Lifetime Risk Of Prostate Cancer Research Articles

Quality of Life of Prostate Cancer Patients Treated with Androgen Deprivation Therapy in Ain Shams University Hospital

Abstract Background Prostate cancer is the second most common cancer in men worldwide, according to data from the World Health Organization (WHO) GLOBOCAN Database. The current lifetime risk of prostate cancer for men living in the United States is estimated to be approximately one in eight. In Egypt according to GLOBOCAN number of new cases of prostate cancer 4767 (7.2%), while 5-syear survival 97.5%. Aim of the Work In this study, we aimed to evaluate the impact of treatment with Androgen Deprivation Therapy on quality of life for prostate cancer patient treated in Ain Shams University Hospital using a questionnaire from European organization of research and treatment -quality of life for cancer patient – prostate (PR 25) on prostate patient an Arabic index validated. Patients and Methods This Cross-sectional study was conducted at tertiary care hospital at Ain Shams University hospitals from August 2022 to February 2023 and performed on a total of 45 prostate cancer patients who attended the outpatient clinic at oncology department at Ain Shams University for hormonal therapy that were diagnosed before 2021. Results Our study results revealed that there was no statistically significant correlation between the quality-of-life (QOL) scores and both age of patient and duration of hormonal treatment. In correlation with the demographic characteristics, our study results revealed that the symptom scale score and Functional scale score showed no statistically significant differences with the medical, surgical history of the patient, history of chemotherapy and radiotherapy, ECOG and Metastasis. Conclusion The quality-of-life scores (QLQ-PR25) revealed that the mean symptom scale was 41.11 (SD ± 10.94) and the functional scale was 67.22 (SD ± 13.86) with no significant correlation with both age of patient and duration of hormonal treatment. However, the study was single arm and lack the control group which may underestimate the sexual and urinary changes or outcomes due to the intervention by ADT in patients with prostate cancer. Consequently, the present study can burden the knowledge and shed some light on future prospective studies with larger sample sizes and control group demonstrating the long-term outcomes of ADT in patients with prostate cancer regarding the HR-QOL.

How a population-based cohort of men estimate lifetime risk of prostate cancer in a survey before entering a prostate cancer screening trial in Sweden?

ObjectivesInvestigating men’s perceived lifetime risk of prostate cancer.DesignSurvey-based study to men invited for prostate-specific antigen (PSA) screening in the GÖTEBORG-2 trial between September 2015 and June 2020.Setting38 775 men in...

Impact of Family History and Germline Genetic Risk Single Nucleotide Polymorphisms on Long-Term Outcomes of Favorable-Risk Prostate Cancer.

Family history and germline genetic risk single nucleotide polymorphisms (SNPs) have been separately shown to stratify lifetime risk of prostate cancer. Here, we evaluate the combined prognostic value of family history of prostate and other related cancers and germline risk SNPs among patients with favorable-risk prostate cancer. A total of 1367 participants from the prospective Health Professionals Follow-up Study diagnosed with low- or favorable intermediate-risk prostate cancer from 1986 to 2017 underwent genome-wide SNP genotyping. Multivariable Cox regression was used to estimate the association between family history, specific germline risk variants, and a 269 SNP polygenic risk score with prostate cancer‒specific death. Family history of prostate, breast, and/or pancreatic cancer was observed in 489 (36%) participants. With median follow-up from diagnosis of 14.9 years, participants with favorable-risk prostate cancer with a positive family history had a significantly higher risk of prostate cancer‒specific death (HR 1.95, 95% CI 1.15-3.32, P = .014) compared to those without any family history. The rs2735839 (19q13) risk allele was associated with prostate cancer‒specific death (HR 1.81 per risk allele, 95% CI 1.04-3.17, P = .037), whereas the polygenic risk score was not. Combined family history and rs2735839 risk allele were each associated with an additive risk of prostate cancer‒specific death (HR 1.78 per risk factor, 95% CI 1.25-2.53, P = .001). Family history of prostate, breast, or pancreatic cancer and/or a 19q13 germline risk allele are associated with an elevated risk of prostate cancer‒specific death among favorable-risk patients. These findings have implications for how family history and germline genetic risk SNPs should be factored into clinical decision-making around favorable-risk prostate cancer.

