Elevated Risk Of Prostate Cancer Research Articles

Nutritional Supplement With Fermented Soy in Men With an Elevated Risk of Prostate Cancer and Negative Prostate Biopsies: General and Oncological Results From the Prospective PRAECAP Trial

Introduction & ObjectivesTo investigate the effect of a dietary supplement containing fermented soy on PSA, IPSS, changes in prostate volume and prostate cancer development after a 6-month challenge in men at increased risk of prostate cancer and negative previous biopsies. Materials & MethodsPatients with an elevated risk of PCa, defined by either 1 of the following criteria: PSA > 3 ng/ml, suspect lesion at digital rectal examination (DRE), suspect lesion at transrectal ultrasound (TRUS) / magnetic resonance imaging (MRI) and previous negative prostate biopsies (at least 8 cores) within 12 months before inclusion. Statistical analysis was carried out using a non-parametric one-sided paired Wilcoxon rank sum test, chi-square test and Fisher's exact test. ResultsIn this trial, 94 patients where eligible for analysis. A PSA response was detected in 81% of the cases. In 25.8% (24/93) of patients, a decrease of at least 3 points on the IPSS was observed. The median prostate volume did not statistically change after 6 months (p=0.908). Patients with PSA modulation required fewer investigations and had fewer positive biopsies (p<0.001) and significantly fewer ISUP≥3 lesions (p=0.02). ConclusionsWe observed a significantly lower PSA level after a 6-month challenge with a fermented soy-containing supplement, and an effect on IPSS in a subset of patients. Prescribing a fermented soy supplement in patients with an increased PCa risk could lead to a better selection of patients at real increased risk of having occult PCa.

Current Understanding of Androgen Signaling in Prostatitis and its Treatment: A Review.

Chronic prostatitis is a highly prevalent condition that significantly impacts the quality of life and fertility of men. Because of its heterogeneous nature, there is no definitive treatment, which requires ongoing research into its etiology. Additionally, the association between prostatitis and an elevated risk of prostate cancer highlights the importance of comprehending androgen involvement in prostatitis. This paper examines the current understanding of androgen signaling in prostatitis and explores contemporary therapeutic approaches. We reviewed Medline articles comprehensively, using keywords such as nonbacterial prostatitis, prostatitis infertility, androgen role in prostatitis, and chronic pelvic pain. Several cellular targets are linked to androgen signaling. Notably, the major tyrosine phosphatase activity (cPAcP) in normal human prostate is influenced by androgen signaling, and its serum levels inversely correlate with prostate cancer progression. Androgens also regulate membrane-associated zinc and pyruvate transporters transduction in prostate cells, suggesting promising avenues for novel drug development aimed at inhibiting these molecules to reduce cancer tumor growth. Various therapies for prostatitis have been evaluated, including antibiotics, anti-inflammatory medications (including bioflavonoids), neuromodulators, alpha-blockers, 5α-reductase inhibitors, and androgen receptor antagonists. These therapies have demonstrated varying degrees of success in ameliorating symptoms. In conclusion, aging decreases circulating T and intraprostatic DHT, altering the proper functioning of the prostate, reducing the ability of androgens to maintain normal Zn2+ levels, and diminishing the secretion of citrate, PAcP, and other proteins into the prostatic fluid. The Zn2+-transporter decreases or is absent in prostate cancer, so the pyruvate transporter activates. Consequently, the cell ATP increases, inducing tumor growth.

A MicroRNA Approach to Evaluate Elevated Prostate Cancer Risk in Cancer-Free Men

A MicroRNA Approach to Evaluate Elevated Prostate Cancer Risk in Cancer-Free Men

Interleukins-6 −174G/C (rs1800795) and −572C/G (rs1800796) polymorphisms and prostate cancer risk

