High Incidence Of Prostate Cancer Research Articles

PSA Stratification for Predicting Advanced Prostate Cancer Events in Men Approaching Age-Limits for Recommended Screening.

To quantify the ability of various PSA values in predicting the likelihood of developing metastatic or fatal prostate cancer in older men. We used a random sample of patients in the United States Veterans Health Administration to identify 80,706 men who had received PSA testing between ages 70 to 75. Our primary endpoint was time to development of either metastatic prostate cancer or death from prostate cancer. We used cumulative/dynamic modeling to account for competing events (death from non-prostate cancer causes) in studying both the discriminative ability of PSA as well as for positive predictive value and negative predictive value at three time points. PSA demonstrated time-dependent predictive discrimination, with receiver operating characteristic area under the curve at 5, 10, and 14 years decreasing from 0.83 to 0.77 to 0.73, respectively, but without statistically significant difference when stratified by race. At PSA thresholds between 1 and 8 ng/mL, the positive predictive value of developing advanced prostate cancer was significantly greater in Black than White patients. For instance, at a PSA > 3, at 5, 10, and 14 years, White patients had 2.4%, 2.9%, and 3.7% risk of an event, whereas Black patients had 4.3%, 6.5%, and 8.3% risk. In men aged 70 to 75 deciding whether to cease PSA testing with borderline-elevated PSA values, the risk of developing metastatic or fatal prostate cancer is quantifiable and relatively low. Risk assessment in this setting must account for the higher incidence of prostate cancer in Black men.

Variants in Vitamin D-related Genes and Prostate Cancer Risk in Black Men.

The relationship between vitamin D and prostate cancer has primarily been characterized among White men. However, Black men have higher prostate cancer incidence and mortality rates, chronically low circulating vitamin D levels, and ancestry-specific genetic variants in vitamin D-related genes. Here, we examine six critical genes in the vitamin D pathway and prostate cancer risk in Black men. We assessed a total of 69 candidate variants in six genes ( GC, CYP27A1, CYP27B1, CYP24A1, VDR , and RXRA ) including functional variants previously associated with prostate cancer and circulating 25(OHD) in White men. Associations with prostate cancer risk were examined using genome-wide association study data for approximately 10,000 prostate cancer cases and 10,000 controls among Black men and over 85,000 cases and 91,000 controls among White men. A statistical significance threshold of 0.000724 was used to account for the 69 variants tested. None of the variants examined were significantly associated with prostate cancer risk among Black men after multiple comparison adjustment. Four variants tested P<0.05 in Black men, including two in RXRA (rs41400444 OR=1.09, 95% CI: 1.01-1.17, P = 0.024 and rs10881574 OR = 0.93, 0.87-1.00, P = 0.046) and two in VDR (rs2853563 OR = 1.07, 1.01-1.13, P = 0.017 and rs1156882 OR = 1.06, 1.00-1.12, P = 0.045). Two variants in VDR were also positively associated with risk in White men (rs11568820 OR = 1.04, 1.02-1.06, P = 0.00024 and rs4516035 OR = 1.03, 1.01-1.04, P = 0.00055). We observed suggestive non-significant associations between genetic variants in RXRA and VDR and prostate cancer risk in Black men. Future research exploring the relationship of vitamin D with cancer risk in Black men will need larger sample sizes to identify ancestry-specific variants relevant to risk in this population.

Management of the Devastated Bladder Outlet after Prostate CANCER Treatment.

Devastating complications of the bladder outlet resulting from prostate cancer treatments are relatively uncommon. However, the combination of the high incidence of prostate cancer and patient longevity after treatment have raised awareness of adverse outcomes deteriorating patients' quality of life. This narrative review discusses the diagnostic work-up and management options for bladder outlet obstruction resulting from prostate cancer treatments, including those that require urinary diversion. The devastated bladder outlet can be a consequence of the treatment of benign conditions, but more frequently from complications of pelvic cancer treatments. Regardless of etiology, the initial treatment ladder involves endoluminal options such as dilation and direct vision internal urethrotomy, with or without intralesional injection of anti-fibrotic agents. If these conservative strategies fail, surgical reconstruction should be considered. Although surgical reconstruction provides the best prospect of durable success, reconstructive procedures are also associated with serious complications. In the worst circumstances, such as prior radiotherapy, failed reconstruction, devastated bladder outlet with end-stage bladders, or patient's severe comorbidities, reconstruction may neither be realistic nor justified. Urinary diversion with or without cystectomy may be the best option for these patients. Thorough patient counseling before treatment selection is of utmost importance. Outcomes and repercussions on quality of life vary extensively with management options. Meticulous preoperative diagnostic evaluation is paramount in selecting the right treatment strategy for each individual patient. The risk of bladder outlet obstruction, and its severest form, devastated bladder outlet, after treatment of prostate cancer is not negligible, especially following radiation. Management includes endoluminal treatment, open or robot-assisted laparoscopic reconstruction, and urinary diversion in the worst circumstances, with varying success rates.

Machine-learning Algorithm-based Risk Prediction and Screening-detected Prostate Cancer in A Benign Prostate Hyperplasia Cohort.

