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Genetic studies have identified single nucleotide polymorphisms (SNPs) associated with the risk of prostate cancer (PC). It remains unclear whether such genetic variants are associated with disease aggressiveness. The NCI-SPORE Genetics Working Group retrospectively collected clinicopathologic information and genotype data for 36 SNPs which at the time had been validated to be associated with PC risk from 25,674 cases with PC. Cases were grouped according to race, Gleason score (Gleason ≤6, 7, ≥8) and aggressiveness (non-aggressive, intermediate, and aggressive disease). Statistical analyses were used to compare the frequency of the SNPs between different disease cohorts. After adjusting for multiple testing, only PC-risk SNP rs2735839 (G) was significantly and inversely associated with aggressive (OR = 0.77; 95 % CI 0.69–0.87) and high-grade disease (OR = 0.77; 95 % CI 0.68–0.86) in European men. Similar associations with aggressive (OR = 0.72; 95 % CI 0.58–0.89) and high-grade disease (OR = 0.69; 95 % CI 0.54–0.87) were documented in African-American subjects. The G allele of rs2735839 was associated with disease aggressiveness even at low PSA levels (

While the total PSA level remains a useful predictor for both current and future prostate cancer risk, adjunctive measurements have been developed that increase the specificity for prostate cancer detection. These parameters are also useful predictors of prostate cancer aggressiveness. [ABSTRACT FROM AUTHOR]

While retropubic prostatectomy has been the unchallenged standard of care for the treatment of localized prostate cancer for more than a decade, the perineal approach is undergoing a resurgence in popularity and supporters of robot-assisted prostatectomy are growing. The authors debate the advantages and disadvantages of these 3 approaches. [ABSTRACT FROM AUTHOR]

Despite the high prevalence of prostate cancer and an annual mortality second only to lung cancer, a very small percentage of men with untreated disease die from it. Whether to treat early -- and how -- continue to be complex issues. [ABSTRACT FROM AUTHOR]

Objective: To evaluate measurement of percentage of free prostate-specific antigen (PSA) in serum to improve the specificity of prostate cancer screening in men with serum PSA levels between 4.1 and 10.0 ng/mL.Design: Retrospective, nonrandomized analysis using a research assay for measuring free PSA in frozen serum from men with a spectrum of prostate sizes and digital rectal examination results.Setting: General community outpatient prostate cancer screening program at a university center.Patients: One hundred thirteen men aged 50 years or older, 99% of whom were white, with serum PSA concentrations of 4.1 to 10.0 ng/mL, including 63 men with histologically confirmed benign prostatic hyperplasia, 30 with prostate cancer with an enlarged gland, and 20 with cancer with a normal-sized gland. All study volunteers had undergone prostatic ultrasonography and biopsy.Main Outcome Measures: Percentage of free PSA in serum and percentage of free PSA cutoff that maintained at least 90% sensitivity for prostate cancer detection.Results: Median percentage of free PSA was 9.2% in men with cancer and a normal-sized gland, 15.9% in men with cancer and an enlarged gland, and 18.8% in men with benign prostatic hyperplasia (P < .001). The percentage of free PSA cutoff was higher in men with an enlarged gland and in those with a palpably benign gland. In men with an enlarged, palpably benign gland, a free PSA cutoff of 23.4% or lower detected at least 90% of cancers and would have eliminated 31.3% of negative biopsies.Conclusions: Measurement of percentage of free serum PSA improves specificity of prostate cancer screening in selected men with elevated total serum PSA levels and can reduce unnecessary prostate biopsies with minimal effects on the cancer detection rate; however, further studies are needed to define optimal cutoffs. Final evaluation of PSA screening also must consider the ability of current treatments to improve the prognosis of screen-detected prostate cancer. [ABSTRACT FROM AUTHOR]

Introduction: Although prostate MRI and tissue-based gene expression (genomic) tests improve staging and estimates of prostate cancer prognosis, their association with the intensity of treatment patients receive is not well understood., Methods: We performed a retrospective cohort study of Medicare beneficiaries diagnosed with clinically localized prostate cancer in 2013 through 2017 in the Surveillance, Epidemiology, and End Results database. The primary study outcome was the receipt of treatment intensification in the first 12 months after diagnosis (defined as the addition of androgen deprivation therapy among patients receiving radiation or pelvic lymphadenectomy among those undergoing radical prostatectomy). We assessed associations between the receipt of prostate MRI and genomic testing and treatment intensification, adjusting for clinical and sociodemographic factors and further stratifying the analyses by risk status., Results: We identified 37,064 patients with clinically localized prostate cancer, including 6,398, 22,011, and 5976 with low, intermediate, and high D'Amico-risk disease, respectively. Among all treated patients, receipt of prostate MRI was associated with increased odds of treatment intensification (odds ratio 1.76, 95% CI 1.65-1.88, P < .001). In contrast, genomic testing was not significantly associated. Among treated patients with high-risk disease, genomic testing was associated with decreased odds of intensified treatment (odds ratio 0.59, 95% CI 0.35-1.00, P = .05)., Conclusions: Prostate MRI was associated with intensified treatment across risk strata, while genomic testing was associated with lower intensity of treatment among high-risk disease. Additional study is needed to determine whether use of imaging and risk stratification tools leads to improved long-term patient outcomes.