Prostate cancer (PCa) is an aggressive cancer influenced by a complex interplay of genetic and environmental factors. Amongst these risk factors, the impact of Interleukin6 (IL6) gene polymorphisms in PCa risk has received a lot of attention. IL-6 is a cytokine that has been implicated in the pathogenesis of several malignancies, including PCa. Two IL-6 gene polymorphisms, − 174 G/C (rs1800795) and − 572 C/G (rs1800796), have received intellectual attention due to their potential role as modulators of prostate cancer risk. The main objective of this research was to comprehensively explore the potential associations between IL-6 rs1800795 and rs1800796 polymorphisms, and their impact on the occurrence of PCa. A case-control study was carried out with a well-defined cohort comprising 110 PCa cases and 110 controls (total n = 220). The genotyping of rs1800795 and rs1800796 was carefully performed using the highly sensitive and accurate Polymerase Chain Reaction-High Resolution Melting Curve (PCR-HRM) technique. The assessment of genetic associations was evaluated using various R packages, such as Haplo-Stats, SNP stat, pheatmap, and LD heatmap. The present study applied odds ratio (OR) analysis to reveal significant evidence of strong associations between the genotypes of rs1800795 and rs1800796 and the susceptibility to PCa. The findings of this study underscore the noteworthy impact of genetic variations in the IL-6 gene on the development of prostate cancer. Specifically, the C/G and G/G genotypes of rs1800795 demonstrated increased PCa risk, with odds ratios (OR) of 1.650 (95% CI = 1.068–2.549, p = 0.032) and 2.475 (95% CI = 1.215–5.043, p < 0.001), respectively. Similarly, the G/C genotype of rs1800796 exhibited an OR of 2.374 (95% CI = 1.363–4.130, p = 0.012) for elevated prostate cancer risk, while the C/C genotype had an OR of 1.81 (95% CI = 1.02–3.22, p = 0.7). Furthermore, our haplotype analysis have revealed an association between haplotype 4 (C-G) and increased risk of PCa (OR = 1.69, 95% CI = 1.05–2.73, p = 0.032). In conclusion, this case-control analysis presents compelling evidence for a significant association between IL-6 variants (rs1800795 and rs1800796) and increased susceptibility to prostate cancer.

Prediction of clinically significant prostate cancer through urine metabolomic signatures: A large-scale validated study

PurposeCurrently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict clinically significant PC (sPC) in men at risk.MethodsUrine samples from 928 men, namely, 660 PC patients and 268 benign subjects, were analyzed by gas chromatography/quadrupole time-of-flight mass spectrophotometry (GC/Q-TOF MS) metabolomic profiling to construct four predictive models. Model I discriminated between PC and benign cases. Models II, III, and GS, respectively, predicted sPC in those classified as having favorable intermediate risk or higher, unfavorable intermediate risk or higher (according to the National Comprehensive Cancer Network risk groupings), and a Gleason sum (GS) of ≥ 7. Multivariable logistic regression was used to evaluate the area under the receiver operating characteristic curves (AUC).ResultsIn Models I, II, III, and GS, the best AUCs (0.94, 0.85, 0.82, and 0.80, respectively; training cohort, N = 603) involved 26, 24, 26, and 22 metabolites, respectively. The addition of five clinical risk factors (serum prostate-specific antigen, patient age, previous negative biopsy, digital rectal examination, and family history) significantly improved the AUCs of the models (0.95, 0.92, 0.92, and 0.87, respectively). At 90% sensitivity, 48%, 47%, 50%, and 36% of unnecessary biopsies could be avoided. These models were successfully validated against an independent validation cohort (N = 325). Decision curve analysis showed a significant clinical net benefit with each combined model at low threshold probabilities. Models II and III were more robust and clinically relevant than Model GS.ConclusionThis urine test, which combines urine metabolic markers and clinical factors, may be used to predict sPC and thereby inform the necessity of biopsy in men with an elevated PC risk.

Do Obesity-Related Traits Affect Prostate Cancer Risk through Serum Testosterone? A Mendelian Randomization Study.