Prostate cancer (PCa) is lethal. Our aim in this retrospective cohort study was to use machine learning-based methodology to predict PCa risk in patients with benign prostate hyperplasia (BPH), identify potential risk factors, and optimize predictive performance. The dataset was extracted from a clinical information database of patients at a single institute from January 2000 to December 2020. Patients newly diagnosed with BPH and prescribed alpha blockers/5-alpha-reductase inhibitors were enrolled. Patients were excluded if they had a previous diagnosis of any cancer or were diagnosed with PCa within 1 month of enrolment. The study endpoint was PCa diagnosis. The study utilized the extreme gradient boosting (XGB), support vector machine (SVM) and K-nearest neighbors (KNN) machine-learning algorithms for analysis. The dataset used in this study included 5,122 medical records of patients with and without PCa, with 19 patient characteristics. The SVM and XGB models performed better than the KNN model in terms of accuracy and area under curve. Local interpretable model-agnostic explanation and Shapley additive explanations analysis showed that body mass index (BMI) and late prostate-specific antigen (PSA) were important features for the SVM model, while PSA velocity, late PSA, and BMI were important features for the XGB model. Use of 5-alpha-reductase inhibitor was associated with a higher incidence of PCa, with similar survival outcomes compared to non-users. Machine learning can enhance personalized PCa risk assessments for patients with BPH but more research is necessary to refine these models and address data biases. Clinicians should use them as supplementary tools alongside traditional screening methods.

Association between patient ethnicity and prostate cancer diagnosis following a prostate-specific antigen test: a cohort study of 730,000 men in primary care in the UK

BackgroundBlack men have higher prostate-specific antigen (PSA) levels and higher prostate cancer incidence and mortality than White men, while Asian men tend to have lower prostate cancer incidence and mortality than White men. Much of the evidence comes from the USA, and information from UK populations is limited.MethodsThis retrospective cohort study used data on patients registered at general practices in England contributing to the Clinical Practice Research Datalink (CPRD) Aurum dataset. Those eligible were men aged 40 and over with a record of ethnicity and a PSA test result recorded between 2010 and 2017 with no prior cancer diagnosis.The aim was to assess the incidence of prostate cancer following a raised PSA test result in men from different ethnic groups. Additionally, incidence of advanced prostate cancer was investigated. Cancer incidence was estimated from multi-level logistic regression models adjusting for potential confounding factors.Results730,515 men with a PSA test were included (88.9% White). Black men and men with mixed ethnicity had higher PSA values, particularly for those aged above 60 years. In the year following a raised PSA result (using age-specific thresholds), Black men had the highest prostate cancer incidence at 24.7% (95% CI 23.3%, 26.2%); Asian men had the lowest at 13.4% (12.2%, 14.7%); incidence for White men was 19.8% (19.4%, 20.2%). The peak incidence of prostate cancer for all groups was in men aged 70–79. Incidence of prostate cancer diagnosed at an advanced stage was similar between Black and White men.ConclusionsMore prostate cancer was diagnosed in Black men with a raised PSA result, but rates of advanced prostate cancer were not higher in this group. In this large primary care-based cohort, the incidence of prostate cancer in men with elevated PSA levels increases with increasing age, even when using age-adjusted thresholds, with Black men significantly more likely to be diagnosed compared to White or Asian men. The incidence of advanced stage prostate cancer at diagnosis was similar for Black and White men with a raised PSA result, but lower for Asian men.

The Impact of Inherited Genetic Variation on DNA Methylation in Prostate Cancer and Benign Tissues of African American and European American Men.

American men of African ancestry (AA) have higher prostate cancer incidence and mortality rates compared with American men of European ancestry (EA). Differences in genetic susceptibility mechanisms may contribute to this disparity. To gain insights into the regulatory mechanisms of prostate cancer susceptibility variants, we tested the association between SNPs and DNA methylation (DNAm) at nearby CpG sites across the genome in benign and cancer prostate tissue from 74 AA and 74 EA men. Genome-wide SNP data (from benign tissue) and DNAm were generated using Illumina arrays. Among AA men, we identified 6,298 and 2,641 cis-methylation QTLs (meQTL; FDR of 0.05) in benign and tumor tissue, respectively, with 6,960 and 1,700 detected in EA men. We leveraged genome-wide association study (GWAS) summary statistics to identify previously reported prostate cancer GWAS signals likely to share a common causal variant with a detected meQTL. We identified nine GWAS-meQTL pairs with strong evidence of colocalization (four in EA benign, three in EA tumor, two in AA benign, and three in AA tumor). Among these colocalized GWAS-meQTL pairs, we identified colocalizing expression quantitative trait loci (eQTL) impacting four eGenes with known roles in tumorigenesis. These findings highlight epigenetic regulatory mechanisms by which prostate cancer-risk SNPs can modify local DNAm and/or gene expression in prostate tissue. Overall, our findings showed general consistency in the meQTL landscape of AA and EA men, but meQTLs often differ by tissue type (normal vs. cancer). Ancestry-based linkage disequilibrium differences and lack of AA representation in GWAS decrease statistical power to detect colocalization for some regions.

