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Multiparametric MRI (mpMRI) and prostate-specific membrane antigen (PSMA) PET/CT are complementary imaging modalities used in the presurgical evaluation of patients with prostate cancer (PCa). The purpose of this study was to characterize clinically significant PCa (csPCa) detected and not detected by PSMA PET/CT and mpMRI, focusing on tumors detected solely by PSMA PET/CT and overlooked by mpMRI. Methods: We conducted a single-center, retrospective analysis of patients who underwent both PSMA PET/CT and mpMRI within 3 mo of each other and before radical prostatectomy. Two nuclear medicine physicians and 2 radiologists, in a masked manner, independently contoured PCa lesions on PSMA PET/CT and mpMRI, respectively. A consensus read was done with a third reader for each modality, and a majority rule was applied (2:1). After centralized imaging, a pathologic review was done by a genitourinary pathologist. We assessed agreement between imaging modalities and correlation with pathology. Logistic regression models explored associations between clinicopathologic variables and tumor detection on imaging. Results: In total, 132 csPCa tumors from 100 patients were identified on surgical pathology. PSMA PET/CT showed higher lesion-level (87% vs. 80%) and patient-level (98% vs. 94%) sensitivity than mpMRI. Tumors detected on both imaging modalities were larger and had higher grade groups than those not detected by one or both imaging modalities. On multivariable analysis, csPCa tumors undetected by mpMRI but detected by PSMA PET/CT were smaller than those detected by both modalities. Most tumors showing aggressive pathologic features, such as the large cribriform pattern (94.7%) and the intraductal carcinoma (96%), were correctly detected by both imaging modalities. Limitations included selection bias in a surgical cohort. Conclusion: PSMA PET/CT tends to detect smaller csPCa not detected by mpMRI. Larger tumors on pathology with higher grade groups are more likely to be correctly detected by both imaging modalities. These findings provide insights for refining presurgical evaluation strategies in PCa., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background and Objective: Prostate-specific membrane antigen (PSMA) radioguided salvage pelvic lymph node dissection (S-PLND) has emerged as a feasible treatment option for prostate cancer recurrence following initial surgery. This study aims to evaluate the feasibility and short-term outcomes of PSMA radioguided S-PLND., Methods: From a prospective trial of 99m Tc-PSMA-I&S followed by PSMA radioguided robotic surgery, we evaluated patients treated for node-only recurrence following radical therapy. The primary outcome was serum prostate-specific antigen (PSA) response 3 mo after surgery., Key Findings and Limitations: Among 14 patients (enrolled from June 2021 to June 2023), the median age was 65 yr. One patient had undergone primary whole gland ultrasound ablation, while the rest received prior prostatectomy. The median (interquartile range) time from primary treatment to PSMA positron emission tomography (PET) was 4.1 (2.9-8.3) yr, and 21 total pelvic targets were noted on PSMA PET: one in eight patients (67%), two in five patients (29%), and three in one patient (7%). Targets were successfully detected intraoperatively and removed in 13/14 (93%) patients. Cancer was noted on histopathology in 90% (19/21) of PSMA PET targets, 94% (17/18) of single-photon emission computed tomography targets, and 82% (14/17) of gamma probe targets. There were no adverse effects due to the radiotracer, and there were no complications after surgery. PSA at 3 mo was <0.2 ng/ml in two (14%) patients, and a ≥50% decline was noted in five (36%) patients. After a mean follow-up of 8.3 mo, the median time to next treatment was 11.7 mo, which was noted in nine patients., Conclusions and Clinical Implications: PSMA radioguided S-PLND is feasible and safe. However, the clinical role and the honing of technique and patient selection will be required in prospective studies., Patient Summary: In 14 patients who had prostate cancer recurrence after their initial treatment, performing surgery using radioactive tags to location is possible. However, futures studies are still needed to improve the technique., (© 2024 The Author(s).)

Background and Objective: We characterized tumor prostate-specific membrane antigen (PSMA) levels as a reflection of cancer biology and treatment sensitivities for treatment-naïve prostate cancer., Methods: We first correlated PSMA positron emission tomography (PET) maximum standardized uptake values (SUVmax) in primary prostate cancer with tumor FOLH1 (PSMA RNA abundance) to establish RNA as a proxy (n = 55). We then discovered and validated molecular pathways associated with PSMA RNA levels in two large primary tumor cohorts. We validated those associations in independent cohorts (18 total; 5684 tumor samples) to characterize the pathways and treatment responses associated with PSMA., Key Findings and Limitations: PSMA RNA abundance correlates moderately with SUVmax (ρ = 0.41). In independent cohorts, androgen receptor signaling is more active in tumors with high PSMA. Accordingly, patients with high PSMA tumors experienced longer cancer-specific survival when managed with androgen deprivation therapy for biochemical recurrence (adjusted hazard ratio [AHR] 0.54 [0.34-0.87]; n = 174). PSMA low tumors possess molecular markers of resistance to radiotherapy. Consistent with this, patients with high PSMA tumors experience longer time to recurrence following primary radiotherapy (AHR 0.50 [0.28-0.90]; n = 248). In the SAKK09/10 trial (n = 224), patients with high PSMA tumors who were managed with salvage radiotherapy experienced longer time to progression in the 64-Gy arm (restricted mean survival time [RMST] +7.60 [0.05-15.16]), but this effect was mitigated in the 70-Gy arm (RMST 3.52 [-3.30 to 10.33]). Limitations include using PSMA RNA as a surrogate for PET SUVmax., Conclusions and Clinical Implications: PSMA levels in treatment-naïve prostate cancer differentiate tumor biology and treatment susceptibilities. These results warrant validation using PET metrics to substantiate management decisions based on imaging., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Biochemical recurrence (BCR) after primary definitive treatment for prostate cancer (PCa) is a heterogeneous disease state. While BCR is associated with worse oncologic outcomes, risk factors that impact outcomes can vary significantly, necessitating avenues for risk stratification. We sought to identify prognostic risk factors at the time of recurrence after primary radical prostatectomy or radiotherapy, and prior to salvage treatment(s), associated with adverse oncologic outcomes., Methods: We performed a systematic review of prospective studies in EMBASE, MEDLINE, and ClinicalTrials.gov (from January 1, 2000 to October 16, 2023) according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines (CRD42023466330). We reviewed the factors associated with oncologic outcomes among patients with BCR after primary definitive treatment., Key Findings and Limitations: A total of 37 studies were included (total n = 10 632), 25 after prostatectomy (total n = 9010) and 12 after radiotherapy (total n = 1622). Following recurrence after prostatectomy, factors associated with adverse outcomes include higher pathologic T stage and grade group, negative surgical margins, shorter prostate-specific antigen doubling time (PSADT), higher prostate-specific antigen (PSA) prior to salvage treatment, shorter time to recurrence, the 22-gene tumor RNA signature, and recurrence location on molecular imaging. After recurrence following radiotherapy, factors associated with adverse outcomes include a shorter time to recurrence, and shorter PSADT or higher PSA velocity. Grade group, T stage, and prior short-term hormone therapy (4-6 mo) were not clearly associated with adverse outcomes, although sample size and follow-up were generally limited compared with postprostatectomy data., Conclusions and Clinical Implications: This work highlights the recommendations and level of evidence for risk stratifying patients with PCa recurrence, and can be used as a benchmark for personalizing salvage treatment based on prognostics., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: To characterize the relationship between Decipher genomic classifier scores and prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-based metastatic spread., Materials and Methods: We identified patients from four institutions who underwent PSMA PET/CT scans pretreatment for primary staging or postradical prostatectomy (RP) for suspected recurrence and had Decipher transcriptomic data available from biopsy or RP specimens. PSMA PET/CT-based patterns of spread were classified as localized (miT + N0M0) or nonlocalized (miN1M0 or miM1a-c). We calculated the association between Decipher scores and the risk of nonlocalized disease on PSMA PET/CT using multivariable logistic regression for pretreatment patients and multivariable Cox regression for post-RP patients. We also compared select transcriptomic signatures between patients with localized and nonlocalized diseases., Results: Five hundred eighty-six patients were included (pretreatment: n = 329; post-RP: n = 257). Higher Decipher scores were associated with nonlocalized disease on PSMA PET/CT both pretreatment (odds ratio, 1.18 [95% CI, 1.03 to 1.36] per 0.1 increase in Decipher score, P = .02) and post-RP (hazard ratio, 1.15 [95% CI, 1.05 to 1.27] per 0.1 increase in Decipher score, P = .003). In the pretreatment setting, nonlocalized disease was associated with higher rates of TP53 mutations and lower rates of PAM50 luminal A subtype compared with localized disease. In the post-RP setting, overexpression of signatures related to metabolism, DNA repair, and androgen receptor signaling were associated with higher rates of nonlocalized disease., Conclusion: Higher Decipher scores were associated with nonlocalized disease identified on PSMA PET/CT both pretreatment and post-RP. There were several transcriptomic differences between localized and nonlocalized diseases in both settings.

