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Background Personalized genomic classifiers have transformed the management of prostate cancer (PCa) by identifying the most aggressive subsets of PCa. Nevertheless, the performance of genomic classifiers to risk classify African American men is thus far lacking in a prospective setting. Methods This is a prospective study of the Decipher genomic classifier for National Comprehensive Cancer Network low- and intermediate-risk PCa. Study-eligible non–African American men were matched to African American men. Diagnostic biopsy specimens were processed to estimate Decipher scores. Samples accrued in NCT02723734, a prospective study, were interrogated to determine the genomic risk of reclassification (GrR) between conventional clinical risk classifiers and the Decipher score. Results The final analysis included a clinically balanced cohort of 226 patients with complete genomic information (113 African American men and 113 non–African American men). A higher proportion of African American men with National Comprehensive Cancer Network–classified low-risk (18.2%) and favorable intermediate-risk (37.8%) PCa had a higher Decipher score than non–African American men. Self-identified African American men were twice more likely than non–African American men to experience GrR (relative risk [RR] = 2.23, 95% confidence interval [CI] = 1.02 to 4.90; P = .04). In an ancestry-determined race model, we consistently validated a higher risk of reclassification in African American men (RR = 5.26, 95% CI = 1.66 to 16.63; P = .004). Race-stratified analysis of GrR vs non-GrR tumors also revealed molecular differences in these tumor subtypes. Conclusions Integration of genomic classifiers with clinically based risk classification can help identify the subset of African American men with localized PCa who harbor high genomic risk of early metastatic disease. It is vital to identify and appropriately risk stratify the subset of African American men with aggressive disease who may benefit from more targeted interventions.

Participation in cancer research trials by minority populations is imperative in reducing disparities in clinical outcomes. Even with increased awareness of the importance of minority patient inclusion in clinical research to improve cancer care and survival, significant barriers persist in accruing and retaining minority patients into clinical trials. This study sought to identify and address barriers to minority accrual to a minimal risk clinical research study in real-time.

Association of ICS subtypes and race in A. Discovery, B. DVAHS validation and C. TCGA dataset.

Table S1

Castration-resistant prostate cancer (CRPC) is a lethal stage of disease in which androgen receptor (AR) signaling is persistent despite androgen deprivation therapy (ADT). Most studies have focused on investigating cell-autonomous alterations in CRPC, while the contributions of the tumor microenvironment are less well understood. Here we sought to determine the role of tumor-associated macrophages in CRPC, based upon their role in cancer progression and therapeutic resistance. In a syngeneic model that reflected the mutational landscape of CRPC, macrophage depletion resulted in a reduced transcriptional signature for steroid and bile acid synthesis, indicating potential perturbation of cholesterol metabolism. As cholesterol is the precursor of the five major types of steroid hormones, we hypothesized that macrophages were regulating androgen biosynthesis within the prostate tumor microenvironment. Macrophage depletion reduced androgen levels within prostate tumors and restricted AR nuclear localization in vitro and in vivo. Macrophages were also cholesterol-rich and were able to transfer cholesterol to tumor cells in vitro. AR nuclear translocation was inhibited by activation of liver X receptor (LXR)-β, the master regulator of cholesterol homeostasis. Consistent with these data, macrophage depletion extended survival during ADT and the presence of macrophages correlated with therapeutic resistance in patient-derived explants. Taken together, these findings support the therapeutic targeting of macrophages in CRPC.Significance:These results suggest that macrophage-targeted therapies can be combined with androgen deprivation therapy to treat patients with prostate cancer by limiting cholesterol bioavailability and the production of intratumoral androgens.See related commentary by Al-Janabi and Lewis, p. 5399

Key resources

Abundance of lipids in macrophages and importance of mevalonate pathway in prostate cancer cells

Additional details on LC-MS/MS sample preparation and RNA sequencing

Purpose:The role of immune-oncologic mechanisms of racial disparities in prostate cancer remains understudied. Limited research exists to evaluate the molecular underpinnings of immune differences in African American men (AAM) and European American men (EAM) prostate tumor microenvironment (TME).Experimental Design:A total of 1,173 radiation-naïve radical prostatectomy samples with whole transcriptome data from the Decipher GRID registry were used. Transcriptomic expressions of 1,260 immune-specific genes were selected to assess immune-oncologic differences between AAM and EAM prostate tumors. Race-specific differential expression of genes was assessed using a rank test, and intergene correlational matrix and gene set enrichment was used for pathway analysis.Results:AAM prostate tumors have significant enrichment of major immune-oncologic pathways, including proinflammatory cytokines, IFNα, IFNγ, TNFα signaling, ILs, and epithelial–mesenchymal transition. AAM TME has higher total immune content score (ICSHIGH) compared with 0 (37.8% vs. 21.9%, P = 0.003). AAM tumors also have lower DNA damage repair and are genomically radiosensitive as compared with EAM. IFITM3 (IFN-inducible transmembrane protein 3) was one of the major proinflammatory genes overexpressed in AAM that predicted increased risk of biochemical recurrence selectively for AAM in both discovery [HRAAM = 2.30; 95% confidence interval (CI), 1.21–4.34; P = 0.01] and validation (HRAAM = 2.42; 95% CI, 1.52–3.86; P = 0.0001) but not in EAM.Conclusions:Prostate tumors of AAM manifest a unique immune repertoire and have significant enrichment of proinflammatory immune pathways that are associated with poorer outcomes. Observed immune-oncologic differences can aid in a genomically adaptive approach to treating prostate cancer in AAM.

BACKGROUND Native African men (NAM) experience a disproportionate burden of prostate cancer (PCa) and have higher mortality rates compared to European American men (EAM). While socioeconomic status has been implicated as a driver of this disparity, little is known about the genomic mechanisms and distinct biological pathways that are associated with PCa of native men of African origin. METHODS To understand biological factors that contribute to this disparity we utilized a total of 406 multi-institutional localized PCa samples, collected by Men of African Descent and Carcinoma of the Prostate biospecimen network and Moffitt Cancer Center/University of Pennsylvania Health science system. We performed comparative genomics and immunohistochemistry to identify the biomarkers that are highly enriched in NAM from west Africa and compared them with African American Men (AAM) and EAM. Quantified messenger RNA expression and Median H scores based on immune reactivity of staining cells, were compared using Mann Whitney test. For gene expression analysis, p values were further adjusted for multiple comparisons using false discovery rates. RESULTS Immunohistochemical analysis on selected biomarkers showed a consistent association between ETS related gene (ERG) status and race with 83% of NAM exhibiting tumors that lacked TMPRSS2-ERG translocation (ERGnegative ) as compared to AAM (71%) and EAM (52%). A higher proportion of NAM (29%) were also found to be double negative (ERGnegative and PTENLoss ) as compared to AAM (6%) and EAM (7%). NAM tumors had significantly higher immunoreactivity (H-score) for PSMA, and EZH2, whereas they have lower H-score for PTEN, MYC, AR, RB and Racemase, (all p