Abstract 4801: Clinical polygenic model to stratify risk of any, metastatic, and fatal prostate cancer in a randomized controlled trial of precision screening

Abstract Introduction: Lifetime risk of prostate cancer (PCa) is strongly associated with three factors: ancestry, family history, and genetics. We previously developed a polygenic hazard score (PHS) for PCa comprised of 290 common genetic variants (PHS290). When accounting for family history and ancestry (self-reported or genetically determined), PHS290 remained a powerful independent predictor of age at PCa diagnosis, metastatic PCa diagnosis, and PCa death. Additional variants associated with PCa susceptibility or benign elevation of prostate-specific antigen (PSA) have since been published. Here, we evaluate their impact on lifetime risk predictions for metastatic and fatal PCa and develop an updated polygenic score. This score will inform the design of the Prostate Cancer, Genetic Risk, and Equitable Screening Study (ProGRESS, ClinicalTrials.gov ID NCT05926102), a nationwide randomized controlled trial evaluating precision PCa screening in the VA healthcare system. Methods: We utilized a machine learning approach to update the PHS. Over 450 variants associated with PCa, aggressive PCa, benign prostatic hyperplasia, or benign PSA elevation were evaluated for inclusion. First, we identified pairs of variants with highly correlated genotype (defined as R2 > 0.95) and utilized univariable Cox proportional hazards models (using age at diagnosis of PCa) to exclude one variant from each pair. We then evaluated all remaining candidate variants for inclusion in a new PHS using a LASSO-regularized Cox proportional hazards model. We combined the new PHS with clinical predictors (ancestry and family history) to create a comprehensive, quantitative polygenic score in a diverse, population-based cohort of n=590,750 (Million Veteran Program). Both self-reported and genetic ancestry (based on 2,309 ancestry informative markers) were assessed. We estimated hazard ratios (HRs) to compare men with high versus low polygenic score and evaluated absolute predictions of any, metastatic, and fatal PCa. Results: The updated polygenic score included 356 variants, as well as family history and genetic ancestry. When comparing the highest to the lowest quintile of the population for polygenic score, the HRs for any PCa, metastatic PCa, and fatal PCa were 5.6, 5.8, and 5.2 respectively. These HRs are all greater than those achieved with PHS290, which yielded 5.2, 4.9, and 4.4 respectively. Risk stratification improved within each ancestry group, including within the >100,000 participants of African ancestry—a group known to have elevated risk of fatal PCa. Absolute risk prediction was accurate for both metastatic and fatal PCa. Conclusion: The polygenic score accurately predicts risk of metastatic and fatal PCa in multiple ancestry groups. A clinical polygenic model has potential utility for precision PCa screening and will now be evaluated prospectively in the ProGRESS trial. Citation Format: Anna M. Dornisch, Roshan Karunamuni, Kara N. Maxwell, Julie Lynch, Isla P. Garraway, Adam Kibel, Charles A. Brunette, Morgan E. Danowski, Kyung M. Lee, Scott L. DuVall, J M. Gaziano, Brent S. Rose, Richard L. Hauger, Jason L. Vassy, Tyler M. Seibert. Clinical polygenic model to stratify risk of any, metastatic, and fatal prostate cancer in a randomized controlled trial of precision screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4801.

PSMA-targeted radiotheranostics in modern nuclear medicine: then, now, and what of the future?