Background and Objective: Adherence to guideline recommendations can improve the quality of care for patients with prostate cancer (PCa). Our aim was to assess adherence to guidelines for locoregional PCa by international region., Methods: The study cohort comprised patients diagnosed with locoregional PCa in the 10-country Movember TrueNTH Global Registry (n = 62 688; 2013-2022). We assessed adherence to four quality metrics: (1) active surveillance for low-risk PCa; (2) definitive treatment within 12 mo of diagnosis for unfavorable-risk PCa; (3) no staging imaging for favorable-risk PCa; and (4) staging imaging for unfavorable-risk PCa. For χ 2 analyses, we combined the three most recent years of data entered by region for each outcome, with adjustment for multiple tests (p = 0.05 ÷ 4 = 0.0125). We also conducted multivariable logistic regression and temporal analyses., Key Findings and Limitations: Active surveillance rates for low-risk PCa ranged from 85% in Australia/New Zealand (vs USA: adjusted odds ratio [aOR] 1.042, 95% confidence interval [CI] 0.740-1.520) to 14% in Central Europe (aOR 0.028, 95% CI 0.022-0.036). For patients with unfavorable-risk disease, the highest uptake rate for treatment within 12 mo of diagnosis was in Central Europe (98%; aOR 2.885, 95% CI 1.260-6.603), compared to 70% in Italy (aOR 0.031, 95%CI 0.014-0.072). The proportion of patients with favorable-risk disease who did not undergo imaging ranged from 94% in the USA to 30% in Italy (aOR 0.004, 95% CI 0.002-0.008), while the rate of imaging for unfavorable-risk PCa ranged from 8% in Hong Kong (aOR 65.222, 95% CI 43.676-97.398) to 39% in the USA (all χ 2 p < 0.0125). Regional temporal trends also varied., Conclusions and Clinical Implications: In this international study comparing adherence to quality care metrics for the quality of care for locoregional PCa, we identified regional variance, possibly because of regional differences in cultural attitudes and health care structures. These benchmarks highlight opportunities for interventions to improve adherence to evidence-based guidelines., Patient Summary: Our study shows that adherence to recommended management goals for patients with prostate cancer varies greatly by global region., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Opinion Statement: PSMA-PET has been a practice-changing imaging biomarker for the management of men with PCa. Research suggests improved accuracy over conventional imaging and other PET radiotracers in many contexts. With multiple approved PSMA-targeting radiotracers, PSMA PET will become even more available in clinical practice. Its increased use requires an understanding of the prospective data available and caution when extrapolating from prior trial data that utilized other imaging modalities. Future trials leveraging PSMA PET for treatment optimization and management decision-making will ultimately drive its clinical utility., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Prostate cancer (PCa) is a clinically heterogeneous disease. The creation of an expression-based subtyping model based on prostate-specific biological processes was sought., Methods: Unsupervised machine learning of gene expression profiles from prospectively collected primary prostate tumors (training, n = 32,000; evaluation, n = 68,547) was used to create a prostate subtyping classifier (PSC) based on basal versus luminal cell expression patterns and other gene signatures relevant to PCa biology. Subtype molecular pathways and clinical characteristics were explored in five other clinical cohorts., Results: Clustering derived four subtypes: luminal differentiated (LD), luminal proliferating (LP), basal immune (BI), and basal neuroendocrine (BN). LP and LD tumors both had higher androgen receptor activity. LP tumors also had a higher expression of cell proliferation genes, MYC activity, and characteristics of homologous recombination deficiency. BI tumors possessed significant interferon γactivity and immune infiltration on immunohistochemistry. BN tumors were characterized by lower androgen receptor activity expression, lower immune infiltration, and enrichment with neuroendocrine expression patterns. Patients with LD tumors had less aggressive tumor characteristics and the longest time to metastasis after surgery. Only patients with BI tumors derived benefit from radiotherapy after surgery in terms of time to metastasis (hazard ratio [HR], 0.09; 95% CI, 0.01-0.71; n = 855). In a phase 3 trial that randomized patients with metastatic PCa to androgen deprivation with or without docetaxel (n = 108), only patients with LP tumors derived survival benefit from docetaxel (HR, 0.21; 95% CI, 0.09-0.51)., Conclusions: With the use of expression profiles from over 100,000 tumors, a PSC was developed that identified four subtypes with distinct biological and clinical features., Plain Language Summary: Prostate cancer can behave in an indolent or aggressive manner and vary in how it responds to certain treatments. To differentiate prostate cancer on the basis of biological features, we developed a novel RNA signature by using data from over 100,000 prostate tumors-the largest data set of its kind. This signature can inform patients and physicians on tumor aggressiveness and susceptibilities to treatments to help personalize cancer management., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Data on advanced prostate cancer (PCa) suggest more prior systemic therapies might reduce tumor immune responsiveness. In treatment-naïve primary PCa, recent work correlated intratumoral plasma cell content with enhanced tumor immune-responsiveness. We sought to identify features of localized PCa at a high risk of recurrence following local treatment with high plasma cell content to help focus future immune-based neoadjuvant trials., Methods: We performed retrospective analyses of molecular profiles from three independent cohorts of over 1300 prostate tumors. We used Wilcoxon Rank Sum to compare molecular pathways between tumors with high and low intratumoral plasma cell content and multivariable Cox proportional hazards regression analyses to assess metastasis-free survival., Results: We validated an expression-based signature for intratumoral plasma cell content in 113 primary prostate tumors with both RNA-expression data and digital image quantification of CD138+ cells (plasma cell marker) based on immunohistochemisty. The signature showed castration-resistant tumors (n = 101) with more prior systemic therapies contained lower plasma cell content. In high-grade primary PCa, tumors with high plasma cell content were associated with increased predicted response to immunotherapy and decreased response to androgen-deprivation therapy. Master regulator analyses identified upregulated transcription factors implicated in immune (e.g. SKAP1, IL-16, and HCLS1), and B-cell activity (e.g. VAV1, SP140, and FLI-1) in plasma cell-high tumors. Master regulators overactivated in tumors with low plasma cell content were associated with shorter metastasis-free survival following radical prostatectomy., Conclusions: Markers of plasma cell activity might be leveraged to augment clinical trial targeting and selection and better understand the potential for immune-based treatments in patients with PCa at a high risk of recurrence following local treatment., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose of Review: Multimodality therapy including radical prostatectomy, radiation therapy, and hormone therapy are frequently deployed in the management of localized prostate cancer. We sought to perform a critical appraisal of the most contemporary literature focusing on the multimodality management of localized prostate cancer., Recent Findings: Men who are ideal candidates for multimodality therapy include those with unfavorable intermediate-risk disease, high-risk disease, and very high-risk disease. Enhancements in both systemic agents (including second-generation antiandrogens) as well as localized therapies (such as stereotactic body radiotherapy and brachytherapy) are refining the optimal balance between the use of systemic and local therapies for localized prostate cancer. Genomic predictors are emerging as critical tools for more precisely allocating treatment intensification with multimodality therapies as well as treatment de-intensification. Close collaboration among medical oncologists, surgeons, and radiation oncologists will be critical for coordinating evidence-based multimodality therapies when clearly indicated and for supporting shared decision-making in areas where the evidence is mixed., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Inflammatory bowel disease (IBD) has been implicated as a risk factor for prostate cancer, however, the mechanism of how IBD leads to prostate tumorigenesis is not known. Here, we investigated whether chronic intestinal inflammation leads to pro-inflammatory changes associated with tumorigenesis in the prostate., Methods: Using clinical samples of men with IBD who underwent prostatectomy, we analyzed whether prostate tumors had differences in lymphocyte infiltrate compared to non-IBD controls. In a mouse model of chemically-induced intestinal inflammation, we investigated whether chronic intestinal inflammation could be transferred to the wild-type mouse prostate. In addition, mouse prostates were evaluated for activation of pro-oncogenic signaling and genomic instability., Results: A higher proportion of men with IBD had T and B lymphocyte infiltration within prostate tumors. Mice with chronic colitis showed significant increases in prostatic CD45 + leukocyte infiltration and elevation of three pro-inflammatory cytokines-TIMP-1, CCL5, and CXCL1 and activation of AKT and NF-kB signaling pathways. Lastly, mice with chronic colitis had greater prostatic oxidative stress/DNA damage, and prostate epithelial cells had undergone cell cycle arrest., Conclusions: These data suggest chronic intestinal inflammation is associated with an inflammatory-rich, pro-tumorigenic prostatic phenotype which may explain how gut inflammation fosters prostate cancer development in men with IBD., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Context: Several studies have investigated selection and sequencing of systemic agents to manage recurrent prostate cancer following local definitive treatment., Objective: To define the incidence of recurrent prostate cancer in different countries, and systematically review management options and efficacy of first-line systemic therapies for patients with prostate cancer previously treated with definitive radical prostatectomy or radiation therapy., Evidence Acquisition: We performed a systematic review of studies published from January 2010 to December 2021 in MEDLINE, EMBASE, or ClinicalTrials.gov according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Quality was assessed using the Grades of Recommendation, Assessment, Development and Evaluation methodology. The potential regional burdens of recurrent prostate cancer were estimated by analyzing various regional registry data., Evidence Synthesis: A total of 40 studies met the inclusion criteria and an additional landmark study published after the query was included in this review. Patients with metastatic recurrent disease derive benefit from the addition of androgen receptor signaling inhibitors to androgen deprivation therapy, while docetaxel should be reserved for patients with a high-volume metastatic burden by conventional imaging. Patients with biochemical-only recurrent disease benefit from continuous or intermittent androgen deprivation therapy if they possess high-risk features such as short prostate-specific antigen doubling time or high serum prostate-specific antigen. Current limitations to the published literature include no consideration of contemporary positron emission tomography imaging for evaluating metastatic recurrence or burden and few quality of life assessments., Conclusions: This systematic review summarizes the findings and recommendations for first-line systemic therapy for patients with recurrent prostate cancer following local therapy., Patient Summary: We performed a systematic evaluation and summary of all studies published within the past decade on the topic of medications used to treat prostate cancer after it has recurred following radiation therapy or surgery. This review can be used to inform guidelines for prostate cancer management., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: B7 homolog 3 (B7-H3) is an immunomodulatory molecule that is highly expressed in prostate cancer (PCa) and belongs to the B7 superfamily, which includes PD-L1. Immunotherapies (antibodies, antibody-drug conjugates, and chimeric antigen receptor T cells) targeting B7-H3 are currently in clinical trials; therefore, elucidating the molecular and immune microenvironment correlates of B7-H3 expression may help to guide trial design and interpretation. The authors tested the interconnected hypotheses that B7-H3 expression is associated with genetic racial ancestry, immune cell composition, and androgen receptor signaling in PCa., Methods: An automated, clinical-grade immunohistochemistry assay was developed by to digitally quantify B7-H3 protein expression across 2 racially diverse cohorts of primary PCa (1 with previously reported transcriptomic data) and pretreatment and posttreatment PCa tissues from a trial of intensive neoadjuvant hormonal therapy., Results: B7-H3 protein expression was significantly lower in self-identified Black patients and was inversely correlated with the percentage African ancestry. This association with race was independent of the significant association of B7-H3 protein expression with ERG/ETS and PTEN status. B7-H3 messenger RNA expression, but not B7-H3 protein expression, was significantly correlated with regulatory (FOXP3-positive) T-cell density. Finally, androgen receptor activity scores were significantly correlated with B7-H3 messenger RNA expression, and neoadjuvant intensive hormonal therapy was associated with a significant decrease in B7-H3 protein expression., Conclusions: The current data underscore the importance of studying racially and molecularly diverse PCa cohorts in the immunotherapy era. This study is among the first to use genetic ancestry markers to add to the emerging evidence that PCa in men of African ancestry may have a distinct biology associated with B7-H3 expression., Lay Summary: B7-H3 is an immunomodulatory molecule that is highly expressed in prostate cancer and is under investigation in clinical trials. The authors determined that B7-H3 protein expression is inversely correlated with an individual's proportion of African ancestry. The results demonstrate that B7-H3 messenger RNA expression is correlated with the density of tumor T-regulatory cells. Finally, in the first paired analysis of B7-H3 protein expression before and after neoadjuvant intensive hormone therapy, the authors determined that hormone therapy is associated with a decrease in B7-H3 protein levels, suggesting that androgen signaling may positively regulate B7-H3 expression. These results may help to guide the design of future clinical trials and to develop biomarkers of response in such trials., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Tumors with mutations associated with homologous recombination deficiency (HRD) are uncommon in prostate cancer (PCa) and variably responsive to PARP inhibition. To better identify tumors with HRD, we developed a transcriptomic signature for HRD in PCa (HRD-P)., Methods: By using an established mutational signature, we created and validated HRD-P in six independent PCa cohorts (primary PCa, n = 8224; metastatic castration-resistant PCa [mCRPC], n = 328). Molecular and clinical features were compared between HRD-P+ tumors and those with single HR-gene mutations., Results: HRD-P+ tumors were more common than tumors with single HR-gene mutations in primary (201/491, 41% vs 32/491 6.5%) and mCRPC (126/328, 38% vs 82/328, 25%) cases, and HRD-P+ was more predictive of genomic instability suggestive of HRD. HRD-P+ was associated with a shorter time to recurrence following surgery and shorter overall survival in men with mCRPC. In a prospective trial of mCRPC treated with olaparib (n = 10), all three men with HRD-P+ experienced prolonged (>330 days) PSA progression-free survival., Conclusion: These results suggest transcriptomics can identify more patients that harbor phenotypic HRD than single HR-gene mutations and support further exploration of transcriptionally defined HRD tumors perhaps in conjunction with genomic markers for therapeutic application., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Homeobox B13 (HOXB13) expression regulates normal prostate development and mutations are associated with prostate cancer (PCa) formation., Objective: To assess the role of HOXB13 mRNA expression in PCa progression following radical prostatectomy., Design, Setting, and Participants: Genome-wide expression profiles were queried from two retrospective prostatectomy cohorts with follow-up data (Mayo Clinic, n=780; Johns Hopkins Medical Institute [JHMI], n=355), and a prospective genomic registry (n=5239)., Outcome Measurements and Statistical Analysis: Multivariable Cox regressions were used to analyze metastasis-free survival (MFS)., Results and Limitations: HOXB13 expression in primary PCa increased with increasing tumor grade and with high metastatic potential based on a genomic signature. The highest quartile of HOXB13 expression was associated with worse MFS compared with the lowest quartile (Mayo Clinic: adjusted hazard ratio [AHR] 1.46, 95% confidence interval [CI] 1.03-2.06, and JHMI: AHR 1.80, 95% CI 1.02-3.19). The combinations of high HOXB13 expression and low expression of its binding partner, MEIS1 (AHR 2.03, 95% CI 1.54-2.66) or MEIS2 (AHR 1.73, 95% CI 1.33-2.26), portended worse MFS. Additionally, high HOXB13 expression in combination with low MEIS1/2 expression correlated with high expression of androgen receptor-mediated genes. The retrospective nature of this study subjects the findings to a bias due to unmeasured variables., Conclusions: Primary PCa tumors with increased HOXB13 expression have an increased propensity for metastases following prostatectomy, particularly in the setting of low MEIS1/2 expression. High androgen receptor output may account for worse outcomes for these tumors and suggests heightened sensitivity to androgen suppression., Patient Summary: Using genomic data from a large number of prostate cancer (PCa) tumors, we found that increased expression of homeobox B13 (HOXB13), a gene related to normal prostate development, was associated with worse outcomes following surgery for PCa. A biomarker signature suggests that these tumors would be more susceptible to androgen suppression, a common treatment for PCa. Take Home  Messagece:: In multiple large cohorts, prostate cancer tumors with high homeobox B13 (HOXB13) expression and low expression of its binding partner MEIS1/2 were enriched with high androgen receptor output and had an increased propensity for metastases following surgery., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Combination therapy with docetaxel and androgen deprivation therapy (ADT) prolongs overall survival (OS) in men with metastatic hormone-sensitive prostate cancer. We assessed the benefits and adverse effects of docetaxel and ADT in relation to advancing age., Methods: We performed a post hoc analysis of the CHAARTED trial comparing docetaxel and ADT vs. ADT alone (n = 773). Patients were stratified in age groups <60, 60-70, and >70 years old. Multivariable-adjusted progression-free survival (PFS) and OS were assessed using Kaplan-Meier curves and compared using multivariable Cox regressions with calculated interaction terms between age group and treatment arm. In the combination arm, the incidence of ≥1 adverse event (grade ≥3) and the number of adverse events per patient were compared for each age group using multivariable logistic and linear regressions, respectively., Results: After adjusting for clinical variables, docetaxel's effect did not vary by age group for PFS and OS. There was no significant difference in the odds ratio of ≥1 adverse event (P > .1 for age groups 60-70 and >70 years old compared with <60 years old). However, men age >70 years old experienced +0.37 more adverse events per patient compared with men age <60 years old (95% CI, 0.11-0.64; P = .006)., Conclusions: PFS and OS were similar across age groups for the combination of docetaxel and ADT compared with ADT. Older men experienced a modest increase in adverse events per patient, highlighting the importance of balancing treatment benefits and adverse effects in this age group., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021. Published by Elsevier Inc.)

