African American Prostate Cancer Patients Research Articles

Abstract 2146: Race-related differential immunoreactivity of enolase autoantibodies in patients with prostate cancer

Abstract INTRODUCTION AND OBJECTIVE: Enolase-1 (ENO1) and -2 (ENO2) are implicated in tumor metabolic and aggressive functions. Like prostate specific membrane antigen (PSMA), they localize to the tumor cell surface and are potential theranostics targets. ENO autoantibodies were reported by our group in prostate cancer (PCa) patients but their immunoreactivity to ENO1/2 isoforms was not defined. Differential ENO immunoreactivity in docetaxel-resistant (DR) PCa cells between African American (AA) and European American (EA) PCa patients was also reported. Our objective was to investigate the role of ENO isoforms in the race-related differential ENO immunoreactivity of PCa patients. METHODS: PCa patient sera (41 AA, 68 EA) were obtained from Loma Linda University Biospecimen Laboratory. Western blotting (WB) analysis, using patient sera and monoclonal antibodies to ENO1 and ENO2, was done against lysates from docetaxel-sensitive (DS) and DR PCa cell lines and against recombinant (rec) ENO1 and ENO2 to assess ENO isoform expression and detect ENO autoantibodies. Scratch-wound assay was performed to evaluate AA and EA anti-ENO driven inhibition of DR PCa cell migration. Student’s T-test and Chi-squared analyses were performed with p<0.05 deemed significant. RESULTS: ENO1 expression was robust in all assessed DS and DR cell lines. ENO2 was detected in DS cells but was significantly reduced in DR cells. PSMA expression was lost in cells expressing ENO1 and neuroendocrine markers. Anti-ENO EA sera reacted in WB with the expected 50 kD band in both DS and DR PCa cells, but anti-ENO AA sera reacted preferentially with this band in DS cells. Strong immunoreactivity was noted against recENO1 in AA and EA sera (7% vs 28%, p<0.01) and against recENO2 in AA and EA sera (24% vs 35%, p=0.23). EA, but not AA, ENO autoantibodies significantly inhibited DR cell migration, and their pre-absorption with recENO1 diminished this inhibitory effect. CONCLUSIONS: Autoantibodies to ENO1 and ENO2 were identified in EA and AA PCa patient sera. Weaker ENO1 immunoreactivity was seen in sera from AA PCa patients, corresponding with weaker inhibition of DR PCa cell migration compared to EA patient sera. Unlike PSMA and ENO2, ENO1 expression was robust in neuroendocrine-like DR PCa cell lines. Future studies will correlate the presence of ENO autoantibodies with clinicopathologic parameters in a larger patient cohort. Defining mechanisms underlying the race-related differential ENO immunoreactivity may identify novel biological determinants of PCa health disparities and uncover the theranostic potential of tumor surface ENO1. Citation Format: Kai Wen Cheng, Carlos J. Diaz Osterman, Krystal Santiago, Michael Reeves, Diano Lozano, Pedro Ochoa, Alfonso Duran, Saied Mirshahidi, Brian R. Hu, Frankis Almaguel, Carlos A. Casiano. Race-related differential immunoreactivity of enolase autoantibodies in patients 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 2146.

Abstract 6159: Single cell analysis of circulating peripheral blood mononuclear cells in African American men with prostate cancer and their association with lethal disease

Abstract Prostate cancer is a leading cause of cancer-related deaths among men in the United States and affects African American (AA) men more so than other men. We and others previously described a distinct tumor immunobiology in AA prostate cancer patients. Furthermore, we discovered a serum proteome-defined suppression of tumor immunity signature that is prevalent among these patients and associated with lethal prostate cancer. In the current study, we sought to investigate the composition of circulating peripheral blood mononuclear cells (PBMCs) in AA and European American (EA) prostate cancer patients and their association with patient group and lethal prostate cancer. We obtained high-quality RNA-sequencing data for 277336 single cells representing circulating PBMCs from 59 AA and EA men. In the analysis, being an AA patients associated with an increased abundance of exhausted T cells, higher numbers of plasma B cells and CD16+ monocytes. Gene signatures indicative of T cell exhaustion and Treg activity were generally elevated in AA PBMCs while T cell effector function features were decreased. Within the overall cell population, interferon gene signatures were robustly elevated in AA than EA patients. This gene signature pattern that we observed in AA patients also associated with lethal prostate cancer, namely the T cell exhaustion, Treg activity and elevated interferon signaling gene signatures, may contribute to immune dysfunction and immune injury; pointing to potential clinical implications. Lastly, the interferon-induced transmembrane protein (IFITM3), interferon alpha inducible protein (IFI6), cysteine rich protein-1 (CRIP1), and the RAC family small GTPase2 (RAC2) were notably upregulated in AA patient-derived immune cells. In summary, we show that circulating immune cell populations and the associated gene signatures differ between men of African and European descent. Those elevated in AA patients correlated with lethal prostate cancer. Citation Format: Md Shakir Uddin Ahmed, Tiffany Dorsey, Stefan Ambs. Single cell analysis of circulating peripheral blood mononuclear cells in African American men with prostate cancer and their association with lethal disease [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 6159.