Introduction: Although prostate magnetic resonance imaging (MRI) is commonly used in the diagnosis, staging and active surveillance of prostate cancer, little is known about patient perspectives on MRI., Methods: We performed a qualitative study consisting of in-depth, semi-structured interviews of patients with low- and intermediate-risk prostate cancer managed with active surveillance. Interviews focused on experiences with and knowledge of prostate MRI and MRI-ultrasound fusion biopsy during active surveillance. We purposively sampled patients who received prostate MRI as part of their clinical care, conducted interviews until reaching thematic saturation and performed conventional content analysis to analyse data., Results: Twenty patients aged 51-79 years (mean = 68 years) participated in the study. At diagnosis, 17 (85%) had a Gleason grade group 1, and three (15%) had a grade group 2 tumour. Overall, participants viewed prostate MRI as a valuable tool that accurately localizes and monitors prostate cancer over time, and they considered prostate MRI central to active surveillance monitoring. We identified five thematic categories related to MRI use: (1) the experiential aspects of undergoing an MRI scan; (2) the experience of visualizing one's own prostate and prostate cancer; (3) adequacy of provider explanations of MRI results; (4) confidence in prostate MRI in decision-making; and (5) the role of prostate MRI in longitudinal follow-up, including an interest in using MRI to modify the timing of, or replace, prostate biopsy., Conclusion: Patients value prostate MRI as a tool that enhances their confidence in the initial diagnosis and monitoring of prostate cancer. This work can inform future studies to optimize patient experience, education and counselling during active surveillance for prostate cancer., Competing Interests: None., (© 2024 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Importance: Germline gene panel testing is recommended for men with advanced prostate cancer (PCa) or a family history of cancer. While evidence is limited for some genes currently included in panel testing, gene panels are also likely to be incomplete and missing genes that influence PCa risk and aggressive disease., Objective: To identify genes associated with aggressive PCa., Design, Setting, and Participants: A 2-stage exome sequencing case-only genetic association study was conducted including men of European ancestry from 18 international studies. Data analysis was performed from January 2021 to March 2023. Participants were 9185 men with aggressive PCa (including 6033 who died of PCa and 2397 with confirmed metastasis) and 8361 men with nonaggressive PCa., Exposure: Sequencing data were evaluated exome-wide and in a focused investigation of 29 DNA repair pathway and cancer susceptibility genes, many of which are included on gene panels., Main Outcomes and Measures: The primary study outcomes were aggressive (category T4 or both T3 and Gleason score ≥8 tumors, metastatic PCa, or PCa death) vs nonaggressive PCa (category T1 or T2 and Gleason score ≤6 tumors without known recurrence), and metastatic vs nonaggressive PCa., Results: A total of 17 546 men of European ancestry were included in the analyses; mean (SD) age at diagnosis was 65.1 (9.2) years in patients with aggressive PCa and 63.7 (8.0) years in those with nonaggressive disease. The strongest evidence of association with aggressive or metastatic PCa was noted for rare deleterious variants in known PCa risk genes BRCA2 and ATM (P ≤ 1.9 × 10-6), followed by NBN (P = 1.7 × 10-4). This study found nominal evidence (P < .05) of association with rare deleterious variants in MSH2, XRCC2, and MRE11A. Five other genes had evidence of greater risk (OR≥2) but carrier frequency differences between aggressive and nonaggressive PCa were not statistically significant: TP53, RAD51D, BARD1, GEN1, and SLX4. Deleterious variants in these 11 candidate genes were carried by 2.3% of patients with nonaggressive, 5.6% with aggressive, and 7.0% with metastatic PCa., Conclusions and Relevance: The findings of this study provide further support for DNA repair and cancer susceptibility genes to better inform disease management in men with PCa and for extending testing to men with nonaggressive disease, as men carrying deleterious alleles in these genes are likely to develop more advanced disease.