Racial disparities in prostate cancer have not been well characterized on a genomic level. Here we show the results of a multi-institutional retrospective analysis of 1,152 patients (596 African-American men (AAM) and 556 European-American men (EAM)) who underwent radical prostatectomy. Comparative analyses between the race groups were conducted at the clinical, genomic, pathway, molecular subtype, and prognostic levels. The EAM group had increased ERG (P, Walter Rayford, Alp Tuna Beksac et al. investigated gene expression alterations in African-American and European-American men who underwent radical prostatectomy for prostate cancer. The observed differences include higher expression of inflammation genes and lower expression of mismatch repair genes in African-American men.

Survival outcomes of grade group 5 (GG5) prostate cancer (PCa) after standard of care therapy (SOC) remain poor. Evidence suggest that high dose rate brachytherapy (HDR) and androgen depravation therapy (ADT) can serve as immune modulators. We hypothesize that the combination of HDR, ADT, and immune checkpoint inhibitors (ICI) may synergize to improve immune response and disease control. Here we report an interim analysis of a single-center single-arm phase II trial exploring this novel combination therapy with nivolumab for GG5 PCa. Patients were enrolled from 9/2018 to 4/2021 and required to have GG5 PCa with > 30% positive cores and receive ICI plus SOC regimen, comprising ADT, external beam RT (EBRT), and HDR. ICI (240 mg) was administered every 2 weeks for 4 doses beginning 4 weeks prior to HDR. HDR consisted of two 1150 cGy implants. EBRT followed HDR and consisted of 4500 cGy in 25 fractions. Total ADT length and elective nodal radiotherapy were per physician discretion. Biopsies were taken at time of diagnosis, HDR, and 1-month post HDR. Biopsy tumor samples underwent genomic profiling. Major pathologic response (MPR) was defined as < 17% positive cores. Wilcoxon test and Area Under the Curve (AUC) Receiver Operating Characteristics (ROC) curves were used for statistical analyses. Toxicity was evaluated according to CTCAE v5.0. The historic control cohort consisted of all patients treated with SOC between 1/2013 to 11/2021 and met all study inclusion/exclusion criteria. Cox regression was used to calculate 2-year (2Y) risk of metastasis with censorship at 24 months (m). Median follow up (mFUP) defined from diagnostic biopsy. Of 34 patients who received 2 or more doses of ICI, 1 patient (3%) experienced a dose limiting toxicity of autoimmune hepatitis (AH). The incidence of all grade 3 toxicity related to ICI at 3 and 6 months were both 3% (n=1; AH and QT prolongation, respectively). There was no grade 4+ toxicity at 3 m, nor any grade 3+ toxicity at 6 m. Two subjects were withdrawn from study, leaving 32 evaluable for clinical outcomes. mFUP of ICI cohort was 32 m with a 2Y PSA failure rate of 6%. CD8A, STING, ANPEP, and multiple immune signatures were associated with an early MPR (p < 0.05) with ICI. The Ricketts_Immunosuppression genomic signature strongly correlated with MPR to ICI (AUC = 0.7, p = 0.01). The control cohort consisted of 59 patients with a mFUP of 35 m and a 2Y PSA failure rate of 19%. ICI demonstrated an 88% reduction in 2Y risk of metastasis compared to controls (HR = 0.12, 95% CI, 0.02 - 1.0, p = 0.05). Combination of ICI with SOC for GG5 PCa is safe and associated with a clinically significant improvement in disease control. Key genomic features were identified to predict for early MPR to ICI. Ricketts_Immunosuppression was identified as a potential biomarker for ICI-sensitive tumor subtypes. Final analyses are anticipated in late 2023. Clinical trial information: NCT03543189. Citation Format: John Michael Bryant, Maria Sandoval, Ryan Putney, Corrado Caslini, Shivanshu Awasthi, Esther Katende, Angelina Fink, Syeda Mahrukh H Naqvi, Youngchul Kim, Jingsong Zhang, Jong Park, Amparo Serna, Julio Pow-Sang, Michael Poch, Roger Li, Brandon Manley, Arash Naghavi, Javier Torres-Roca, G. Daniel Grass, Sungjune Kim, Kujtim Latifi, Dylan Hunt, Peter A. Johnstone, Jasreman Dhillon, Rohit Jain, Daniel Fernandez, Kosj Yamoah. Combination of nivolumab with standard of care in the management of grade group 5 prostate cancer: Interim analysis of a phase II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT157.

Prostate cancer (PCa) is the second leading cause of cancer-related death in men in United States. African American men (AAM) have higher rates of PCa incidence and mortality compared with European American men (EAM). While socioeconomics, access to optimal care and life-style factors contribute towards these disparities, underlying biologic differences in AAM remain important drivers of PCa disparities. In the current work, we aimed to explore the interplay between oxidative stress and inflammatory signaling in promoting progression of PCa in AAM. Oxidative stress results from excessive reactive oxygen species (ROS) generated mainly via membrane bound oxidases, peroxisomes or the mitochondrial electron transport chain (ETC). We performed a robust comparative genomics to determine whether there is a race dependent expression of genes related to ROS in publicly available PCa datasets. We then prospectively examined the differential gene expression of these genesets in PCa from clinically matched AAM and EAM in the VANDAAM prospective study. VANDAAM is a validation study of DecipherTM genomic testing in 243 men with localized PCa. We then combined computational and experimental approaches to explore the molecular mechanisms and consequences of exacerbated oxidative stress. We found that ETC complex I, III related genes are the most differentially expressed in AAM compared with EAM. To examine whether AAM vs EAM cell lines exhibits differential sensitivity to ETC modulation, we blocked key ETC enzymes using complex I inhibitor, rotenone, and complex III inhibitor, antimycin A. We used 2 types of mitochondria-specific labels that distinguish respiring and ROS-generating mitochondria. While the relative levels of respiring mitochondria remain constant, we found that antimycin A induced higher level of mitochondrial ROS in AAM PCa cell lines compared with EAM PCa cell lines. To understand the interplay between mitochondrial ETC complex I & III and immune microenvironment, we computed the correlational discordance of ETC complex I & III expression scores and expression of >1200 immune-related genes between AAM vs EAM in VANDAAM cohort. These analyses suggest that ETC complex I & III correlate with several immunosuppressive genes including the macrophage markers CD68 and CD163 and T cell exhaustion markers. In addition, intersecting discordant genes from several datasets suggests enrichment of inflammatory cytokines and type I interferon signature which we then validated using ex vivo culture of PCa tissues. In summary, we discovered a role of mitochondrial electron transport chain in regulating inflammatory circuits in PCa of AAM. Unraveling roles of mitochondria in promoting immune suppression will have significant impact on understanding the intersection between social pressures and biological stress responses. Citation Format: Asmaa El-Kenawi, Ryan Putney, Shivanshu Awasthi, Amparo Serna, Corrado Caslini, Jasreman Dhillon, Kosj Yamoah. Stress-mediated reactive oxygen species from mitochondria dysregulates the tumor microenvironment in prostate cancer of African American men [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 1956.