This study aimed to investigate whether testosterone mediates or confounds the effect of obesity-related traits on prostate cancer (PCa) using Mendelian randomization (MR) analysis. Data of obesity-related traits (body mass index [BMI], waist-to-hip ratio [WHR], and waist-to-hip ratio adjusted for body mass index [WHRadjBMI]) were obtained from up to 806,834 people of European ancestry; data of testosterone (bioavailable testosterone [BT], total testosterone [TT], and sex hormone-binding globulin [SHBG]) were extracted from up to 194,453 participants in the UK Biobank; and the summary-level data of PCa (79,194 cases and 61,112 controls) were obtained from the PRACTICAL consortium. The results supported the causal relationship between higher BMI and a reduced risk of PCa (OR = 0.91, 95% confidence interval [CI]: 0.86-0.96). Furthermore, increased BT levels were associated with an elevated risk of PCa (OR = 1.15, 95% CI: 1.06-1.24). Importantly, our analysis revealed a unidirectional causal effect-higher BMI was linked to lower BT levels (beta = -0.27, 95% CI: -0.3--0.24), but not the other way around. This suggests that BT may mediate the effect of BMI on PCa rather than confound it. Our multivariable MR results further demonstrated that considering BT as a mediator led to the weakening of BMI's effect on PCa risk (OR = 0.97, 95% CI: 0.90-1.05), while the impact of BT on PCa remained unchanged when accounting for BMI. Moreover, we identified a significant indirect effect of BMI on PCa risk (OR = 0.96, 95% CI: 0.94-0.98). Our study provided genetic evidence that serum BT can mediate the effect of BMI on the risk of PCa, indicating the possible mechanism by which obesity reduces PCa risk.

Neighbourhood social deprivation and risk of prostate cancer.

Striking geographic variations in prostate cancer incidence suggest an aetiological role for spatially-distributed factors. We assessed whether neighbourhood social deprivation, which can reflect limited social contacts, unfavourable lifestyle and environmental exposures, is associated with prostate cancer risk. In 2005-2012, we recruited 1931 incident prostate cancer cases and 1994 controls in a case-control study in Montreal, Canada. Lifetime residential addresses were linked to an area-based social deprivation index around recruitment (2006) and about 10 years earlier (1996). Logistic regression estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Men residing in areas characterised by greater social deprivation had elevated prostate cancer risks (ORs of 1.54 and 1.60 for recent and past exposures, respectively; highest vs lowest quintiles), independently from area- and individual-level confounders and screening patterns. The increase in risk with recent high social deprivation was particularly elevated for high-grade prostate cancer at diagnosis (OR 1.87, 95% CI 1.32-2.64). Associations were more pronounced for neighbourhoods with higher proportions of separated/divorced or widowed individuals in the past, and with higher percentages of residents living alone recently. These novel findings, suggesting that neighbourhood-level social deprivation increases the risk of prostate cancer, point out to potential targeted public health interventions.

Blood pressure, calcium channel blockers, and the risk of prostate cancer: a Mendelian randomization study.

Observational studies have found some evidence of an association between elevated blood pressure and prostate cancer risk; however, the results are inconclusive. We tested whether systolic blood pressure (SBP) influences prostate cancer risk and evaluated the effect of calcium channel blockers (CCB) on the disease using Mendelian randomization (MR) approach. We used 278 genetic variants associated with SBP and 16 genetic variants in CCB genes as instrumental variables. Effect estimates were obtained from the UK Biobank sample of 142,995 males and from PRACTICAL consortium (79,148 cases and 61,106 controls). For each 10mm Hg increase in SBP the estimated effect was OR 0.96 (0.90-1.01) for overall prostate cancer; and OR 0.92 (0.85-0.99) for aggressive prostate cancer. The MR-estimated effect of a 10mm Hg- SBP lowering through CCB genetic variants was OR 1.22 (1.06-1.42) for all prostate cancers and OR 1.49 (1.18-1.89) for aggressive prostate cancer. The results of our study did not support a causal relationship between SBP and prostate cancer; however, we found weak evidence of a protective effect of high SBP on aggressive prostate cancer and we found that blocking calcium channel receptors may increase prostate cancer risk.

Impact of an Expanded Definition of Family History on Outcomes of Active Surveillance for Prostate Cancer.

