Tissue-based genomics: which test and when.

PURPOSE OF REVIEW: The clinical course of localized prostate cancer varies widely, ranging from indolent disease unlikely to require treatment to aggressive cancers meriting intensive, multimodal therapy. Management recommendations have traditionally been determined based on clinical and pathologic factors, including serum prostate - specific antigen (PSA), clinical stage, and Gleason score. Unfortunately, these factors have limited ability to describe the underlying biology of a given tumor. Tissue-based genomic tests have emerged as a promising tool to more accurately characterize prostate cancer biology and projected clinical course. The current review article summarizes available data describing the clinical use of genomic assays, with a specific focus on three critical scenarios. RECENT FINDINGS: We reviewed the potential role of tissue-based genomic assays in determining: the appropriateness of active surveillance versus definitive therapy, patients that will benefit from adjuvant radiation therapy following radical prostatectomy, and men most likely to benefit from concurrent androgen deprivation therapy with primary radiotherapy. SUMMARY: Current literature suggests that commercially available genomic tests provide prognostic information independent of traditional risk factors that may augment clinical decision-making. Additional data will better clarify the optimal use of each test across common clinical scenarios.

Robotic assisted simple prostatectomy: recent advances.

PURPOSE OF REVIEW: Robotic assisted simple prostatectomy (RASP) represents a minimally invasive evolution of traditional open simple prostatectomy for the surgical treatment of severe lower urinary tract symptoms (LUTS) because of benign prostatic enlargement (BPE). Aim of the present review is to summarize the most recent evidence on this novel procedure, and to better define its current role in the surgical armamentarium for the treatment of BPE. RECENT FINDINGS: Several studies demonstrated that RASP can be safely and effectively performed in centers with sufficient expertise. The procedure can duplicate its open counterpart with the advantage of lower perioperative morbidity, and ultimately faster patient recovery. Overall, the status of RASP seems to be well beyond that of an 'investigational' procedure, and guidelines should be amended accordingly.Nevertheless, it remains to be determined what the place of the RASP procedure in the surgical armamentarium for the treatment of symptomatic BPE will be. Over the most recent years, few comparative studies have been reported, allowing in part to draw some conclusions. RASP seems to be attractive when compared with open simple prostatectomy as it can offer less blood loss, and shorter hospital stay. However, its advantages over transurethral enucleation techniques - such as HoLEP - remain unclear. There are some specific indications, such as the presence of concomitant bladder diverticula or stones, for example, where a robotic approach could represent an appealing solution. Ultimately, further research should look at a cost analysis to determine which technique can be more cost effective. Last, the issue of the learning curve for the different procedures for symptomatic BPE remain to be further scrutinized. SUMMARY: RASP offers potential advantages over other available techniques for the treatment of large prostate glands. In centers, wherever a solid robotic program is already in place, this procedure is likely to be increasingly implemented.

Effects of vesical and perfusion pressure on perfusate flow, and flow on vesical pressure, in the isolated perfused working pig bladder reveal a potential mechanism for the regulation of detrusor compliance.

AIMS: Although there is evidence that deficits in bladder blood flow negatively impact bladder function, the effects of vesical, and perfusion pressures on bladder perfusion (perfusate flow), and of perfusate flow on vesical pressure, remain poorly understood. The present study used the isolated perfused working pig bladder model to examine the relationships between blood flow, and vesical and perfusion pressures. METHODS: Vesical arteries of pig bladders obtained from a local slaughterhouse were cannulated and perfused with Krebs-Henseleit solution at different pressures, and with carbachol to cause bladder contraction. The urethra of each bladder was cannulated to permit filling (10 mL/min), isovolumetric contraction and emptying. A ureter was cannulated with a pressure sensor to monitor vesical pressure. RESULTS: When at rest (50 mL vesical volume), bladder vesical pressure was 8.06 ± 1.5 mmHg and perfusate flow driven by a pressure gradient of 105 mmHg was 22.5 ± 2 mL/min (58.9 ± 7.8 mL/min-100 g). During filling, vesical pressure increased and flow decreased, but not necessarily in-parallel. Perfusate flow decreased transiently during isovolumetric contraction, and flow increased during emptying. A reduction in perfusion pressure from ∼105 to ∼40 mmHg reduced flow from ∼70 to ∼20 mL/min-100g, and reduced flow correlated with reduced vesical pressure. CONCLUSION: Perfusate flow is dependent on bladder perfusion pressure, and not necessarily reciprocally dependent on vesical pressure. Vesical pressure is highly sensitive to the level of perfusate flow, which supports the hypothesis that vesical pressure is dependent on the level of detrusor smooth muscle contractile activity (tone), and that compliance is dependent on bladder perfusion.