Abstract B123: A descriptive study of substance use and cardiovascular issues among Nigerian men with prostate cancer

Abstract Introduction: Black males face a higher incidence of prostate cancer compared to other racial and ethnic groups. Cardiovascular disorders, including hypertension and metabolic syndrome, are more frequently observed in black men with prostate cancer, significantly impacting their quality of life, treatment outcomes, and related challenges. Socioeconomic disparities and stress also pose significant challenges for black men who engage in substance use, such as tobacco or alcohol. The purpose of this study was to explore the prevalence of cardiovascular issues and substance abuse specifically among black males diagnosed with prostate cancer. Methods: This descriptive, cross-sectional study examined associations between substance abuse, cardiovascular co-morbidities, and diagnoses of prostate cancer in men in Nigeria, Africa. It utilized data collected from the Prostate Cancer Transatlantic Consortium (CaPTC) Familial Cohort Study, an ongoing longitudinal cohort study initiated in 2018 which explores risk factors of prostate cancer among African Black men in Nigeria, Cameroon, and the United States (U.S.). Descriptive statistics generated association tables for variables captured. Results: From 708 participants who resided in Nigeria, 117 reported prostate cancer diagnoses compared to 580 who denied any cancer diagnoses. Median age of participants was 50, most were married (98.1%), Christian (65.8%), college educated (29.4%), with professional occupations (29.4%) and an average household income of 1,000,000 + Naira (24.2%). Marijuana use and alcohol consumption were identified to have statistically significant associations with prostate cancer diagnoses (p=0.003, p&amp;lt;0.001, respectively), while smoking (p=0.13), weight (p=0.22), and annual physicals (p=0.39) were not found to be significant predictors of prostate cancer diagnoses. Conclusion: Both marijuana and alcohol use were found to have significant associations with prostate cancer diagnoses in Nigerian men. Further research is directed to explore similar associations in Black men of other locations to confirm. This study provides a glimpse of associations of substance use and cardiovascular concerns in black males with prostate cancer. It is crucial for interventions to identify and understand the role of substance dependence and cardiovascular disorders in black males with prostate cancer to effectively address all risk factors, implementing lifestyle modifications, and providing culturally appropriate care, ultimately improving outcomes and reducing health disparities. Citation Format: Brittany M. Norris, Marvin Fullwood, Daniel Lee, Folakemi Odedina. A descriptive study of substance use and cardiovascular issues among Nigerian men with prostate cancer [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 B123.

Abstract A048: Community-based knowledge-to-action: Early detection of prostate cancer in Black men, shared decision-making tools, and clinical toolkits — a scoping literature review

Abstract Black men have a 70-80% higher incidence of prostate cancer (PCa) and 120% higher rate of death from prostate cancer compared with men of other races and ethnicities in the US. This disparity in prostate cancer-related death represents the largest racial inequity of any cancer in the US. We conducted semi-structured interviews with Black men in Washington State assessing their knowledge, attitudes, and experiences around early detection of PCa. Findings revealed equity-related barriers Black men encounter in accessing prostate-specific antigen (PSA) tests, including: lack of information on the benefits and harms of PCa screening for patients and primary care providers (PCPs), perceived lack of understanding by PCPs of racial inequities in PCa outcomes, and lack of trusted relationships with PCPs to support PCa screening discussion and shared-decision making (SDM). A scoping review of scientific literature was conducted to identify existing studies reporting use, evaluation, or design of evidence-based or community-based toolkits used to increase SDM for PSA testing in Black men. The tools have the potential to be implemented in future clinical protocols or practice for encouraging PSA testing in Black men. Our search included papers indexed in PubMed, Embase, or CINAHL that evaluated the effectiveness or efficacy of SDM tools for PSA testing interventions and programs involving Black men from 2011-2022. Of 1,112 papers identified, our inclusion/exclusion criteria for the search yielded 8 studies, 4 of which were evidence-based interventions or evaluations that resulted in knowledge increase or awareness of PCa screening, and 4 of which were in community-based approaches or some form of community-engaged method. Cross-study comparisons were possible, as some focused on pre- and post-tests with emphasis on an increase in knowledge prevalence or the proportion of men who used the decision-making tools. The currently-available tools increased awareness of screening but did not increase the application or intent to engage in PSA testing or dialogue with providers. Our scoping review demonstrates a gap in knowledge and a need to create an evidence-based, community-based, patient-centered SDM intervention that will increase awareness, education, and support for PCa early detection among Black men through accessible, culturally relevant, and accurate clinical SDM that can be used in future practice or clinical trials. We have acquired funding through a cancer center support grant for further work in creating a community-engaged tool that will utilize a Community-Based Knowledge-to-Action approach in developing a collaborative, SDM toolkit for Black men and their providers to use that will give accurate, relevant information about PCa risk, PSA testing, and increased likelihood to engage in PSA testing for Black men. Citation Format: Dante Morehead, Jenney Lee, Ben Young, Victor Tolbert, John Masembe, Sung Min Kim, Katherine Briant, Erika Wolff, John Gore, Yaw Nyame. Community-based knowledge-to-action: Early detection of prostate cancer in Black men, shared decision-making tools, and clinical toolkits — a scoping literature review [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 A048.