Background: Tissue-based gene expression (genomic) tests provide estimates of prostate cancer aggressiveness and are increasingly used for patients considering or engaged in active surveillance. However, little is known about patient experiences with genomic testing and its role in their decision-making., Methods: We performed a qualitative study consisting of in-depth, semi-structured interviews of patients with low- or favourable-intermediate-risk prostate cancer managed with active surveillance. We purposively sampled to include patients who received biopsy-based genomic testing as part of clinical care. The interview guide focused on experiences with genomic testing during patients' decision-making for prostate cancer management and understanding of genomic test results. We continued interviews until thematic saturation was reached, iteratively created a code key and used conventional content analysis to analyse data., Results: Participants' ( n  = 20) mean age was 68 years (range 51-79). At initial biopsy, 17 (85%) had a Gleason grade group 1, and 3 (15%) had a grade group 2 prostate cancer. The decision to undergo genomic testing was driven by both participants and physicians' recommendations; however, some participants were unaware that testing had occurred. Overall, participants understood the role of genomic testing in estimating their prostate cancer risk, and the test results increased their confidence in the decision for active surveillance. Participants had some misconceptions about the difference between tissue-based gene expression tests and germline genetic tests and commonly believed that tissue-based tests measured hereditary cancer risk. While some participants expressed satisfaction with their physicians' explanations, others felt that communication was limited and lacked sufficient detail., Conclusion: Patients interact with and are influenced by the results of biopsy-based genomic testing during active surveillance for prostate cancer, despite gaps in understanding about test results. Our findings indicate areas for improvement in patient counselling in order to increase patient knowledge and comfort with genomic testing., Competing Interests: ML, MRC and TMS report research collaborations with Veracyte Inc., (© 2023 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Purpose: It is unknown whether compliance with recommended monitoring tests during observation of localized prostate cancer has changed over time., Materials and Methods: We performed a retrospective cohort study of Medicare beneficiaries diagnosed with low- or intermediate-risk prostate cancer in 2004-2016 who were initially managed with observation for a minimum of 12 months. The primary objective was to examine rates of PSA testing, prostate biopsy, and prostate MRI. We used multivariable mixed effects Poisson regression to determine whether rates of PSA testing and prostate biopsy increased over time. In addition, we identified clinical, sociodemographic, and provider factors associated with the frequency of monitoring tests during observation., Results: We identified 10,639 patients diagnosed at a median age of 73 (IQR 69-77) years. The median follow-up time was 4.3 (IQR 2.7-6.6) years after diagnosis. Among patients managed without treatment for 5 years, 98% received at ≥1 PSA test, 48.0% ≥1 additional prostate biopsy, and 31.0% ≥1 prostate MRI. Among patients managed with observation for ≥12 months, mixed effects Poisson regression revealed that rates of PSA testing and biopsy increased over time (per calendar year: RR 1.02, 95% CI: 1.02-1.03 and RR 1.10, 95% CI: 1.08-1.11, respectively). Clinical and sociodemographic factors including age, clinical risk, race/ethnicity, census tract poverty, and region were associated with rates of biopsy and PSA testing., Conclusions: Use of recommended monitoring tests including repeat prostate biopsy remains low among Medicare beneficiaries undergoing observation for low- and intermediate-risk prostate cancer.

The NCCN Guidelines for Prostate Cancer Early Detection provide recommendations for individuals with a prostate who opt to participate in an early detection program after receiving the appropriate counseling on the pros and cons. These NCCN Guidelines Insights provide a summary of recent updates to the NCCN Guidelines with regard to the testing protocol, use of multiparametric MRI, and management of negative biopsy results to optimize the detection of clinically significant prostate cancer and minimize the detection of indolent disease.

Importance: Active surveillance (AS) is endorsed by clinical guidelines as the preferred management strategy for low-risk prostate cancer, but its use in contemporary clinical practice remains incompletely defined., Objective: To characterize trends over time and practice- and practitioner-level variation in the use of AS in a large, national disease registry., Design, Setting, and Participants: This retrospective analysis of a prospective cohort study included men with low-risk prostate cancer, defined as prostate-specific antigen (PSA) less than 10 ng/mL, Gleason grade group 1, and clinical stage T1c or T2a, newly diagnosed between January 1, 2014, and June 1, 2021. Patients were identified in the American Urological Association (AUA) Quality (AQUA) Registry, a large quality reporting registry including data from 1945 urology practitioners at 349 practices across 48 US states and territories, comprising more than 8.5 million unique patients. Data are collected automatically from electronic health record systems at participating practices., Exposures: Exposures of interest included patient age, race, and PSA level, as well as urology practice and individual urology practitioners., Main Outcomes and Measures: The outcome of interest was the use of AS as primary treatment. Treatment was determined through analysis of electronic health record structured and unstructured clinical data and determination of surveillance based on follow-up testing with at least 1 PSA level remaining greater than 1.0 ng/mL., Results: A total of 20 809 patients in AQUA were diagnosed with low-risk prostate cancer and had known primary treatment. The median age was 65 (IQR, 59-70) years; 31 (0.1%) were American Indian or Alaska Native; 148 (0.7%) were Asian or Pacific Islander; 1855 (8.9%) were Black; 8351 (40.1%) were White; 169 (0.8%) were of other race or ethnicity; and 10 255 (49.3%) were missing information on race or ethnicity. Rates of AS increased sharply and consistently from 26.5% in 2014 to 59.6% in 2021. However, use of AS varied from 4.0% to 78.0% at the urology practice level and from 0% to 100% at the practitioner level. On multivariable analysis, year of diagnosis was the variable most strongly associated with AS; age, race, and PSA value at diagnosis were all also associated with odds of surveillance., Conclusions and Relevance: This cohort study of AS rates in the AQUA Registry found that national, community-based rates of AS have increased but remain suboptimal, and wide variation persists across practices and practitioners. Continued progress on this critical quality indicator is essential to minimize overtreatment of low-risk prostate cancer and by extension to improve the benefit-to-harm ratio of national prostate cancer early detection efforts.