Background: Despite consensus guidelines, many men with low-grade prostate cancer are not managed with active surveillance. Patient perception of the nomenclature used to describe low-grade prostate cancers may partly explain this discrepancy., Methods: A randomized online survey was administered to men without a history of prostate cancer, presenting a hypothetical clinical scenario in which they are given a new diagnosis of low-grade prostate cancer. The authors determined whether diagnosis nomenclature was associated with management preference and diagnosis-related anxiety using ratings given on a scale from 1 to 100, adjusting for participant characteristics through multivariable linear regression., Results: The survey was completed by 718 men. Compared with Gleason 6 out of 10 prostate cancer, the term grade group 1 out of 5 prostate cancer was associated with lower preference for immediate treatment versus active surveillance (β = -9.3; 95% CI, -14.4, -4.2; P < .001), lower diagnosis-related anxiety (β = -8.3; 95% CI, -12.8, -3.8; P < .001), and lower perceived disease severity (β = -12.3; 95% CI, -16.5, -8.1; P < .001) at the time of initial diagnosis. Differences decreased as participants received more disease-specific education. Indolent lesion of epithelial origin, a suggested alternative term for indolent tumors, was not associated with differences in anxiety or preference for active surveillance., Conclusions: Within a hypothetical clinical scenario, nomenclature for low-grade prostate cancer affects initial perception of the disease and may alter subsequent decision making, including preference for active surveillance. Disease-specific education reduces the differential impact of nomenclature use, reaffirming the importance of comprehensive counseling and clear communication between the clinician and patient., (© 2021 American Cancer Society.)

