kittles, Adam B. Murphy, Clayton Yates. Multi-omics analysis reveals high chronic inflammation in African Americans compared to Native African Men with prostate cancer [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 7467.

Abstract B004: Dealing with prostate cancer racial disparity: Galeterone and next-generation galeterone analog VNPP433-3β potently inhibits proliferation of prostate cancer cells from African American patient by degrading AR and Mnk1/2

Abstract Prostate cancer incidence and mortality rates are remarkably higher in African-American (AA) men as compared to their European-American (EA) counterparts even after factoring in socio economic status. The disproportionate incidence of prostate cancer and associated mortality in African men is currently becoming more evident as Several studies have reported significant variations in genetic, molecular, epigenetic, microRNA, and cell signaling pathways in patients of Caucasian and African race. As androgen is implicated in prostate cancer progression and about 90% of the cases are Androgen-dependent, blocking androgen action is an effective strategy in treating prostate cancer. Previously, we reported that galeterone and VNPP433-3β, a next generation galeterone analog potently inhibit metastatic castration resistant prostate cancer of Caucasian origin in vitro and in vivo by degrading AR/AR-V7 and Mnk1/2. Since the prostate cancer patients of African descent express significant levels of AR and Mnk1/2, we investigated the efficacy of galeterone and VNPP433-3β in treating prostate cancer of African men. Cell proliferation assay using the cell lines MDA-PCa 2b and RC77 T/E derived from AA prostate cancer patient demonstrates that galeterone and VNPP433-3β can effectively inhibit prostate cancer of African descent at very low concentration. These cell lines are Androgen-sensitive and further biochemical studies reveal that galeterone and VNPP433-3β degrade AR and Mnk1/2 in RC77 T/E and MDA-PCa 2b cell lines, thereby inhibiting its proliferation. Galeterone and VNPP433-3β significantly decrease the half-life of AR in these cell lines by increasing the rate of ubiquitination and proteasomal degradation of AR. Therefore, galeterone and VNPP433-3β hold significant promise for the clinical management of prostate cancer in patients of African descent Citation Format: Elizabeth Thomas, Retheesh Sulochana Thankan, Puranik Purushottachar, Vincent C.O. Njar. Dealing with prostate cancer racial disparity: Galeterone and next-generation galeterone analog VNPP433-3β potently inhibits proliferation of prostate cancer cells from African American patient by degrading AR and Mnk1/2 [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 B004.

Abstract B111: Population genetics identifies distinct subsets of prostate cancer risk variants between men of European, African and East Asian ancestry

Abstract Introduction Genome-wide association studies (GWAS) have identified Single Nucleotide Polymorphisms (SNPs) or variants associated with prostate cancer risk. The contribution of human genetic variation to racial disparities in prostate cancer is still not clearly understood. Men of African ancestry have the highest risk of prostate cancer, followed by European ancestry and lowest in men with East Asian ancestry. Prostate cancer is the most common cancer in human males, but non-human large primates do not develop prostate cancer naturally. This study investigated the population genetics of prostate cancer SNPs to identify those that were unique to ancestral groups, and also comparative genomics of human risk alleles and orthologous alleles in primates. Methods Prostate cancer SNPs were obtained from previous GWAS studies in the GWAS Catalog (https://www.ebi.ac.uk/gwas/home), and the GWAS Diversity Monitor Database (https://gwasdiversitymonitor.com). SNPs identified from discovery stages in AFR and EAS populations were included even when they did not replicate in EUR populations. Using Ensemble Release 109 (https://www.ensembl.org), the risk allele frequencies (RAF) in European (EUR), African (AFR) and East Asian (EAS) populations were obtained from the 1000 Genomes project and other population genetics data available on Ensembl. Population RAFs were used to identify variants that were present in only one ancestral group and not shared by other ancestral groups. A SNP was considered unique to a population if it was present in &amp;gt;1% of that population, but present in &amp;lt;.01% of the others. The risk alleles in Homo sapiens were compared to the orthologous ancestral primate allele using genome alignments from 10 primate species. Results 520 prostate cancer-associated SNPs were identified. 484 were shared between EUR, AFR and EAS populations. 10 SNPs were unique to EUR (on chromosomes 1, 2, 5, 8, 11, 17, 21, 22), 19 to AFR (on chromosomes 1, 5, 6, 8, 13, 17, 22) and 7 to EAS (on chromosomes 2, 10, 12, 13) populations. The gene sets involved by these SNPs were different in each ancestral group, with some overlap between EUR and AFR genes sets, but no overlap with the EAS genes set. The risk allele for all the 36 SNPs that were unique to EUR, AFR or EAS populations was different from the ancestral primate allele. Conclusion Prostate cancer SNPs unique to EUR, AFR and EAS populations were identified and are likely to be driving the genetic component of prostate cancer racial disparities. The genes involved were different between populations, which could have biological consequences and lead to distinct cancer phenotypes in men from different ancestral groups. The unique SNPs all had alleles different from the ancestral primate allele, suggesting that these variants emerged after human speciation and ‘Out of Africa’ human migration events. Citation Format: Chidi N. Molokwu, Evi O. Useh, Suresh Venugopal. Population genetics identifies distinct subsets of prostate cancer risk variants between men of European, African and East Asian ancestry [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 B111.