Abstract B049: Investigating standard of care treatments for cancers and their efficacy in Pacific Islander populations

Abstract Lung, Colorectal, and Pancreatic cancers are among the deadliest due to lack of early detection methods and few effective treatments. Among these cancers, patients who come from White or Black backgrounds have been shown to have the highest incidence and mortality when compared to other racial groups including Pacific Islanders. Although, most data aggregate Asian Americans and Pacific Islanders together, previous studies show that the trends in cancer rates and treatment efficacy is drastically different among these two groups. The Surveillance, Epidemiology and End Results (SEERs) Program conducted by the NIH is one such database that shows Asian Americans and Pacific Islanders as having the lowest incidence and mortality for all three of the top deadly cancers. The SEER is a database that collects cancer statistics from 33 different registries including Hawai'i, four California registries, Alaska, Texas and Utah, which are states with the highest populations of Pacific Islanders. The SEER also identifies White and Black Patients to have the highest incidence of Prostate Cancer but former studies have shown that Pacific Islanders surpass White non-Hispanics which the SEER establishes as the second highest in prostate cancer incidence. By disaggregating the data to analyze Pacific Islanders compared to other racial and ethnic groups, we can determine the true trends of cancer rates and mortality in the Pacific Islander Community. Through this work we will also determine if the standard of care treatments available to patients of these most deadly cancers is effective in those with a Pacific Islander background. Our data and data from other studies have shown that standard of care treatments are more effective in patients of European descent and are not as effective with patients from other communities due to the trials and tools used focusing a majority on caucasian patients. This is due to afflictions such as diabetes, obesity, history of smoking or drinking, and other criteria that may disqualify patients for clinical trials and treatments, however the communities most effected and have the highest prevalence of these criteria are people of color including Pacific Islanders. Our work is meant to do two things 1) lay a foundation to start collecting disaggregated data to get true trends of cancer statistics and 2) to understand the efficacy of treatments on the Pacific Islander community that is usually collected with Asian Americans which may mask the true effect on the microminority community of Pacific Islanders. Citation Format: Daniel J. Salas-Escabillas, Nicholas A. Sowizral, Sarah McNally, Sela V. Panapasa. Investigating standard of care treatments for cancers and their efficacy in Pacific Islander populations [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 B049.

Incidence and risk factors of prostate cancer among the Northern and Eastern parts of the United Arab Emirates population.

Prostate cancer (PCa) is a prevalent disease worldwide. However, the incidence and patient-specific risk factors of PCa in the Middle East, specifically in the United Arab Emirates,have not been previously reported. We conducted a retrospective cohort study on 2377 men diagnosed with either benign prostatic hyperplasia (BPH) or PCa in the Northern and Eastern regions of the United Arab Emirates, excluding the Western part, which includes Abu Dhabi. The study spanned from January 2012 and December 2021. To calculate the PCa incidence rate, we utilized the world age-standardized incidence rates (W-ASIR) categorized by age groups. Patient-specific risk factors of PCa were identified through a multivariate logistic regression analysis of clinical data. A total of 247 cases of PCa and 2130 cases of BPH were included in the study. In our cohort, the W-ASIR for PCa was 21.3 per 100,000 men. The incidence of PCa showed an increasing trend with age, with the highest incidence observed among men aged 70 years and older. Accordingly, multivariate analysis revealed that age over 70 was associated with an increased risk of PCa (OR: 2.546, 95% confidence interval [CI]: 1.892-3.425, p < 0.01). On the other hand, preexisting conditions such as hypertensionand diabetes mellituswere found to lower the risk of PCa (OR: 0.222, 95% CI: 0.163-0.302, p < 0.001) and (OR: 0.364, 95% CI: 0.205-0.648, p < 0.001), respectively. Additionally, metformin intake was associated with a reduced risk of PCa (OR: 0.385, 95% CI: 0.190-0.782, p = 0.008); while insulin usage increased the risk of PCa (OR: 2.586, 95% CI: 1.539-4.344, p < 0.001). Anti-BPH medications such as phosphodiesteraseinhibitors (OR: 0.223, 95% CI: 0.069-0.723, p = 0.012) or 5-α reductase (OR: 0.206, 95% CI: 0.110-0.389, p < 0.000), were found to lower the risk of PCa. The findings underscore the high incidence of PCa in the United Arab Emirates, with age being a significant factor. Furthermore, the study highlights the influence of certain comorbidities and medications on the risk of developing PCa within the United Arab Emiratespopulation.

Stereotactic Radiotherapy Deserts are Under-Represented among Radiation Oncology Alternative Payment Model Sites

