A Ten Year Experience of Men's Health Events in a Socioeconomically Diverse City in the United States - Lessons Learned.

Community-based health events provide an opportunity to increase knowledge, awareness, and screening for acute and chronic diseases among individuals living in a socioeconomically diverse community. Because there are limited reports of such events, here we describe our ten-year experience of annual men's health fairs. This retrospective study of the Michigan Institute of Urology Foundation evaluated Men's Health Events held in Detroit, Michigan, from 2012 to 2021. Over 10 years, 11,129 men were screened and > 100,000 screenings were performed. The majority of the attendees were African-American men (61%), had a college degree (67%) or a high school diploma (26%), and had an annual income of <$35K (47%) or $35-60 K (30%). From 2012 to 2021, participants who saw a doctor in the past year rose from 62 to 70%; the median age of men rose from 52 to 58; their median testosterone levels increased from 353 ng/dL to 412 ng/dL, and men with concerning prostate-specific antigen values (≥ 4 ng/mL) doubled from 5% to 10%. Among participants, 59% had cholesterol levels of < 200 mg/dL, 28% of 200-240 mg/dL, and 13% of > 240 mg/dL; 7% had glucose levels of < 70 mg/dL, 68% of 70-105 mg/dL, and 25% of > 105 mg/dL ; 24% had ≥ 140 mmHg systolic and 18% had ≥ 90 mmHg diastolic blood pressure. Our findings suggest that community health events are successful at attracting and screening diverse community members. Such events should emphasize screening of high-risk individuals for acute and chronic diseases and promote other health-related behaviors.

Treatment Intensification Patterns and Utilization in Patients with Metastatic Castration-Sensitive Prostate Cancer.

INTRODUCTION: Patients with mCSPC experience a longer overall survival with treatment intensification by addition of novel hormonal therapy (NHT) or docetaxel to androgen deprivation vs androgen deprivation alone. Real-world data report, however, that nearly half of mCSPC patients do not receive treatment intensification. In this study, treatment patterns and utilization of treatment intensification in mCSPC patients were described using the IQVIA Anonymized Patient Longitudinal Data, a dataset of fully adjudicated pharmacy and medical claims. PATIENTS AND METHODS: Reports on first line (1L) treatment patterns were obtained for years 2015 to 2021. Medicaid, Medicare, Medicare part D, cash transactions, and commercial data were included for years 2012 to 2021. RESULTS: Nationwide, of 66,844 men with newly diagnosed mCSPC since 2015, on average 25% were prescribed NHT, and another 12% were prescribed chemotherapy. No differences were noted in treatment patterns based on U.S. regions and/or rural vs. urban communities. The disparity was observed in prescribing patterns between oncology and urology providers. Oncology providers prescribed 1L NHT on average 32% of the time, while urology providers did so 12% of the time. Furthermore, oncology providers prescribed chemotherapy on average 20% of the time, resulting in 52% of men with mCSPC receiving treatment intensification as 1L therapy. Patients' age group, community or health insurance did not account for the disparity between the 2 specialties. CONCLUSION: Both medical oncology and urology providers need to improve their treatment intensification efforts for men with mCSPC to increase their patients' overall survival.

Deconstructing, Addressing, and Eliminating Racial and Ethnic Inequities in Prostate Cancer Care.

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

DNA Repair Pathways and Their Association With Lethal Prostate Cancer in African American and European American Men.