Abstract A106: Examining the role of social connection on allostatic load and quality of life in African American prostate cancer survivors

Abstract Background. Racial disparities in prostate cancer (PC) survivorship persist despite clinical advancements. Chronic stress may contribute to these disparities, with allostatic load (AL) considered a measure of such stress. Associations between AL and survivorship outcomes such as quality of life (QoL) are documented, yet less is known about factors influencing these relationships. Social connections (SC) (e.g., social networks, social support) are associated with improved QoL in survivors, yet which aspects of SC and which pathways linking SC to QoL remain unclear. Additionally, little is known about the SC of African American PC survivors (AAPCS) and how these relate to QOL, stress, and AL. This study explores the relationship between SC, stress (perceived and AL) and QOL in in 48 AAPCS enrolled in Men Moving Forward, a randomized trial to improve body composition through lifestyle change. Methods. At baseline, participants completed surveys including: the Cohen Social Network Index assessing 3 aspects of social networks: network size (# of ties with regular contact), diversity (# of roles with regular contact) and embeddedness (# of domains with 4 or more regular contacts); Patient-Reported Outcomes Measurement Information System (PROMIS) measures of social support (companionship, emotional and informational support); the perceived stress scale, and PROMIS measures of physical function, anxiety, depression, fatigue, sleep disturbance, social function, and pain intensity. The latter were used to generate summative physical (PQOL) and mental (MQOL) health standardized T-scores (U.S. population mean=50, SD=10). AL scores used 15 criterion reflecting neuroendocrine, cardiovascular, immune, and metabolic systems. Each criterion was assigned a score of 0 or 1: 1 if in the high-risk range based on clinical guidelines. An index score was generated by summing high-risk indicators. Pearson correlations were used to explore the relationship between aspects of SC and QOL and SC and stress variables. Results. The average AL score was 5.8 (SD ± 2.3) of a maximum 15. No significant correlations were found between any SC domains and AL. However, negative associations were identified between network size (r=-.313, p=0.030), emotional support (r=-.319, p = 0.027), companionship (r=-.313, p=0.030) and perceived stress. A positive association was found between loneliness and perceived stress (r=.521, p&amp;lt;0.000). MQOL was positively related to network size (r=.364, p=0.011), emotional support (r=.366, p=0.011), and companionship (r=.288, p=0.047). Loneliness was negatively associated with MQOL (r=-.626, p&amp;lt;0.000) and PQOL (r=-.407, p=0.006). Conclusions. These findings suggest SC has a positive impact on survivorship in AAPCS, and that structural and functional aspects of SC may be involved. Currently, limited resources are available for PC survivors, and even fewer are tailored for AAPCS. Future efforts to improve survivorship for AAPCS should consider assessing social networks and access to social support when initiating survivorship care. Citation Format: Iwalola A. Awoyinka, Kathryn Flynn, Deepak Kilari, Kathryn Bylow, Jennifer Knight, Jamila Kwarteng, Anjishnu Banerjee, Kirsten M. Beyer, Staci Young, Patricia Sheean, Paula Papanek, Melinda Stolley. Examining the role of social connection on allostatic load and quality of life in African American prostate cancer survivors [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 A106.