Little is known regarding the potential relationship between clonal hematopoiesis (CH) of indeterminate potential (CHIP), which is the expansion of hematopoietic stem cells with somatic mutations, and risk of prostate cancer, the fifth leading cause of cancer death of men worldwide. We evaluated the association of age-related CHIP with overall and aggressive prostate cancer risk in two large whole-exome sequencing studies of 75 047 European ancestry men, including 7663 prostate cancer cases, 2770 of which had aggressive disease, and 3266 men carrying CHIP variants. We found that CHIP, defined by over 50 CHIP genes individually and in aggregate, was not significantly associated with overall (aggregate HR = 0.93, 95% CI = 0.76-1.13, P = 0.46) or aggressive (aggregate OR = 1.14, 95% CI = 0.92-1.41, P = 0.22) prostate cancer risk. CHIP was weakly associated with genetic risk of overall prostate cancer, measured using a polygenic risk score (OR = 1.05 per unit increase, 95% CI = 1.01-1.10, P = 0.01). CHIP was not significantly associated with carrying pathogenic/likely pathogenic/deleterious variants in DNA repair genes, which have previously been found to be associated with aggressive prostate cancer. While findings from this study suggest that CHIP is likely not a risk factor for prostate cancer, it will be important to investigate other types of CH in association with prostate cancer risk., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

HOXB13, a homeodomain transcription factor, critically regulates androgen receptor (AR) activities and androgen-dependent prostate cancer (PCa) growth. However, its functions in AR-independent contexts remain elusive. Here we report HOXB13 interaction with histone deacetylase HDAC3, which is disrupted by the HOXB13 G84E mutation that has been associated with early-onset PCa. Independently of AR, HOXB13 recruits HDAC3 to lipogenic enhancers to catalyze histone deacetylation and suppress lipogenic regulators such as fatty acid synthase. Analysis of human tissues reveals that the HOXB13 gene is hypermethylated and downregulated in approximately 30% of metastatic castration-resistant PCa. HOXB13 loss or G84E mutation leads to lipid accumulation in PCa cells, thereby promoting cell motility and xenograft tumor metastasis, which is mitigated by pharmaceutical inhibition of fatty acid synthase. In summary, we present evidence that HOXB13 recruits HDAC3 to suppress de novo lipogenesis and inhibit tumor metastasis and that lipogenic pathway inhibitors may be useful to treat HOXB13-low PCa., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Although the Decipher genomic classifier has been validated as a prognostic tool for several prostate cancer endpoints, little is known about its role in assessing the risk of biopsy reclassification for patients on active surveillance, a key event that often triggers treatment., Objective: To evaluate the association between Decipher genomic classifier scores and biopsy Gleason upgrading among patients on active surveillance., Design Setting and Participants: This was a retrospective cohort study among patients with low- and favorable intermediate-risk prostate cancer on active surveillance who underwent biopsy-based Decipher testing as part of their clinical care., Outcome Measurements and Statistical Analysis: We evaluated the association between the Decipher score and any increase in biopsy Gleason grade group (GG) using univariable and multivariable logistic regression. We compared the area under the receiver operating characteristic curve (AUC) for models comprising baseline clinical variables with or without the Decipher score., Results and Limitations: We identified 133 patients for inclusion with a median age of 67.7 yr and median prostate-specific of 5.6 ng/ml. At enrollment, 75.9% had GG1 and 24.1% had GG2 disease. Forty-three patients experienced biopsy upgrading. On multivariable logistic regression, the Decipher score was significantly associated with biopsy upgrading (odds ratio 1.37 per 0.10 unit increase, 95% confidence interval [CI] 1.05-1.79; p = 0.02). The Decipher score was associated with upgrading among patients with biopsy GG 1 disease, but not GG2 disease. The discriminative ability of a clinical model (AUC 0.63, 95% CI 0.51-0.74) was improved by integration of the Decipher score (AUC 0.69, 95% CI 0.58-0.80)., Conclusions: The Decipher genomic classifier score was associated with short-term biopsy Gleason upgrading among patients on active surveillance., Patient Summary: The results from this study indicate that among patients with prostate cancer undergoing active surveillance, those with higher Decipher scores were more likely to have higher-grade disease found over time. These findings indicate that the Decipher test might be useful for guiding the intensity of monitoring during active surveillance, such as more frequent biopsy for patients with higher scores., (© 2022 The Author(s).)