Background: Altered DNA damage response (DDR) has emerged as an important mechanism for the development of aggressive prostate cancer among men of European ancestry but not other ancestry groups. Because common mechanisms for aggressive disease are expected, we explored a large panel of DDR genes and pathways to demonstrate that DDR alterations contribute to development of aggressive prostate cancer in both African American and European American men. Methods: We performed a case-case study of 764 African American and European American men with lethal or indolent prostate cancer treated at 4 US hospitals. We calculated carrier frequencies of germline pathogenic or likely pathogenic sequence variants within 306 DDR genes, summarized by DDR pathway, and compared lethal cases against indolent cases using 2-sided Fisher's exact tests. Secondary analysis examined if carrier frequencies differed by ancestry. Results: Lethal cases were more likely to carry a pathogenic sequence variant in a DDR gene compared with indolent cases (18.5% vs 9.6%, P = 4.30 × 10-4), even after excluding BRCA2 (14.6% vs 9.6%, P = .04). The carrier frequency was similar among lethal cases of African (16.7% including and 15.8% excluding BRCA2) and lethal cases of European (19.3% including and 14.2% excluding BRCA2) ancestry. Three DDR pathways were statistically significantly associated with lethal disease: homologous recombination (P = .003), Fanconi anemia (P = .002), and checkpoint factor (P = .02). Conclusions: Our findings suggest that altered DDR is an important mechanism for aggressive prostate cancer not only in men of European but also of African ancestry. Therefore, interrogation of entire DDR pathways is needed to fully characterize and better define genetic risk of lethal disease.

Pro-inflammatory cytokines and chemokines initiate multiple prostate cancer biologic pathways of cellular proliferation, heterogeneity and metastasis in a racially diverse population and underlie the genetic/biologic mechanism of racial disparity: Update.

Pro-inflammatory cytokine and chemokines genes drive prostate cancer progression and metastasis: molecular mechanism update and the science that underlies racial disparity. comprehensive review article. Isaac J. Powell, S. Chinni, S.S. Reddy, Alexander Zaslavsky, Navnath Gavande Introduction: In 2013 we reported that with the use of bioinformatics and ingenuity pathway network analysis we were able to identify functional driver genes that were differentially expressed among a large population of African American men (AAM) and European American men (EAM). Pro-inflammatory cytokine genes were found to be more interactive and more expressed among AAM and have been found to be functional drivers of aggressive prostate cancer (CaP) and aggressiveness in other solid tumors. We examined these genes and biological pathways initiated by these cytokines in primary CaP tissue. Method We unravel the gene network and identified biologic pathways that impacted activation of the androgen receptor, mesenchymal epithelial transition (invasion) and chemokines associated with metastasis in the CaP tissue from 639 radical prostatectomy specimens. Results Biologic pathways identified by unraveling pro-inflammatory genes from our network, more expressed among AAM compared to EAM, were tumor necrosis factor (TNF), IL1b, IL6, and IL8. IL6 and IL8 are downstream of TNF activity and are known activators of androgen receptor and through mediators promote CaP cell proliferation. TNF and IL1b mediate tumor cell invasiveness through the activation of MMP (matrix metalloproteinase) which down regulates E-Cadherin to initiate epithelial mesenchymal transition which allows cells to become invasive in the microenvironment. Ultimately our network analysis indicates that TNF and IL1b activate CXCR4 receptor on CaP cells, which facilitates metastatic progression reportedly by binding to CXCL12 on lipid rafts and tumor implantation in the bone marrow. Conclusion Our retrospective biologic mechanistic model reveals a set of pro-inflammatory cytokines and chemokines that drive CaP aggressiveness, tumor heterogeneity, progression and metastasis. A prospective multi-institutional study needs to be conducted for clinical validation as well consideration of targeted therapy.

The extrema of circulating miR-17 are identified as biomarkers for aggressive prostate cancer.

MicroRNAs (miRNAs) constitute short non-coding RNAs that can post-transcriptionally modulate the expression of many oncogenes and tumor suppressor genes engaged in key cellular processes. Deregulated serum miRNA signatures have been detected in various solid cancers including prostate cancer, suggesting that circulating miRNAs could function as non-invasive biomarkers of tumor emergence and progression. To determine whether serum miRNA expression levels are different between patients with aggressive and non-aggressive prostate cancer, we analyzed a panel of miRNAs from the blood of African American (AA) prostate cancer patients using a new recursive partitioning method that allows hypothesis testing of each split. We observed that both extrema of circulating miR-17, i.e. upregulation and downregulation, are associated with aggressive prostate cancer. A similar effect was observed in tumor samples from a separate dataset representing a different population of prostate cancer patients and in AA prostate cancer samples from the TCGA. The dual effect is consistent with the contradictory findings on the role of miR-17 in prostate cancer progression, whereby it controls important oncogenic and tumor-suppressive genes.