Purpose: The role of immune-oncologic mechanisms of racial disparities in prostate cancer remains understudied. Limited research exists to evaluate the molecular underpinnings of immune differences in African American men (AAM) and European American men (EAM) prostate tumor microenvironment (TME). Experimental Design: A total of 1,173 radiation-naïve radical prostatectomy samples with whole transcriptome data from the Decipher GRID registry were used. Transcriptomic expressions of 1,260 immune-specific genes were selected to assess immune-oncologic differences between AAM and EAM prostate tumors. Race-specific differential expression of genes was assessed using a rank test, and intergene correlational matrix and gene set enrichment was used for pathway analysis. Results: AAM prostate tumors have significant enrichment of major immune-oncologic pathways, including proinflammatory cytokines, IFNα, IFNγ, TNFα signaling, ILs, and epithelial–mesenchymal transition. AAM TME has higher total immune content score (ICSHIGH) compared with 0 (37.8% vs. 21.9%, P = 0.003). AAM tumors also have lower DNA damage repair and are genomically radiosensitive as compared with EAM. IFITM3 (IFN-inducible transmembrane protein 3) was one of the major proinflammatory genes overexpressed in AAM that predicted increased risk of biochemical recurrence selectively for AAM in both discovery [HRAAM = 2.30; 95% confidence interval (CI), 1.21–4.34; P = 0.01] and validation (HRAAM = 2.42; 95% CI, 1.52–3.86; P = 0.0001) but not in EAM. Conclusions: Prostate tumors of AAM manifest a unique immune repertoire and have significant enrichment of proinflammatory immune pathways that are associated with poorer outcomes. Observed immune-oncologic differences can aid in a genomically adaptive approach to treating prostate cancer in AAM.

African American men (AA) are more than twice as likely to die of prostate cancer (PCa) compared to European American men (EA). Among many contributing factors, unraveling the metabolic derangements in PCa of AA holds a promise in reducing health disparity. We recently discovered that aminopeptidase N (ANPEP, CD13) represents one of the differentially expressed genes in PCa of AA compared with EA. While ANPEP plays regulatory and/or modulatory functions in many immune and metabolic pathological conditions, its role in PCa remains unknown. We sought to investigate the metabolic functions of ANPEP in PCa development and exploit its role as a therapeutic vulnerability, particularly in AA men. Accordingly, we prospectively examined the differential gene expression of PCa from clinically matched AA and EA in the VANDAAM clinical trial. The VANDAAM study is a validation study of DecipherTM genomic testing in 240 men with localized PCa. Our findings indicate that ANPEP is the top differentially expressed gene between AA and EA men. To explore the molecular mechanisms of ANPEP in PCa in unbiased fashion, we combined computational and experimental approaches. Our preliminary computational analyses revealed that ANPEP correlates with signatures of cholesterol transport, estrogen and androgen receptor (AR) signaling. Based on our recent study demonstrating dominance of these signatures in macrophage-rich PCa, we reasoned that ANPEP expression may be driven in part by high macrophage infiltration in AA. Thus, we compared immune cell repertoire in patients with high ANPEP and low ANPEP by deconvoluting immune cell content using the in silico approach, CIBERSORT. These analyses illustrated that only AA patients with high ANPEP expression significantly accumulated high content of M1 inflammatory macrophages. Immune phenotyping of prostate tumors demonstrated that ANPEP indeed represents a marker of M1 inflammatory macrophages and tumor-associated macrophages. In conclusion, these findings suggest that ANPEP is a macrophage related protein in PCa with a potential role in cholesterol transport and / or androgen signaling. Future work will focus on the functional role of ANPEP activity in the tumor immune microenvironment using Liquid chromatography-high resolution mass spectrometry (LC-HRMS) and explants derived from AA and EA prostate cancer patients. Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

BACKGROUND In prostate cancer (PCa), lack of androgen receptor (AR) regulated TMPRSS2-ETS-related gene (ERG) gene fusion (ERGnegative ) status has been associated with African American race; however, the implications of ERG status for the location of dominant tumors within the prostate remains understudied. METHODS An African American-enriched multiinstitutional cohort of 726 PCa patients consisting of both African American men (AAM; n = 254) and European American men (EAM; n = 472) was used in the analyses. Methods of categorical analysis were used. Messenger RNA (mRNA) expression differences between anterior and posterior tumor lesions were analyzed using Wilcoxon rank-sum tests with multiple comparison corrections. RESULTS Anti-ERG immunohistochemistry staining showed that the association between ERG status and anterior tumors is independent of race and is consistently robust for both AAM (ERGnegative 81.4% vs. ERGpositive 18.6%; p = .005) and EAM (ERGnegative 60.4% vs. ERGpositive 39.6%; p

BACKGROUND: To determine whether combining brachytherapy with immunotherapy is safe in prostate cancer (PCa) and provides synergistic effects, we performed a Phase I/II trial on the feasibility, safety, and benefit of concurrent delivery of anti-PD-1 (nivolumab) with high-dose-rate (HDR) brachytherapy and androgen deprivation therapy (ADT) in patients with Grade Group 5 (GG5) PCa. METHODS: Eligible patients were aged 18 years or older with diagnosis of GG5 PCa. Patients received ADT, nivolumab every two weeks for four cycles, with two cycles prior to first HDR, and two more cycles prior to second HDR, followed by external beam radiotherapy. The primary endpoint was to determine safety and feasibility. This Phase I/II trial is registered with ClinicalTrials.gov (NCT03543189). RESULTS: Between September 2018 and June 2019, six patients were enrolled for the Phase I safety lead-in with a minimum observation period of 3 months after nivolumab administration. Overall, nivolumab was well tolerated in combination with ADT and HDR treatment. One patient experienced a grade 3 dose-limiting toxicity (elevated Alanine aminotransferase and Aspartate aminotransferase) after the second cycle of nivolumab. Three patients (50%) demonstrated early response with no residual tumor detected in ≥4 of 6 cores on biopsy post-nivolumab (4 cycles) and 1-month post–HDR. Increase in CD8+ and FOXP3+/CD4+ T cells in tissues, and CD4+ effector T cells in peripheral blood were observed in early responders. CONCLUSION: Combination of nivolumab with ADT and HDR is well tolerated and associated with evidence of increased immune infiltration and antitumor activity.