In 1853, the perception of prostate cancer (PCa) as a rare ailment prevailed, was described by the eminent Londoner surgeon John Adams. Rapidly forward to 2018, the landscape dramatically altered. Currently, men face a one-in-nine lifetime risk of PCa, accentuated by improved diagnostic methods and an ageing population. With more than three million men in the United States alone grappling with this disease, the overall risk of succumbing to stands at one in 39. The intricate clinical and biological diversity of PCa poses serious challenges in terms of imaging, ongoing monitoring, and disease management. In the field of theranostics, diagnostic and therapeutic approaches that harmoniously merge targeted imaging with treatments are integrated. A pivotal player in this arena is radiotheranostics, employing radionuclides for both imaging and therapy, with prostate-specific membrane antigen (PSMA) at the forefront. Clinical milestones have been reached, including FDA- and/or EMA-approved PSMA-targeted radiodiagnostic agents, such as [18F]DCFPyL (PYLARIFY®, Lantheus Holdings), [18F]rhPSMA-7.3 (POSLUMA®, Blue Earth Diagnostics) and [68Ga]Ga-PSMA-11 (Locametz®, Novartis/ ILLUCCIX®, Telix Pharmaceuticals), as well as PSMA-targeted radiotherapeutic agents, such as [177Lu]Lu-PSMA-617 (Pluvicto®, Novartis). Concurrently, ligand-drug and immune therapies designed to target PSMA are being advanced through rigorous preclinical research and clinical trials. This review delves into the annals of PSMA-targeted radiotheranostics, exploring its historical evolution as a signature molecule in PCa management. We scrutinise its clinical ramifications, acknowledge its limitations, and peer into the avenues that need further exploration. In the crucible of scientific inquiry, we aim to illuminate the path toward a future where the enigma of PCa is deciphered and where its menace is met with precise and effective countermeasures. In the following sections, we discuss the intriguing terrain of PCa radiotheranostics through the lens of PSMA, with the fervent hope of advancing our understanding and enhancing clinical practice.

Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program.

Genetic scores may provide an objective measure of prostate cancer risk and thus inform screening decisions. We evaluated whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with prostate cancer risk in a diverse population, including Black men, who have higher average risk of prostate cancer death but are often treated as a homogeneously high-risk group. This was a retrospective analysis of the Million Veteran Program, a national, population-based cohort study of US military veterans conducted 2011-2021. Cox proportional hazards analyses tested for association of genetic and other risk factors (including self-reported race and ethnicity and family history) with age at death from prostate cancer, age at diagnosis of metastatic (nodal or distant) prostate cancer, and age at diagnosis of any prostate cancer. A total of 590 750 male participants were included. Median age at last follow-up was 69 years. PHS290 was associated with fatal prostate cancer in the full cohort and for each racial and ethnic group (P < .001). Comparing men in the highest 20% of PHS290 with those in the lowest 20% (based on percentiles from an independent training cohort), the hazard ratio for fatal prostate cancer was 4.42 (95% confidence interval = 3.91 to 5.02). When accounting for guideline-recommended risk factors (family history, race, and ethnicity), PHS290 remained a strong independent predictor of any, metastatic, and fatal prostate cancer. PHS290 stratified US veterans of diverse ancestry for lifetime risk of prostate cancer, including metastatic and fatal cancer. Predicting genetic risk of lethal prostate cancer with PHS290 might inform individualized decisions about prostate cancer screening.

MP43-10 IMPACT OF FAMILY HISTORY AND GERMLINE GENETIC RISK VARIANTS ON LONG-TERM OUTCOMES OF ACTIVE SURVEILLANCE-ELIGIBLE PROSTATE CANCER