Background: The work-up and diagnosis of indeterminate lung nodules at time of bladder cancer diagnosis may delay or change treatment., Objective: To quantify the incidence of synchronous and metachronous lung cancers in adults with bladder cancer and compare these rates to the incidence of bladder cancer metastases in the lung., Methods: We retrospectively analyzed all adults diagnosed with bladder cancer in the Surveillance, Epidemiology and End Results (SEER) registry (2010- 2015) and identified second primary lung cancers defined as being either synchronous (diagnosed within 6 months of bladder cancer diagnosis) or metachronous (more than 6 months following index bladder cancer diagnosis). The risk of second primary lung cancers were reported as a standardized incidence ratio (SIR) reflecting observed and expected case ratios., Results: A total of 88,335 patients diagnosed with bladder cancer were included. Among adults with NMIBC ( n  = 66,071) and MIBC ( n  = 18,879), 0.3% and 3.9% had bladder cancer metastatic to the lungs at diagnosis. Synchronous second primary lung cancers were diagnosed in 0.4% and 0.7% of patients with NMIBC and MIBC, respectively. Compared to the general population, the SIR for synchronous lung cancers among adults with NMIBC was 2.5 (95% CI 2.3- 2.9) and was 4.7 (95% CI 4.0- 5.6) for adults with MIBC., Conclusions: Bladder cancer metastatic to the lung is more common in adults with MIBC compared to NMIBC. There are similar frequencies of synchronous second primary lung cancers regardless of initial bladder cancer stage., Competing Interests: Disclosures for Gary D Steinberg:Is a member of Clinical Trial Protocol Committees for the following companies: Merck, BMS, Janssen, Cold Genesys, Pfizer, PhotoCure, Fidia He has or has been a scientific advisor/consultant within the past 5 years for the following companies: Heat Biologics, Cold Genesys, PhotoCure, Merck, Roche/Genentech, Ciclomed, Taris Biomedical, MDxHealth, Fidia Farmaceuticals, Urogen, Ferring, Aduro, Boston Scientific, Bristol Myers Squibb, Astra Zeneca, Pfizer, Janssen, Epivax Oncology, Natera, FKD, Ferring, EnGene Bio, SesenBio, BioCanCell, Nucleix, Ipsen, Combat Medical, Astellas, Fergene, Dendreon, Abbvie, Seattle Genetics. He has equity stock/options: Epivax Oncology, UrogenDisclosures for Arjun BalarGenentech: Fees for Contracted Research (institution), Consultant/Advisory Role, Speaking Engagements. Incyte: Fees for Consultant/Advisory Role. Janssen: Fees for Consultant/Advisory Role. Merck: Fees for Contracted Research (institution), Consultant/Advisory Role, Speaking Engagements, Steering/Scientific Advisory Committee. Pfizer: Fees for Consultant/Advisory Role. AstraZeneca/Medimmune: Fees for Consultant/Advisory Role, Contracted Research (institution), Speaking Engagements. Nektar: Fees for Consultant Advisory Role, Contracted Research, Steering Committee Membership. Seattle Genetics: Fees for Consultant/Advisory Role, Contracted Research (institution). Immunomedics: Fees for contracted research (Institution), Fees for Consultant/Advisory Role. EpiVax Oncology: Equity, Scientific Advisory Board Member. Jacob Taylor, Adam Weiner, Binhuan Wang and Richard S Matulewicz have nothing to disclose., (© 2021 – The authors. Published by IOS Press.)

Background: More than 3.6 million men in the United States harbor a diagnosis of prostate cancer (PCa). The authors sought to provide in-depth analyses of the causes of death for contemporary survivors., Methods: The authors performed a population-based cohort study in the United States (2000-2016) to assess causes of death for men diagnosed with PCa stratified by demographics and tumor stage. Using general population data, they calculated standardized mortality ratios (SMRs) as observed-to-expected death ratios., Results: In total, 752,092 men with PCa, including 200,302 who died (27%), were assessed. A total of 29,048 men with local/regional disease (17%) died of PCa, whereas more than 4-fold men died of other causes (n = 143,719 [83%]). SMRs for death from noncancer causes (0.77; 95% confidence interval [CI], 0.77-0.78) suggested that these men were less likely than the general population to die of most other causes. The most common noncancer cause of death was cardiac-related (23%; SMR, 0.76; 95% CI, 0.75-0.77). Among men with distant PCa, 90% of deaths occurred within 5 years of diagnosis. Although deaths due to PCa composed the majority of deaths (74%), SMRs suggested that men with distant PCa were at heightened risk for death from most other noncancer causes (1.50; 95% CI, 1.46-1.54) and, in particular, for cardiac-related death (SMR, 1.48; 95% CI, 1.41-1.54) and suicide (SMR, 2.32; 95% CI, 1.78-2.96). Further analyses demonstrated that causes of death varied by patient demographics., Conclusions: Causes of death during PCa survivorship vary by patient and tumor characteristics. These data provide valuable information regarding health care prioritization during PCa survivorship., Lay Summary: Men with early-stage prostate cancer are 4-fold more likely to die of other causes, whereas those with advanced prostate cancer are at increased risk for several causes not related to prostate cancer in comparison with the general population. These findings can help guide physicians taking care of men with a diagnosis of prostate cancer., (© 2021 American Cancer Society.)