In bundled payment models including the proposed Radiation Oncology Alternative Payment Model (RO-APM), reimbursement favors shorter treatment paradigms like stereotactic radiotherapy (SRT). However, SRT requires specialized equipment, staff, and quality assurance procedures not available across the US. To understand the geospatial distribution of SRT and its impact on bundled payment models, we investigated the interplay between SRT resources with sociodemographic characteristics and oncologic outcomes for an index site of prostate cancer (PC). We constructed an ecologic study model using data from the HRSA Area Health Resources, AMA Physician Masterfile, USDA Agriculture Economic Research Service, Medicare Provider and Service Files, and NIH Cancer State Profiles. SRT use was operationalized as the presence of Medicare SRT billing codes. Sociodemographic variables included county racial distributions, %poverty, and rural vs. urban classification. Provider to patient at risk density (PPRD) was defined as number of radiation oncologists per 100,000 males ≥65 years. PC incidence and death rates were evaluated. Uni- and multivariable logistic regressions examined links between SRT use, proposed RO-APM status, PPRD, sociodemographic variables, and PC oncologic outcomes at the US county level. All listed statistics demonstrated p <0.05. SRT use was identified in 13% of all 3140 counties and in 49% of counties with documented RO providers. In univariable analyses, odds of SRT use was higher in counties that were metro [odds ratio (OR) 19.9] and with higher %Black constituents (OR 6.95); odds decreased with higher %poverty (OR 0.92). Among counties with RO providers, odds of SRT use increased with higher PPRD (OR 1.01). Odds of SRT use was associated with higher PC incidence (1.01) but lower death rates (OR 0.99). SRT use was more common in participating RO-APM counties (OR 2.66); moreover, magnitude and direction of associations between sociodemographic variables and RO-APM participation were similar to those for SRT use. In multivariable analysis, SRT use remained significantly associated with metro status, %Black constituents, PPRD, and PC death rates. Both SRT use and proposed RO-APM participation were most prevalent in metro counties with higher PPRD and %Black populations, likely reflecting presence of densely populated cities with high health resources. If SRT is incentivized in future reimbursement models, then rural, lower resource communities without SRT may be disadvantaged. Lack of association between SRT and PC incidence indicates the presence of "SRT deserts"-counties with high oncologic need but no SRT. To enable visualization of SRT deserts and encourage interventions aimed at reducing disparities in SRT access, our results will be included in an interactive web platform (bit.ly/density maps).

Cancer incidence in World Trade Center rescue and recovery workers by race and ethnicity.

It is unclear whether differences in health outcomes by racial and ethnic groups among World Trade Center (WTC) rescue and recovery workers reflect those of the population of New York State (NYS) or show distinct patterns. We assessed cancer incidence in WTC workers by self-reported race and ethnicity, and compared it to population figures for NYS. A total of 61,031 WTC workers enrolled between September 11, 2001andJanuary 10, 2012were followed to December 31, 2015. To evaluate the association between race/ethnicity and cancer risk, Poissonregression analysis was used to estimate hazard ratios (HR) adjusted for WTC exposure, age, calendar year, sex and, for lung cancer, cigarette smoking. In comparison to Whites, Black workers had a higher incidence of prostate cancer (HR = 1.99, 95% CI = 1.69-2.34) and multiple myeloma (HR = 3.57, 95%CI = 1.97-6.45), and a lower incidence of thyroid (HR = 0.41, 95%CI = 0.22-0.78) and colorectal cancer (HR = 0.57; 95%CI = 0.33-0.98). Hispanic workers had a higher incidence of liver cancer (HR = 4.03, 95%CI = 2.23-7.28). Compared with NYS population, White workers had significantly higher incidence of prostate cancer (HR = 1.26, 95%CI = 1.18-1.35) and thyroid cancer (HR = 1.80, 95%CI = 1.55-2.08), while Black workers had significantly higher incidence of prostate cancer (HR = 1.22, 95%CI = 1.05-1.40). Cancer incidence in WTC workers generally reflects data from the NYS population, but some differences were identified that merit further investigation.

Racial differences in serum chemokines in prostate cancer patients.

This study aimed to understand the differential levels of inflammatory chemokines in association with higher prostate cancer incidence and mortality in African American (AA) men than in Caucasians (CA). The authors used a chemokine assay to simultaneously measure 40 chemokines and cytokines levels in the serum of preoperative prostate cancer patients and healthy controls of AA and CA races. Selected chemokines (CXCL2, CXCL5, and CCL23) serum level was validated in 211 serum samples from prostate cancer patients and healthy controls. Differential expression of CXCL5 and CCL23 was analyzed using immunohistochemistry in a representative cohort of prostate tumor tissues of AA and CA races. Race-specific comparisons from 211 serum samples showed significantly higher levels of CXCL2 (control: 3104.0 pg/mL vs. cancer: 2451.0 pg/mL) and CXCL5 (control: 5189.0 pg/mL vs. cancer: 5459.0 pg/mL) in AA men than in CAs (CXCL2; control: 1155.0 pg/mL vs. cancer: 889.3 pg/mL, and CXCL5; control: 1183.0 pg/mL vs. cancer: 977.5 pg/mL). CCL23 differed significantly within and between the races with a lower level in AA cancer cases (454.5 vs. 966.6 pg/mL) than healthy controls (740.5 vs. 1263.0 pg/mL). Patient age, prostate-specific antigen, or Gleason scores were not significantly associated with these chemokines. Immunostaining for CXCL5 and CCL23 in a representative cohort of archival prostate tissues displayed significantly higher CXCL5 in prostate tumors than in adjacent benign tissues, whereas CCL23 was nondetectable in most of the analyzed tumor tissues. Lower levels of CCL23 in AA prostate cancer patient sera and tumor tissues and high CXCL2 and CXCL5 may contribute to aggressive prostate cancer, as often seen in AA men. The disproportionate levels of serum chemokines associated with race warrant further exploration to improve equitability in precision oncology to benefit prostate cancer patients.

New insights into molecular signaling pathways and current advancements in prostate cancer diagnostics & therapeutics.