BACKGROUND: Emerging evidence suggests that a subset of Black men with National Comprehensive Cancer Network (NCCN) low-risk prostate cancer (PCa) may harbor high volume and genomically aggressive disease. However, limited, and ambiguous research exist to evaluate the risk of extreme Gleason reclassification in Black men with low-risk PCa. METHODS: This retrospective cohort study included 45,674 low-risk PCa patients who underwent prostatectomy and were not on active surveillance, from National Cancer Database (NCDB). A propensity score matched-pair design was employed, and the final cohort was limited to 1:1 matched 12,340 patients. Gleason score reclassification was used as primary endpoint. As such, any migration to pathologic Gleason score ≥7(3 + 4) was identified as overall, whereas migration to ≥7(4 + 3) was defined as extreme reclassification. A conditional Poisson regression model was used to estimate the risk of reclassification. Whereas spline model was used to estimate the impact of increasing time to treatment as a non-linear function on Gleason reclassification between race group. RESULTS: Upon matching there were no differences in the baseline characteristics between race groups. In a matched cohort, higher proportion of low-risk Black men (6.6%) reported extreme reclassification to pathologic Gleason score than White men (5.0%), p < 0.001. In a conditional Poisson regression model adjusted for time to treatment, the risk of overall (RR = 1.09, 95% CI, 1.05–1.13, p < 0.001) and extreme (RR = 1.30, 95% CI, 1.12–1.50, p = 0.004) reclassification was significantly higher in Black men as compared to their White counterpart. In spline model, the probability of Gleason reclassification in Black men was elevated with increasing time to treatment, especially after 180 days (53% vs. 43% between Black and White men). CONCLUSION: Risk of Gleason score reclassification is disparately elevated in Black men with low-risk PCa. Furthermore, time to treatment can non-linearly impact Gleason reclassification in Black men.

Castration-resistant prostate cancer (CRPC) is a lethal stage of disease in which androgen receptor (AR) signaling is persistent despite androgen deprivation therapy (ADT). Most studies have focused on investigating cell-autonomous alterations in CRPC, while the contributions of the tumor microenvironment are less well understood. Here we sought to determine the role of tumor-associated macrophages in CRPC, based upon their role in cancer progression and therapeutic resistance. In a syngeneic model that reflected the mutational landscape of CRPC, macrophage depletion resulted in a reduced transcriptional signature for steroid and bile acid synthesis, indicating potential perturbation of cholesterol metabolism. As cholesterol is the precursor of the five major types of steroid hormones, we hypothesized that macrophages were regulating androgen biosynthesis within the prostate tumor microenvironment. Macrophage depletion reduced androgen levels within prostate tumors and restricted AR nuclear localization in vitro and in vivo. Macrophages were also cholesterol-rich and were able to transfer cholesterol to tumor cells in vitro. AR nuclear translocation was inhibited by activation of liver X receptor (LXR)-β, the master regulator of cholesterol homeostasis. Consistent with these data, macrophage depletion extended survival during ADT and the presence of macrophages correlated with therapeutic resistance in patient-derived explants. Taken together, these findings support the therapeutic targeting of macrophages in CRPC. Significance: These results suggest that macrophage-targeted therapies can be combined with androgen deprivation therapy to treat patients with prostate cancer by limiting cholesterol bioavailability and the production of intratumoral androgens. See related commentary by Al-Janabi and Lewis, p. 5399

Purpose: To evaluate early-stage prostate cancer (PCa) radiotherapy treatment patterns and outcomes among Ghanaian men (GM) compared with US men (USM). Materials and Methods: This retrospective study consists of 987 National Comprehensive Cancer Network low risk, favorable intermediate risk, and unfavorable intermediate risk PCa patient subgroups; GM (173) and USM (814). Differences in baseline covariates and clinical characteristics between GM and USM were analyzed using χ2 and Mann-Whitney test while Cox Proportional Hazards model was used to assess freedom from biochemical failure differences between the study groups. Results: Median follow-up for this study was 40 months. GM were diagnosed at a younger median age (64 vs. 68 y, P

Purpose/Objective(s) Prostate cancer (PCa) is a complex disease, with risk factors and outcomes influenced by a combination of socioeconomic and biological factors. African American men (AAM) in the U.S. have higher incidence and mortality rates of PCa than European American men (EAM). Nonetheless, emerging studies have shown comparable outcomes across racial groups when treated in equal access settings. The Veterans Affairs (VA) healthcare system provides a unique environment to thoroughly investigate PCa disparities between AAM and EAM across the disease continuum, within relatively equal access-to-care settings. Materials/Methods This retrospective analysis consists of 7.8 million veterans undergoing routine care within VA hospitals nation-wide from 2005 to 2019. We compared PCa incidence, clinical presentation, treatment, and PCa specific outcomes among AAM and EAM veterans. Methods of categorical analysis were used to investigate the differences between race groups. We then assessed the likelihood of adverse clinical characteristics by race using logistic regression. In survival analysis, time-to-metastasis was used as a primary end point. Finally, we estimated the risk of distant metastasis in conjunction with treatment and baseline clinical characteristics using a multivariable cox proportional hazard model. Results Consistent with population-level data, AAM had an almost 2-fold greater risk of developing PCa than EAM within the relatively equal access-to-care VA network, with age-adjusted incidence rates of 96.7 and 40.1 per 100,000, respectively. Despite similar screening patterns, AAM also had a higher age-adjusted rate of metastasis at diagnosis compared with EAM - 5.66 and 2.37 per 100,000, respectively. AAM were more likely to have higher baseline PSA (aOR = 1.86, 95% CI, 1.77-1.95, P Conclusion This comprehensive analysis reveals a national-level PCa incidence disparity in a relatively equal access-to-care network. AAM display a higher burden of both localized and metastatic PCa, placing them at a higher risk of adverse outcomes across the PCa continuum. Consequently, timely diagnosis and equitable treatment delivery are likely critical factors for reducing disparities in disease outcomes.