Potential vascular mechanisms in an ex vivo functional pig bladder model.

AIMS: Chronic ischemia is a recognized factor in the pathophysiology of underactive bladder (UAB). Although relative ischemia (ie, low blood flow) is known to occur during filling, little is known regarding the pathophysiology that leads to UAB. Therefore, we developed an ex vivo functional porcine model to investigate the role of transient ischemia and whether autoregulation, a mechanism that maintains tissue oxygenation in certain vital organs, also exists in the bladder. METHODS: Using bladders from slaughtered pigs, we prepared an isolated perfused model where we studied the effects of bladder perfusion flow rate on perfusion pressure and tissue oxygenation during the filling phase. Bladders were perfused at an initial flow rate of 20 mL/min and then clamped in a sequentially decreasing stepwise manner down to no flow and back to the initial flow rate. RESULTS: We found a linear relationship between flow rate and perfusion pressure until the flow rate decreased below 5 mL/min at which point the vascular resistance decreased; however, tissue pO2 remained stable after an initial decline. CONCLUSIONS: These findings suggest that there may be an intrinsic autoregulatory mechanism in the bladder that allows it to undergo cyclic episodes of relative ischemia during its normal function. Factors that overcome this mechanism such as complete or chronic ischemia may be critical in the progression to detrusor underactivity and thereby highlight the importance of intervention during the early phases of this disease process.

Artificial intelligence applications in prostate cancer.

Artificial intelligence (AI) applications have enabled remarkable advancements in healthcare delivery. These AI tools are often aimed to improve accuracy and efficiency of histopathology assessment and diagnostic imaging interpretation, risk stratification (i.e., prognostication), and prediction of therapeutic benefit for personalized treatment recommendations. To date, multiple AI algorithms have been explored for prostate cancer to address automation of clinical workflow, integration of data from multiple domains in the decision-making process, and the generation of diagnostic, prognostic, and predictive biomarkers. While many studies remain within the pre-clinical space or lack validation, the last few years have witnessed the emergence of robust AI-based biomarkers validated on thousands of patients, and the prospective deployment of clinically-integrated workflows for automated radiation therapy design. To advance the field forward, multi-institutional and multi-disciplinary collaborations are needed in order to prospectively implement interoperable and accountable AI technology routinely in clinic.

The Future State of Race/Ethnicity in Urology: Urology Workforce Projection From 2021-2061.

OBJECTIVE: To project the proportion of the urology workforce that is from under-represented in medicine (URiM) groups between 2021-2061. METHODS: Demographic data were obtained from AUA Census and ACGME Data Resource Books. The number of graduating urology residents and proportion of URiM graduating residents were characterized with linear models. Stock and Flow models were used to project future population numbers and proportions of URiM practicing urologists, contingent on assumptions regarding trainee demographics, retirement trends, and growth in the field. RESULTS: Currently, there is an increase in the percentage of URiM graduates by 0.145% per year. If historical trends continue, URiM urologists will likely comprise 16.2% of urology residency graduates and 13.3% of the practicing urological workforce in 2061. These percentages would constitute an underrepresentation of URiM urologists relative to the projected 44.2% of the U.S. population who would identify as American Indian/Alaskan Native, Black/African American, Latinx/Hispanic and Native Hawaiian/Pacific Islander by 2060.1 An increase in the percentage of URiM graduates by 0.845% per year would result in 44.2% URiM urology residency graduates and 26.1% URiM practicing urologists by 2061. An interactive app was designed to allow for a range of assumptions to be explored and for future data to be incorporated. CONCLUSION: URiM physician representation within urology over the next 40years will remain disproportionately low compared to that of the projected share of people of color in the general U.S. POPULATION: In order to achieve the AUA's Diversity, Equity and Inclusion goals, a concerted effort to implement interventions to recruit, train, and retain a generation of racially diverse urologists appears necessary.