Despite family history being an established risk factor for prostate cancer, the role of a broader definition of family history inclusive of not just prostate cancer but other genetically related malignancies has not been investigated in the active surveillance population. Here, we evaluate the impact of an expanded definition of family history on active surveillance outcomes. Patients undergoing active surveillance for prostate cancer at Massachusetts General Hospital from 1997-2019 with detailed data available on family cancer history were identified. Primary outcome was biopsy progression-free survival, and secondary outcomes were treatment-free survival, adverse pathological features at prostatectomy, and biochemical recurrence after treatment. Statistical analyses were conducted using the Kaplan-Meier method and Cox regression. Among 855 evaluable patients, 300 (35.1%) patients had any family history of prostate cancer, and 95 (11.1%) had a family history of related malignancies suggestive of a hereditary cancer syndrome. Family history of prostate cancer alone was not associated with biopsy progression, whereas family history suggestive of a hereditary cancer syndrome was associated with a significantly increased risk of biopsy progression (HR 1.43, 95%CI 1.01-2.02), independent of other known clinicopathological risk factors in multivariable analysis. Similarly, family history suggestive of a hereditary cancer syndrome was associated with significantly lower treatment-free survival (HR 1.58, 95%CI 1.14-2.18) in multivariable analysis. No significant association was found between family history and adverse features on surgical pathology or biochemical recurrence. An expanded family history suggestive of a hereditary cancer syndrome is an independent predictor of biopsy progression during active surveillance. Men with such a family history may still be offered active surveillance but should be counseled regarding the higher risk of disease progression.

Perfluoroalkyl substances exposure in firefighters: Sources and implications

Firefighters are at risk of occupational exposure to long-chain per- and poly-fluoroalkyl substances (PFASs), most notably from PFASs present in Class B aqueous film-forming foam (AFFF). Firefighters have been found to have elevated serum levels of long-chain PFASs. Due to the persistence of PFAS chemicals in the human body and their ability to bioaccumulate, firefighters experience the latent and cumulative effects of PFAS-containing AFFF exposure that occurs throughout their careers. This article summarizes the history of AFFF use by firefighters and current AFFF use practices. In addition, this paper describes PFAS levels in firefighter serum, PFAS serum removal pathways, PFAS exposure pathways, and occupational factors affecting PFAS levels in firefighters. International, national, and state agencies have concluded that PFOA, a long-chain PFAS, is potentially carcinogenic and that carcinogens have an additive effect. From the cancer types that may be associated with PFAS exposure, studies on cancer risk among firefighters have shown an elevated risk for thyroid, kidney, bladder, testicular, prostate, and colon cancer. Thus, exposure to PFAS-containing AFFF may contribute to firefighter cancer risk and warrants further research.

Biological Effects of Human Exposure to Environmental Cadmium

Cadmium (Cd) is a toxic metal for the human organism and for all ecosystems. Cd is naturally found at low levels; however, higher amounts of Cd in the environment result from human activities as it spreads into the air and water in the form of micropollutants as a consequence of industrial processes, pollution, waste incineration, and electronic waste recycling. The human body has a limited ability to respond to Cd exposure since the metal does not undergo metabolic degradation into less toxic species and is only poorly excreted. The extremely long biological half-life of Cd essentially makes it a cumulative toxin; chronic exposure causes harmful effects from the metal stored in the organs. The present paper considers exposure and potential health concerns due to environmental cadmium. Exposure to Cd compounds is primarily associated with an elevated risk of lung, kidney, prostate, and pancreatic cancer. Cd has also been linked to cancers of the breast, urinary system, and bladder. The multiple mechanisms of Cd-induced carcinogenesis include oxidative stress with the inhibition of antioxidant enzymes, the promotion of lipid peroxidation, and interference with DNA repair systems. Cd2+ can also replace essential metal ions, including redox-active ones. A total of 12 cancer types associated with specific genes coding for the Cd-metalloproteome were identified in this work. In addition, we summarize the proper treatments of Cd poisoning, based on the use of selected Cd detoxifying agents and chelators, and the potential for preventive approaches to counteract its chronic exposure.

HOGG1 rs1052133 Polymorphism and Prostate Cancer Risk: A Chinese Case-Control Study and Meta-Analysis.

BACKGROUND We performed a case-control study and an updated meta-analysis to assess the relationship between the hOGG1 rs1052133 polymorphism and prostate cancer (PCa) risk. MATERIAL AND METHODS We recruited 160 PCa cases and 243 healthy controls. For the meta-analysis, relevant studies were recruited from diverse databases up to April 2022. Genetic risk was evaluated by using an odds ratio (OR) with a corresponding 95% confidence interval (95% CI). The genotypes of this polymorphism were genotyped via the SNaPshot genotyping method. RESULTS In the case-control study, we failed to identify any association between the hOGG1 rs1052133 polymorphism and PCa risk. Negative results were also obtained when stratified analyses were performed based on the patient's prostatic-specific antigen (PSA) level and Gleason score, as well as tumor, node, and metastasis (TNM) stage. To enlarge the sample size, we performed a restricted updated meta-analysis by recruiting 10 case-control studies (including the current one), and the results suggested that genotypes of rs1052133 polymorphism were significantly associated with an elevated risk of PCa in 2 genetic models - the heterozygote and dominant models. In the stratification analysis by population ethnicity, a significant association of this polymorphism with susceptibility to PCa was found both in the Asian populations and White populations. CONCLUSIONS Our case-control and updated meta-analysis study suggest that the hOGG1 rs1052133 polymorphism is a susceptibility factor for PCa, but still needs to be further verified in the Chinese population.