You have accessJournal of UrologyCME1 May 2022MP43-10 IMPACT OF FAMILY HISTORY AND GERMLINE GENETIC RISK VARIANTS ON LONG-TERM OUTCOMES OF ACTIVE SURVEILLANCE-ELIGIBLE PROSTATE CANCER Florian Rumpf, Anna Plym, Jane Vaselkiv, Mark Preston, Adam Kibel, Lorelei Mucci, and Keyan Salari Florian RumpfFlorian Rumpf More articles by this author , Anna PlymAnna Plym More articles by this author , Jane VaselkivJane Vaselkiv More articles by this author , Mark PrestonMark Preston More articles by this author , Adam KibelAdam Kibel More articles by this author , Lorelei MucciLorelei Mucci More articles by this author , and Keyan SalariKeyan Salari More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002609.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: A family history of prostate cancer (PCa) and BRCA/DNA repair gene-associated cancers are risk factors for developing prostate cancer. In the last decade, >260 PCa-associated single nucleotide polymorphisms (SNPs) have been identified through large-scale genome-wide association studies that strongly stratify lifetime risk of prostate cancer. Few studies have examined the prognostic value of family history or PCa germline risk variants in patients with favorable-risk PCa eligible for active surveillance (AS). Here, we evaluate the impact of a positive family history and germline risk SNPs on outcomes on AS-eligible patients. METHODS: In a prospective cohort of 39,427 U.S. men in the Health Professionals Follow-up Study, 1,367 were diagnosed with clinically favorable-risk (NCCN very low-, low-, or favorable intermediate-risk) PCa from 1986 to 2016 and underwent genome-wide SNP genotyping. During the 30-year follow-up, 263 patients experienced disease recurrence and 52 patients died of PCa. A polygenic risk score was derived from 269 SNPs associated with development of PCa. Two loci associated with PCa survival were also assessed. Multivariable Cox proportional hazards models were used to estimate the association between family history of prostate, breast, or pancreatic cancer, germline risk SNPs, and PCa recurrence or death through 2019. RESULTS: The median follow up time from diagnosis was 14.1 years. A family history of prostate, breast, or pancreatic cancer was observed in 494 (36%) patients. Men with a positive family history had an 83% greater risk of PCa-specific death (95% CI 1.06-3.17, p=0.03), and greater than that of men with a family history of PCa alone. The polygenic risk score was not associated with either PCa recurrence or death. However, focusing on 2 loci on 8q24 and 19q13 with the strongest evidence in the literature for association with PCa aggressiveness, we observed a significant association between rs2735839 on 19q13 and PCa-specific death (HR 1.81, 95% CI 1.04-3.17, p=0.037). Using a risk score giving one point each to a positive family history and rs2735839 risk allele, each point of the heritable risk score was associated with a 72% increased risk of PCa-specific death (95% CI 1.16-2.54, p=0.006). CONCLUSIONS: Our study found that patients with AS-eligible PCa with a family history of prostate, breast, or pancreatic cancer or a 19q13 germline risk allele had elevated risks of PCa-specific death. These findings have implications for how germline genetic risk should be factored into AS selection criteria. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e744 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Florian Rumpf More articles by this author Anna Plym More articles by this author Jane Vaselkiv More articles by this author Mark Preston More articles by this author Adam Kibel More articles by this author Lorelei Mucci More articles by this author Keyan Salari More articles by this author Expand All Advertisement PDF DownloadLoading ...

Combined Effect of a Polygenic Risk Score and Rare Genetic Variants on Prostate Cancer Risk

Although prostate cancer is known to have a strong genetic basis and is influenced by both common and rare variants, the ability to investigate the combined effect of such genetic risk factors has been limited to date. We conducted an investigation of 81 094 men from the UK Biobank, including 3568 prostate cancer cases, to examine the combined effect of rare pathogenic/likely pathogenic/deleterious (P/LP/D) germline variants and common prostate cancer risk variants, measured using a polygenic risk score (PRS), on prostate cancer risk. The absolute risk of prostate cancer for HOXB13, BRCA2, ATM, and CHEK2 P/LP/D carriers ranged from 9% to 56%, and the absolute risk in noncarriers ranged from 2% to 31%, by age 85 yr, for men in the lowest and highest PRS decile, respectively. The high-penetrant HOXB13 G84E prostate cancer risk variant was most common in cases in the lowest PRS quintile (4.4%) and least common in cases in the highest PRS quintile (0.5%; p = 0.005), whereas there was no statistically significant difference in frequencies by PRS in controls. While rare and common variants strongly and distinctly influence prostate cancer onset, consideration of rare and common variants in conjunction will lead to more precise estimates of a man’s lifetime risk of prostate cancer. Patient summaryWe found that the risk of prostate cancer conveyed by rare variants could vary depending on an individual’s genetic profile of common risk variants. This implies that in order to comprehensively assess genetic risk of prostate cancer, it is important to consider both rare and common variants.

The effect of assessing genetic risk of prostate cancer on the use of PSA tests in primary care: A cluster randomized controlled trial.

BackgroundAssessing genetic lifetime risk for prostate cancer has been proposed as a means of risk stratification to identify those for whom prostate-specific antigen (PSA) testing is likely to be most valuable. This project aimed to test the effect of introducing a genetic test for lifetime risk of prostate cancer in general practice on future PSA testing.Methods and findingsWe performed a cluster randomized controlled trial with randomization at the level of general practices (73 in each of two arms) in the Central Region (Region Midtjylland) of Denmark. In intervention practices, men were offered a genetic test (based on genotyping of 33 risk-associated single nucleotide polymorphisms) in addition to the standard PSA test that informed them about lifetime genetic risk of prostate cancer and distinguished between “normal” and “high” risk. The primary outcome was the proportion of men having a repeated PSA test within 2 years. A multilevel logistic regression model was used to test the association.After applying the exclusion criteria, 3,558 men were recruited in intervention practices, with 1,235 (34.7%) receiving the genetic test, and 4,242 men were recruited in control practices. Men with high genetic risk had a higher propensity for repeated PSA testing within 2 years than men with normal genetic risk (odds ratio [OR] = 8.94, p < 0.01). The study was conducted in routine practice and had some selection bias, which is evidenced by the relatively large proportion of younger and higher income participants taking the genetic test.ConclusionsProviding general practitioners (GPs) with access to a genetic test to assess lifetime risk of prostate cancer did not reduce the overall number of future PSA tests. However, among men who had a genetic test, knowledge of genetic risk significantly influenced future PSA testing.Trial registrationThis study is registered with ClinicalTrials.gov, number NCT01739062.