Dysregulated translation is a common feature of cancer. Uncovering its governing factors and underlying mechanism are important for cancer therapy. Here, we report that enhancer of zeste homologue 2 (EZH2), previously known as a transcription repressor and lysine methyltransferase, can directly interact with fibrillarin (FBL) to exert its role in translational regulation. We demonstrate that EZH2 enhances rRNA 2'-O methylation via its direct interaction with FBL. Mechanistically, EZH2 strengthens the FBL-NOP56 interaction and facilitates the assembly of box C/D small nucleolar ribonucleoprotein. Strikingly, EZH2 deficiency impairs the translation process globally and reduces internal ribosome entry site (IRES)-dependent translation initiation in cancer cells. Our findings reveal a previously unrecognized role of EZH2 in cancer-related translational regulation.

Background: There is insufficient data to recommend screening for bladder cancer (BC). For future BC screening trials, it is important to understand how and if tumor (T) stage can act as a surrogate outcome marker for overall (OS) and cancer-specific (CSS) survival., Objective: To characterize OS and CSS between primary tumor (T) stages in non-metastatic bladder cancer (BC) patients., Methods: Non-metastatic BC patients were identified in the National Cancer Database (NCDB; 2004-2015) (n = 343,163) and National Cancer Institute Surveillance, Epidemiology, and End Results database (SEER) (n = 130,751). Cox multivariable regression compared relationships between T stage (LGTa, HGTa, Tis, LGT1, HGT1, T2-T4) and OS or CSS for all patients and sub-cohorts., Results: Compared to stage LGTa as a reference, overall (SEER; NCDB) and cancer-specific (SEER) survival significantly declined with increasing T stage. Using SEER, OS ranged from HGTa (HR 1.16, CI 1.13-1.21, p  < 0.001) to T4 (HR 5.70, CI 5.41-6.00, p  < 0.001) with a steep inflection between HGT1 (HR 1.68, CI 1.63-1.73, p  < 0.001) and T2 (HR 3.39, CI 3.30-3.49, p  < 0.001), which was verified with NCDB. The association of stage and CSS was even more pronounced: HGTa (84% 10 year-CSS, HR 1.94, CI 1.81-2.08, p  < 0.001), Tis (82% 10 year-CSS, HR 2.28, CI 2.09-2.47, p  < 0.001), LGT1 (84% 10 year-CSS, HR 2.30, CI 2.11-2.51, p  < 0.001), HGT1 (72% 10 year-CSS, HR 4.24, CI 4.01-4.47, p  < 0.001), T2 (48% 10 year-CSS, HR 12.18, CI 11.57-12.82, p  < 0.001), T3 (45% 10 year-CSS, HR 14.60, CI 13.63-15.64, p  < 0.001), and T4 (29% 10 year-CSS, HR 22.76, CI 21.19-24.44, p  < 0.001)., Conclusions: Earlier T stage at diagnosis was associated with better OS largely due to differences in CSS. A clinically significant difference between Stage I and Stage II was verified herein in multiple cohorts. Therefore, earlier stage at diagnosis, specifically preventing muscle invasive BC, could potentially improve survival., Competing Interests: JJM: Honoraria (Cold Genesys; Janssen); Consulting or Advisory Role (AstraZeneca, Ferring, Merck), Research Funding (Epizyme, Merck Sharp & Dohme) YL: Stock and other Ownership Interests (Vessi Medical); Consulting or Advisory Role (AstraZeneca; Augmenix; BioCancell; Cepheid; MDxhealth; Merck; Nucleix; pacific edge; Photocure; Urogen pharma; Vessi Medical); Research Funding (Abbott Molecular (Inst); Augmenix; BioCancell (Inst); Cepheid; Cepheid (Inst); GenomeDx (Inst); MDxHealth (Inst); pacific edge; pacific edge (Inst); Photocure (Inst) LFC, ABW, XM and SLW have no conflicts of interest to report., (© 2021 – The authors. Published by IOS Press.)

Context: Molecular biomarkers aim to address the established limitations of clinicopathologic factors to accurately risk stratify patients with prostate cancer (PCa). Questions remain as to whether sufficient evidence supports adoption of these biomarkers for clinical use., Objective: To perform a systematic review of the available evidence supporting the clinical utility of the Decipher genomic classifier (GC)., Evidence Acquisition: The review was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines by searching PubMed and conference abstracts from January 2010 to June 2020. Evidence was then graded using the criteria of Simon et al (Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 2009;101:1446-52) and American Urology Association (AUA) criteria., Evidence Synthesis: In total, 42 studies and 30407 patients were included. GC performance data were available for localized, postprostatectomy, nonmetastatic castration-resistant, and metastatic hormone-sensitive PCa as part of retrospective studies (n=12141), prospective registries (n=17053), and prospective and post hoc randomized trial analyses (n=1213). In 32 studies (n=12600), the GC was independently prognostic for all study endpoints (adverse pathology, biochemical failure, metastasis, and cancer-specific and overall survival) on multivariable analysis and improved the discrimination over standard of care in 24 studies (n=8543). GC use changed the management in active surveillance (number needed to test [NNT]=9) and postprostatectomy (NNT=1.5-4) settings in five studies (n=4331). Evidence strength was levels 1 and 2 by the Simon criteria for all disease states other than high-risk PCa, and grades A and B by AUA criteria depending on disease state., Conclusions: Consistent data are now present from diverse levels of evidence, which when viewed together, have demonstrated clinical utility of the GC in PCa. The utility of the GC is strongest for intermediate-risk PCa and postprostatectomy decision-making., Patient Summary: In this paper, we review the evidence of the Decipher genomic classification tool for men with prostate cancer. We found consistent evidence that the test helps identify which cancers are more or less aggressive, which in turn aids in personalized treatment decision-making., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Upfront chemotherapy prolongs overall survival for men with metastatic, hormone-sensitive prostate cancer (mHSPC) based on data from clinical trials. We sought to assess the association between upfront chemotherapy and overall survival in men with mHSPC in a real-world cohort., Methods: We performed a retrospective cohort study of men with de novo, treatment-naïve metastatic prostate cancer from a large, national cancer database in the United States (2014-2015). Men in the upfront chemotherapy group received chemotherapy within 4 months of diagnosis (n = 1033, 28%) versus no chemotherapy or chemotherapy later than 12 months after diagnosis (controls; n = 2704, 72%). Overall survival was assessed using Kaplan-Meier estimates and compared using multivariable Cox regression analysis., Results: After a median follow-up of 23 months, median overall survival was 35.7 months in the upfront chemotherapy group and 32.5 months for controls (log-rank p < 0.001). After adjusting for patient and clinical variables, upfront chemotherapy was associated with longer overall survival (hazard ratio 0.78, 95% confidence interval 0.68-0.89, p < 0.001). In exploratory analyses, the association between upfront chemotherapy and overall survival did not differ by age groups, race, or number of comorbidities (all interaction p > 0.2)., Conclusions: In this real-world cohort, upfront chemotherapy for mHSPC was associated with longer overall survival. These data support the continued use of chemotherapy for men with mHSPC regardless of race or age if they are fit for chemotherapy and underscore the importance of evaluating cancer therapeutics outside of clinical trials to demonstrate treatment efficacy in populations that may be underrepresented in clinical trials.

Black men die more often of prostate cancer yet, interestingly, may derive greater survival benefits from immune-based treatment with sipuleucel-T. Since no signatures of immune-responsiveness exist for prostate cancer, we explored race-based immune-profiles to identify vulnerabilities. Here we show in multiple independent cohorts comprised of over 1,300 patient samples annotated with either self-identified race or genetic ancestry, prostate tumors from Black men or men of African ancestry have increases in plasma cell infiltrate and augmented markers of NK cell activity and IgG expression. These findings are associated with improved recurrence-free survival following surgery and nominate plasma cells as drivers of prostate cancer immune-responsiveness.