Abstract 2565: Vitamin D deficiency and outcomes in prostate cancer patients: A real-world database

Abstract Introduction: Vitamin D is essential for many bodily functions, including bone health and the prevention of osteoporosis and rickets. In recent years, the importance of vitamin D metabolism in immune system regulation and cancer prevention has been studied with increased focus. With the advent of cancer immunotherapies this has become more important. Multiple recent publications document that vitamin D deficiency is prevalent in cancer patients. This has also been observed specifically in prostate cancer patients, with a high percentage of these deficient patients being of African- American ancestry. It has been theorized that high levels of vitamin D deficiency among African American prostate cancer patients could contribute to worse cancer outcomes and increased health disparities. However, routine vitamin D testing has not been commonly performed in the oncologic community. We hypothesized that deficient levels of vitamin D could lead to inferior prostate cancer outcomes in men with a wide range of ethnic and socio-economic backgrounds. In this project we recorded vitamin D levels in prostate cancer patients at a large community oncology group and evaluated them by stage, pathologic data, survival, race/ethnicity, and other clinical features. Methods: This study is a retrospective, observational study of the data from the electronic medical records of patients with prostate cancer who received vitamin D level testing at Florida Cancer Specialists & Research Institute from 2008- 2023, throughout the state of Florida. All data used in this study will constitute secondary data, it will have been collected originally for clinical use in the general oncology practice setting. No date parameters or patient limits will be applied to this study, and all eligible patients are included. Results: 451 patients with prostate cancer had determination of vitamin D levels, out of a total of 27,772 prostate cancer patients in the database. 38% of the prostate cancer patients analyzed had low 25-OH vitamin D levels (<32 ng/ml). Patients with low vitamin D levels had an average Gleason score of 7.46. Patients with low vitamin D levels who died had an average survival of 144 months. Patients with low vitamin D levels who presented with localized disease had a 35% chance of eventually developing castrate-resistant disease. 45% of the low vitamin D group developed metastatic disease during their course of treatment. Further comparisons of vitamin D levels with pathologic data, survival/longevity, race/ethnicity, and clinical course will be evaluated and presented. Citation Format: Lowell L. Hart, James Reeves, Stacey Garofalo, William Amick. Vitamin D deficiency and outcomes in prostate cancer patients: A real-world database [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 2565.

Abstract 7645: Differentially expressed genes as prognostic markers in racial disparities of prostate cancer

Abstract Racial disparities in prostate cancer are prevalent, with African American (AA) men experiencing 60% greater incidence and 2 to 3 times higher mortality than Caucasian American (CA) men. Consequently, there is a pressing need for improved means of interrogating race/ethnicity-based prostate cancer biology in order to identify biomarkers to help stratify men at high-risk for prostate cancer-specific progression and death and offer treatment recommendation that would mostly benefit AA men undergoing early aggressive therapies. Current predictive models rely on clinical variables but do not account for these disparities. The overall goal is to construct a race-specific prostate cancer prognostic prediction model for risk assessment. Here we performed comprehensive bioinformatics analysis using the data from 17 pairs of gene expression array from AA and CA cohorts and identified 63 differentially expressed genes (DEGs) by race. Among them, chemokine receptor 4 (CXCR4), viz. p-Akt (Ser473), fatty acid synthase (FASN), interleukin-6 (IL-6) and matrix metallopeptidase 9 (MMP-9) gene expressions were significantly altered in AA groups. Immunohistochemistry was performed on 163 prostate cancer patient specimens to validate DEG expression and immunoreactive scores (IRS) were calculated. CXCR4 exhibited significantly higher expression in AA tumors, with > 85% of AA prostate tumors showing weak to strong CXCR4 expression, compared to < 5% in CA specimens. While immunostaining for IL-6, FASN, MMP9 and p-Akt did not provide a significant distinction between CA and AA cases. IRS analysis confirmed higher expression of CXCR4 in AA cancers, compared to CA prostate cancer (p < 0.001). MMP9 and IL6 expression were moderately higher in AA cancer compared to CA prostate cancer (p < 0.05). In contrast, FASN expression was significantly higher in CA cancer, compared to AA prostate cancer (p < 0.001). We further investigated the impact of these genes on biochemical recurrence-free survival (BCRFS) using Kaplan-Meier analysis to examine the differences between low-risk versus high-risk groups. BCRFS analysis demonstrated that CXCR4 is a determinant factor of recurrence risk in AA prostate cancer patients. The activation of the PI3K-Akt signaling pathway, particularly in AA patients, suggests its role in prostate cancer aggressiveness. Taken together, this study demonstrates the importance of differential expression of biomarkers which constitute the bulk tumors in driving cancer. The distinct gene expression patterns, especially the upregulation of CXCR4, in AA prostate cancer highlight its potential as a prognostic biomarker and a target for personalized treatment strategies. These findings encourage further study into the role of population-specific difference in adding CXCR4 in risk model construction, especially in machine learning models. Citation Format: Amel A. Ahmed, Shiv Verma, Ibrahim M. Atawia, Daniel L. Shen, Gregory T. MacLennan, Pingfu Fu, Sanjay Gupta. Differentially expressed genes as prognostic markers in racial disparities of 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 7645.