Abstract C086: Prostate cancer: Integrative multi-omics profiling in patients of African descent

Abstract In the United States and globally, prostate cancer (PCa) mortality rates are highest among men of African descent. Previous studies suggested that tumor subtypes or gene expression profiles had the greatest influence on overall racial/ethnic survival accounting for 24% of the disparities in PCa and remains even when controlled for access to care and stage at presentation. Moreover, the tumor microenvironment plays an essential role in tumor progression, aggressiveness, therapeutic response, and patient outcomes. Additionally, the association of the genomic findings with patient ancestry and other characteristics, such as tumor biology and transcriptomic alterations, remains poorly understood. Here we performed a multi-Omics approach to unravel the complexity of tumor heterogeneity and understand disease progression &amp; distinct tumor biology influenced by genetic ancestry. We performed Spatial NanoString high-plex GeoMx-DSP (Digital Spatial Profiler) at the protein and RNA levels for a total of 118 treatment-naive PCa patients (around 500 ROIs). Simultaneously, we ran matched genome-wide sequencing (whole transcriptome) for these patients. The cohort comprised 87 AAM, 3 unknown, and 28 EAM self-reported individuals. To verify the self-reported race, the genomic ancestry was qualified using genotype and Admixture analysis. To further validate differentially expressed genes at the protein level, we performed multi-plex histological staining of 40 markers to determine the spatial resolution and neighborhood clustering within the tumor and the microenvironment. In parallel, we performed scMultiOmics sequencing (scRNA &amp; scATAC-Seq) at a single-cell resolution (6000 cells/sample at 25K reads per cell) from an additional 12 patients (9 AAM &amp; 3 EAM). We will use the multi-omics integration method (CoGap) to build a structural, spatial map that reflects tissue/system phenotype and to understand the complementary role of multi-omics (genome, transcriptome, and metabolite) interrelation/influence on the disease processes. Our results demonstrate that patients who self-report as AAM or Nigerian are assigned to high African (&amp;gt; 70%) Ancestry with either Yoruba (Nigeria) and/or Bantu subpopulation in the Sub-Saharan area. Additionally, high African Ancestry patients are diagnosed at a younger age and show advanced pathology stages compared to patients with European Ancestry. Moreover, AAM with high African Ancestry has significantly (p-value 0.05) higher CD8 +ve cells infiltration. Interestingly, segmentation and gating of the immune cell populations showed increased expression of CD8+ve cells colocalization with PD-1 signaling within African Ancestry patients. Our study provides new insight into how genetic ancestry impacts immune signatures in AAM and contributes to PCa racial disparities. Our findings could lead to new therapeutic strategies using immune modulators drugs to decrease the global disease burden, especially among men at high risk for PCa, such as AAM of African descent. Citation Format: Isra Elhussin, Ezra Baraban, Tamara L. Lotan, Cathy Handy Marshall, Emmanuel Antonarakis, Moray J. Campbell, Melissa Davis, Michael Dixon, Isaac Kim, Stefan Ambs, Rick Kittles, Adam B. Murphy, Clayton Yates. Prostate cancer: Integrative multi-omics profiling in patients of African descent [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 C086.

Survival Outcomes by Race and Ethnicity in Veterans With Nonmetastatic Castration-Resistant Prostate Cancer

Racial and ethnic disparities in prostate cancer are poorly understood. A given disparity-related factor may affect outcomes differently at each point along the highly variable trajectory of the disease. To examine clinical outcomes by race and ethnicity in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) within the US Veterans Health Administration. A retrospective, observational cohort study using electronic health care records (January 1, 2006, to December 31, 2021) in a nationwide equal-access health care system was conducted. Mean (SD) follow-up time was 4.3 (3.3) years. Patients included in the analysis were diagnosed with prostate cancer from January 1, 2006, to December 30, 2020, that progressed to nmCRPC defined by (1) increasing prostate-specific antigen levels, (2) ongoing androgen deprivation, and (3) no evidence of metastatic disease. Patients with metastatic disease or death within the landmark period (3 months after the first nmCRPC evidence) were excluded. The primary outcome was time from the landmark period to death or metastasis; the secondary outcome was overall survival. A multivariate Cox proportional hazards model, Kaplan-Meier estimates, and adjusted survival curves were used to evaluate outcome differences by race and ethnicity. Of 12 992 patients in the cohort, 826 patients identified as Hispanic (6%), 3671 as non-Hispanic Black (28%; henceforth Black), 7323 as non-Hispanic White (56%; henceforth White), and 1172 of other race and ethnicity (9%; henceforth other, including American Indian or Alaska Native, Asian, Native Hawaiian or Other Pacific Islander, unknown by patient, and patient declined to answer). Median time elapsed from nmCRPC to metastasis or death was 5.96 (95% CI, 5.58-6.34) years for Black patients, 5.62 (95% CI, 5.11-6.67) years for Hispanic patients, 4.11 (95% CI, 3.96-4.25) years for White patients, and 3.59 (95% CI, 3.23-3.97) years for other patients. Median unadjusted overall survival was 6.26 (95% CI, 6.03-6.46) years among all patients, 8.36 (95% CI, 8.0-8.8) years for Black patients, 8.56 (95% CI, 7.3-9.7) years for Hispanic patients, 5.48 (95% CI, 5.2-5.7) years for White patients, and 4.48 (95% CI, 4.1-5.0) years for other patients. The findings of this cohort study of patients with nmCRPC suggest that differences in outcomes by race and ethnicity exist; in addition, Black and Hispanic men may have considerably improved outcomes when treated in an equal-access setting.