Screening of BRCA2 mutated men for detection of prostate cancer: Preliminary results from a national high volume cancer center.

e16567 Background: Up to 10% of cases of Prostate Cancer (PCa) are hereditary. Germline pathogenic mutations in BRCA2 gene confer the highest risk (2.5 to 8.6 fold in men ≤ 65 yr). Beyond periodic Prostate Specific Antigen (PSA) dosage and digital rectal examination (DRE), a targeted screening for carriers is still undefined. Prostate Health Index (PHI), a combination of the tPSA, fPSA and proPSA tests, may be a more accurate biomarker than PSA only to detect PCa. We evaluated how to better screen BRCA2 mutated men for PCa. Methods: We reviewed the genealogical trees of all women tested positive for germline BRCA2 pathogenic mutation at our clinic. We offered targeted BRCA2 mutational analysis to all first/second degree relative men between 40 and 69 yr. A targeted screening program (annual PSA and PHI dosages and DRE) was proposed to all men tested positive. In case of PSA and/or PHI values out of range ( &gt; 4ng/ml and &gt; 20, respectively) we proceeded with a multiparametric Magnetic Resonance Imaging (mpMRI) and fusion biopsy of suspected lesions. Results: From June 2008 to October 2018 610 breast/ovarian cancer patients had BRCA test: 35 (5.7%) tested positive for BRCA1 pathogenic mutation, 32 (5.2%) for BRCA2 pathogenic mutation. From October 2017 90 relatives were checked for the familial mutation and 24 (27%) (12 women, 12 men) tested positive for BRCA2 mutation. All the 12 men (median age 48 yr, IQR 44 to 60) accepted to join our screening program. During the first year all men had negative DRE. Median PSA was 0.70 (IQR 0.43 to 1.02), median PHI was 17.56 (IQR 11.85 to 24.06). One patient with out of range PHI value already had mpMRI resulted negative. During the second year 4 men underwent screening so far: they had negative DRE. Median PSA was 0.57 (IQR 0.38-0.77), median PHI was 16.88 (IQR 11.87-21.90). Two men had PHI out of range and will undergo mpMRI. Conclusions: An accurate review of the genealogical trees of breast/ovarian cancer BRCA2 mutated patients allows to identify male relatives potentially carriers of the same mutation. These men have a high lifetime risk of PCa and require an appropriate screening, currently absent. Our approach may be leveraged as proof of concept of selection and screening program in carriers of BRCA2 mutations.

Lifetime risk of prostate cancer overdiagnosis in Australia: quantifying the risk of overdiagnosis associated with prostate cancer screening in Australia using a novel lifetime risk approach

ObjectivesTo quantify the risk of overdiagnosis associated with prostate cancer screening in Australia using a novel lifetime risk approach.DesignModelling and validation of the lifetime risk method using publicly available population...

Dynamic Patterns of Testosterone Levels in Individuals and Risk of Prostate Cancer among Hypogonadal Men: A Longitudinal Study

We investigated whether dynamic patterns of testosterone levels contribute to risk of prostate cancer. We used data on 376 untreated men with hypogonadism (testosterone 12.1 nmol/l or less) recruited from a urology office in Germany. Age at study entry served as a surrogate for age at the first detection of testosterone below 12.1 nmol/l. We derived 3 indicators, including the coefficient of variation, the ratio of the largest decline relative to the mean and the median of maximum declines, to measure the dynamic patterns of testosterone in an individual. Our findings suggest that the later that testosterone dropped below 12.1 nmol/l in a man, the less the lifetime risk of prostate cancer in that individual (HR 0.68, 95% CI 0.57-0.82). Further declines or dynamic variations of testosterone were associated with increased risk of prostate cancer (high vs low coefficient of variation HR 4.88, 95% CI 1.97-12.08, high vs low ratio of largest decline relative to mean HR 8.45, 95% CI 2.82-25.37 and high vs low median of maximum declines HR 2.70, 95% CI 1.15-6.35). To our knowledge this study is the first to provide evidence of the association between dynamic patterns of testosterone and prostate cancer development. This may have substantial clinical impacts on prostate cancer prevention.