Consumption of flavonoids and risk of hormone-related cancers: a systematic review and meta-analysis of observational studies

BackgroundFlavonoids seem to have hormone-like and anti-hormone properties so that the consumption of flavonoids may have potential effects on hormone-related cancers (HRCs), but the findings have been inconsistent so far. This meta-analysis was aimed to explore the association between flavonoids intake and HRCs risk among observational studies.MethodsQualified articles, published on PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) from January 1999 to March 2022 and focused on relationships between flavonoids (total, subclass of and individual flavonoids) and HRCs (breast, ovarian, endometrial, thyroid, prostate and testicular cancer), were retrieved for pooled analysis. Random effects models were performed to calculate the pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Funnel plots and Begg’s/Egger’s test were used to evaluate the publication bias. Subgroup analyses and sensitivity analyses were conducted to explore the origins of heterogeneity.ResultsAll included studies were rated as medium or high quality. Higher consumption of flavonols (OR = 0.85, 95% CI: 0.76–0.94), flavones (OR = 0.85, 95% CI: 0.77–0.95) and isoflavones (OR = 0.87, 95% CI: 0.82–0.92) was associated with a decreased risk of women-specific cancers (breast, ovarian and endometrial cancer), while the higher intake of total flavonoids was linked to a significantly elevated risk of prostate cancer (OR = 1.11, 95% CI: 1.02–1.21). A little evidence implied that thyroid cancer risk was augmented with the higher intake of flavones (OR = 1.24, 95% CI: 1.03–1.50) and flavanones (OR = 1.31, 95% CI: 1.09–1.57).ConclusionsThe present study suggests evidence that intake of total flavonoids, flavonols, flavones, flavanones, flavan-3-ols and isoflavones would be associated with a lower or higher risk of HRCs, which perhaps provides guidance for diet guidelines to a certain extent.Trial registrationThis protocol has been registered on PROSPERO with registration number CRD42020200720.

MP37-07 DOES VASECTOMY INDUCE SEMEN MICROBIOME DYSBIOSIS?

You have accessJournal of UrologyCME1 May 2022MP37-07 DOES VASECTOMY INDUCE SEMEN MICROBIOME DYSBIOSIS? Maria Camila Suarez, Joseph M. Israeli, Kajal Khodamoradi, and Ranjith Ramasamy Maria Camila SuarezMaria Camila Suarez More articles by this author , Joseph M. IsraeliJoseph M. Israeli More articles by this author , Kajal KhodamoradiKajal Khodamoradi More articles by this author , and Ranjith RamasamyRanjith Ramasamy More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002591.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Some observational studies have implied a link between vasectomy and an elevated risk of prostatitis and prostate cancer. Because inflammation within the semen could be a possible explanation, we hypothesized that vasectomy is a cause of dysbiosis in the seminal microbiota. We investigated the impact of vasectomy on semen microbiome, mainly using semen samples obtained from men before and after vasectomy. METHODS: Semen samples were obtained from men before and 3 months after vasectomy. To control external variables, vasectomies were performed by the same urologist. Microbial diagnosis (MicroGenDX laboratory in Lubbock, TX, USA) consisted of a rapid screening quantitative and qualitative real-time polymerase chain reaction test, followed by DNA pyrosequencing using 16S ribosomal RNA. Microorganism's specie, relative abundances and antimicrobial resistance were documented. Quantitative variables were analyzed with t-test. Beta-diversity among groups and paired-samples was calculated by Bray-Curtis dissimilarity. Relative abundance of 4 microorganism associated with prostatitis and prostate cancer was compared between groups. RESULTS: A total of 26 patients were included in the study and 119 bacteria were identified. The mean age at collection of the semen sample was 37 years old. No statistically significant differences were observed between the microbiota of semen samples obtained before and after vasectomy. The most frequent organisms and with the highest relative abundances by before and after vasectomy were Enterococcus faecalis, Corynebacterium tuberculostearicum and Staphylococcus epidermidis, respectively. Beta-diversity among groups and between paired sample was 0.29 and 0.22, respectively. The relative abundance of 4 bacteria that have been associated with prostatitis and prostate cancer was characterized (figure). Overall, 27% of the samples displayed antibiotic resistance, most commonly to aminoglycosides, and none of the groups exhibited a significant higher resistance (p=.4). CONCLUSIONS: Our data suggests that seminal microbiome does not change after vasectomy. The relative abundance of bacteria that have been associated to prostatitis and prostate cancer do not appear to be increased after vasectomy, suggesting that it remains a safe procedure and does not promote semen microbiota dysbiosis. Source of Funding: Los Padres Foundation © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e610 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Maria Camila Suarez More articles by this author Joseph M. Israeli More articles by this author Kajal Khodamoradi More articles by this author Ranjith Ramasamy More articles by this author Expand All Advertisement PDF DownloadLoading ...