Purpose: To determine whether phosphodiesterase-5 inhibitor documentation is associated with biochemical relapse-free and overall survival of patients with prostate cancer treated with radical prostatectomy., Materials and Methods: We undertook a retrospective cohort analysis of 3,100 patients with prostate cancer treated with radical prostatectomy between 2003 and 2015. The patients were categorized as a phosphodiesterase- 5- inhibitor user or non-user. The biochemical relapse-free and overall survival at 5-years and 10-years were determined., Results: Of the patients, 1,372 reported phosphodiesterase-5 inhibitor documentation, and 1,728 did not. The biochemical recurrence-free survival for non-users at 5- and 10-years follow-up was 87.6% and 85.3%, respectively, and the overall survival at these time intervals was 97.9% and 94.5%. The biochemical recurrence-free survival for phosphodiesterase-5 inhibitor users was 94.3% and 93.2% at 5- and 10-years follow-up, respectively, and overall survival was 99.2% and 95.8% at these intervals. The hazard ratio for biochemical recurrence-free survival was 0.44 (CI 0.34-0.56) and for overall survival was 0.65 (CI 0.45-0.94). On the multivariate analysis, phosphodiesterase-5 inhibitor documentation was associated with a lower risk of biochemical recurrence and death when corrected for the other variables. Age at surgery and Gleason scores >8 was associated with a higher risk of death. Higher pathological stage, higher Gleason score, presence of lymph node metastases, and nonwhite race were associated with a higher risk of recurrence., Conclusion: This retrospective analysis revealed a significant association of postoperative phosphodiesterase-5 inhibitor documentation with biochemical recurrence-free- and overall survival in patients with localized prostate cancer treated with radical prostatectomy. Larger scale studies are warranted to investigate the clinical significance of this association., Competing Interests: Conflict of interest No authors have any conflicts of interest with subjects in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion ( MAST3 , p = 6.9×10 -7 and GAB2 , p = 2.0×10 -6 ). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS- versus treatment for the initial management of patients with low-risk PC., Competing Interests: Declaration of Interests The authors declare no competing interests.

Purpose: We examined the demographic and clinicopathological parameters associated with the time to convert from active surveillance to treatment among men with prostate cancer., Materials and Methods: A multi-institutional cohort of 7,279 patients managed with active surveillance had data and biospecimens collected for germline genetic analyses., Results: Of 6,775 men included in the analysis, 2,260 (33.4%) converted to treatment at a median followup of 6.7 years. Earlier conversion was associated with higher Gleason grade groups (GG2 vs GG1 adjusted hazard ratio [aHR] 1.57, 95% CI 1.36-1.82; ≥GG3 vs GG1 aHR 1.77, 95% CI 1.29-2.43), serum prostate specific antigen concentrations (aHR per 5 ng/ml increment 1.18, 95% CI 1.11-1.25), tumor stages (cT2 vs cT1 aHR 1.58, 95% CI 1.41-1.77; ≥cT3 vs cT1 aHR 4.36, 95% CI 3.19-5.96) and number of cancerous biopsy cores (3 vs 1-2 cores aHR 1.59, 95% CI 1.37-1.84; ≥4 vs 1-2 cores aHR 3.29, 95% CI 2.94-3.69), and younger age (age continuous per 5-year increase aHR 0.96, 95% CI 0.93-0.99). Patients with high-volume GG1 tumors had a shorter interval to conversion than those with low-volume GG1 tumors and behaved like the higher-risk patients. We found no significant association between the time to conversion and self-reported race or genetic ancestry., Conclusions: A shorter time to conversion from active surveillance to treatment was associated with higher-risk clinicopathological tumor features. Furthermore, patients with high-volume GG1 tumors behaved similarly to those with intermediate and high-risk tumors. An exploratory analysis of self-reported race and genetic ancestry revealed no association with the time to conversion.

Background: There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive vs nonaggressive disease., Methods: Participants were 5545 European-ancestry men, including 2775 nonaggressive and 2770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency < 0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are 2-sided., Results: BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D BRCA2 alleles (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.94 to 5.25, P = 8.58 × 10-7) and 0.65% of aggressive and 0.11% of nonaggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79 × 10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P = .02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than nonaggressive cases (carrier frequencies = 14.2% vs 10.6%, respectively; P = 5.56 × 10-5). However, this difference was non-statistically significant (P = .18) on excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI = -1.65 to 0.48, P = 3.71 × 10-4)., Conclusions: Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease., Objective: To detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa., Design, Setting, and Participants: A two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls., Outcome Measurements and Statistical Analysis: Frequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls., Results and Limitations: Eleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa., Conclusions: Our approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease., Patient Summary: Multiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa., (Copyright © 2020 European Association of Urology. All rights reserved.)

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.)