Prostate adenocarcinoma accounts for more than 20% of deaths among males due to cancer. It is the fifth-leading cancer diagnosed in males across the globe. The mortality rate is quite high due to prostate cancer. Despite the fact that advancements in diagnostics and therapeutics have been made, there is a lack of effective drugs. Metabolic pathways are altered due to the triggering of androgen receptor (AR) signaling pathways, and elevated levels of dihydrotestosterone are produced due to defects in AR signaling that accelerate the growth of prostate cancer cells. Further, PI3K/AKT/mTOR pathways interact with AR signaling pathway and act as precursors to promote prostate cancer. Prostate cancer therapy has been classified into luminal A, luminal B, and basal subtypes. Therapeutic drugs inhibiting dihydrotestosterone and PI3K have shown to give promising results to combat prostate cancer. Many second-generation Androgen receptor signaling antagonists are given either as single agent or with the combination of other drugs. In order to develop a cure for metastasized prostate cancer cells, Androgen deprivation therapy (ADT) is applied by using surgical or chemical methods. In many cases, Prostatectomy or local radiotherapy are used to control metastasized prostate cancer. However, it has been observed that after 1.5 years to 2 years of Prostatectomy or castration, there is reoccurrence of prostate cancer and high incidence of castration resistant prostate cancer is seen in population undergone ADT. It has been observed that Androgen derivation therapy combined with drugs like abiraterone acetate or docetaxel improve overall survival rate in metastatic hormone sensitive prostate cancer (mHSPC) patients. Scientific investigations have revealed that drugs inhibiting poly ADP Ribose polymerase (PARP) are showing promising results in clinical trials in the prostate cancer population with mCRPC and DNA repair abnormalities. Recently, RISUG adv (reversible inhibition of sperm under guidance) has shown significant results against prostate cancer cell lines and MTT assay has validated substantial effects of this drug against PC3 cell lines. Current review paper highlights the advancements in prostate cancer therapeutics and new drug molecules against prostate cancer. It will provide detailed insights on the signaling pathways which need to be targeted to combat metastasized prostate cancer and castration resistant prostate cancer.

Genetic ancestry associations with somatic mutations in a real-world cohort of over 3,000 patients with prostate cancer.

5034 Background: Disparities in incidence and outcomes of prostate cancer among racial groups have been reported. Black men have a higher incidence of prostate cancer compared to White men and are more likely to be diagnosed at a later stage, resulting in poorer outcomes. These differences are likely due to a combination of genetic, socioeconomic, and healthcare access factors. Furthermore, evidence has revealed racial differences in molecular profiles of prostate cancer, such as a higher incidence of ERF mutations and increased transcriptional activation of the androgen receptor signaling and inflammatory pathways in tumors derived from Black men compared to White men, suggesting that underlying biology may contribute to these disparities. Here, we aimed to identify differences in the mutational profiles of prostate cancers by race and genetic ancestry in a de-identified real-world cohort of 3,804 patients that underwent the Tempus xT 648-gene NGS tumor profiling test. Methods: We used 654 ancestry-informative markers to estimate continental ancestry likelihoods for five regions: Africa (AFR), Americas (AMR), East Asia (EAS), Europe (EUR), and South Asia (SAS). We imputed Asian (ASN, n=122), Hispanic/Latino/Native American (HLN, n=300), Non-Hispanic Black (NHB, n=619) and Non-Hispanic White (NHW, n=2,679) categories using genetic ancestry thresholds based on literature and validated with available metadata. Associations between either race/ethnicity categories or continental ancestry proportions and somatic variants (copy number alterations (CNAs), small nonsynonymous, OncoKB L1/2 &amp; R1, and predicted driver somatic mutations) were assessed for 109 prostate cancer-related genes using logistic regression models. Likelihood ratio tests were used to compare models with and without race/ethnicity or ancestry terms, and the Benjamini-Hochberg method was used to adjust p-values and control the FDR at 5%. Results: NHB and ASN men had lower odds of having a PTEN CNA compared to NHW men (OR=0.58 and 0.40, p=0.0001 and 0.009, respectively). Confirming this finding was a positive association between EUR ancestry and PTEN CNAs (OR=1.07 per doubling of EUR ancestry proportion, p=0.0007). NHB men were also less likely to have actionable OncoKB somatic mutations in the PIK3CA gene when compared to NHW men (OR=0.48, p=0.03). Increased AFR ancestry was associated with the presence of nonsynonymous predicted driver mutations in SPOP (OR=1.04, p=0.04), while both EAS and SAS ancestries were associated with fewer such mutations in TP53 (OR=0.95 in both cases, p=0.02 and 0.003). Conclusions: Analysis of a large real-world cohort leveraging genetic ancestry inferred from NGS data confirms previously known associations between the presence of somatic alterations in prostate cancer genes and race/ethnicity, and identifies novel associations of potential precision therapeutic relevance.