Abstract 773: Overexpression of phosphoserine phosphatase (PSPH) in prostate cancer and in tumor microenvironment promotes tumor cell proliferation

Abstract Reprogrammed cellular metabolism is one of the key features of cancer and tumor microenvironment. L-3-phosphoserine phosphatase (PSPH) is one of the five rate-limiting enzymes in the biosynthesis of serine from glucose that supports cell proliferation. Here, we aim to study the role of PSPH in prostate cancer (PCa) and its tumor microenvironment. We find that PSPH not only is overexpressed in prostate cancer cell lines compared to normal prostate epithelial cells (PrEC) and benign prostate epithelial cells (BPH-1), but also exhibits a higher level in patient-derived carcinoma-associated fibroblasts (CAFs) compared to the matched benign associated fibroblasts (BAFs), which are derived from fresh radical prostatectomy specimens of African American (AA) and European American (EA) men. Notably, MDAPCa2b cells derived from an AA prostate cancer patient and AA CAFs have even higher expression of PSPH protein. The mRNA levels of PSPH are also significantly elevated in prostate cancer tissues in AA men compared to EA men and predict poor survival in PCa patients. Knock-down of PSPH expression significantly inhibits the proliferation and colony formation of prostate cancer cells. Growth of xenograft tumors derived from PSPH knockdown MDAPCa2b cells has also been suppressed markedly. Gene expression profiling revealed that suppression of PSPH expression by shRNAs in LNCaP and MDAPCa2b cells is associated with the regulation of gene expression related to metabolism, immunity, extracellular matrix remodeling, and Ion channels. Similarly, analysis of publicly available PCa RNA seq databases also demonstrates that PSPH amplification or over-expression is associated with alterations of gene expression related to metabolism and immunity. Our results suggest that PSPH is upregulated in prostate cancer cells and their surrounding fibroblasts to support tumor growth via reprogramming metabolic pathways and transcriptomes. Citation Format: Liankun Song, Noriko Yokoyama, Jun Xie, Yunjie Hu, Zhenyu (Arthur) Jia, Beverly Wang, Dan Mercola, Edward Uchio, Thomas Ahlering, Michael Lilly, Xiaolin Zi. Overexpression of phosphoserine phosphatase (PSPH) in prostate cancer and in tumor microenvironment promotes tumor cell proliferation [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 773.

Abstract C040: Single cell analysis of circulating peripheral blood mononuclear cells in African American men with prostate cancer and their association with lethal disease

Abstract Prostate cancer is a leading cause of cancer-related deaths among men in the United States and affects African American (AA) men more so than other men. We and others previously described a distinct tumor immunobiology in AA prostate cancer patients. Furthermore, we discovered a serum proteome-defined suppression of tumor immunity signature that is prevalent among these patients and associated with lethal prostate cancer. In the current study, we sought to investigate the composition of circulating peripheral blood mononuclear cells (PBMCs) in AA and European American (EA) prostate cancer patients and their association with patient group and lethal prostate cancer. We obtained high-quality RNA-sequencing data for 277642 single cells representing circulating PBMCs from 59 AA and EA men. In the analysis, being an AA patients associated with an increased abundance of exhausted CD8+T cells and higher numbers of macrophages that classified as tumor-associated macrophages, whereas metallothionine-expressing macrophages were decreased in these men. Gene signatures indicative of T cell exhaustion were generally elevated in AA PBMCs while T cell effector function features were decreased. Within the myeloid cell population, cytokine and NFKB signatures were more prevalent in AA than EA patients. This gene signature pattern that we observed in AA patients also associated with lethal prostate cancer, namely the T cell exhaustion and elevated cytokine gene signatures, pointing to potential clinical implications. Lastly, the interferon-induced transmembrane protein (IFITM3), interferon alpha inducible protein (IFI6), cysteine rich protein-1 (CRIP1), and the RAC family small GTPase2 (RAC2) were notably upregulated in AA patient-derived immune cells. In summary, we show that circulating immune cell populations and the associated gene signatures differ between men of African and European descent. Those elevated in AA patients correlated with lethal prostate cancer. Citation Format: Md Shakir U. Ahmed, Tiffany Dorsey, Stefan Ambs. Single cell analysis of circulating peripheral blood mononuclear cells in African American men with prostate cancer and their association with lethal disease [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 C040.

A Problem in NIH and Federally Funded Prostate Cancer Interventional Clinical Trials.

Obesity, diagnosed in 41.1% of African American (AA) men, is a risk factor for prostate cancer (PCa) recurrence, progression, and increased mortality. Obesity is associated with aggressive PCa only in AA men and not White American (WA) men. The overall health of AA PCa patients is also more likely to be adversely affected by comorbid type 2 diabetes (T2D), often an outcome of obesity and a cause of reduced odds of PCa survival. This evidence suggests that preventing and controlling comorbid obesity and T2D in AA men diagnosed with PCa should be a research funding priority. The aim of this study is to determine if federally funded PCa clinical trials controlled T2D and obesity. Completed interventional PCa clinical trials conducted in the USA, funded by the NIH or other federal agency, which included males aged 18-64years, and reported study protocols were included in the study. We examined the intervention modalities used in the trials to determine if any attempted to control obesity and T2D. Fifty-eight trials met the study inclusion criteria. Of these 11 were excluded from the analysis as they did not report AA men. A total of 5802 men participated in the remaining 47 trials. Of these, 917 (15.8%) were AA and 4885 (84.2%) were WA men. Forty (85.1%) trials used pharmaceutical medication therapies or other clinical procedures. None of the medications or clinical procedures used were indicated for treatment of obesity and T2D. 5 (10.6%) trials addressed treatment preferences, survivorship, coping, function, and incontinence among PCa patients. Only 2 (4.25%) trials examined weight loss and diet. None of the completed federally funded PCa clinical trials that included AA men used methods to control T2D. Only an insignificant number (4.25%) attempted to control obesity. This gap in therapeutic optimization to control these comorbid conditions indicates a critical area in need of federal funding priority.