Assessing the Clinical Utility of Published Prostate Cancer Polygenic Risk Scores in a Large Biobank Data Set.

BACKGROUND AND OBJECTIVE: Polygenic risk scores (PRSs) have been developed to identify men with the highest risk of prostate cancer. Our aim was to compare the performance of 16 PRSs in identifying men at risk of developing prostate cancer and then to evaluate the performance of the top-performing PRSs in differentiating individuals at risk of aggressive prostate cancer. METHODS: For this case-control study we downloaded 16 published PRSs from the Polygenic Score Catalog on May 28, 2021 and applied them to Michigan Genomics Initiative (MGI) patients. Cases were matched to the Michigan Urological Surgery Improvement Collaborative (MUSIC) registry to obtain granular clinical and pathological data. MGI prospectively enrolls patients undergoing surgery at the University of Michigan, and MUSIC is a multi-institutional registry that prospectively tracks demographic, treatment, and clinical variables. The predictive performance of each PRS was evaluated using the area under the covariate-adjusted receiver operating characteristic curve (aAUC), and the association between PRS and disease aggressiveness according to prostate biopsy data was measured using logistic regression. KEY FINDINGS AND LIMITATIONS: We included 18 050 patients in the analysis, of whom 15 310 were control subjects and 2740 were prostate cancer cases. The median age was 66.1 yr (interquartile range 59.9-71.6) for cases and 56.6 yr (interquartile range 42.6-66.7) for control subjects. The PRS performance in predicting the risk of developing prostate cancer according to aAUC ranged from 0.51 (95% confidence interval 0.51-0.53) to 0.67 (95% confidence interval 0.66-0.68). By contrast, there was no association between PRS and disease aggressiveness. CONCLUSIONS AND CLINICAL IMPLICATIONS: Prostate cancer PRSs have modest real-world performance in identifying patients at higher risk of developing prostate cancer; however, they are limited in distinguishing patients with indolent versus aggressive disease. PATIENT SUMMARY: Risk scores using data for multiple genes (called polygenic risk scores) can identify men at higher risk of developing prostate cancer. However, these scores need to be refined to be able to identify men with the highest risk for clinically significant prostate cancer.

Prostate Cancer Foundation Screening Guidelines for Black Men in the United States.

BACKGROUND: In the United States, Black men are at highest risk for being diagnosed with and dying from prostate cancer. Given this disparity, we examined relevant data to establish clinical prostate-specific antigen (PSA) screening guidelines for Black men in the United States. METHODS: A comprehensive literature search identified 1848 unique publications for screening. Of those screened, 287 studies were selected for full-text review, and 264 were considered relevant and form the basis for these guidelines. The numbers were reported according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: Three randomized controlled trials provided Level 1 evidence that regular PSA screening of men 50 to 74 years of age of average risk reduced metastasis and prostate cancer death at 16 to 22 years of follow-up. The best available evidence specifically for Black men comes from observational and modeling studies that consider age to obtain a baseline PSA, frequency of testing, and age when screening should end. Cohort studies suggest that discussions about baseline PSA testing between Black men and their clinicians should begin in the early 40s, and data from modeling studies indicate prostate cancer develops 3 to 9 years earlier in Black men compared with non-Black men. Lowering the age for baseline PSA testing to 40 to 45 years of age from 50 to 55 years of age, followed by regular screening until 70 years of age (informed by PSA values and health factors), could reduce prostate cancer mortality in Black men (approximately 30% relative risk reduction) without substantially increasing overdiagnosis. CONCLUSIONS: These guidelines recommend that Black men should obtain information about PSA screening for prostate cancer. Among Black men who elect screening, baseline PSA testing should occur between ages 40 and 45. Depending on PSA value and health status, annual screening should be strongly considered. (Supported by the Prostate Cancer Foundation.).

Are recurrence rates for "traditional" transvaginal prolapse repairs really that high? What does the evidence show?