Context Prostate cancer (PCa) is a complex disease that disproportionately impacts Black men in the USA. The structural factors that drive heterogeneous outcomes for patients of differing backgrounds are probably the same ones that result in population-level disparities. The relative contribution of drivers along the PCa disease continuum is an active area of investigation and debate. Objective To critically synthesize the available evidence on PCa disparities from a population-level perspective in comparison to data from “equal access and equal care settings” and to provide a consensus summary of the state of PCa disparities. Evidence acquisition A plenary panel on PCa disparities presented at the Prostate Cancer Foundation meeting on October 24, 2019 and ensuing discussions are reported here. We used a systematic literature review approach and the Preferred Reporting Items for Systematic Reviews and Meta-analyses to select the most relevant publications. A total of 3333 publications between 2011 and 2021 were retrieved, of which 52 were included in the review; an additional 13 articles on screening guidelines, seminal clinical trials, and statistical methodology were used in the evidence synthesis. Evidence synthesis Race disparities in PCa are a result of a complex interaction between socioeconomic factors impacting access to care and ancestral/genetic factors that may influence tumor biology. Black men in the USA continue to have a nearly 1.8 times higher population-level incidence rate than White men. Failure to account for the race-specific incidence burden would continue to lead to residual disparity even after achieving relatively similar outcomes after primary treatment, resulting in a higher long-term mortality burden. Selection bias remains possible in PCa studies, which often rely on highly specific cohorts of Black men with higher use of health care resources that may not represent the average Black patient in the USA. Novel methods including mediation analysis and genetic ancestry rather than self-identified race can optimize analytical models investigating racial disparities and may lead to a better understanding of PCa genomic diversity and behavior. Conclusions Our findings emphasize the importance of racially diverse studies, including precision -omics, prevention, and targeted therapy initiatives, to elucidate mechanisms underlying racial differences in outcomes and response to therapy. We propose novel approaches for studying and addressing PCa disparities. Contemporary methods, particularly in the domain of mediation analysis, can promote scientific rigor in understanding these disparities. Patient summary Inaccurate data interpretation or lack of data altogether for Black men can impact policy and ultimately affect millions of individuals of African origin worldwide. Our review identifies a need to develop and prioritize a strategy for including Black and other men with prostate cancer in intervention studies and randomized clinical trials to halt the widening prostate cancer disparities.

Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP–SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 (P –9) and 3145 (P –5) SNP–SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved KLK3. The 3 most common gene–gene interactions were KLK3-COL4A1:COL4A2, KLK3-CDH13, and KLK3-TGFBR3. Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified KLK3 SNP–SNP interactions were supported by gene expression and protein–protein interaction results. Our findings suggest KLK3 SNP interactions may play an important role in PCa aggressiveness.

PURPOSE Prostate cancer (PCa) is the leading cause of male cancer deaths in Africa. In USA, African American men (AA) experience higher mortality rate compared to European American men (EA). While socioeconomics factors contribute toward these disparities, distinct molecular mechanisms in AA remain important drivers. For example, in previous work, we discovered that PCa form AA men harbored a significantly higher expression of Aminopeptidase N (ANPEP) as compared with EA. Aminopeptidase N regulates immune cell function and mediates tumor cell migration but its role in PCa remains uninvestigated. METHODS We explored ANPEP expression related to a range of genomic classifiers in multiple datasets. We then prospectively examined the differentially expressed genes in PCa tissues collected from 120 AA and 120 EA patients enrolled on the VANDAAM clinical trial. We further correlated ANPEP expression with various signatures related to immune and metabolic activity. We also experimentally examined the expression of ANPEP in different components of tumor microenvironment. RESULTS In the VANDAAM study, ANPEP represents the top differentially expressed gene between AA and EA men. Our data driven approach revealed that ANPEP correlates with signature of cholesterol transport and androgen signaling. Interestingly, these signatures dominate in PCa with high macrophage infiltration. Deconvolution of immune cell content using computational approaches indeed demonstrated that only AA patients with high ANPEP expression significantly accumulated high content of inflammatory macrophages. Further experimental findings showed that ANPEP indeed represents a marker of tumor-associated macrophages, a type of immune cells known to contribute to PCa progression. CONCLUSION We have identified ANPEP as a macrophage-related gene with a potential role in cholesterol metabolism and AR signaling in AA. Future work will focus on the functional role of ANPEP activity in the tumor immune microenvironment using Liquid chromatography-high resolution mass spectrometry and explants derived from AA and EA PCa patients.

Health disparities between American men of African and European descent (AA and EA, respectively) can be attributed to multiple factors, including disparities in socioeconomic status, access to healthcare, lifestyle, ancestry, and molecular aberrations. Numerous clinical trials and research studies are being performed to identify new and better therapeutic approaches to detect and treat prostate cancer. Of potential concern is the fact that the majority of the patients enrolled on these trials are EA. This disproportionate enrollment of EA could have implications when disease management recommendations are proposed without regard to the existing disparities in prostate cancer between races. With increasing advancements in immunotherapies, the immunological disparities between men of diverse ethnicities will need to be fully explored to develop novel and effective therapeutic approaches for prostate cancer patients globally. To help address this need, this review fully describes inequalities in prostate cancer at the immunological level between AA and EA.

Grade group 4 and 5 (GG-45) prostate cancer (PCa) patients are at the highest risk of lethal outcomes, yet lack genomic risk stratification for prognosis and treatment selection. Here, we assess whether transcriptomic interactions between tumor immune content score (ICS) and the Decipher genomic classifier can identify most lethal subsets of GG-45 PCa. We utilized whole transcriptome data from 8071 tumor tissue (6071 prostatectomy and 2000 treatment-naive biopsy samples) to derive four immunogenomic subtypes using ICS and Decipher. When compared across all grade groups, GG-45 samples had the highest proportion of most aggressive subtype—ICSHigh/DecipherHigh. Subsequent analyses within the GG-45 patient samples (n = 1420) revealed that the ICSHigh/DecipherHigh subtype was associated with increased genomic radiosensitivity. Additionally, in a multivariable model (n = 335), ICSHigh/DecipherHigh subtype had a significantly higher risk of distant metastasis (hazard ratio [HR] = 5.41; 95% confidence interval [CI], 2.76–10.6; p ≤ 0.0001) and PCa-specific mortality (HR = 10.6; 95% CI, 4.18–26.94; p ≤ 0.0001) as compared with ICSLow/DecipherLow. The novel immunogenomic subtypes establish a very strong synergistic interaction between ICS and Decipher in identifying GG-45 patients who experience the most lethal outcomes. Patient summary In this analysis, we identified a novel interaction between the total immune content of prostate tumors and genomic classifier to identify the most lethal subset of patients with grade groups 4 and 5. Our results will aid in the subtyping of aggressive prostate cancer patients who may benefit from combined immune-radiotherapy modalities.