Risk of Becoming Lost to Follow-up During Active Surveillance for Prostate Cancer.

Active surveillance (AS) has emerged as the preferred management strategy for many men with prostate cancer (PC); however, insufficient longitudinal monitoring may increase the risk of poor outcomes. We sought to determine rates of patients becoming lost to follow-up (LTFU) and associated risk factors in a large AS cohort. The Michigan Urologic Surgery Improvement Collaborative (MUSIC) maintains a prospective registry of PC patients from 44 academic and community urology practices. Over a 6-yr period (2011-2017), we identified patients managed with AS. LTFU was defined as any 18-mo period where no pertinent surveillance testing was entered in the registry. With a median surveillance period of 32 mo, the estimated 2-yr LTFU-free probability calculated by Kaplan-Meier method was 90% (95% confidence interval [CI]=89-92%). Both African American race (hazard ratio [HR]: 2.77, 95% CI=1.81-4.24) and Charlson comorbidity index ≥1 (HR: 1.55, 95% CI=1.08-2.23) were independently associated with increased risk of LTFU. There was variability in rates of estimated 2-yr LTFU-free survival across MUSIC practices, ranging from 52% (95% CI=21-100%) to 99% (95% CI=97-100%), with a median of 96% (interquartile range: 94-98%), although this did not reach statistical significance (p=0.076). These data reveal opportunities for urology practices to identify systems to reduce rates of LTFU and improve the long-term safety of AS. PATIENT SUMMARY: With a median observation period of 32 mo, an estimated 10% of patients will be lost to follow-up at the 2 yr time point while on AS. African American men and generally unhealthy patients were at increased risk, and there was variability from one urology practice to another. There is ample opportunity to improve the quality of the performance of AS.

Exogenous IL-6 induces mRNA splice variant MBD2_v2 to promote stemness in TP53 wild-type, African American PCa cells.

African American men (AAM) are at higher risk of being diagnosed with prostate cancer (PCa) and are at higher risk of dying from the disease compared to European American men (EAM). We sought to better understand PCa molecular diversity that may be underlying these disparities. We performed RNA-sequencing analysis on high-grade PCa to identify genes showing differential tumor versus noncancer adjacent tissue expression patterns unique to AAM or EAM. We observed that interleukin-6 (IL-6) was upregulated in the nonmalignant adjacent tissue in AAM, but in EAM IL-6 expression was higher in PCa tissue. Enrichment analysis identified that genes linked to the function of TP53 were overrepresented and downregulated in PCa tissue from AAM. These RNA-sequencing results informed our subsequent investigation of a diverse PCa cell line panel. We observed that PCa cell lines that are TP53 wild-type, which includes cell lines derived from AAM (MDA-PCa-2b and RC77T), did not express detectable IL-6 mRNA. IL-6 treatment of these cells downregulated wild-type TP53 protein and induced mRNA and protein expression of the epigenetic reader methyl CpG binding domain protein 2 (MBD2), specifically the alternative mRNA splicing variant MBD2_v2. Further investigation validated that upregulation of this short isoform promotes self-renewal and expansion of PCa cancer stem-like cells (CSCs). In conclusion, this report contributes to characterizing gene expression patterns in high-grade PCa and adjacent noncancer tissues from EAM and AAM. The results we describe here advance what is known about the biology associated with PCa race disparities and the molecular signaling of CSCs.

A study of circulating microRNAs identifies a new potential biomarker panel to distinguish aggressive prostate cancer.