Pelvic organ prolapse (POP) is a common and bothersome condition. Multiple methods for surgical repair exist, and much attention has been given to improving the efficacy of repair by implementing mesh interposition. Standard (native tissue-based) repairs in the anterior compartment have long been thought to be associated with high anatomical recurrence rates and the currently available randomized controlled trials (RCTs) support this thinking. However, subjective improvement in pelvic pressure and bulging and quality of life indices are similarly improved in both standard and mesh-augmented repairs. No RCTs are available to compare standard and mesh-augmented repairs in the posterior compartment. Despite the presence of RCTs, the data is often inconsistent and questions remain regarding the optimal criteria to describe POP recurrence. While there is a role for both types of repair, the optimal patient scenario is not known.

The Other Pandemic, Racism, in Urology.

Racism is deeply ingrained in our society with lasting effects within medicine. The COVID-19 pandemic further highlighted racial disparities in the medical field, including in the field of Urology. This has led to investigation regarding the effects of racism on education, patient care, and research within Urology. This article aims to review current literature on the "other pandemic," structural racism, within medicine and specifically urology and provide ways to combat its impact.

Evolving a national clinical trials learning health system.

Clinical trials generate key evidence to inform decision making, and also benefit participants directly. However, clinical trials frequently fail, often struggle to enroll participants, and are expensive. Part of the problem with trial conduct may be the disconnected nature of clinical trials, preventing rapid data sharing, generation of insights and targeted improvement interventions, and identification of knowledge gaps. In other areas of healthcare, a learning health system (LHS) has been proposed as a model to facilitate continuous learning and improvement. We propose that an LHS approach could greatly benefit clinical trials, allowing for continuous improvements to trial conduct and efficiency. A robust trial data sharing system, continuous analysis of trial enrollment and other success metrics, and development of targeted trial improvement interventions are potentially key components of a Trials LHS reflecting the learning cycle and allowing for continuous trial improvement. Through the development and use of a Trials LHS, clinical trials could be treated as a system, producing benefits to patients, advancing care, and decreasing costs for stakeholders.

The Impact of a Statewide Active Surveillance Initiative: A Roadmap for Increasing Active Surveillance Utilization Nationwide.

Active surveillance (AS) is recommended as a management option for men with favorable-risk (low risk and favorable intermediate risk) prostate cancer; however, national rates remain low. The Michigan Urological Surgery Improvement Collaborative (MUSIC) established a quality improvement (QI) initiative in June 2014 to increase AS utilization. In this report, we analyze the rates of AS utilization over time in the state of Michigan (MUSIC) for men with favorable-risk prostate cancer and compare these to rates for other men diagnosed with favorable-risk prostate cancer in the USA outside the state of Michigan. While the variables that influence AS utilization were the same in both cohorts, we found that the AS utilization rates and the rate of increase were significantly higher in MUSIC. We conclude that the QI initiative started in MUSIC should serve as a roadmap to increasing AS use nationwide. PATIENT SUMMARY: Active surveillance (AS), which involves close monitoring with blood tests and scans, is recommended for management of favorable-risk prostate cancer to avoid or delay unnecessary treatment. Our results show that a quality improvement program in Michigan increased AS use for prostate cancer patients in the state. This program should be used to increase AS uptake throughout the USA.

Increasing Use of Shorter-Course Radiotherapy for Prostate Cancer.