Abstract 1409: RNA sequencing reveals that African Americans carrying wild-type CYP3A5 differentially express genes known to promote aggressive prostate cancer

Abstract Background: African American men (AAs) have the highest incidence of prostate cancer (PC) and often develop therapeutic resistance leading to high mortality. The androgen receptor (AR) is paramount in the growth and progression of PC, and insufficient blockade of AR leads to therapeutic resistance. Our previous work shows that CYP3A5 facilitates the activation of AR, promoting the transcription of genes supporting PC growth. CYP3A5 is polymorphic, and the wild-type (wt; *1) variant encoding the full-length active protein is expressed in 73% of AAs and only in 5% of non-Hispanic White Americans (NHWA). The race-linked expression of wt-CYP3A5*1 in AAs can lead to hyperactive AR contributing to therapeutic resistance. We performed an RNA sequencing study utilizing samples from AAs and NWHA patients to understand the allelic influence of CYP3A5 on PC severity. Methods: Illumina RNA sequencing was performed using RNA from 13 AA and 12 NHWA prostatic adenocarcinomas. CYP3A5 genotyping separated them into two groups: a) carrying wt-CYP3A5 (*1/*1 and *1/*3; N=14); and b) mutant CYP3A5 (*3/*3; N=11) variants. The samples’ ancestry was confirmed using markers previously described. Differentially expressed genes (DEGs) between wt-*1 and mutant-*3 CYP3A5 carrying groups were identified using DESeq2, at a false discovery rate of adjusted p &amp;lt; 0.05. Alternately we also used the Kallisto method for quantifying the abundances of the transcript from RNA seq data. Results: Aligned RNA reads with the human genome using DESeq2 resulted in the identification of 30 DEGs between the two groups, of these, 14 genes are known to be dysregulated in PC and promote aggressive disease (SEMG2, ZNRF3, CCL18, U3, MT-ND6, SCARNA9, NRCAM, LINC00853, TCF4, SLC38A6, HHLA3, DECR1, THTPA, and NEFH). Aberrant TCF4 along with ZNRF3 is known to promote PC growth via Wnt-beta catenin signaling. SLC38A6 is a glutamine transporter and is often upregulated in PC to promote glutamine uptake in an AR-dependent manner. NEFH is an intermediate filament protein that is downregulated in PC metastasis. Kallisto method identified 84 DEGs, 11 of those genes overlap with the previous DFGs identified using the transcriptome alignment method. The additional DFGs identified with the Kallisto method include aberrant expression of multiple genes (MT-CO1/2, MT-ND1/6) involved in mitochondrial dysfunction known to contribute towards cell growth and tumorigenesis beyond the Warburg effect. The wt-*1 CYP3A5 expressing group also shows increased expression of several pseudogenes, dysregulation of pseudogenes has been observed in several cancers and can act as a master regulator for gene expression, promoting tumorigenesis. Conclusion: The presence of wt-*1 CYP3A5 may be one of the factors leading to aggressive PC in AAs as it shows differential expression of several genes known to accelerate PC growth. Citation Format: Jeetesh Sharma, Richard Tillett, Shirley Shen, Jabril Johnson, Rick A. Kittles, Mohammad Saleem Bhat, Oscar Goodman Jr, Edwin C. Oh, Ranjana Mitra. RNA sequencing reveals that African Americans carrying wild-type CYP3A5 differentially express genes known to promote aggressive 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 1409.

MP12-02 RACE REPORTING IN PROSTATE CANCER FOCAL THERAPY CLINICAL TRIALS

You have accessJournal of UrologyCME1 Apr 2023MP12-02 RACE REPORTING IN PROSTATE CANCER FOCAL THERAPY CLINICAL TRIALS Dhaval Jivanji, Arshia Sandozi, Katiana Vazquez-Rivera, Karis Buford, Mariela Martinez, David Silver, and Ariel Schulman Dhaval JivanjiDhaval Jivanji More articles by this author , Arshia SandoziArshia Sandozi More articles by this author , Katiana Vazquez-RiveraKatiana Vazquez-Rivera More articles by this author , Karis BufordKaris Buford More articles by this author , Mariela MartinezMariela Martinez More articles by this author , David SilverDavid Silver More articles by this author , and Ariel SchulmanAriel Schulman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003227.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Focal therapy has emerged as a primary treatment for localized prostate cancer, but there is limited evidence about its impact on oncological outcomes. Furthermore, there is a paucity of data looking at focal therapy in diverse racial populations. The objective of this study is to elucidate the current state of representation of non-white men in clinical trials investigating focal therapy. METHODS: PubMed and clinicaltrials.gov were queried using the search terms “prostate cancer” and “focal therapy” to identify all published and completed clinical trials between 2015-2022. Study characteristics were extracted and those that reported race information were further analyzed. Trials were excluded if focal therapy was used in combination with other treatments or used as salvage therapy. RESULTS: In total, 69 clinical trials (63 manuscripts, 6 completed clinical trials) were found to meet our inclusion criteria. HIFU (n=24, 34.8%), brachytherapy (n=9, 8.7%) and cryoablation (n=9, 8.7%) were the top three modalities studied. We found that 12/69 (17.4%) trials provided data on race which enrolled 945 patients. Within these studies, African American men only represented 4.3% of subjects (n=41). White subjects made up the vast majority of participants (n=871, 92.2%) followed by Multiracial subjects (n=18, 1.9%) and Asian subjects (n=8, 0.9%). CONCLUSIONS: Race was reported in only 17.4% of clinical trials studying focal therapy over the past eight years. Of the trials reporting race, African American men constituted <5% of study participants despite having the highest incidence of prostate cancer in the United States. It is incumbent upon future studies to report race data and to establish clinical trial enrollment protocol to address this discordance. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e133 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Dhaval Jivanji More articles by this author Arshia Sandozi More articles by this author Katiana Vazquez-Rivera More articles by this author Karis Buford More articles by this author Mariela Martinez More articles by this author David Silver More articles by this author Ariel Schulman More articles by this author Expand All Advertisement PDF downloadLoading ...