Inflammatory bowel disease (IBD) is an established risk factor for colorectal cancer. Recent reports suggesting IBD is also a risk factor for prostate cancer (PC) require further investigation. We studied 218 084 men in the population-based UK Biobank cohort, aged 40 to 69 at study entry between 2006 and 2010, with follow-up through mid-2015. We assessed the association between IBD and subsequent PC using multivariable Cox regression analyses, adjusting for age at assessment, ethnic group, UK region, smoking status, alcohol drinking frequency, body mass index, Townsend Deprivation Index, family history of PC and previous prostate-specific antigen testing. Mean age at study entry was 56 years, 94% of the men were white, and 1.1% (n = 2311) had a diagnosis of IBD. After a median follow-up of 78 months, men with IBD had an increased risk of PC (adjusted hazard ratio [aHR] = 1.31, 95% confidence interval [CI] = 1.03-1.67, P = .029). The association with PC was only among men with the ulcerative colitis (UC; aHR = 1.47, 95% CI = 1.11-1.95, P = .0070), and not Crohn's disease (aHR 1.06, 95% CI = 0.63-1.80, P = .82). Results are limited by lack of data on frequency of health care interactions. In a large-scale, prospective cohort study, we detected an association between IBD, and UC specifically, with incident PC diagnosis., (© 2020 UICC.)

Introduction: We sought to assess the impact of Affordable Care Act Dependent Care Expansion (ACA-DCE), which allowed dependent coverage for adults aged 19-25, and Medicaid expansion on outcomes for men with testicular cancer., Methods: Using a US-based cancer registry, we performed adjusted difference-in-difference (DID) analyses comparing outcomes between men aged 19-25 (n = 8,026) and 26-64 (n = 33,303) pre- (2007-2009) and post-ACA-DCE (2011-2016) and between men in states that expanded Medicaid (n = 2,296) to men in those that did not (n = 2,265)pre- (2011-2013) and post-Medicaid expansion (2015-2016)., Results: In ACA-DCE analysis, rates of uninsurance decreased (DID -5.64, 95% confidence interval [CI] -7.23 to -4.04%, p<0.001) among patients aged 19-25 relative to older patients aged 26-64. There was no significant DID in advanced stage at diagnosis (stage≥II; p = 0.6) or orchiectomy more than 14 days after diagnosis (p = 0.6). For patients who received chemotherapy or radiotherapy as their first course of treatment, treatment greater than 60 days after diagnosis decreased (DID -4.84%, 95% CI -8.22 to -1.45%, p = 0.005) among patients aged 19-25 relative to patients aged 26-64. In Medicaid expansion states, rates of uninsurance decreased (DID -4.20%, 95% CI -7.67 to -0.73%, p = 0.018) while patients receiving chemotherapy or radiotherapy greater than 60 days after diagnosis decreased (DID -8.76, 95% CI -17.13 to -0.38%, p = 0.040) compared to rates in non-expansion states. No significant DIDs were seen for stage (p = 0.8) or time to orchiectomy (p = 0.1)., Conclusions: Men with testicular cancer had lower uninsurance rates and decreased time to delivery of chemotherapy or radiotherapy following ACA-DCE and Medicaid expansions. Time to orchiectomy and stage at diagnosis did not change following either insurance expansion., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To determine the use of surgical resection of metastatic disease in a large national sample and its association with overall survival., Methods: The National Cancer Database was queried for patients with metastatic bladder cancer (2004-2016). Overall survival was assessed using Kaplan-Meier and multivariable Cox analyses. The associations between covariates and use of metastasectomy were assessed with multivariable logistic regression., Results: Of the 16 382 patients with metastatic bladder cancer included, 6.8% underwent metastasectomy. Its use increased over time (4.7% in 2004 to 6.6% in 2016; per year odds ratio 1.02, 95% confidence interval 1.00-1.04, P = 0.019). Median survival was 7.0 months for patients who received metastasectomy and 5.1 months for those who did not (hazard ratio 0.85, 95% confidence interval 0.79-0.91, P < 0.001). In subgroup analyses, metastasectomy predicted longer survival in patients with lung (hazard ratio 0.73, 95% confidence interval 0.61-0.88, P = 0.001) or brain metastases (hazard ratio 0.58, 95% confidence interval 0.35-0.96, P = 0.035) and in patients with variant histology (hazard ratio 0.80, 95% confidence interval 0.69-0.93, P = 0.003)., Conclusions: In a national sample, the use of metastasectomy for bladder cancer is low. Furthermore, metastasectomy is associated with longer survival overall and in multiple subgroups. However, these results should be validated in future studies., (© 2020 The Japanese Urological Association.)

Context: Treatment decisions for elderly men with prostate cancer are complicated by the intersection of competing risks of cancer, potential complications of treatment, and individual patients' comorbidities., Objective: To perform a systematic review of data guiding the assessment of elderly prostate cancer patients that addresses the risk from cancer and treatment, and to discuss a patient-centered approach to incorporating these factors into decision making., Evidence Acquisition: Evidence was gathered via a systematic review of the current literature. The search strategy used the terms prostate cancer, elderly, geriatric, >75 yr of age, risk assessment, and treatment in several combinations, and was limited to phase ≥ II clinical trials published between January 2008 and November 2018. Additional supporting literature for the discussion was pulled by hand search., Evidence Synthesis: The benefits of treatment identified for systemic therapies commonly used to treat men with prostate in general extend to elderly patients. Evidence supports a multifaceted assessment of the risks of cancer and aging, and an understanding of the side effects of treatment to optimally guide therapeutic decision making for elderly patients. There is little evidence defining a geriatric risk stratification system specific to prostate cancer, and recommendations are predominantly based on adapted geriatric oncology approaches and expert consensus., Conclusions: The care of elderly men with prostate cancer should incorporate a review of cancer risk, an assessment of aging, and an understanding of the effects of treatment to provide the patient with thorough and personalized guidance for treatment decisions. Future studies of elderly men with prostate cancer can define and validate ideal risk stratification methods as well as management approaches that may be distinct from those for younger populations., Patient Summary: Treatment decisions for elderly men with prostate cancer require consideration of the risk posed by the cancer coupled with an understanding of the patient's general health status., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: The absence of health insurance coverage has been associated with worse outcomes for patients with metastatic renal cell carcinoma (mRCC). Medicaid expansion in the United States was an important provision of the Affordable Care Act, which increased the number of low-income individuals eligible for Medicaid starting in January 2014 in several states. The effect of Medicaid expansion on access to healthcare for patients with mRCC is unknown., Materials and Methods: We performed a retrospective cohort study of 6844 patients aged < 65 years with mRCC at diagnosis within the National Cancer Database. We compared the time to treatment and the rates of no insurance before (2012-2013) and after (2015-2016) expansion between patients living in states that had and had not expanded Medicaid using difference-in-difference (DID) analyses. DIDs were calculated using linear regression analysis with adjustment for sociodemographic covariates., Results: The rate of no insurance did not change in the expansion states compared with the nonexpansion states (DID, -0.55%; 95% confidence interval, -3.32% to 2.21%; P = .7). The percentage of patients receiving treatment within 60 days of diagnosis had increased in the expansion states from 43% to 49% and in the nonexpansion states from 42% to 46% after expansion. No change was found in treatment within 60 days of diagnosis among all patients (DID, 2.81%; 95% confidence interval, -2.61% to 8.22%; P = .3)., Conclusions: Medicaid expansion was not associated with improved healthcare access for patients with mRCC as reflected by timely treatment. Future work should assess the association between Medicaid expansion and oncologic outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The objective of this study was to determine the effect of Medicaid expansion under the Patient Protection and Affordable Care Act (January 1, 2014) on the epidemiology of high-risk prostate-specific antigen (PSA) levels (≥20 ng/mL) at the time of prostate cancer (PCa) diagnosis. The authors hypothesized that better access to care would result in a reduction of high-risk features at diagnosis., Methods: A retrospective cohort study was performed of 122,324 men aged <65 years who were diagnosed with PCa within the National Cancer Database. Difference-in-difference (DID) analyses adjusting for sociodemographic variables using linear regression compared PSA levels at diagnosis before expansion (2012-2013) and after expansion (2015-2016) between men residing in states that did or did not expand Medicaid., Results: From 2012 to 2016, the proportion of men with PSA levels ≥20 ng/mL increased (from 18.9% to 19.8%) in nonexpansion states and decreased (from 19.9% to 18.2%) in expansion states. Compared with men in nonexpansion states, men in expansion states experienced a decline in PSA ≥20 ng/mL (DID, -2.33%; 95% CI, -3.21% to -1.44%; P < .001). Accordingly, the proportion of men presenting with high-risk disease decreased in expansion states relative to nonexpansion states (DID, -1.25%; 95% CI, -2.26% to 0.25%; P = .015). A similar statistically significant decrease in PSA levels ≥20 ng/mL was noted among black men (DID, -3.11%; 95% CI, -5.25% to 0.96%; P = .005)., Conclusions: In Medicaid expansion states, there was an associated decrease in the proportion of young men presenting with PSA ≥20 ng/mL at the time of PCa diagnosis. These results suggest that Medicaid expansion improved access to PCa screening. Longer term data should assess oncologic outcomes., (© 2020 American Cancer Society.)