Importance: Randomized clinical trials have demonstrated the noninferiority of shorter radiotherapy (RT) courses (termed hypofractionation) compared with longer RT courses in patients with localized prostate cancer. Although shorter courses are associated with cost-effectiveness, convenience, and expanded RT access, their adoption remains variable. Objective: To identify the current practice patterns of external beam RT for prostate cancer in the US. Design, Setting, and Participants: This cohort study obtained data from the National Cancer Database, which collects hospital registry data from more than 1500 accredited US facilities on approximately 72% of US patients with cancer. Patients were included in the sample if they had localized prostate adenocarcinoma that was diagnosed between 2004 and 2020 and underwent external beam RT with curative intent. Analyses were conducted between February and March 2023. Exposures: Radiotherapy schedules, which were categorized as ultrahypofractionation (≤7 fractions), moderate hypofractionation (20-30 fractions), and conventional fractionation (31-50 fractions). Main Outcomes and Measures: Longitudinal pattern in RT fractionation schedule was the primary outcome. Multivariable logistic regression was performed to evaluate the variables associated with shorter RT courses. Covariables included age, National Comprehensive Cancer Network risk group, rurality, race, facility location, facility type, median income, insurance type or status, and Charlson-Deyo Comorbidity Index. Results: A total of 313 062 patients with localized prostate cancer (mean [SD] age, 68.8 [7.7] years) were included in the analysis. There was a temporal pattern of decline in the proportion of patients who received conventional fractionation, from 76.0% in 2004 to 36.6% in 2020 (P for trend <.001). From 2004 to 2020, use of moderate hypofractionation increased from 22.0% to 45.0% (P for trend <.001), and use of ultrahypofractionation increased from 2.0% to 18.3% (P for trend <.001). By 2020, the most common RT schedule was ultrahypofractionation for patients in the low-risk group and moderate hypofractionation for patients in the intermediate-risk group. On multivariable analysis, treatment at a community cancer program (compared with academic or research program; odds ratio [OR], 0.54 [95% CI, 0.52-0.56]; P < .001), Medicaid insurance (compared with Medicare; OR, 1.49 [95% CI, 1.41-1.57]; P < .001), Black race (compared with White race; OR, 0.90 [95% CI, 0.87-0.92]; P < .001), and higher median income (compared with lower median income; OR, 1.28 [95% CI, 1.25-1.31]; P < .001) were associated with receipt of shorter courses of RT. Conclusions and Relevance: Results of this cohort study showed an increase in the use of shorter courses of RT for prostate cancer from 2004 to 2020; a number of social determinants of health appeared to be associated with reduced adoption of shorter treatment courses. Realignment of reimbursement models may be necessary to enable broader adoption of ultrahypofractionation to support technology acquisition costs.

Understanding the Role of Urology Practice Organization and Racial Composition in Prostate Cancer Treatment Disparities.

PURPOSE: Black men have a higher risk of prostate cancer diagnosis and mortality but are less likely to receive definitive treatment. The impact of structural aspects on treatment is unknown but may lead to actionable insights to mitigate disparities. We sought to examine the associations between urology practice organization and racial composition and treatment patterns for Medicare beneficiaries with incident prostate cancer. METHODS: Using a 20% sample of national Medicare data, we identified beneficiaries diagnosed with prostate cancer between January 2010 and December 2015 and followed them through 2016. We linked urologists to their practices with tax identification numbers. We then linked patients to practices on the basis of their primary urologist. We grouped practices into quartiles on the basis of their proportion of Black patients. We used multilevel mixed-effects models to identify treatment associations. RESULTS: We identified 54,443 patients with incident prostate cancer associated with 4,194 practices. Most patients were White (87%), and 9% were Black. We found wide variation in racial practice composition and practice segregation. Patients in practices with the highest proportion of Black patients had the lowest socioeconomic status (43.1%), highest comorbidity (9.9% with comorbidity score ≥ 3), and earlier age at prostate cancer diagnosis (33.5% age 66-69 years; P < .01). Black patients had lower odds of definitive therapy (adjusted odds ratio, 0.87; 95% CI, 0.81 to 0.93) and underwent less treatment than White patients in every practice context. Black patients in practices with higher proportions of Black patients had higher treatment rates than Black patients in practices with lower proportions. Black patients had lower predicted probability of treatment (66%) than White patients (69%; P < .05). CONCLUSION: Despite Medicare coverage, we found less definitive treatment among Black beneficiaries consistent with ongoing prostate cancer treatment disparities. Our findings are reflective of the adverse effects of practice segregation and structural racism, highlighting the need for multilevel interventions.

Analysis of the Tumor Immune Microenvironment (TIME) in Clear Cell Renal Cell Carcinoma (ccRCC) Reveals an M0 Macrophage-Enriched Subtype: An Exploration of Prognostic and Biological Characteristics of This Immune Phenotype.