Abstract 6114: Race-associated base excision repair defects alter the DNA damage landscape in prostate cancer

Abstract Prostate cancer is the most diagnosed cancer among men in the United States. African American men are diagnosed with and succumb to prostate cancer at higher rates than other demographic groups. However, the biological drivers contributing to poorer outcomes in African American men compared to European American men with prostate cancer are still poorly defined. One understudied area is DNA repair defects, which drive genomic instability in cancers. Defects in homologous recombination are often at the forefront of repair defects examined and exploited for therapeutic intervention. However, defects in other DNA repair pathways may contribute to poor disease outcomes and chemoresistance. We demonstrated that defects in the base excision repair (BER) pathway contribute to chemoresistance and alter growth in breast cancer. Others have also shown chemoresistant effects from dysregulated BER protein expression in gastric, colorectal, and ovarian cancers. Examination of the TCGA database show dysregulation of key BER protein like X-ray cross complementing protein 1 (XRCC1) and DNA polymerase β (POLβ) are common across several cancers. Therefore, we decided to explore DNA damage and repair defects in prostate cancer to explore if altered DNA repair contributes to poorer outcomes in African American men. To measure DNA repair defects in formalin-fixed paraffin-embedded (FFPE) tissues, we employed a novel assay, Repair Assisted Damage Detection (RADD), which measures DNA lesions within the tissues. RADD fluorescently tags DNA lesions for quantification and is compatible with immunohistochemistry detection of DNA repair or other proteins of interest. Using the tissue microarrays, we used RADD to discover that prostate tumors from African American patients have more uracil and pyrimidine lesions, elevated uracil DNA glycosylase (UNG) levels, and reduced XRCC1 levels than European American tumors, which indicate defects in the BER pathway. In addition, these men had higher uracil monophosphate (UMP) and lower expression of folate cycle metabolites, suggesting that metabolic rewiring may also contribute to the dysregulation of BER. Defects in the BER pathway may offer new therapeutic opportunities for African American prostate cancer patients. These defects may be targeted by therapeutics which pressure the BER pathways. This work demonstrates that functional detection of DNA repair defects through RADD offers new insight into race-specific DNA repair defects offering new molecular targets or therapeutic strategies to reduce racial disparities in prostate cancer. Citation Format: Kaveri Goel, Kimiko Krieger, Manoj Sonavane, Arun Sreekumar, Natalie R. Gassman. Race-associated base excision repair defects alter the DNA damage landscape in prostate cancer [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 6114.

PD32-03 ASSOCIATION BETWEEN TRUST, OUTCOMES AND RACIAL DISPARITY IN PROSTATE CANCER CARE

You have accessJournal of UrologyCME1 Apr 2023PD32-03 ASSOCIATION BETWEEN TRUST, OUTCOMES AND RACIAL DISPARITY IN PROSTATE CANCER CARE Sumedha Chhatre, Joseph Gallo, Thomas Guzzo, Knashawn Morales, Neha Vapiwala, Keith Van Arsdalen, Alan Wein, S Bruce Malkowicz, and Ravishankar Jayadevappa Sumedha ChhatreSumedha Chhatre More articles by this author , Joseph GalloJoseph Gallo More articles by this author , Thomas GuzzoThomas Guzzo More articles by this author , Knashawn MoralesKnashawn Morales More articles by this author , Neha VapiwalaNeha Vapiwala More articles by this author , Keith Van ArsdalenKeith Van Arsdalen More articles by this author , Alan WeinAlan Wein More articles by this author , S Bruce MalkowiczS Bruce Malkowicz More articles by this author , and Ravishankar JayadevappaRavishankar Jayadevappa More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003325.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Trust is an important aspect of healthcare and of the patient-physician relationship. Differences in levels of trust among patients may help explain variations in care seeking and use of medical services. However, these associations remain understudied. Objective is to study the association between patient-physician trust and treatment choice and outcomes among low, intermediate and high-risk, White and African American prostate cancer patients. METHODS: We used data from a multi-centered randomized controlled study among localized prostate cancer patients. Trust was measured at baseline using Patient Trust - Wake Forest Physician Trust Scale (PTWF). Outcomes were assessed at baseline, and at 3, 6, 12 and 24-month follow-up. Treatments were robotic-assisted laparoscopic radical prostatectomy, radiation therapy and active surveillance. Participants were categorized into risk groups as: low risk (PSA <10 ng/ml, Gleason ≤6, clinical stage T1-2a), intermediate risk (PSA 10 -20 ng/ml, Gleason 7, clinical stage T2b), and high risk was (PSA >20, Gleason ≥8, clinical stage T2c-3a). Association between treatment type, and trust (PTWF score) and race for each risk category was assessed using multinomial logistic models. RESULTS: Of the 743 localized prostate cancer patients recruited for the study, 82% were White and 14% were African American. Retention rate was >75% during follow-up. Proportion of risk categories was: 34% low-risk, 32% intermediate-risk and 34% high-risk. Baseline trust was comparable between White and African American patients (mean=19.5, standard deviation (std)=6.1 vs. mean=20.5, std=6.8, p=0.8032). Also, baseline trust was comparable between intervention group and usual care group (mean=19.3, std=6.0 vs mean=19.8, std=6.4; p=0.397). Results of multinomial regression indicated that trust and race were not associated with treatment choice independently. CONCLUSIONS: This is one of the largest study that has assessed the relationship between trust, race and outcomes in localized prostate cancer patients. We observed that baseline trust was comparable between White and African American patients. Also, neither trust, not race was associated with treatment choice and outcomes. Thus, other factors such as patient-centered preference assessment, may be associated with treatment choice in prostate cancer patients. Source of Funding: PCORI CE-12-11-4973 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e908 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sumedha Chhatre More articles by this author Joseph Gallo More articles by this author Thomas Guzzo More articles by this author Knashawn Morales More articles by this author Neha Vapiwala More articles by this author Keith Van Arsdalen More articles by this author Alan Wein More articles by this author S Bruce Malkowicz More articles by this author Ravishankar Jayadevappa More articles by this author Expand All Advertisement PDF downloadLoading ...