Key Points Question Are there racial and ethnic disparities associated with the incidence, clinical stage, and outcomes of prostate cancer among men treated in the Veterans Affairs health care system? Findings In this cohort study of 7.8 million patients, compared with White veterans, African American (or Black) veterans displayed increased risk of developing localized and de novo metastatic prostate cancer across nationwide Veterans Affairs centers. Despite equitable treatment response, a persistent residual metastatic burden of nearly 2-fold was observed for African American veterans across National Comprehensive Cancer Network risk groups, when factoring in the higher incidence rate. Meaning Treatment in an equal-access setting may partially address institution-specific disparities, but overall racial disparity gaps remain., Importance Prostate cancer (PCa) disproportionately affects African American men, but research evaluating the extent of racial and ethnic disparities across the PCa continuum in equal-access settings remains limited at the national level. The US Department of Veterans Affairs (VA) Veterans Hospital Administration health care system offers a setting of relatively equal access to care in which to assess racial and ethnic disparities in self-identified African American (or Black) veterans and White veterans. Objective To determine the extent of racial and ethnic disparities in the incidence of PCa, clinical stage, and outcomes between African American patients and White patients who received a diagnosis or were treated at a VA hospital. Design, Setting, and Participants This retrospective cohort study included 7 889 984 veterans undergoing routine care in VA hospitals nationwide from 2005 through 2019 (incidence cohort). The age-adjusted incidence of localized and de novo metastatic PCa was estimated. Treatment response was evaluated, and PCa-specific outcomes were compared between African American veterans and White veterans. Residual disparity in PCa outcome, defined as the leftover racial and ethnic disparity in the outcomes despite equal response to treatment, was estimated. Exposures Self-identified African American (or Black) and White race and ethnicity. Main Outcomes and Measures Time to distant metastasis following PCa diagnosis was the primary outcome. Descriptive analyses were used to compare baseline demographics and clinic characteristics. Multivariable logistic regression was used to evaluate race and ethnicity association with pretreatment clinical variables. Multivariable Cox regression was used to estimate the risk of metastasis. Results Data from 7 889 984 veterans from the incidence cohort were used to estimate incidence, whereas data from 92 269 veterans with localized PCa were used to assess treatment response. Among 92 269 veterans, African American men (n = 28 802 [31%]) were younger (median [IQR], 63 [58-68] vs 65 [62-71] years) and had higher prostate-specific antigen levels (>20 ng/mL) at the time of diagnosis compared with White men (n = 63 467; [69%]). Consistent with US population-level data, African American veterans displayed a nearly 2-fold greater incidence of localized and de novo metastatic PCa compared with White men across VA centers nationwide. Among veterans screened for PCa, African American men had a 29% increased risk of PCa detection on a diagnostic prostate biopsy compared with White (hazard ratio, 1.29; 95% CI, 1.27-1.31; P, This cohort study assesses the extent of racial and ethnic disparities in the incidence, clinical stage, and outcomes of prostate cancer among African American and White men treated in the Veterans Affairs health care system.

In prostate cancer (PCa), lack of TMPRSS2-ETS gene fusion (ETSnegative) has been a hallmark of tumor in African American (AA) as compared with European American (EA) men. To elucidate biologic features associated with ETSnegative PCa in AA men, we identified aminopeptidase N (ANPEP) as ETS-regulated gene with preferential overexpression in AA. Aminopeptidase N is involved in endocytosis, cholesterol, amino acid transport and peptide hydrolysis. In the current work, we sought to investigate the role of ANPEP in a PCa development and exploit its role in PCa metabolism as a therapeutic vulnerability, particularly in AA tumors. Methods To understand the role of ANPEP in PCa progression and therapeutic vulnerability, we determined the expression of ANPEP in different component of tumor microenvironment. We also developed a consumption and release metabolomic platform to assess the impact of ANPEP on transport of cholesterol, fatty acids and a number of relevant amino acids. Additionally, we assessed the availability of these metabolites and their end products in plasma samples of PCa patients. Results Using publicly available datasets, we showed that prostate tumors form AA men harbor the highest expression of ANPEP as compared with other groups. Using further data mining and experimental approaches, we found that aminopeptidase N is predominantly expressed on macrophages compared with prostate tumor cells, T cell, B cells, neutrophils and dendritic cells. Expression of ANPEP predominantly correlated with various amino acid transporters which also tend to be differentially expressed by ETS status. We have successfully developed a metabolomics-based approach to assess the consumption of more than 15 metabolites in prostate cancer cells and patient derived explants. Conclusion We have identified ANPEP as a macrophage-related gene with a potential role in tumor metabolism. Future work will focus on investigating functional role of ANPEP in the tumor immune microenvironment using our unique metabolic consumption/release assay in explants derived from AA and EA prostate cancer patients. Citation Format: Asmaa E. El-Kenawi, Shivanshu Awasthi, Amparo N. Serna, Jasreman Dhillon, Kosj Yamoah. ANPEP: A potential regulator of tumor-immune metabolic interactions in African American men with prostate cancer [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-153.

Purpose Data on prostate cancer (PCa) treatment in Africa remains under-reported. We present a review of the management of PCa at the cancer center of the largest tertiary referral facility in Ghana, with emphasis on curative treatment. Methods We retrospectively reviewed data on 1,074 patients seen at the National Center for Radiotherapy and Nuclear Medicine from 2003 to 2016. Patient and disease characteristics at presentation are presented using descriptive statistics. The χ2 and Fisher’s exact tests and Mann-Whitney U test were used to analyze differences between categorical and continuous variables, respectively. Methods of survival analysis were used to evaluate the relative risk of biochemical disease-free survival (bDFS). Results Seventy percent of the study population presented with localized disease. High-risk disease presentation accounted for 64.4% of these patients. Only 57.6% of patients with localized disease received curative radiotherapy. The 5-year overall survival for the curative cohort was 96% (interquartile range, 93% to 98%). The 5-year bDFS rates for low-, intermediate-, and high-risk groups were 95%, 70%, and 48%, respectively. Both Gleason score and pretreatment prostate-specific antigen were significant predictors for bDFS in multivariable analysis. Conclusion We show that the majority of patients with PCa have locally advanced disease at the time of presentation for radiotherapy. bDFS was significantly better for low- and intermediate-risk than for high-risk disease. These data emphasize the dire need to re-evaluate screening and patient education of PCa in regions of the world with high incidence and mortality as well as the need for improved access to care and treatment delivery.