There is a need to optimize the treatment of clear cell renal cell carcinoma (ccRCC) patients at high recurrence risk after nephrectomy. We sought to elucidate the tumor immune microenvironment (TIME) of localized ccRCC and understand the prognostic and predictive characteristics of certain features. The discovery cohort was clinically localized patients in the TCGA-Kidney Renal Clear Cell Carcinoma (KIRC) project (n = 382). We identified an M0 macrophage-enriched cluster (n = 25) in the TCGA-KIRC cohort. This cluster's median progression-free survival (PFS) and overall survival (OS) were 40.4 and 45.3 months, respectively, but this was not reached in the others (p = 0.0003 and <0.0001, respectively). Gene set enrichment (GSEA) analysis revealed an enrichment of epithelial to mesenchymal transition and cell cycle progression genes within this cluster, and these patients also had a lower predicted response to immune checkpoint blockade (ICB) (4% vs. 20-34%). An M0-enriched cluster (n = 9) with shorter PFS (p = 0.0006) was also identified in the Clinical Proteomics Tumor Analysis Consortium (CPTAC) cohort (n = 94). Through this characterization of the TIME in ccRCC, a cluster of patients defined by enrichment in M0 macrophages was identified that demonstrated poor prognosis and lower predicted ICB response. Pending further validation, this signature can identify localized ccRCC patients at high risk of recurrence after nephrectomy and who may require therapeutic approaches beyond ICB monotherapy.

Evaluation of Social Determinants of Health and Prostate Cancer Outcomes Among Black and White Patients: A Systematic Review and Meta-analysis.

Importance: As the field of medicine strives for equity in care, research showing the association of social determinants of health (SDOH) with poorer health care outcomes is needed to better inform quality improvement strategies. Objective: To evaluate the association of SDOH with prostate cancer-specific mortality (PCSM) and overall survival (OS) among Black and White patients with prostate cancer. Data Sources: A MEDLINE search was performed of prostate cancer comparative effectiveness research from January 1, 1960, to June 5, 2020. Study Selection: Two authors independently selected studies conducted among patients within the United States and performed comparative outcome analysis between Black and White patients. Studies were required to report time-to-event outcomes. A total of 251 studies were identified for review. Data Extraction and Synthesis: Three authors independently screened and extracted data. End point meta-analyses were performed using both fixed-effects and random-effects models. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed, and 2 authors independently reviewed all steps. All conflicts were resolved by consensus. Main Outcomes and Measures: The primary outcome was PCSM, and the secondary outcome was OS. With the US Department of Health and Human Services Healthy People 2030 initiative, an SDOH scoring system was incorporated to evaluate the association of SDOH with the predefined end points. The covariables included in the scoring system were age, comorbidities, insurance status, income status, extent of disease, geography, standardized treatment, and equitable and harmonized insurance benefits. The scoring system was discretized into 3 categories: high (≥10 points), intermediate (5-9 points), and low (<5 points). Results: The 47 studies identified comprised 1 019 908 patients (176 028 Black men and 843 880 White men; median age, 66.4 years [IQR, 64.8-69.0 years]). The median follow-up was 66.0 months (IQR, 41.5-91.4 months). Pooled estimates found no statistically significant difference in PCSM for Black patients compared with White patients (hazard ratio [HR], 1.08 [95% CI, 0.99-1.19]; P = .08); results were similar for OS (HR, 1.01 [95% CI, 0.95-1.07]; P = .68). There was a significant race-SDOH interaction for both PCSM (regression coefficient, -0.041 [95% CI, -0.059 to 0.023]; P < .001) and OS (meta-regression coefficient, -0.017 [95% CI, -0.033 to -0.002]; P = .03). In studies with minimal accounting for SDOH (<5-point score), Black patients had significantly higher PCSM compared with White patients (HR, 1.29; 95% CI, 1.17-1.41; P < .001). In studies with greater accounting for SDOH variables (≥10-point score), PCSM was significantly lower among Black patients compared with White patients (HR, 0.86; 95% CI, 0.77-0.96; P = .02). Conclusions and Relevance: The findings of this meta-analysis suggest that there is a significant interaction between race and SDOH with respect to PCSM and OS among men with prostate cancer. Incorporating SDOH variables into data collection and analyses are vital to developing strategies for achieving equity.

Comprehensive genomic profiling and treatment patterns across ancestries in advanced prostate cancer: a large-scale retrospective analysis.