Prostate cancer is one of the most common cancers in men worldwide. Currently available diagnostic and prognostic tools for this disease, such as prostate specific antigen, suffer from lack of specificity and sensitivity, resulting in over- and misdiagnosis. Hence, there is an urgent need for clinically relevant biomarkers capable of distinguishing between aggressive and nonaggressive forms of prostate cancer to aid in stratification, management and therapeutic decisions. To address this unmet need, we investigated the patterns of expression of a panel of 68 plasma-derived microRNAs (miRNAs) in a cohort of African American (AA) and European American (EA) prostate cancer patients (n = 114). miRNA qPCR results were analyzed using in-depth statistical methods, and a bioinformatics analysis was conducted to identify potential targets of the differentially expressed miRNAs. Our data demonstrate that a new previously unreported circulating miRNA signature consisting of a combination of interacting miRNAs (miR-17/miR-192) and an independent miRNA (miR-181a) are capable of segregating aggressive and nonaggressive prostate cancer in both AA and EA patients. The interacting miRNAs outperformed independent miRNAs in identifying aggressiveness. Our results suggest that these circulating miRNAs may constitute novel biomarkers of prostate cancer aggressiveness in both races and warrant further investigation.

Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations.

African-American men have the highest incidence of and mortality from prostate cancer. Whether a biological basis exists for this disparity remains unclear. Exome sequencing (n = 102) and targeted validation (n = 90) of localized primary hormone-naïve prostate cancer in African-American men identified several gene mutations not previously observed in this context, including recurrent loss-of-function mutations in ERF, an ETS transcriptional repressor, in 5% of cases. Analysis of existing prostate cancer cohorts revealed ERF deletions in 3% of primary prostate cancers and mutations or deletions in ERF in 3% to 5% of lethal castration-resistant prostate cancers. Knockdown of ERF confers increased anchorage-independent growth and generates a gene expression signature associated with oncogenic ETS activation and androgen signaling. Together, these results suggest that ERF is a prostate cancer tumor-suppressor gene. More generally, our findings support the application of systematic cancer genomic characterization in settings of broader ancestral diversity to enhance discovery and, eventually, therapeutic applications.Significance: Systematic genomic sequencing of prostate cancer in African-American men revealed new insights into prostate cancer, including the identification of ERF as a prostate cancer gene; somatic copy-number alteration differences; and uncommon PIK3CA and PTEN alterations. This study highlights the importance of inclusion of underrepresented minorities in cancer sequencing studies. Cancer Discov; 7(9); 973-83. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 920.

gsSKAT: Rapid gene set analysis and multiple testing correction for rare-variant association studies using weighted linear kernels.

Next-generation sequencing technologies have afforded unprecedented characterization of low-frequency and rare genetic variation. Due to low power for single-variant testing, aggregative methods are commonly used to combine observed rare variation within a single gene. Causal variation may also aggregate across multiple genes within relevant biomolecular pathways. Kernel-machine regression and adaptive testing methods for aggregative rare-variant association testing have been demonstrated to be powerful approaches for pathway-level analysis, although these methods tend to be computationally intensive at high-variant dimensionality and require access to complete data. An additional analytical issue in scans of large pathway definition sets is multiple testing correction. Gene set definitions may exhibit substantial genic overlap, and the impact of the resultant correlation in test statistics on Type I error rate control for large agnostic gene set scans has not been fully explored. Herein, we first outline a statistical strategy for aggregative rare-variant analysis using component gene-level linear kernel score test summary statistics as well as derive simple estimators of the effective number of tests for family-wise error rate control. We then conduct extensive simulation studies to characterize the behavior of our approach relative to direct application of kernel and adaptive methods under a variety of conditions. We also apply our method to two case-control studies, respectively, evaluating rare variation in hereditary prostate cancer and schizophrenia. Finally, we provide open-source R code for public use to facilitate easy application of our methods to existing rare-variant analysis results.

REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants.

The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP, SiPhy, phyloP, and phastCons. REVEL was trained with recently discovered pathogenic and rare neutral missense variants, excluding those previously used to train its constituent tools. When applied to two independent test sets, REVEL had the best overall performance (p < 10-12) as compared to any individual tool and seven ensemble methods: MetaSVM, MetaLR, KGGSeq, Condel, CADD, DANN, and Eigen. Importantly, REVEL also had the best performance for distinguishing pathogenic from rare neutral variants with allele frequencies <0.5%. The area under the receiver operating characteristic curve (AUC) for REVEL was 0.046-0.182 higher in an independent test set of 935 recent SwissVar disease variants and 123,935 putatively neutral exome sequencing variants and 0.027-0.143 higher in an independent test set of 1,953 pathogenic and 2,406 benign variants recently reported in ClinVar than the AUCs for other ensemble methods. We provide pre-computed REVEL scores for all possible human missense variants to facilitate the identification of pathogenic variants in the sea of rare variants discovered as sequencing studies expand in scale.