Background Prostate cancer (PCa) tumors harboring translocations of ETS family genes with the androgen responsive TMPRSS2 gene (ETS+ tumors) provide a robust biomarker for detecting PCa in approximately 70% of patients. ETS+ PCa express high levels of the androgen receptor (AR), yet PCa tumors lacking ETS fusions (ETS−) also express AR and demonstrate androgen-regulated growth. In this study, we evaluate the differences in the AR-regulated transcriptomes between ETS+ and ETS− PCa tumors. Methods 10,608 patient tumors from three independent PCa datasets classified as ETS+ (samples overexpressing ERG or other ETS family members) or ETS− (all other PCa) were analyzed for differential gene expression using false-discovery-rate adjusted methods and gene-set enrichment analysis (GSEA). Results Based on the expression of AR-dependent genes and an unsupervised Principal Component Analysis (PCA) model, AR-regulated gene expression alone was able to separate PCa samples into groups based on ETS status in all PCa databases. ETS status distinguished several differentially expressed genes in both TCGA (6.9%) and GRID (6.6%) databases, with 413 genes overlapping in both databases. Importantly, GSEA showed enrichment of distinct androgen-responsive genes in both ETS− and ETS+ tumors, and AR ChIP-seq data identified 131 direct AR-target genes that are regulated in an ETS-specific fashion. Notably, dysregulation of ETS-dependent AR-target genes within the metabolic and non-canonical WNT pathways was associated with clinical outcomes. Conclusions ETS status influences the transcriptional repertoire of the AR, and ETS− PCa tumors appear to rely on distinctly different AR-dependent transcriptional programs to drive and sustain tumorigenesis.

Significant racial disparities in prostate cancer (PCa) outcomes have been reported, with African‐American men (AAM) more likely to endure adverse oncologic outcomes. Despite efforts to dissipate racial disparities in PCa, a survival gap persists and it remains unclear to what extent this disparity can be explained by known clinicodemographic factors. In this study, we leveraged our large institutional database, spanning over 25 years, to investigate whether AAM continued to experience poor PCa outcomes and factors that may contribute to racial disparities in PCa. A total of 7307 patients diagnosed with PCa from 1989 through 2015 were included. Associations of race and clinicodemographic characteristics were analyzed using chi‐square for categorical and Mann–Whitney U‐test for continuous variables. Racial differences in prostate cancer outcomes were analyzed using competing risk analysis methods of Fine and Gray. Median follow‐up time was 106 months. There were 2304 deaths recorded, of which 432 resulted from PCa. AAM were more likely to be diagnosed at an earlier age (median 60 vs. 65 years, P = 60 years), racial differences in PCSM were more pronounced, with AAM experiencing higher rates of PCSM (HR, 2.05, 95% CI, 1.26–3.34, P = 0.003). After adjustment of clinicodemographic and potential risk factors, AAM continue to experience an increased risk of mortality from PCa, especially older AAM. Furthermore, AAM are more likely to be diagnosed at an early age and more likely to have higher comorbidity indices.

Purpose/objective(s) The management of oligometastatic bladder cancer is unclear. Prior data implies site and burden of metastases vary in prognoses. This study evaluates treatment trends, examines the effect of local therapy on survival, and explores if immunotherapy influences outcomes in patients with de novo oligometastatic bladder urothelial carcinoma. Materials/methods A retrospective analysis of the National Cancer Database (NCDB) was performed by identifying bladder urothelial carcinoma patients with metastases (M1 stage) at diagnosis between 2004 and 2016. Local therapy was classified as high-intensity [HT] (i.e., definitive surgery, radiation [RT] dose > 50 Gy) or low-intensity [LT] (i.e., non-definitive surgery, RT dose Results A total of 11,998 patients were identified with metastases at diagnosis. The median age was 72 years (IQR: 62-80), the majority were Caucasian (87.5%) and male (71.2%). The median follow-up time was 5.5 months (IQR: 2.27-12.62). Patients were treated with definitive surgery (n = 849; 7.1%), perioperative CT (n = 404; 3.4%), CT alone (n = 4,030; 33.6%), RT alone (n = 1,026; 8.6%), CTRT (n = 1,451; 12.1%) or no therapy (n = 3,343; 33.6%). HT and LT were given to 1,083 (9%) and 8,867 (73.9%) patients, respectively. Differences were noted in median OS among treatment groups, such as perioperative CT (OS 16.4 months) or CTRT (> 50 Gy) (12.4 months); P Conclusion This population-based study suggests local aggressive therapy, either surgical or RT (> 50 Gy) is associated with an improved OS benefit in patients with de novo metastatic bladder urothelial carcinoma.

PURPOSE/OBJECTIVE(S) A phase I/II study combining nivolumab with androgen deprivation therapy (ADT) and high dose brachytherapy (HDR) followed by external beam radiotherapy (EBRT) indicated that the regimen is well tolerated and effective with radiographic and pathologic evidence of increased antitumor activity. In the present study we sought to utilize MR-based imaging characteristics to define parameters of antitumor response to HDR+EBRT and nivolumab in patients with Grade Group (GG) 5 prostate cancer. MATERIALS/METHODS Eligible patients received ADT in combination with nivolumab and HDR followed by EBRT delivered using MR-guided radiotherapy. Data from 12 patients were analyzed using MRI from diagnosis, once-weekly treatment from fractions 5, 10, 15 and 25 and 3-month follow up. Images were fused and analyzed using an image analysis package. At time of enrollment the dominant tumor (ROI) was contoured and tracked at different timepoints. The change in T2 value was assessed using voxel data at diagnosis and follow up. The delta (δ) of average change was estimated between partial and complete responders from diagnosis and follow up. The same analysis was done on the treatment MR using steady-state coherent sequences. All data were normalized against the prostate values. RESULTS Median follow up was 17 months. Complete radiographic response (CR) was seen in 6 out of 12 patients. A δ T2 was estimated between baseline and follow up T2 tumor ROI. Partial responders had higher δ of 62.5 as compared to complete responders with δ of 28. When compared longitudinally over 5 fractions, on average change in steady-state coherent sequence over time was higher in partial responders than complete responders. CONCLUSION Our preliminary results show a greater δ in T2 signal in partial responders consistent with continued tumor response on weekly imaging, while complete responders showed minimal change over time. This finding suggests that CR may derive a rapid and early response to nivolumab, ADT and HDR than the partial responders. Furthermore, tracking δ in T2 signal and steady-state coherent sequences may be a reliable tool for defining tumor response in real-time and needs further validation in a larger cohort. This study was registered under NCT03543189.