BACKGROUND: Men of African ancestry experience the greatest burden of prostate cancer globally, but they are under-represented in genomic and precision medicine studies. Therefore, we sought to characterise the genomic landscape, comprehensive genomic profiling (CGP) utilisation patterns, and treatment patterns across ancestries in a large, diverse, advanced prostate cancer cohort, to determine the impact of genomics on ancestral disparities. METHODS: In this large-scale retrospective analysis, the CGP-based genomic landscape was evaluated in biopsy sections from 11 741 patients with prostate cancer, with ancestry inferred using a single nucleotide polymorphism-based approach. Admixture-derived ancestry fractions for each patient were also interrogated. Independently, clinical and treatment information was retrospectively reviewed for 1234 patients in a de-identified US-based clinicogenomic database. Prevalence of gene alterations, including actionable gene alterations, was assessed across ancestries (n=11 741). Furthermore, real-world treatment patterns and overall survival was assessed in the subset of patients with linked clincogenomic information (n=1234). FINDINGS: The CGP cohort included 1422 (12%) men of African ancestry and 9244 (79%) men of European ancestry; the clinicogenomic database cohort included 130 (11%) men of African ancestry and 1017 (82%) men of European ancestry. Men of African ancestry received more lines of therapy before CGP than men of European ancestry (median of two lines [IQR 0-8] vs one line [0-10], p=0·029). In genomic analyses, ancestry-specific mutational landscapes were observed, but the prevalence of alterations in AR, the DNA damage response pathway, and other actionable genes were similar across ancestries. Similar genomic landscapes were observed in analyses that accounted for admixture-derived ancestry fractions. After undergoing CGP, men of African ancestry were less likely to receive a clinical study drug compared with men of European ancestry (12 [10%] of 118 vs 246 [26%] of 938, p=0·0005). INTERPRETATION: Similar rates of gene alterations with therapy implications suggest that differences in actionable genes (including AR and DNA damage response pathway genes) might not be a main driver of disparities across ancestries in advanced prostate cancer. Later CGP utilisation and a lower rate of clinical trial enrolment observed in men of African ancestry could affect genomics, outcomes, and disparities. FUNDING: American Society for Radiation Oncology, Department of Defense, Flatiron Health, Foundation Medicine, Prostate Cancer Foundation, and Sylvester Comprehensive Cancer Center.

Use of the Decipher genomic classifier among men with prostate cancer in the United States.

BACKGROUND: Management of localized or recurrent prostate cancer since the 1990s has been based on risk stratification using clinicopathological variables, including Gleason score, T stage (based on digital rectal exam), and prostate-specific antigen (PSA). In this study a novel prognostic test, the Decipher Prostate Genomic Classifier (GC), was used to stratify risk of prostate cancer progression in a US national database of men with prostate cancer. METHODS: Records of prostate cancer cases from participating SEER (Surveillance, Epidemiology, and End Results) program registries, diagnosed during the period from 2010 through 2018, were linked to records of testing with the GC prognostic test. Multivariable analysis was used to quantify the association between GC scores or risk groups and use of definitive local therapy after diagnosis in the GC biopsy-tested cohort and postoperative radiotherapy in the GC-tested cohort as well as adverse pathological findings after prostatectomy. RESULTS: A total of 572 545 patients were included in the analysis, of whom 8927 patients underwent GC testing. GC biopsy-tested patients were more likely to undergo active active surveillance or watchful waiting than untested patients (odds ratio [OR] =2.21, 95% confidence interval [CI] = 2.04 to 2.38, P < .001). The highest use of active surveillance or watchful waiting was for patients with a low-risk GC classification (41%) compared with those with an intermediate- (27%) or high-risk (11%) GC classification (P < .001). Among National Comprehensive Cancer Network patients with low and favorable-intermediate risk, higher GC risk class was associated with greater use of local therapy (OR = 4.79, 95% CI = 3.51 to 6.55, P < .001). Within this subset of patients who were subsequently treated with prostatectomy, high GC risk was associated with harboring adverse pathological findings (OR = 2.94, 95% CI = 1.38 to 6.27, P = .005). Use of radiation after prostatectomy was statistically significantly associated with higher GC risk groups (OR = 2.69, 95% CI = 1.89 to 3.84). CONCLUSIONS: There is a strong association between use of the biopsy GC test and likelihood of conservative management. Higher genomic classifier scores are associated with higher rates of adverse pathology at time of surgery and greater use of postoperative radiotherapy.In this study the Decipher Prostate Genomic Classifier (GC) was used to analyze a US national database of men with prostate cancer. Use of the GC was associated with conservative management (ie, active surveillance). Among men who had high-risk GC scores and then had surgery, there was a 3-fold higher chance of having worrisome findings in surgical specimens.