Background: Signal regulatory protein β1 (SIRPB1) is a signal regulatory protein member of the immunoglobulin superfamily and is capable of modulating receptor tyrosine kinase-coupled signaling. Copy number variations at the SIRPB1 locus were previously reported to associate with prostate cancer aggressiveness in patients, however, the role of SIRPB1 in prostate carcinogenesis is unknown., Methods: Fluorescence in situ hybridization and laser-capture microdissection coupled with quantitative polymerase chain reaction was utilized to determine SIRPB1 gene amplification and messenger RNA expression in prostate cancer specimens. The effect of knockdown of SIRPB1 by RNA interference in PC3 prostate cancer cells on cell growth in colony formation assays and cell mobility in wound-healing, transwell assays, and cell cycle analysis was determined. Overexpression of SIPRB1 in C4-2 prostate cancer cells on cell migration, invasion, colony formation and cell cycle progression and tumor take rate in xenografts was also determined. Western blot assay of potential downstream SIRPB1 pathways was also performed., Results: SIRPB1 gene amplification was detected in up to 37.5% of prostate cancer specimens based on in silico analysis of several publicly available datasets. SIRPB1 gene amplification and overexpression were detected in prostate cancer specimens. The knockdown of SIRPB1 significantly suppressed cell growth in colony formation assays and cell mobility. SIRPB1 knockdown also induced cell cycle arrest during the G 0 /G 1 phase and enhancement of apoptosis. Conversely, overexpression of SIPRB1 in C4-2 prostate cancer cells significantly enhanced cell migration, invasion, colony formation, and cell cycle progression and increased C4-2 xenograft tumor take rate in nude mice. Finally, this study presented evidence for SIRPB1 regulation of Akt phosphorylation and showed that Akt inhibition could abolish SIRPB1 stimulation of prostate cancer cell proliferation., Conclusions: These results suggest that SIRPB1 is a potential oncogene capable of activating Akt signaling to stimulate prostate cancer proliferation and could be a biomarker for patients at risk of developing aggressive prostate cancer., (© 2020 Wiley Periodicals, Inc.)

The EPHB4 receptor is implicated in the development of several epithelial tumors and is a promising therapeutic target, including in prostate tumors in which EPHB4 is overexpressed and promotes tumorigenicity. Here, we show that high expression of EPHB4 correlated with poor survival in prostate cancer patients and EPHB4 inhibition induced cell death in both hormone sensitive and castration-resistant prostate cancer cells. EPHB4 inhibition reduced expression of the glucose transporter, GLUT3, impaired glucose uptake, and reduced cellular ATP levels. This was associated with the activation of endoplasmic reticulum stress and tumor cell death with features of immunogenic cell death (ICD), including phosphorylation of eIF2α, increased cell surface calreticulin levels, and release of HMGB1 and ATP. The changes in tumor cell metabolism after EPHB4 inhibition were associated with MYC downregulation, likely mediated by the SRC/p38 MAPK/4EBP1 signaling cascade, known to impair cap-dependent translation. Together, our study indicates a role for EPHB4 inhibition in the induction of immunogenic cell death with implication for prostate cancer therapy.

Background: Prostate cancer is the most common cancer in American men that ranges from low risk states amenable to active surveillance to high-risk states that can be lethal especially if untreated. There is a critical need to develop relatively non-invasive and clinically useful methods for screening, detection, prognosis, disease monitoring, and prediction of treatment efficacy. In this review, we focus on important advances as well as future efforts needed to drive clinical innovation in this area of urine biomarker research for prostate cancer detection and prognostication., Methods: We provide a review of current literature on urinary biomarkers for prostate cancer. We evaluate the strengths and limitations of a variety of approaches that vary in sampling strategies and targets measured; discuss reported urine tests for prostate cancer with respect to their technical, analytical, and clinical parameters; and provide our perspectives on critical considerations in approaches to developing a urine-based test for prostate cancer., Results: There has been an extensive history of exploring urine as a source of biomarkers for prostate cancer that has resulted in a variety of urine tests that are in current clinical use. Importantly, at least three tests have demonstrated high sensitivity (~90%) and negative predictive value (~95%) for clinically significant tumors; however, there has not been widespread adoption of these tests., Conclusions: Conceptual and methodological advances in the field will help to drive the development of novel urinary tests that in turn may lead to a shift in the clinical paradigm for prostate cancer diagnosis and management.