The Association Between Vasectomy and Prostate Cancer

ImportanceDespite 3 decades of study, there remains ongoing debate regarding whether vasectomy is associated with prostate cancer.ObjectiveTo determine if vasectomy is associated with prostate cancer.Data SourcesThe MEDLINE, EMBASE, Web of Science, and Scopus databases were searched for studies indexed from database inception to March 21, 2017, without language restriction.Study SelectionCohort, case-control, and cross-sectional studies reporting relative effect estimates for the association between vasectomy and prostate cancer were included.Data Extraction and SynthesisTwo investigators performed study selection independently. Data were pooled separately by study design type using random-effects models. The Newcastle-Ottawa Scale was used to assess risk of bias. Main Outcomes and MeasuresThe primary outcome was any diagnosis of prostate cancer. Secondary outcomes were high-grade, advanced, and fatal prostate cancer.ResultsFifty-three studies (16 cohort studies including 2 563 519 participants, 33 case-control studies including 44 536 participants, and 4 cross-sectional studies including 12 098 221 participants) were included. Of these, 7 cohort studies (44%), 26 case-control studies (79%), and all 4 cross-sectional studies were deemed to have a moderate to high risk of bias. Among studies deemed to have a low risk of bias, a weak association was found among cohort studies (7 studies; adjusted rate ratio, 1.05; 95% CI, 1.02-1.09; P < .001; I2 = 9%) and a similar but nonsignificant association was found among case-control studies (6 studies; adjusted odds ratio, 1.06; 95% CI, 0.88-1.29; P = .54; I2 = 37%). Effect estimates were further from the null when studies with a moderate to high risk of bias were included. Associations between vasectomy and high-grade prostate cancer (6 studies; adjusted rate ratio, 1.03; 95% CI, 0.89-1.21; P = .67; I2 = 55%), advanced prostate cancer (6 studies; adjusted rate ratio, 1.08; 95% CI, 0.98-1.20; P = .11; I2 = 18%), and fatal prostate cancer (5 studies; adjusted rate ratio, 1.02; 95% CI, 0.92-1.14; P = .68; I2 = 26%) were not significant (all cohort studies). Based on these data, a 0.6% (95% CI, 0.3%-1.2%) absolute increase in lifetime risk of prostate cancer associated with vasectomy and a population-attributable fraction of 0.5% (95% CI, 0.2%-0.9%) were calculated.Conclusions and RelevanceThis review found no association between vasectomy and high-grade, advanced-stage, or fatal prostate cancer. There was a weak association between vasectomy and any prostate cancer that was closer to the null with increasingly robust study design. This association is unlikely to be causal and should not preclude the use of vasectomy as a long-term contraceptive option.

Elevated Risk of Prostate Cancer Among Men With Lynch Syndrome

Prostate cancer has been described as a component tumor of Lynch syndrome (LS), with tumors obtained from mutation carriers demonstrating the DNA mismatch repair deficiency phenotype. Previous studies quantifying prostate cancer risk in LS have provided conflicting results. We examined cancer histories of probands and their first- through fourth-degree relatives for 198 independent mutation-positive LS families enrolled in two US familial cancer registries. Modified segregation analysis was used to calculate age-specific cumulative risk or penetrance estimates, with accompanying Wald-type CIs. Cumulative lifetime risks and hazard ratio (HR) estimates for prostate cancer were calculated and compared with those of the general population. Ninety-seven cases of prostate cancer were observed in 4,127 men. Median age at prostate cancer diagnosis was 65 years (range, 38 to 89 years), with 11.53% of affected individuals diagnosed before age 50 years. The cumulative risk of prostate cancer at ages 60 and 80 years was 6.30% (95% CI, 2.47 to 9.96) and 30.0% (95% CI, 16.54 to 41.30), as compared with the population risk of 2.59% and 17.84%, respectively. The overall prostate cancer HR among carriers was 1.99 (95% CI, 1.31 to 3.03). The cumulative lifetime risk of prostate cancer in individuals with LS is two-fold higher than in the general population and is slightly higher in carriers diagnosed before age 60 years (HR, 2.48; 95% CI, 1.34 to 4.59). These estimates are clinically valuable to quantify risk for both patients and providers.