Hormonal and genotoxic estrogen-androgen carcinogenesis in the NBL rat prostate: A role for aromatase.

Androgens are generally thought to cause prostate cancer, but the data from animal studies suggest that they must be aromatized to estrogen and act in concert with genotoxic estrogen metabolites. The objective of this study was to determine whether treatment with testosterone (T) combined with a nonestrogenic estrogen metabolite and a nongenotoxic estrogenic compound would all be necessary and sufficient for the induction of a high incidence of prostate cancer in the susceptible NBL rat strain. NBL rats were treated with low-dose testosterone via slow-release Silastic implants and with the marginally estrogenic genotoxic catechol estrogen 4-hydroxyestradiol (4OH-E2) and the nongenotoxic estrogen 2-fluoroestradiol (2F-E2) and in one experiment the aromatase inhibitor letrozole via custom-made slow-release pellets. Animals were euthanized 52 weeks after implantation and their pituitaries and prostate complexes weighed and fixed in formalin. Hematoxylin and eosin (H&E)-stained step sections were prepared and examined microscopically for proliferative lesions. Animals treated with 2F-E2, with or without the other compounds, had enlarged pituitaries demonstrating its estrogenicity. Animals treated with T, with or without the other compounds, had enlarged prostates consistent with its androgenicity. Rats treated with T plus 2F-E2 and 4OH-E2 developed a high incidence of prostatic cancer (89%), while, surprisingly, rats treated with T plus only 2F-E2 also had a high incidence of prostate cancer (95%) contradicting our initial hypothesis. To test whether the formation of E2 from T by aromatase could lead to estrogen genotoxicity and prostate carcinogenesis we then rats treated with T and 2F-E2 also with letrozole and found that it reduced prostate cancer incidence by about 50%. These findings indicate that long-term treatment with a nongenotoxic estrogen (2F-E2) and T as well as uninhibited prostatic aromatase activity generating genotoxic E2 are all required for induction of a high incidence of prostatic adenocarcinomas in NBL rats. These and previous data indicate that androgen receptor-mediated action, estrogen receptor mediation, and estrogen genotoxicity are all required and sufficient for hormonal carcinogenesis in the NBL rat prostate. Interference with the estrogen genotoxicity is a potential approach to prostate cancer chemoprevention.

The androgen-thyroid hormone crosstalk in prostate cancer and the clinical implications.

There is increasing evidence that thyroid hormones (THs) work in an integrative fashion with androgen receptors (ARs) to regulate gonadal differentiation and reproductive function. Studies reveal that THs have interactions with the AR promoter region and increase AR expression. THs also have a role in the regulation of enzymes involved in the biosynthesis of androgens, such as 5α-reductase, which is essential in the conversion of testosterone into its active form, 5α-dihydrotestosterone. Additionally, the presence of androgen response elements in the promoter regions of TH-related genes, such as deiodinases and TH receptor isoforms, has been identified in some vertebrates, indicating a mutual interaction between THs and ARs. Since the androgen signaling pathway, mediated by ARs, plays a key role in the formation and progression of prostate cancer (PCa), the existence of crosstalk between THs and ARs supports the epidemiologic and experimental evidence indicating a relationship between the high incidence of PCa and hyperthyroidism. This article aims to review the role of androgen-TH crosstalk in PCa and its implication in clinical management. As life expectancy is growing these days, it can increase the number of patients with PCa and the critical relevance of the disease. In order to gain better knowledge about PCa and to improve clinical management, it is essential to get better insight into the key factors related to the formation and progression of this cancer.

Standardized prostate cancer incidence and mortality rates following initial non-malignant biopsy result.

To compare the incidence of subsequent prostate cancer diagnosis and death following an initial non-malignant systematic transrectal ultrasonography (TRUS) biopsy with that in an age- and calendar-year matched population over a 20-year period. This population-based analysis compared a cohort of all men with initial non-malignant TRUS biopsy in Denmark between 1995 and 2016 (N = 37 231) with the Danish population matched by age and calendar year, obtained from the NORDCAN 9.1 database. Age- and calendar year-corrected standardized prostate cancer incidence (SIR) and prostate cancer-specific mortality ratios (SMRs) were calculated and heterogeneity among age groups was assessed with the Cochran's Q test. The median time to censoring was 11 years, and 4434 men were followed for more than 15 years. The corrected SIR was 5.2 (95% confidence interval [CI] 5.1-5.4) and the corrected SMR was 0.74 (95% CI 0.67-0.81). Estimates differed among age groups (P < 0.001 for both), with a higher SIR and SMR among younger men. Men with non-malignant TRUS biopsy have a much higher incidence of prostate cancer but a risk of prostate cancer death below the population average. This underlines that the oncological risk of cancers missed in the initial TRUS biopsy is low. Accordingly, attempts to increase the sensitivity of initial biopsy are unjustified. Moreover, current follow-up after non-malignant biopsy is likely to be overaggressive, particularly in men over the age of 60 years.