Objective: To evaluate prognostic markers, prostate-specific antigen, prostate health index (PHI), and prostate volume indexed measures (prostate-specific antigen density and prostate health index density) for predicting positive prostate cancer biopsies in magnetic resonance (MR) transrectal ultrasound fused versus nonfused transrectal ultrasonography biopsy., Methods: A retrospective cohort of 211 patients that had at least 1 suspected MR lesion, Prostate Imaging-Reporting and Data System ≥3, and subsequent biopsy (2015-2017). Clinical characteristics and prognostic biomarkers were evaluated as predictors of prostate cancer detection by type of biopsy guidance (fused vs nonfused)., Results: One-hundred twenty-one patients had nonfused and 90 had fused biopsies. PHI and PHID had greater area under the receiver operating characteristics curve (AUC) in predicting positive biopsies than prostate-specific antigen or PSAD for both nonfused and fused biopsy. PHI 0.78 (95% CI 0.67-0.88) and PHID 0.82 (95% CI 0.73-0.91) had the greatest AUC for predicting biopsy results for nonfused and fused biopsies, respectively. Multiple-variable models did not improve model fit compared to single variables. Based on Youden's index, a cut-off value of 45.9 for PHI in nonfused and 0.64 for PHID in fused biopsies would reduce the number of negative biopsies by 77.3% and 63.4%, respectively, but the percentage of missed clinically significant cancer biopsies would be 19% and 12%, respectively., Conclusion: Our findings demonstrate that the choice of prognostic biomarkers for predicting positive biopsies is a function of the biopsy guidance method. Volume indexed derivatives appear to have greater value when a MRI-US fused method is used., (Copyright © 2019 Elsevier Inc. 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.)

Background: Long term dietary consumption of genistein by Chinese men is associated with decreased PCa metastasis and mortality. Short term treatment of US men with prostate cancer (PCa) with genistein decreases MMP-2 in prostate tissue. MEK4 regulates MMP-2 expression, drives PCa metastasis, and genistein inhibits MEK4, decreases MMP-2 expression and dietary dosing inhibits human PCa metastasis in mice. This study examines short- versus long-term treatment effects of genistein in humans and in vitro., Methods and Findings: US men with localized PCa were treated on a phase II trial with genistein (N = 14) versus not (N = 14) for one month prior to radical prostatectomy. Prostate epithelial cells were removed from fresh frozen tissue by laser capture microdissection, and the expression of 12,000 genes profiled. Genistein significantly altered the expression of four genes, three had established links to cancer cell motility and metastasis. Of these three, one was a non-coding transcript, and the other two were BASP1 and HCF2. Genistein increased BASP1 expression in humans, and its engineered over expression and knockdown demonstrated that it suppressed cell invasion in all six human prostate cell lines examined. Genistein decreased HCF2 expression in humans, and it was shown to increase cell invasion in all cell lines examined. The expression of MMP-2, MEK4 and BASP1 was then measured in formalin fixed prostate tissue from N = 38 Chinese men living in China and N = 41 US men living in the US, both cohorts with localized PCa. MMP-2 was 52% higher in Chinese compared to US tissue (P < 0.0001), MEK4 was 48% lower (P < 0.0001), and BASP1 was unaltered. Treatment of PC3 human PCa cells in vitro for up to 8 weeks demonstrated that short term genistein treatment decreased MMP-2, while long term treatment increased it, both changes being significant (P<0.05) compared to untreated control cells. Long term genistein-treated cells retained their responsiveness to genistein's anti-motility effect., Conclusions: Genistein inhibits pathways in human prostate that drive transformation to a lethal high motility phenotype. Long term treatment induces compensatory changes in biomarkers of efficacy. The current strategy of using such biomarkers after short term intervention as go/no-go determinants in early phase chemoprevention trials should be carefully examined., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: This does not alter our adherence to PLOS ONE policies on sharing data and materials. Patents awarded: 1. Catalytic Enantioselective Synthesis of Flavanones and Chromanones (US Patent # 7,851,640). Role: inventor. 2. Inhibition and Treatment of Prostate Cancer Metastasis (US Patent #s: 8,481,760, 8,742,141). Role: inventor. 3. Inhibition of Cancer Cell Motility (U.S. Patent #: 9,839,625). Role: inventor. Description: Work in point #1 describes the synthesis of new compounds that have the potential to inhibit cancer cell motility. Work in points 2 and 3 describes a different class of new compounds that do inhibit cancer cell motility and metastasis, and also identify a novel biological target for inhibiting those processes. That novel biological target involves selective modulation of HSP90 activity. Patents pending: Cell free screen for measuring effect of small molecules on client protein interactions with the HSP90B/CDC37 complex and resultant functional effects (US Patent Pending: U.S. Serial No. 62/628,243 -- VA ID No. 2017-383; A&A Ref. 30452.43USP1) Description: work in this pending application describes an in vitro method for screening of compounds that are selective HSP90 modulator Division of Hematology & Medical Oncology www.ohsu.edu/cancer. Cover Letter Page 2 of 2, Ownership interests: Raymond Bergan has the following relationships with Third Coast Therapeutics (3CRx) Inc.: cofounder, co-owner, member board of directors, Chief Scientific Officer. The focus of 3CRx is to move therapeutics licensed under above patents into human clinical trials to assess whether they will inhibit cancer cell motility and metastasis.