Abstract A080: The immunological signatures of African American prostate cancer as biological determinants of disease disparity

Abstract Background: Prostate cancer (PCa) is currently the second leading cause of cancer-related deaths among men in the United States. African American men suffer the highest incidence of disease morbidity and mortality compared to other racial groups. Although socio-economic, cultural, epidemiological, and genomic factors have been described to contribute to cancer health disparities in African American men, there is a knowledge gap regarding how the tumor immune landscape shapes aggressive disease patterns in this patient population, and whether their tumor microenvironment (TME) is amenable to immune modulation. This study aims to identify distinct and targetable immunosuppressive phenotypes and immunological signatures in prostate tumors of AA patients. Methodology: Peripheral blood from consented African American (AA) and Caucasian American (CA) patients undergoing prostatectomy at Moffitt Cancer Center were analyzed by Luminex multiplex cytokine/chemokine assay and comprehensive immune profiling via multi-parameter flow cytometry. Also, multiparameter immune profiling of freshly resected PCa specimens obtained from these same patients after prostatectomy was performed. In addition, multiplex immunohistochemical staining was performed on prostate tumor tissue microarrays to compare the proportions and phenotypes of T cells in the prostate TME of AA and CA patients. Lastly, the immunomodulatory potential of AZD5153, a bivalent Bromodomain 4 (BRD4) inhibitor was investigated on orthotopic prostate tumor-bearing humanized mouse models under racially defined settings, followed by comprehensive flow cytometry immunophenotypic profiling of tumor-infiltrating immune cells in the resected mice prostate tumors at clinical endpoints. Results: Prostate tumors of AA patients harbored higher proportions of CD4+ regulatory T cells (Tregs) and lower proportions of CD8+ T cells relative to CA patients. Furthermore, the immunophenotypic analysis of T cells showed higher expression of immune checkpoint molecules in AA compared to CA patients. Serum analysis revealed cytokine and chemokine expression signatures that are skewed towards a more immunosuppressive profile in AA compared to CA patients. Treatment with AZD5153 led to an increase in the survival time and a more striking reduction in tumor volume of AA-matched prostate tumor-bearing humanized mice relative to CA-matched prostate tumor-bearing humanized mice. A decrease in the proportion of tumor-infiltrating Tregs and a reduction in the expression of immune checkpoint molecules were also observed in prostate tumors from AA-matched humanized mice relative to CA-matched humanized mice. Conclusion: Our findings support the contributory role of racially distinct immunophenotypes and immune signatures in PCa disparity, and highlight the potential immunotherapeutic benefits of BRD4 inhibitors, such as AZD5153 in AA PCa patients. Citation Format: Saheed O. Oseni, Arup Bag, Oluwaseyi Oluwatola, Natalie DeMars, Dennis Adeegbe. The immunological signatures of African American prostate cancer as biological determinants of disease disparity [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A080.

Molecular and pathological subtypes related to prostate cancer disparities and disease outcomes in African American and European American patients.

Prostate cancer (PCa) disproportionately affects African American (AA) men, yet present biomarkers do not address the observed racial disparity. The objective of this study was to identify biomarkers with potential benefits to AA PCa patients. Differentially expressed genes (DEG) analysis coupled with gene set enrichment analysis (GSEA) and leading-edge genes analysis showed that the keratin family of genes, including KRT8, KRT15, KRT19, KRT34, and KRT80, constituted the single most prominent family of genes enriched in AA compared to European American (EA) PCa cell lines. In PCa patients (TCGA and MSKCC patient cohorts), KRT8, KRT15, and KRT19 expression were relatively higher in AA than in EA patients. The differences in the expression of KRT15 and KRT19, but not KRT8, were enhanced by Gleason score and ERG fusion status; in low Gleason (Gleason ≤ 6 [TCGA cohort] and Gleason ≤ 7 [MSKCC cohort]), the expression of KRT15 and KRT19 was significantly (p ≤ 0.05) higher in AA than in EA patients. Survival analysis revealed that high expression of KRT15 and KRT19 was associated with increased risk of biochemical recurrence in low Gleason category patients in the TCGA patient cohort. Interestingly, KRT15 and KRT19 expression were also associated with an increased risk of death in the metastatic prostate adenocarcinoma cohort, suggesting the potential to predict the risks of disease recurrence and death in the low Gleason category and advanced disease conditions respectively. Gene set enrichment analysis revealed known oncogenic gene signatures, including KRAS and ERBB2, to be enriched in patients expressing high KRT15 and KRT19. Furthermore, high KRT15 and KRT19 were linked to the basal and LumA PCa subtypes, which are associated with poor postoperative androgen deprivation therapy (ADT) response compared to the LumB subtype. Taken together, the present study identifies genes with high expression in AA than in EA PCa. The identified genes are linked to oncogenic gene signatures, including KRAS and ERBB2, and to basal and LumA PCa subtypes that are associated with poor postoperative ADT response. This study, therefore, reveals biomarkers with the potential to address biomarker bias in PCa risk stratification and/or prognosis.