Exploring the Association Between Online Health Information and Racial Disparities in Prostate Cancer

Exploring the Association Between Online Health Information and Racial Disparities in Prostate Cancer

Deregulated microRNAs Involved in Prostate Cancer Aggressiveness and Treatment Resistance Mechanisms.

Prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer deaths among American men. Complex genetic and epigenetic mechanisms are involved in the development and progression of PCa. MicroRNAs (miRNAs) are short noncoding RNAs that regulate protein expression at the post-transcriptional level by targeting mRNAs for degradation or inhibiting protein translation. In the past two decades, the field of miRNA research has rapidly expanded, and emerging evidence has revealed miRNA dysfunction to be an important epigenetic mechanism underlying a wide range of diseases, including cancers. This review article focuses on understanding the functional roles and molecular mechanisms of deregulated miRNAs in PCa aggressiveness and drug resistance based on the existing literature. Specifically, the miRNAs differentially expressed (upregulated or downregulated) in PCa vs. normal tissues, advanced vs. low-grade PCa, and treatment-responsive vs. non-responsive PCa are discussed. In particular, the oncogenic and tumor-suppressive miRNAs involved in the regulation of (1) the synthesis of the androgen receptor (AR) and its AR-V7 splice variant, (2) PTEN expression and PTEN-mediated signaling, (3) RNA splicing mechanisms, (4) chemo- and hormone-therapy resistance, and (5) racial disparities in PCa are discussed and summarized. We further provide an overview of the current advances and challenges of miRNA-based biomarkers and therapeutics in clinical practice for PCa diagnosis/prognosis and treatment.

Abstract B036: Immune cell profiling of human prostate tumors identifies a protective and pathological role for intratumoral mast cells in the development of biochemical recurrence and metastasis

Abstract Background: Immunobiological factors may, in part, contribute to racial disparities in prostate cancer (PCa), the second leading cause of cancer-related death for US men. African American (AA) men face a greater risk of developing PCa and having a poorer outcome of this disease, compared to Caucasian American (CA) men. The goal of this study is to identify immune-specific differences influencing PCa health disparity as well as PCa progression. Methods: Ex vivo tumor biopsies were obtained following radical prostatectomy (RP) from 51 treatment-naïve patients (26 AA, 25 CA) under approved IRB protocols. Total RNA from fresh frozen tissue was isolated and amplified by PCR using NanoString multiplexed target enrichment protocols. We evaluated differences in resulting transcripts by self-reported race, pathology, and other clinical and pathologic features. Relative abundances of immune cell subsets were determined using computational methods, including previously published deconvolution algorithms, to estimate cellular content. Results: We identified differentially expressed genes between AA and CA tumors that are characterized by genes regulating Natural Killer (NK) cell function and Wnt signaling cancer pathways. Among the entire cohort, high expression of two of these differentially expressed genes, DVL2 and MAP3K5, were associated with worse biochemical recurrence (BCR)-free and metastasis-free survival. No difference in immune cell abundance was observed by self-reported race. Strikingly, among the entire cohort, low abundance of intratumoral mast cells was also associated with worse PCa pathology and poorer BCR-free and metastasis-free survival. Conclusions: Using a race-matched military cohort, we found that AA and CA tumors differ in the expression levels of Wnt and NK signaling-related pathways, yet cellular estimations of immune abundance did not significantly differ. Remarkably, the level of mast cell abundance within tumors at time of RP may be protective and prolong BCR-free and metastasis-free survival of patients. These types of in-depth immune profiling assessments have the potential to guide precision medicine and treatment decisions in the clinic. Disclaimer: The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of Uniformed Services University of the Health Sciences (USUHS), The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of Defense (DoD), the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. Citation Format: Cara Schafer, Jiji Jiang, Sally Elsamanoudi, Darryl Nousome, Denise Young, Yingjie Song, Isabell Sesterhenn, Gregory Chesnut, Shyh-Han Tan. Immune cell profiling of human prostate tumors identifies a protective and pathological role for intratumoral mast cells in the development of biochemical recurrence and metastasis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B036.