Castration-resistant prostate cancer (CRPC) is a lethal stage of disease. A wealth of clinical and experimental data supports the persistence of androgen receptor (AR) signaling in many cases of CRPC, despite androgen-deprivation therapy (ADT). Here we sought to determine the role of macrophage cholesterol in CRPC and androgen signaling using a syngeneic model that reflected the mutational landscape of the disease. A transcriptomic analysis of prostate tumors following macrophage depletion revealed lower molecular signatures for steroid and bile acid metabolism, indicating perturbation of cholesterol transport. Since cholesterol is the precursor of steroid hormones, we reasoned that macrophages were regulating androgen biosynthesis within the prostate tumor microenvironment. Indeed, macrophage depletion reduced the levels of androgens within prostate tumors and restricted androgen receptor (AR) nuclear localization in vitro and in vivo. Macrophages were cholesterol rich and had the ability to transfer cholesterol to tumor cells in vitro, and AR nuclear translocation was inhibited by activation of Liver X Receptor (LXR)-β, the master regulator of cholesterol homeostasis. Finally, combining macrophage depletion with androgen deprivation therapy increased survival, supporting the therapeutic potential of targeting macrophages in CRPC. Citation Format: Asmaa El-Kenawi, William Dominguez Viqueira, Min Liu, Shivanshu Awasthi, Jasreman Dhillon, Kosj Yamoah, Xiaoqing Yu, John Koomen, Robert Gatenby, Brian Ruffell. Macrophage tumor cell metabolic interactions induce therapeutic resistance in prostate cancer [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 734.

Most prostate cancer in African American men lacks the ETS (E26 transforming specific) family fusion event (ETS-). We aimed to establish clinically relevant biomarkers in African American men by studying ETS dependent gene expression patterns to identified race specific genes predictive of outcomes.Two multicenter cohorts of a total of 1,427 men were used for the discovery and validation (635 and 792 men, respectively) of race specific predictive biomarkers. We used false discovery rate adjusted q values to identify race and ETS dependent genes which were differentially expressed in African American men who experienced biochemical recurrence within 5 years. Principal component modeling along with survival analysis was done to assess the accuracy of the gene panel in predicting recurrence.We identified 3,047 genes which were differentially expressed based on ETS status. Of these genes 362 were differentially expressed in a race specific manner (false discovery rate 0.025 or less). A total of 81 genes were race specific and over expressed in African American men who experienced biochemical recurrence. The final gene panel included APOD, BCL6, EMP1, MYADM, SRGN and TIMP3. These genes were associated with 5-year biochemical recurrence (HR 1.97, 95% CI 1.27-3.06, p = 0.002) and they improved the predictive accuracy of clinicopathological variables only in African American men (60-month time dependent AUC 0.72).In an effort to elucidate biological features associated with prostate cancer aggressiveness in African American men we identified ETS dependent biomarkers predicting early onset biochemical recurrence only in African American men. Thus, these ETS dependent biomarkers representing ideal candidates for biomarkers of aggressive disease in this patient population.

Background: Commercial gene expression signatures of prostate cancer prognosis were developed and validated in cohorts of predominantly European American men (EAM). Limited research exists on the value of such signatures in African American men (AAM), who have poor prostate cancer outcomes. We explored differences in gene expression between EAM and AAM for three commercially available panels recommended by the National Comprehensive Cancer Network for prostate cancer prognosis. Methods: A total of 232 EAM and 95 AAM patients provided radical prostatectomy specimens. Gene expression was quantified using NanoString for 60 genes spanning the Oncotype DX Prostate, Prolaris, and Decipher panels. A continuous expression-based risk score was approximated for each. Differential expression, intrapanel coexpression, and risk by race were assessed. Results: Clinical and pathologic features were similar between AAM and EAM. Differential expression by race was observed for 48% of genes measured, although the magnitudes of expression differences were small. Coexpression patterns were more strongly preserved by race group for Oncotype DX and Decipher than Prolaris. Poorer prognosis was estimated in EAM versus AAM for Oncotype DX (P < 0.001), whereas negligible prognostic differences were predicted between AAM and EAM using Prolaris or Decipher (P > 0.05). Conclusions: Because of observed racial differences across three commercial gene expression panels for prostate cancer prognosis, caution is warranted when applying these panels in clinical decision-making in AAM. Impact: Differences in gene expression by race for three commercial panels for prostate cancer prognosis indicate that further study of their effectiveness in AAM with long-term follow-up is warranted.

Background: Socioeconomic, environmental, and healthcare utilization factors are likely drivers of the persistent prostate cancer disparities between African-American (AA) and European-American (EA) men. Tumor molecular heterogeneity may also contribute, and Eurocentric studies and initiatives have the potential to widen disparities through the development of prognostic signatures and targeted therapeutics that do not account for genetic diversity. Methods: The Decipher Genomics Resource Information Database (GRID) contains tumor mRNA expression and clinical data generated through use of the Decipher test to predict prostate cancer prognosis. We matched 426 AA and 426 EA patients with localized prostate cancer using a propensity score accounting for age and tumor clinicopathological factors. We then applied five validated prostate cancer molecular subtype classifiers by Alshalalfa et al (Neuroendocrine, Adenocarcinoma), Kamoun et al (S1-S3), Tomlins et al(ERG+, ETS+, SPINK1+, ERG-/ETS-/SPINK1-), You et al (PCS1-PCS3), and Zhang et al (Basal, Luminal) to assign tumor subtypes. Heterogeneity in subtype frequency by self-identified race (SIR) was evaluated using chi-squared tests. Differences in subtype prognostic value by SIR were evaluated in logistic regression models using a high Decipher tumor genomic risk score of ≥0.6 as a surrogate for higher risk of metastases. Results: AA men were more likely to have a Decipher score ≥0.6 than EA men (25.6% vs. 20.0%, p Conclusions: Prostate cancer molecular subtype distributions differed by SIR, with AA men generally more likely to have aggressive subtypes across classification schemes. Furthermore, AA and EA had a heterogeneous risk of metastases (defined by Decipher genomic risk score) for several subtypes. Further research is needed to better define subtyping classifiers and the prognostic value thereof in AA men. Citation Format: Kevin H. Kensler, Mohamed Alshalalfa, Brandon A. Mahal, Yang Liu, Elai Davicioni, Shivanshu Awasthi, Kosj Yamoah, Timothy R. Rebbeck. Racial variation in molecularly-defined prostate cancer subtypes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3509.