Uridine Diphosphate Glucuronosyl Transferase 2B28 (UGT2B28) Promotes Tumor Progression and Is Elevated in African American Prostate Cancer Patients.

Prostate cancer (PCa) is the second most diagnosed cancer in the United States and is associated with metabolic reprogramming and significant disparities in clinical outcomes among African American (AA) men. While the cause is likely multi-factorial, the precise reasons for this are unknown. Here, we identified a higher expression of the metabolic enzyme UGT2B28 in localized PCa and metastatic disease compared to benign adjacent tissue, in AA PCa compared to benign adjacent tissue, and in AA PCa compared to European American (EA) PCa. UGT2B28 was found to be regulated by both full-length androgen receptor (AR) and its splice variant, AR-v7. Genetic knockdown of UGT2B28 across multiple PCa cell lines (LNCaP, LAPC-4, and VCaP), both in androgen-replete and androgen-depleted states resulted in impaired 3D organoid formation and a significant delay in tumor take and growth rate of xenograft tumors, all of which were rescued by re-expression of UGT2B28. Taken together, our findings demonstrate a key role for the UGT2B28 gene in promoting prostate tumor growth.

Navigation programs relevant for African American men with prostate cancer: a scoping review protocol

BackgroundThe excess incidence and mortality due to prostate cancer that impacts African American men constitutes the largest of all cancer disparities. Patient navigation is a patient-centered healthcare system intervention to eliminate barriers to timely, high-quality care across the cancer continuum and improves health outcomes among vulnerable patients. However, little is known regarding the extent to which navigation programs include cultural humility to address prostate cancer disparities among African American men. We present a scoping review protocol of an in-depth examination of navigation programs in prostate cancer care—including navigation activities/procedures, training, and management—with a special focus on cultural context and humility for African American men to achieve health equity.MethodsWe will conduct comprehensive searches of the literature in PubMed, Embase, Web of Science, and CINAHL Complete, using keywords and index terms (Mesh and Emtree) within the three main themes: prostate cancer, patient navigation, and African American men. We will also conduct a search of the gray literature, hand-searching, and reviewing references of included papers and conference abstracts. In a two-phase approach, two authors will independently screen titles and abstracts, and full-text based on inclusion/exclusion criteria. All study designs will be included that present detailed data about the elements of navigation programs, including intervention content, navigator training, and/or management. Data will be extracted from included studies, and review findings will be synthesized and summarized.DiscussionA scoping review focused on cultural humility in patient navigation within the context of eliminating disparities in PCa care among African American men does not yet exist. This review will synthesize existing evidence of patient navigation programs for African American prostate cancer patients and the inclusion of cultural humility. Results will inform the development and implementation of future programs to meet the unique needs of vulnerable prostate cancer patients in safety net settings.Systematic review registrationPROSPERO 2021 CRD42021221412

Serum proteomics links suppression of tumor immunity to ancestry and lethal prostate cancer

There is evidence that tumor immunobiology and immunotherapy response may differ between African American and European American prostate cancer patients. Here, we determine if men of African descent harbor a unique systemic immune-oncological signature and measure 82 circulating proteins in almost 3000 Ghanaian, African American, and European American men. Protein signatures for suppression of tumor immunity and chemotaxis are elevated in men of West African ancestry. Importantly, the suppression of tumor immunity protein signature associates with metastatic and lethal prostate cancer, pointing to clinical importance. Moreover, two markers, pleiotrophin and TNFRSF9, predict poor disease survival specifically among African American men. These findings indicate that immune-oncology marker profiles differ between men of African and European descent. These differences may contribute to the disproportionate burden of lethal prostate cancer in men of African ancestry. The elevated peripheral suppression of tumor immunity may have important implication for guidance of cancer therapy which could particularly benefit African American patients.

Utilizing lesion diameter and prostate specific antigen density to decide on magnetic resonance imaging guided confirmatory biopsy of prostate imaging reporting and data system score three lesions in African American prostate cancer patients managed with active surveillance.