Inherited risk assessment and its clinical utility for predicting prostate cancer from diagnostic prostate biopsies.

Many studies on prostate cancer (PCa) germline variants have been published in the last 15 years. This review critically assesses their clinical validity and explores their utility in prediction of PCa detection rates from prostate biopsy. An integrative review was performed to (1) critically synthesize findings on PCa germline studies from published papers since 2016, including risk-associated single nucleotide polymorphisms (SNPs), polygenic risk score methods such as genetic risk score (GRS), and rare pathogenic mutations (RPMs); (2) exemplify the findings in a large population-based cohort from the UK Biobank (UKB); (3) identify gaps for implementing inherited risk assessment in clinic based on experience from a healthcare system; (4) evaluate available GRS data on their clinical utility in predicting PCa detection rates from prostate biopsies; and (5) describe a prospective germline-based biopsy trial to address existing gaps. SNP-based GRS and RPMs in four genes (HOXB13, BRCA2, ATM, and CHEK2) were significantly and consistently associated with PCa risk in large well-designed studies. In the UKB, positive family history, RPMs in the four implicated genes, and a high GRS (>1.5) identified 8.12%, 1.61%, and 17.38% of men to be at elevated PCa risk, respectively, with hazard ratios of 1.84, 2.74, and 2.39, respectively. Additionally, the performance of GRS for predicting PCa detection rate on prostate biopsy was consistently supported in several retrospective analyses of transrectal ultrasound (TRUS)-biopsy cohorts. Prospective studies evaluating the performance of all three inherited measures in predicting PCa detection rate from contemporary multiparametric MRI (mpMRI)-based biopsy are lacking. A multicenter germline-based biopsy trial to address these gaps is warranted. The complementary performance of three inherited risk measures in PCa risk stratification is consistently supported. Their clinical utility in predicting PCa detection rate, if confirmed in prospective clinical trials, may improve current decision-making for prostate biopsy.

A Prospective Multicenter Comparison Study of Risk-adapted Ultrasound-directed and Magnetic Resonance Imaging–directed Diagnostic Pathways for Suspected Prostate Cancer in Biopsy-naïve Men