Background: Prostate cancer (PCa) is characterized by significant heterogeneity in its molecular, genomic, and immunologic characteristics., Methods: Whole transcriptome RNAseq data from The Cancer Genome Atlas of prostate adenocarcinomas ( n = 492) was utilized. The immune microenvironment was characterized using the CIBERSORTX tool to identify immune cell type composition. Unsupervised hierarchical clustering was performed based on immune cell type content. Analyses of progression-free survival (PFS), distant metastases, and overall survival (OS) were performed using Kaplan-Meier estimates and Cox regression multivariable analyses., Results: Four immune clusters were identified, largely defined by plasma cell, CD4 + Memory Resting T Cells (CD4 MR), and M0 and M2 macrophage content (CD4 MR High Plasma Cell High M0 Low M2 Mid , CD4 MR Low Plasma Cell High M0 Low M2 Low , CD4 MR High Plasma Cell Low M0 High M2 Low , and CD4 MR High Plasma Cell Low M0 Low M2 High ). The two macrophage-enriched/plasma cell non-enriched clusters (3 and 4) demonstrated worse PFS (HR 2.24, 95% CI 1.46-3.45, p = 0.0002) than the clusters 1 and 2. No metastatic events occurred in the plasma cell enriched, non-macrophage-enriched clusters. Comparing clusters 3 vs. 4, in patients treated by surgery alone, cluster 3 had zero progression events ( p < 0.0001). However, cluster 3 patients had worse outcomes after post-operative radiotherapy ( p = 0.018)., Conclusion: Distinct tumor immune clusters with a macrophage-enriched, plasma cell non-enriched phenotype and reduced plasma cell enrichment independently characterize an aggressive phenotype in localized prostate cancer that may differentially respond to treatment.

Purpose: Surgical castration for metastatic prostate cancer is used less frequently than medical castration yet costs less, requires less followup and may be associated with fewer adverse effects. We evaluated temporal trends and factors associated with the use of surgical castration., Materials and Methods: This retrospective cohort study sampled 24,805 men with newly diagnosed (de novo) metastatic prostate cancer from a national cancer registry in the United States (2004 to 2016). Multivariable logistic regression assessed the association between sociodemographic factors and surgery. Multivariable Cox regression evaluated the association between castration type and overall survival., Results: Overall 5.4% of men underwent surgical castration. This figure decreased from 8.5% in 2004 to 3.5% in 2016 (per year later OR 0.89, 95% CI 0.87-0.91, p <0.001). Compared to Medicare, private insurance was associated with less surgery (OR 0.73, 95% CI 0.61-0.87, p <0.001) while Medicaid or no insurance was associated with more surgery (OR 1.68, 95% CI 1.34-2.11, p <0.001 and OR 2.12, 95% CI 1.58-2.85, p <0.001, respectively). Regional median income greater than $63,000 was associated with less surgery (vs income less than $38,000 OR 0.61, 95% CI 0.43-0.85, p=0.004). After a median followup of 30 months castration type was not associated with differences in survival (surgical vs medical HR 1.02, 95% CI 0.95-1.09, p=0.6)., Conclusions: In a contemporary, real-world cohort surgical castration use is low and decreasing despite its potential advantages and similar survival rate compared to medical castration. Men with potentially limited health care access undergo more surgery, perhaps reflecting a provider bias toward the perceived benefit of permanent castration.

Introduction: We define the cost of a contemporary prostate biopsy and the rate and incremental impact of complications on costs., Methods: A retrospective analysis of all Medicare fee-for-service claims for prostate biopsies in the United States from January 31, 2014 to December 1, 2015 was performed. Costs of each biopsy episode (including 30 days after each biopsy) were calculated. The effects of complications, biopsy setting and subsequent inpatient hospitalization were explored., Results: The average cost of the 234,819 biopsies reviewed was $2,020 and 46% of biopsy costs occurred in the 30 days following each biopsy. Biopsies performed in the office setting comprised 66% of the total and were least costly ($1,750) compared to biopsies performed in ambulatory surgical centers ($2,260) and outpatient hospital settings ($2,730, both p <0.001). Biopsies performed in the office setting were associated with fewer complications (10%) compared to the outpatient hospital (19%) or ambulatory surgical center settings (12%, both p <0.001). An uncomplicated biopsy episode cost an average of $1,740, which increased to $4,060 when at least 1 complication occurred (difference +$2,320, p <0.001). The largest charges incurred were related to inpatient admissions, which added $13,840 to the cost of a prostate biopsy (p <0.001) but were rare, constituting only 2.8% of biopsies., Conclusions: Nearly half of costs during prostate biopsy episodes occur due to complications that occur in the days following a biopsy. These data should be used as benchmarks to incentivize interventions to reduce complications and subsequent admissions following biopsies.

Objective: To assess willingness of adults to undergo home screening for urologic cancers via urine dipstick and determine the effect of an educational pamphlet on hematuria on screening willingness and knowledge of hematuria., Materials and Methods: We performed an online survey of adult volunteers throughout the United States from September 25, 2018 to October 15, 2018. The primary outcome was pretest willingness to undergo home screening for hematuria with urine dipstick (4 or 5 out of 5-point Likert). Secondary outcomes included changes in willingness to screen and knowledge on hematuria after exposure to an educational pamphlet., Results: Of 1442 participants, 54% were male and 87% were White. Median age was 48. Pretest willingness to home screen was high (90%). Older age was associated with an increased willingness to screen (per 10-year increase: odds ratio 1.47, 95% confidence interval 1.28-1.68, P <.001). Participants who had not previously discussed hematuria with a health care provider were less willing to screen (odds ratio 0.50, 95% confidence interval 0.27-0.94, P = .033). Patients with risk factors for urologic cancers (ie, smoking and occupational exposures) were equally willing to screen. After pamphlet exposure hematuria knowledge increased (P <.001) while willingness to screen did not change (P = .15)., Conclusion: Willingness to perform home-based screening for urologic cancers by assessing for hematuria is high in an adult population, including those with risk factors. Knowledge of hematuria improves significantly after exposure to an educational pamphlet., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The heterogeneity of androgen receptor (AR)-activity (AR-A) is well-characterized in heavily treated metastatic castration-resistant prostate cancer (mCRPC). However, the diversity and clinical implications of AR-A in treatment-naïve primary prostate cancer is largely unknown. We sought to characterize AR-A in localized prostate cancer and understand its molecular and clinical implications., Experimental Design: Genome-wide expression profiles from prostatectomy or biopsy samples from 19,470 patients were used, all with independent pathology review. This was comprised of prospective discovery ( n = 5,239) and validation ( n = 12,728) cohorts, six retrospective institutional cohorts with long-term clinical outcomes data ( n = 1,170), and The Cancer Genome Atlas ( n = 333)., Results: A low AR-active subclass was identified, which comprised 9%-11% of each cohort, and was characterized by increased immune signaling, neuroendocrine expression, and decreased DNA repair. These tumors were predominantly ERG and basal subtype. Low AR-active tumors had significantly more rapid development of recurrence or metastatic disease across cohorts, which was maintained on multivariable analysis [HR, 2.61; 95% confidence interval (CI), 1.22-5.60; P = 0.014]. Low AR-active tumors were predicted to be more sensitive to PARP inhibition, platinum chemotherapy, and radiotherapy, and less sensitive to docetaxel and androgen-deprivation therapy. This was validated clinically, in that low AR-active tumors were less sensitive to androgen-deprivation therapy (OR, 0.41; 95% CI, 0.21-0.80; P = 0.008)., Conclusions: Leveraging large-scale transcriptomic data allowed the identification of an aggressive subtype of treatment-naïve primary prostate cancer that harbors molecular features more analogous to mCRPC. This suggests that a preexisting subgroup of patients may have tumors that are predisposed to fail multiple current standard-of-care therapies and warrant dedicated therapeutic investigation., (©2019 American Association for Cancer Research.)