The objective of the study is to identify the rate of significant prostate cancer (PCa) detection in PI-RADS3 lesions in AA patients stratified by PSAD threshold of < 0.15 vs. ≥ 0.15ng/ml2and lesion diameter of < 1cm vs ≥ 1cm. We analyzed our institutional database of MRI-TB to identify the rate of significant prostate cancer (PCa) detection in PI-RADS3 lesions in AA patients stratified by PSAD threshold of < 0.15 vs. ≥ 0.15ng/ml2and lesion diameter of < 1cm vs ≥ 1cm. Significant prostate cancer was defined as Gleason grade group 2 or higher on MRI-TB of the PI-RADS 3 lesion. Of 768 patients included in the database, 211 (27.5%) patients identified themselves as AAs. Mean age of AA patients was 63years and mean PSAD was 0.21. Sixty nine (32.7%) AA patients were found to have PI-RADS 3 lesions. Mean PSAD of AA patients with PI-RADS 3 lesions was 0.21ng/ml2as well. Fifty percent of AA patients with PI-RADS 3 lesions had PSAD ≥ 0.15ng/ml2. Significant PCa detection rate for AA patients with PI-RADS 3 lesions was 9% for PSAD of ≥ 0.15 vs. 0.03% percent for AA patients with PSAD < 0.15ng/ml2(OR 7.056, CI 1.017-167.9, P = 0.04). Stratification by lesion diameter (< 1cm vs. > 1cm) resulted in missing 0% of significant PCa when only AA patients with PSAD ≥ 0.15ng/ml2 and lesion diameter ≥ 1cm received MRI-TB. We report on the performance of a reported PSAD density threshold in detecting significant PCa in one of the largest series of AA patients receiving MRI-TB of the prostate. Our results have direct clinical implications when counseling AA patients with PI-RADS 3 lesion on whether they should undergo MRI-TB of such lesions.

Abstract PR-11: Blood levels of TNFRSF9 and PTN predict lethal prostate cancer among African American men

Abstract OBJECTIVE: Differentiating men who have lethal forms of prostate cancer from those with a more slow-growing disease remains a major challenge in clinical oncology. Risk stratification strategies are particularly needed for men of African descent who disproportionately bear the prostate cancer burden. Methods: Using a high throughput proximal extension assay, we simultaneously measured 82 immune-oncological proteins in the blood of 819 prostate cancer patients at diagnosis of whom 394 were African American (AA) and 425 were European American (EA). These patients were followed up for a median of 8.6 years since their diagnosis during which 57 died of prostate cancer while 202 died of all causes. To identify an immune-oncology protein signature predictive of lethal prostate cancer, we applied a cross-validated, regularized Cox regression model. Included in this model were the 82 immune-oncology proteins and 6 covariates of clinical significance (age, education, BMI, smoking history, aspirin use, and diabetes). Results: We did not identify a robust predictive signature of lethal prostate cancer for EA patients. However, for AA patients a signature primarily driven by tumor necrosis factor receptor superfamily member 9 (TNFRSF9) and pleiotrophin (PTN) (both positively associated with the risk of lethal disease) and regular aspirin use (negatively associated with risk) were the top predictors (P &amp;lt; 0.05) based on two selection criteria: the feature frequency and the weight of the features' contribution to the prediction. These features combined predicted prostate cancer-specific mortality with an accuracy of 83.7% (SE=3.8%). The two proteins alone, TNFRSF9 and PTN, predicted prostate cancer-specific mortality with an accuracy of 78.2% (SE=4.2%). AA prostate cancer patients with high levels (&amp;gt; median) of both TNFRSF9 and PTN in their blood at diagnosis had the worst prostate cancer-specific survival. By 10 years, 33% of cases with high levels of both TNFRSF9 and PTN died of prostate cancer compared to only 5% of cases with low levels of both or either of these proteins. Conclusions: Our study describes novel blood markers of lethal prostate cancer that can be used for risk stratification of AA patients at the time of diagnosis. AA patients with high levels of both TNFRSF9 and PTN in their sera had the highest risk of dying from prostate cancer. These markers may also be applicable to African prostate cancer patients since the blood-based immunome of Ghanaian and AA men are similar, as shown by our data. Citation Format: Tsion Zewdu Minas, Julián Candia, Tiffany H. Dorsey, Francine Baker, Wei Tang, Maeve Kiely, Cheryl J. Smith, Symone V. Jordan, Obadi M. Obadi, Anuoluwapo Ajao, Christopher A. Loffredo, Clayton Yates, Michael B. Cook, Stefan Ambs. Blood levels of TNFRSF9 and PTN predict lethal prostate cancer among African American men [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 PR-11.

Lipid Alterations in African American Men with Prostate Cancer.

African-American (AA) men are more than twice as likely to die of prostate cancer (PCa) than European American (EA) men. Previous in silico analysis revealed enrichment of altered lipid metabolic pathways in pan-cancer AA tumors. Here, we performed global unbiased lipidomics profiling on 48 matched localized PCa and benign adjacent tissues (30 AA, 24 ancestry-verified, and 18 EA, 8 ancestry verified) and quantified 429 lipids belonging to 14 lipid classes. Significant alterations in long chain polyunsaturated lipids were observed between PCa and benign adjacent tissues, low and high Gleason tumors, as well as associated with early biochemical recurrence, both in the entire cohort, and within AA patients. Alterations in cholesteryl esters, and phosphatidyl inositol classes of lipids delineated AA and EA PCa, while the levels of lipids belonging to triglycerides, phosphatidyl glycerol, phosphatidyl choline, phosphatidic acid, and cholesteryl esters distinguished AA and EA PCa patients with biochemical recurrence. These first-in-field results implicate lipid alterations as biological factors for prostate cancer disparities.

The HOXB13 variant X285K is associated with clinical significance and early age at diagnosis in African American prostate cancer patients.