Introduction and Objective: Studies have linked Black race to prostate cancer (CaP) risk but most fail to account for established risk factors such as 5-ARI use, prostate volume, socioeconomic status, and hospital setting. We assess whether Black race remains associated with CaP and Gleason ≥3 + 4 CaP, after adjusting for clinical setting and socioeconomic and clinical factors at prostate biopsy, with a focus on men aged 40-54 years, who may be excluded from current screening guidelines., Methods: We recruited 564 men age 40-79 undergoing initial prostate biopsy for abnormal PSA or digital rectal examination (DRE) from three publicly funded and two private hospitals from 2009-2014. Univariate and multivariate analyses examined the associations between hospital type, race, West African Ancestry (WAA), clinical, and sociodemographic risk factors with CaP diagnosis and Gleason ≥3 + 4 CaP. Given changes in CaP screening recommendations, we also assess the multivariate analyses for men aged 40-54., Results: Black and White men had similar age, BMI, and prostate volume. Black men had higher PSA (8.10 ng/mL vs. 5.63 ng/mL) and PSA density (0.22 ng/mL/cm 3 vs. 0.15 ng/mL/cm 3 , all p < 0.001). Blacks had higher frequency of CaP (63.1% vs. 41.5%, p<0.001) and Gleason ≥3+4 CaP relative to Whites in both public (27.7% vs 11.6%, p<0.001) and private (48.4% vs 21.6%, p = 0.002) settings. In models adjusted for age, first degree family history, prostate volume, 5-ARI use, hospital type, income, marital and educational status, Black race was independently associated with overall CaP diagnosis (OR = 2.13, p = 0.002). There was a significant multiplicative interaction with Black race and abnormal DRE for Gleason ≥3 + 4 CaP (OR = 2.93, p = 0.01). WAA was not predictive of overall or significant CaP among Black men. Black race (OR = 5.66, p = 0.02) and family history (OR = 4.98, p = 0.01) were independently positively associated with overall CaP diagnosis for men aged 40 to 54., Conclusions: Black race is independently associated with CaP and Gleason ≥3+4 CaP after accounting for clinical and socioeconomic risk factors including clinical setting and WAA, and has a higher odds ratio of CaP diagnosis in younger men. Further investigation into optimizing screening in Black men aged 40 to 54 is warranted., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Shared decision making is recommended in regard to prostate cancer screening. Decision aids may facilitate this process but the impact of decision aids on screening preferences is poorly understood., Materials and Methods: In an online survey we randomized a national sample of adults to the online decision aids of 1 of 6 professional societies. We compared survey responses before and after decision aid exposure. The primary outcome was the change in participant likelihood of undergoing or recommending prostate cancer screening on a scale of 1-unlikely to 100-extremely likely. Secondary outcomes included change in participant comfort with prostate cancer screening based on the average of 6, 5-point Likert-scale questions., Results: Median age was 53 years in the 1,336 participants and 50% were men. The randomized groups did not differ significantly by race, age, gender, income, marital status or education level. The likelihood of undergoing or recommending prostate cancer screening decreased from 83 to 78 following decision aid exposure (p <0.001). Reviewing the decision aid from the Centers for Disease Control or the American Academy of Family Physicians did not alter the likelihood (each p >0.2). However, the decision aid from the United States Preventive Services Task Force was associated with the largest decrease in screening preference (-16.0, p <0.001). Participants reported increased comfort (from 3.5 to 4.1 of 5) with the decision making process of prostate cancer screening following exposure to a decision aid (p <0.001)., Conclusions: Exposure to a decision aid decreased the participant likelihood of undergoing or recommending prostate cancer screening and increased comfort with the screening process., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

During the prostate-specific antigen-based prostate cancer (PCa) screening era there has been a 53% decrease in the US PCa mortality rate. Concerns about overdiagnosis and overtreatment combined with misinterpretation of clinical trial data led to a recommendation against PCa screening, resulting in a subsequent reversion to more high-risk disease at diagnosis. Re-evaluation of trial data and increasing acceptance of active surveillance led to a new draft recommendation for shared decision making for men aged 55 to 69 years old. Further consideration is needed for more intensive screening in men with high-risk factors. PCa screening significantly reduces PCa morbidity and mortality., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease.

Purpose of Review: To provide an overview of how genetic, serum, and urine biomarkers can help identify men at high risk for prostate cancer (PCa) and aggressive disease and men who would benefit from prostate biopsy., Recent Findings: Screening for PCa is controversial because of concerns about overdiagnosis and overtreatment of nonlife-threatening tumors. Therefore, an approach to screening that includes a detailed family history with genetic testing of risk single nucleotide polymorphisms and high-penetrance genetic variants should be considered. After an elevated serum prostate-specific antigen (PSA) level has been confirmed, obtaining additional information (family history, biomarkers, and imaging) should be considered before recommending a prostate biopsy., Summary: There are now genetic tests that can help identify men who would benefit from PSA testing. Additional biomarker and imaging tests should be offered to those men who are confirmed to have elevated PSA values. These new biomarkers and imaging tests can improve the specificity of PSA testing while missing a small percentage of high-grade tumors. The path forward involves a multiparametric risk assessment based on clinical data and these new tests.