Opinion Statement: Combination systemic therapy is now standard of care for all men with metastatic, hormone-sensitive prostate cancer (mHSPC). Patients with mHSPC should be treated with standard androgen deprivation therapy (ADT) and abiraterone acetate with prednisone or docetaxel (chemohormoanl therapy) unless there are contraindications to combination therapy. Based on the Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) study subgroup analysis, chemohormonal therapy may be most beneficial in men with high-volume disease burden, as men with low-volume metastatic disease do not appear to experience a survival benefit with chemohormonal therapy, while abiraterone in combination with ADT appears to be beneficial across both disease volume subgroups. Decisions regarding whether to use chemohormonal therapy or abiraterone and ADT for men with mHSPC should integrate consideration of volume of disease burden, quality of life effects, duration of therapy, and patient preferences for treatment as there is no formally powered prospective head-to-head comparison of these options demonstrating superiority of one approach over the other. Treatment of the primary tumor with radiation should be considered in men with de novo low-volume metastatic disease as radiation is associated with prolonged survival and a tolerable toxicity profile. Men with de novo high-volume metastatic disease do not appear to have improved survival with radiation of the primary tumor. Numerous clinical trials are ongoing to evaluate treatment approaches that may benefit men with mHSPC. Radical prostatectomy in men with mHSPC in combination with optimal systemic therapy is currently being assessed in a clinical trial, but should not be considered outside of a clinical trial. Metastasis-directed therapy with radiotherapy directed at metastatic lesions is still investigational, but can be considered in clinical trials in men with oligometastatic disease. Multiple studies are enrolling worldwide for men with mHSPC, and these should be considered for all interested patients.

Purpose: Controversy surrounds the benefit of pelvic lymph node irradiation (PLN-RT) in localized prostate cancer (CaP). Our objective was to determine the practice patterns and predictors of PLN-RT in a national cohort., Materials and Methods: The National Cancer Data Base (2005-2015) was leveraged to obtain men diagnosed with nonmetastatic CaP treated with external beam radiotherapy (n = 197,378). Multivariable logistic regressions were used to assess temporal trends and factors associated with PLN-RT., Results: PLN-RT occurred in 37% of patients overall, which increased to 41% by 2015. When stratified by risk group, there was no significant difference in PLN-RT over time in low, favorable intermediate, unfavorable intermediate, or high-risk CaP. PLN-RT increased for men with very high-risk disease (51%-60%; odds ratio per year 1.34, 95% confidence inrerval 1.06-1.70, P = 0.013). Increased odds of PLN-RT was associated with higher risk disease, addition of hormone therapy, treatment at community hospitals, and shorter patient travel distance to treatment facilities. Surprisingly, 26% and 34% of low and favorable intermediate risk CaP received PLN-RT, respectively. Predictors of PLN-RT among these patients included treatment at a community practice and use of brachytherapy or hormone therapy., Conclusions: PLN-RT occurred in about one-third of men receiving external beam radiotherapy and increased over time, mostly in men with very high-risk CaP for unclear reasons. Of concern, over one-quarter of low-risk men receive PLN-RT. Further work is needed to understand the heterogeneity in PLN-RT use. We await the completion of RTO G 09-24 to better understand the role of PLN-RT for men with localized CaP., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: While urothelial carcinoma of the bladder is often considered a multifocal disease, the location of the dominant tumor may be prognostic., Objective: To determine the association between intravesical tumor location and both adverse pathological outcomes as well as overall survival., Design, Settings, and Participants: Patients in the National Cancer Database (2010-2015) with nonmetastatic urothelial carcinoma of the bladder who underwent primary treatment with radical cystectomy (RC; n=3464) or chemoradiotherapy (CRT; n=699)., Outcome Measurements and Statistical Analysis: Multivariable logistic regressions assessed the prognostic ability of tumor location to predict adverse pathology at RC (nodal metastases [pN+] or advanced stage [pT3-4]). Cox regressions were used to determine the effect of tumor location on overall survival in patients treated with RC or CRT., Results and Limitations: Following RC, 822 (24%) patients were pN+ and 1551 (55%) were pT3-4. Trigonal tumors were most likely to have adverse pathology (31% pN+ and 59% pT3-4), while anterior wall tumors were the least (19% pN+ and 50% pT3-4). Relative to the anterior wall, trigone (odds ratio [OR] 1.65, 95% confidence interval [CI] 1.12-2.43, p=0.012) and bladder neck (OR 1.79, 95% CI 1.11-2.90, p=0.018) tumors were associated with increased odds of pN+ and dome (OR 1.56, 95% CI 1.08-2.24, p=0.017) with pT3-4. In those patients treated with primary CRT, trigone involvement was associated with worse survival (HR 1.58, 95% CI 1.17-2.13, p=0.003). Limitations included unmeasured variables and a relatively few number of patients with certain tumor locations., Conclusions: Trigone and bladder neck tumors are associated with increased odds of nodal involvement, and dome with a higher tumor stage at RC. Patients with trigone involvement may have worse overall survival following CRT., Patient Summary: Location of the tumor within the bladder may be associated with worse cancer staging at the time of the surgery and worse survival following chemoradiotherapy., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: There are limited data examining the risk of prostate cancer (PCa) in patients with inflammatory bowel disease (IBD)., Objective: To compare the incidence of PCa between men with and those without IBD., Design, Setting, and Participants: This was a retrospective, matched-cohort study involving a single academic medical center and conducted from 1996 to 2017. Male patients with IBD (cases=1033) were randomly matched 1:9 by age and race to men without IBD (controls=9306). All patients had undergone at least one prostate-specific antigen (PSA) screening test., Outcome Measurements and Statistical Analysis: Kaplan-Meier and multivariable Cox proportional hazard models, stratified by age and race, evaluated the relationship between IBD and the incidence of any PCa and clinically significant PCa (Gleason grade group ≥2). A mixed-effect regression model assessed the association of IBD with PSA level., Results and Limitations: PCa incidence at 10yr was 4.4% among men with IBD and 0.65% among controls (hazard ratio [HR] 4.84 [3.34-7.02] [3.19-6.69], p<0.001). Clinically significant PCa incidence at 10yr was 2.4% for men with IBD and 0.42% for controls (HR 4.04 [2.52-6.48], p<0.001). After approximately age 60, PSA values were higher among patients with IBD (fixed-effect interaction of age and patient group: p=0.004). Results are limited by the retrospective nature of the analysis and lack of external validity., Conclusions: Men with IBD had higher rates of clinically significant PCa when compared with age- and race-matched controls., Patient Summary: This study of over 10000 men treated at a large medical center suggests that men with inflammatory bowel disease may be at a higher risk of prostate cancer than the general population., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: Among veterans, prostate cancer is the most common malignancy and has a higher incidence compared to the rest of the nation. No study has compared the effectiveness of Robotic-assisted-laparoscopic radical prostatectomy (RALP) vs. open radical prostatectomy (ORP) in the Veteran's Affairs (VA) hospital setting during the adoption of RALP., Methods: Institutional Review Board approval was obtained. Retrospective review was completed on Veterans with prostate cancer who underwent ORP or RALP from March 2011 to January 2017 during the introduction of RALP at one VA hospital. Perioperative and functional outcomes between ORP and RALP were compared as well as between the initial 50 and final 53 RALPs., Results: Among 91 ORPs and 153 RALPs, RALP had significant reductions in blood transfusions [2(1.3%) vs. 44(40%), p < 0.001], length of stay [2 days(1-2) vs. 3 days(2-4), p < 0.001], Clavien grade >2 complications [1(0.7%) vs. 20 (22.0%), p < 0.001], urine leak [2(1.3%) vs. 11 (12.1%), p < 0.001], and ICU readmissions [0(0%) vs. 3(3.3%), p < 0.001]. There were no significant differences in positive margin status or functional outcomes. Compared to the first 50 cases, the last 53 RALPs demonstrated a shorter operative time (349 vs. 292 min, p < 0.001), lower EBL (300 vs. 150 mL, p < 0.001), more frequent 1-day length of stay (34% vs. 60%, p = 0.02), and fewer composite adverse events (82% vs. 51%, p = 0.004). Operative time for the final 53 RALPs (292 minutes) was shorter than that of ORP (325 minutes, p = 0.013)., Conclusions: During the introduction of RALP at one VA hospital, RALP was associated with several improved parameters compared to ORP and similar operative times were noted after the first 100 cases of RALPs. RALP is safe to introduce in a VA setting without compromising outcomes., (© Association of Military Surgeons of the United States 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)