Racial differences in the utilization of MRI-guided biopsy before prostate cancer diagnosis.

5093 Background: Most low-risk prostate cancer (PCa) patients undergo active surveillance (AS). Compared with Whites, Blacks are more likely to opt for AS and suffer a higher risk of cancer progression while on AS. A primary concern of AS is the likelihood of missing clinically significant cancer. Transrectal ultrasound-guided biopsy is the most common method for diagnosing and grading PCa; however, this method often misses anterior PCa. Magnetic resonance imaging (MRI) allows clinicians to identify better and detect PCa; however, current guidelines on MRI-guided biopsy (MRI-GB) are inconsistent. This population-based study aimed to examine the utilization of MRI-GB 6 months before PCA diagnosis over time by race in the US. Methods: We used SEER-Medicare data to identify men diagnosed with PCa between January 1, 2012, to December 31, 2017, and excluded patients missing the date of diagnosis, being diagnosed at death, enrolled in HMO, or having no continuous A and B coverage six months before diagnosis. We used the CPT codes to identify prostate biopsy and MRI use. Multivariable logistic regression was used to evaluate racial disparity in MRI use six months before PCa. The model included covariates age, race, SEER region, marital status, state buy-in for Medicare (a poverty indicator), education, income, Charlson comorbidity index, and procedure (MRI) year. Results: Among 38,612 eligible men, MRI use six months before PCa diagnosis increased from 2012 to 2017 (3.2% to 24.3% among Whites, 1.8% to 14.2% among Blacks). Compared with Whites, Blacks were 38% less likely to receive pre-diagnosis MRI (OR=0.62, 95% CI 0.52-0.74). Besides race, having state buy-in for Medicare (OR=0.44; 95% CI 0.30-0.65) and geographic regions (Central vs. West OR=0.40; 95% CI 0.34-0.45) were strong predictors of lower utilization of MRI. Conclusions: The gap in the utilization of MRI may exacerbate racial disparities in PCa. Future studies are needed to identify potential barriers to adopting MRI for PCa workups.

Effect of type of definitive treatment on race-based differences in prostate cancer-specific survival.

Racial and ethnic disparities in prostate cancer (PCa)mortality are partially mediated by inequities in quality of care. Intermediate- and high-risk PCa can be treated with either surgery or radiation, therefore we designed a study to assess the magnitude of race-based differences in cancer-specific survival between these two treatment modalities. Non-HispanicBlack (NHB)and non-HispanicWhite (NHW)men with localized intermediate- and high-risk PCa, treated with surgery or radiation between 2004 and 2015 in the Surveillance, Epidemiologyand End Results database were included in the study and followed until December 2018. Unadjusted and adjusted survival analyses were employed to compare cancer-specific survival by race and treatment modality. A model with an interaction term between race and treatment was used to assess whether the type of treatment amplified or attenuated the effect of race/ethnicity on prostate cancer-specific mortality (PCSM). 15,178 (20.1%) NHB and 60,225 (79.9%) NHW men were included in the study. NHB men had a higher cumulative incidence of PCSM (p = 0.005) and were significantly more likely to be treated with radiation than NHW men (aOR: 1.89, 95% CI: 1.81-1.97,p < 0.001). In the adjusted models, NHB men were significantly more likely to die from PCa compared withNHW men (aHR: 1.18,95% CI:1.03-1.35, p = 0.014), and radiation was associated with a significantly higher odds of PCSM (aHR: 2.10,95% CI:1.85-2.38, p < 0.001) compared with surgery. Finally, the interaction between race and treatment on PCSM was not significant, meaning that no race-based differences in PCSM were found within each treatment modality. NHB men with intermediate- and high-risk PCa had a higher rate of PCSM than NWH men in a large national cancer registry, though NHB and NHW men managed with the same treatment achieved similar PCa survival outcomes. The higher tendency for NHB men to receive radiation was similar in magnitude to the difference in cancer survival between racial and ethnic groups.