Post hoc Analysis for Detecting Individual Rare Variant Risk Associations Using Probit Regression Bayesian Variable Selection Methods in Case-Control Sequencing Studies.

Rare variants (RVs) have been shown to be significant contributors to complex disease risk. By definition, these variants have very low minor allele frequencies and traditional single-marker methods for statistical analysis are underpowered for typical sequencing study sample sizes. Multimarker burden-type approaches attempt to identify aggregation of RVs across case-control status by analyzing relatively small partitions of the genome, such as genes. However, it is generally the case that the aggregative measure would be a mixture of causal and neutral variants, and these omnibus tests do not directly provide any indication of which RVs may be driving a given association. Recently, Bayesian variable selection approaches have been proposed to identify RV associations from a large set of RVs under consideration. Although these approaches have been shown to be powerful at detecting associations at the RV level, there are often computational limitations on the total quantity of RVs under consideration and compromises are necessary for large-scale application. Here, we propose a computationally efficient alternative formulation of this method using a probit regression approach specifically capable of simultaneously analyzing hundreds to thousands of RVs. We evaluate our approach to detect causal variation on simulated data and examine sensitivity and specificity in instances of high RV dimensionality as well as apply it to pathway-level RV analysis results from a prostate cancer (PC) risk case-control sequencing study. Finally, we discuss potential extensions and future directions of this work.

Screening for familial and hereditary prostate cancer.

Prostate cancer (PC) has the highest degree of genetic transmission of any form of malignancy. In some families, the hereditary pattern is so strong as to mimic an autosomal dominance trait. We reviewed the known predisposing genetic markers to assess possible strategies for screening of families at risk. We carried out a systematic literature search using the Pubmed service of the National Center for Biotechnology Information (NCBI) and several gene libraries, including the NCBI SNP Library, the Online Mendelian Inheritance in Man® Catalog of Human Genes and Genetic Disorders (OMIM) and SNPedia to obtain known gene loci, SNPs and satellite markers associated with PC. We further cross referenced information on identified loci comparing data from different articles and gene reference sites. Whenever possible, we recorded the odds ratio (OR) for the allele associated with PC. In multiple different linkage studies, many independent PC associated loci have been identified on separate chromosomes. Genome-wide association studies have added many more markers to the set derived from linkage investigations. A subset of the alleles is associated with early onset and aggressive cancer. Due to the great heterogeneity, the OR for any one allele predicting future development of this malignancy is low. The strongest predictors are the BRCA2 mutations, and the highly penetrant G84E mutation in HOXB13. The presence of multiple risk alleles is more highly predictive than a single allele. Technical limitations on screening large panels of alleles are being overcome. It is appropriate to begin supplementing prostate specific antigen testing with alleles, such as BRCA2 and HOXB13, disclosed by targeted genomic analysis in families with an unfavorable family cancer history. Future population studies of PC should include genomic sequencing protocols, particularly in families with a history of PC and other malignancies.

Considering race and the potential for ERG expression as a biomarker for prostate cancer.

Genomic rearrangement and overexpression of the ERG oncogene (also known as v-ets avian erythroblastosis virus E26 oncogene homolog) is estimated to occur at a rate of 40-50% in prostate cancer. Early evidence suggests that ERG overexpression may be associated with disease progression, and the utilization of ERG levels as a biomarker for prostate cancer is being strongly considered. However, the evidence is incomplete because it relies on studies that primarily focused on men of European ancestry, giving little consideration to African-American men even though African-American men bear a greater disease burden in the form of significantly greater incidence and worse outcomes. In this perspective article we bring to light the issue that the potential use of ERG expression as a biomarker is yet to be solidly established and may have limited utility or varied applicably for African-American men as compared with European-American men.