BackgroundEuropean Association of Urology guidelines recommend a risk-adjusted biopsy strategy for early detection of prostate cancer in biopsy-naïve men. It remains unclear which strategy is most effective. Therefore, we evaluated two risk assessment pathways commonly used in clinical practice. ObjectiveTo compare the diagnostic performance of a risk-based ultrasound (US)-directed pathway (Rotterdam Prostate Cancer Risk Calculator [RPCRC] #3; US volume assessment) and a magnetic resonance imaging (MRI)-directed pathway. Design, setting, and participantsThis was a prospective multicenter study (MR-PROPER) with 1:1 allocation among 21 centers (US arm in 11 centers, MRI arm in ten). Biopsy-naïve men with suspicion of prostate cancer (age ≥50 yr, prostate-specific antigen 3.0–50 ng/ml, ± abnormal digital rectal examination) were included. InterventionBiopsy-naïve men with elevated risk of prostate cancer, determined using RPCRC#3 in the US arm and Prostate Imaging Reporting and Data System scores of 3–5 in the MRI arm, underwent systematic biopsies (US arm) or targeted biopsies (MRI arm). Outcome measurements and statistical analysisThe primary outcome was the proportion of men with grade group (GG) ≥2 cancer. Secondary outcomes were the proportions of biopsies avoided and GG 1 cancers detected. Categorical (nonparametric) data were assessed using the Mann-Whitney U test and χ2 tests. Results and limitationsA total of 1965 men were included in the intention-to-treat population (US arm n = 950, MRI arm n = 1015). The US and MRI pathways detected GG ≥2 cancers equally well (235/950, 25% vs 239/1015, 24%; difference 1.2%, 95% confidence interval [CI] −2.6% to 5.0%; p = 0.5). The US pathway detected more GG 1 cancers than the MRI pathway (121/950, 13% vs 84/1015, 8.3%; difference 4.5%, 95% CI 1.8–7.2%; p < 0.01). The US pathway avoided fewer biopsies than the MRI pathway (403/950, 42% vs 559/1015, 55%; difference −13%, 95% CI −17% to −8.3%; p < 0.01). Among men with elevated risk, more GG ≥2 cancers were detected in the MRI group than in the US group (52% vs 43%; difference 9.2%, 95% CI 3.0–15%; p < 0.01). ConclusionsRisk-adapted US-directed and MRI-directed pathways detected GG ≥2 cancers equally well. The risk-adapted US-directed pathway performs well for prostate cancer diagnosis if prostate MRI capacity and expertise are not available. If prostate MRI availability is sufficient, risk assessment should preferably be performed using MRI, as this avoids more biopsies and detects fewer cases of GG 1 cancer. Patient summaryAmong men with suspected prostate cancer, relevant cancers were equally well detected by risk-based pathways using either ultrasound or magnetic resonance imaging (MRI) to guide biopsy of the prostate. If prostate MRI availability is sufficient, risk assessment should be performed with MRI to reduce unnecessary biopsies and detect fewer irrelevant cancers.

Genetic testing in prostate cancer management: Considerations informing primary care.

Inherited genetic mutations can significantly increase the risk for prostate cancer (PC), may be associated with aggressive disease and poorer outcomes, and can have hereditary cancer implications for men and their families. Germline genetic testing (hereditary cancer genetic testing) is now strongly recommended for patients with advanced/metastatic PC, particularly given the impact on targeted therapy selection or clinical trial options, with expanded National Comprehensive Cancer Network guidelines and endorsement from multiple professional societies. Furthermore, National Comprehensive Cancer Network guidelines recommend genetic testing for men with PC across the stage and risk spectrum and for unaffected men at high risk for PC based on family history to identify hereditary cancer risk. Primary care is a critical field in which providers evaluate men at an elevated risk for PC, men living with PC, and PC survivors for whom germline testing may be indicated. Therefore, there is a critical need to engage and educate primary care providers regarding the role of genetic testing and the impact of results on PC screening, treatment, and cascade testing for family members of affected men. This review highlights key aspects of genetic testing in PC, the role of clinicians, with a focus on primary care, the importance of obtaining a comprehensive family history, current germline testing guidelines, and the impact on precision PC care. With emerging evidence and guidelines, clinical pathways are needed to facilitate integrated genetic education, testing, and counseling services in appropriately selected patients. There is also a need for providers to understand the field of genetic counseling and how best to collaborate to enhance multidisciplinary patient care.

Per- and polyfluoroalkyl substances target and alter human prostate stem-progenitor cells