Recently, a novel HOXB13 variant (X285K) was observed in men of African descent with prostate cancer (PCa) in Martinique. Little is known about this or other variants in HOXB13 which may play a role in PCa susceptibility in African-American (AA) men. We sequenced HOXB13 in an AA population of 1048 men undergoing surgical treatment for PCa at Johns Hopkins Hospital. Seven non-synonymous germline variants were observed in the patient population. While six of these variants were seen only once, X285K was found in eight patients. In a case-case analysis, we find that carriers of this latter variant are at increased risk of clinically significant PCa (1.2% carrier rate in Gleason Score ≥7 PCa vs. 0% in Gleason Score <7 PCa, odds ratio, OR = inf; 95% Confidence Interval, 95%CI:1.05-inf, P = 0.028), as well as PCa with early age at diagnosis (2.4% carrier rate in patients <50 year vs. 0.5% carrier rate in patients ≥50 year, OR = 5.25, 95% CI:1.00-28.52, P = 0.03). While this variant is rare in the AA population (~0.2% MAF), its ancestry-specific occurrence and apparent preferential association with risk for the more aggressive disease at an early age emphasizes its translational potential as an important, novel PCa susceptibility marker in the high-risk AA population.

Cancer-specific survival after radical prostatectomy versus external beam radiotherapy in high-risk and very high-risk African American prostate cancer patients.

To test for differences in cancer-specific mortality (CSM) rates between radical prostatectomy (RP) vs external beam radiotherapy (EBRT) in National Comprehensive Cancer Network (NCCN) high-risk African American patients, as well as Johns Hopkins University (JHU) high-risk and very high-risk patients. Within the Surveillance, Epidemiology, and End Results database (2010-2016), we identified 4165 NCCN high-risk patients, of whom 1944 (46.7%) and 2221 (53.3%) patients qualified for JHU high-risk or very high-risk definitions. Of all 4165 patients, 1390 (33.5%) were treated with RP versus 2775 (66.6%) with EBRT. Cumulative incidence plots and competing risks regression models addressed CSM before and after 1:1 propensity score matching between RP and EBRT NCCN high-risk patients. Subsequently, analyses were repeated separately in JHU high-risk and very high-risk subgroups. Finally, all analyses were repeated after landmark analyses were applied. In the NCCN high-risk cohort, 5-year CSM rates for RP versus EBRT were 2.4 versus 5.2%, yielding a multivariable hazard ratio of 0.50 (95% confidence interval [CI] 0.30-0.84, p = 0.009) favoring RP. In JHU very high-risk patients 5-year CSM rates for RP versus EBRT were 3.7 versus 8.4%, respectively, yielding a multivariable hazard ratio of 0.51 (95% CI: 0.28-0.95, p = 0.03) favoring RP. Conversely, in JHU high-risk patients, no significant CSM difference was recorded between RP vs EBRT (5-year CSM rates: 1.3 vs 1.3%; multivariable hazard ratio: 0.55, 95% CI: 0.16-1.90, p = 0.3). Observations were confirmed in propensity score-matched and landmark analyses adjusted cohorts. In JHU very high-risk African American patients, RP may hold a CSM advantage over EBRT, but not in JHU high-risk African American patients.

Urinary PGE-M in Men with Prostate Cancer.

Simple SummaryElevated levels of urinary prostaglandin E metabolite (PGE-M), a marker of inflammation, have previously been associated with cancer incidence and metastasis. Studies investigating PGE-M in prostate cancer are lacking even though chronic inflammation is a candidate risk factor for the disease. We investigated the association of PGE-M with lethal prostate cancer. We measured PGE-M in the urine of men with prostate cancer and in men without prostate cancer (population controls). Our participants included African American and European American men. Because African American men die more frequently from prostate cancer than European American men, we investigated whether high PGE-M may contribute to the increased mortality among African American prostate cancer patients. We did not observe a relationship between PGE-M and prostate cancer aggressiveness or prostate cancer-specific mortality in our study population, neither in the combined cohort nor in the race/ethnicity stratified analysis. Interestingly, however, we observed a significant relationship between high PGE-M and all-cause mortality in African American men with prostate cancer. Yet, there was no association between high PGE-M and all-cause mortality when these men were regular aspirin users.Urinary PGE-M is a stable metabolite of prostaglandin E2 (PGE2). PGE2 is a product of the inflammatory COX signaling pathway and has been associated with cancer incidence and metastasis. Its synthesis can be inhibited by aspirin. We investigated the association of PGE-M with lethal prostate cancer in a case–control study of African American (AA) and European American men. We measured urinary PGE-M using mass-spectrometry. Samples were obtained from 977 cases and 1022 controls at the time of recruitment. We applied multivariable logistic and Cox regression modeling to examine associations of PGE-M with prostate cancer and participant survival. Median survival follow-up was 8.4 years, with 246 deaths among cases. Self-reported aspirin use over the past 5 years was assessed with a questionnaire. Race/ethnicity was self-reported. Urinary PGE-M levels did not differ between men with prostate cancer and population-based controls. We observed no association between PGE-M and aggressive disease nor prostate-cancer-specific survival. However, we observed a statistically significant association between higher (>median) PGE-M and all-cause mortality in AA cases who did not regularly use aspirin (HR = 2.04, 95% CI 1.23–3.37). Among cases who reported using aspirin, there was no association. Our study does not support a meaningful association between urinary PGE-M and prostate cancer. Moreover, PGE-M levels were not associated with aggressive prostate cancer. However, the observed association between elevated PGE-M and all-cause mortality in AA non-aspirin users reinforces the potential benefit of aspirin to reduce mortality among AA men with prostate cancer.