Per- and polyfluorinated alkyl substances (PFAS) are a large family of widely used synthetic chemicals that are environmentally and biologically persistent and present in most individuals. Chronic PFAS exposure have been linked to increased prostate cancer risk in occupational settings, however, underlying mechanisms have not been interrogated. Herein we examined exposure of normal human prostate stem-progenitor cells (SPCs) to 10 nM PFOA or PFOS using serial passage of prostasphere cultures. Exposure to either PFAS for 3–4 weeks increased spheroid numbers and size indicative of elevated stem cell self-renewal and progenitor cell proliferation. Transcriptome analysis using single-cell RNA sequencing (scRNA-seq) showed 1) SPC expression of PPARs and RXRs able to mediate PFAS effects, 2) the emergence of a new cell cluster of aberrantly differentiated luminal progenitor cells upon PFOS/PFOA exposure, and 3) enrichment of cancer-associated signaling pathways. Metabolomic analysis of PFAS-exposed prostaspheres revealed increased glycolytic pathways including the Warburg effect as well as strong enrichment of serine and glycine metabolism which may promote a pre-malignant SPC fate. Finally, growth of in vivo xenografts of tumorigenic RWPE-2 human prostate cells, shown to contain cancer stem-like cells, was markedly enhanced by daily PFOS feeding to nude mice hosts. Together, these findings are the first to identify human prostate SPCs as direct PFAS targets with resultant reprogrammed transcriptomes and metabolomes that augment a preneoplastic state and may contribute to an elevated prostate cancer risk with chronic exposures.

Cancer incidence in agricultural workers: Findings from an international consortium of agricultural cohort studies (AGRICOH).

Agricultural work can expose workers to potentially hazardous agents including known and suspected carcinogens. This study aimed to evaluate cancer incidence in male and female agricultural workers in an international consortium, AGRICOH, relative to their respective general populations. The analysis included eight cohorts that were linked to their respective cancer registries: France (AGRICAN: n=128,101), the US (AHS: n=51,165, MESA: n=2,177), Norway (CNAP: n=43,834), Australia (2 cohorts combined, Australian Pesticide Exposed Workers: n=12,215 and Victorian Grain Farmers: n=919), Republic of Korea (KMCC: n=8,432), and Denmark (SUS: n=1,899). For various cancer sites and all cancers combined, standardized incidence ratios (SIR) and 95% confidence intervals (CIs) were calculated for each cohort using national or regional rates as reference rates and were combined by random-effects meta-analysis. During nearly 2,800,000 person-years, a total of 23,188 cancers were observed. Elevated risks were observed for melanoma of the skin (number of cohorts=3, meta-SIR=1.18, CI: 1.01-1.38) and multiple myeloma (n=4, meta-SIR=1.27, CI: 1.04-1.54) in women and prostate cancer (n=6, meta-SIR=1.06, CI: 1.01-1.12), compared to the general population. In contrast, a deficit was observed for the incidence of several cancers, including cancers of the bladder, breast (female), colorectum, esophagus, larynx, lung, and pancreas and all cancers combined (n=7, meta-SIR for all cancers combined=0.83, 95% CI: 0.77-0.90). The direction of risk was largely consistent across cohorts although we observed large between-cohort variations in SIR for cancers of the liver and lung in men and women, and stomach, colorectum, and skin in men. The results suggest that agricultural workers have a lower risk of various cancers and an elevated risk of prostate cancer, multiple myeloma (female), and melanoma of skin (female) compared to the general population. Those differences and the between-cohort variations may be due to underlying differences in risk factors and warrant further investigation of agricultural exposures.

Family History of Breast Cancer Is Associated with Elevated Risk of Prostate Cancer: Evidence for Shared Genetic Risks

Introduction: Although breast and prostate cancers arise in different organs and are more frequent in the opposite sex, multiple studies have reported an association between their family history. Analysis of single nucleotide polymorphism data, based on distant relatives, has revealed a small positive genetic correlation between these cancers explained by common variants. The estimate of genetic correlation based on close relatives reveals the extent to which shared genetic risks are explained by both common and rare variants. This estimate is unknown for breast and prostate cancer. Method: We estimated the relative risks, heritability, and genetic correlation of breast cancer and prostate cancer based on the Minnesota Breast and Prostate Cancer Study, a family study of 141 families ascertained for breast cancer. Results: Heritability of breast cancer was 0.34 (95% credible interval: 0.23–0.49) and 0.65 (95% credible interval: 0.36–0.97) for prostate cancer, and the genetic correlation was 0.23. In terms of odds ratios, these values correspond to a 1.3 times higher odds of breast cancer among probands, given that the brother has prostate cancer. Conclusion: This study shows the inherent relation between prostate cancer and breast cancer; an incident of one in a family increases the risk of developing the other. The large difference between estimates of genetic correlation from distant and close relatives, if replicated, suggests that rare variants contribute to the shared genetic risk of breast and prostate cancer. However, the difference could stem from genotype-by-family effects shared between the two types of cancers.