The G84E mutation in the HOXB13 gene is associated with an increased risk of prostate cancer in Poland

The G84E mutation in the HOXB13 gene has been associated with a high lifetime risk of prostate cancer in North America (about 20-fold). The geographical and ethnic extent of this recurrent allele has not yet been determined. We assayed for the presence of the G84E mutation in 3,515 prostate cancer patients and 2,604 controls from Poland and estimated the odds ratio for prostate cancer associated with the allele. The G84E mutation was detected in 3 of 2,604 (0.1%) individuals from the general population in Poland and in 20 of 3,515 (0.6%) men with prostate cancer (Odds ratio [OR] = 5.0; 95% CI: 1.5-16.7; P = 0.008). The allele was present in 4 of 416 (1.0%) men with familial prostate cancer (OR = 8.4, 95% CI: 1.9-37.7; P = 0.005). The G84E mutation predisposes to prostate cancer in Poland, but accounts for only a small proportion of cases. We expect that the G84E founder mutation might be present in other Slavic populations.

Role of lymphotoxin-a and interleukin-17A in human prostate cancer.

212 Background: Infiltrating immune cells have been implicated in prostate carcinogenesis. Murine studies suggest that B-cell-derived lymphotoxin (LT)a may be a key effector in the evolution to castrate-resistant prostate cancer (CRPC) (Ammirante et al, Nature 2011). Lymphotoxin a has also been implicated in the progression of murine fibrosarcoma, where it complements interleukin (IL)-17A, to synergistically enhance NFkB signaling. This interaction may also apply to human prostate cancer since IL-17-producing Th17 cells are abundant in these tumors. However, the role of LTα in human as distinct from murine prostate cancer remains unclear. Clinical validation is vital since murine models poorly recapitulate the behavior of prostate cancer in man. Methods: Serum levels of LTα and IL-17A were measured by ELISA in patients with benign (n=22) and malignant prostate disease (n=87). Samples were from 29 early prostate cancer patients (amenable to radical therapy), 28 with androgen-sensitive (AS) disease and 30 with CRPC. Data were not normally distributed and thus were analyzed by Mann-Whitney U test. Results: Serum LTαand IL-17A were significantly elevated in patients with both CRPC and early stage prostate cancer, compared to those with benign disease. LTαwas significantly raised in CRPC compared to AS disease. IL-17A was significantly higher in the early stage disease compared to AS prostate cancer. Conclusions: Based upon these data, we hypothesize that B-cell derived LTα synergises with Th17 derived IL-17A from the earliest stage of primary tumor development. In support of this, blockade of LTα in prostate cancer-prone (TRAMP) mice delays primary tumor onset and inhibits metastasis. Furthermore, NSAIDs protect more strongly against lifetime risk of prostate cancer in those individuals with an LTα over-producer polymorphism. Prostate cancer preferentially metastasizes to local lymph nodes and bone – sites at which mature B-cells are plentiful. Consequently, tumor-trophic effects of LTα would become increasingly efficient with disease progression. Our data are incompatible with and thus refute the clinical relevance of a role for androgen ablation in promoting LTα-driven CRPC.

Prostate cancer screening based on genotyping for high risk founder alleles

Inherited factors contribute to the lifetime risk of prostate cancer. These factors include a positive family history of cancer and a mutation in one of several prostate cancer susceptibility genes, A number of genome-wide association studies (GWAS) have identified over a number of single nucleotide polymorphisms that have been confirmed to be associated with prostate cancer risk We evaluated whether or not genotyping of 18 different prostate cancer founder alleles in the Polish population is helpful in identifying high-risk individuals and for determining optimal screening regimens. A serum PSA level was measured and a digital rectal examination was performed on 2907 unaffected men aged 40-90. All men were genotyped for three founder alleles in BRCA1 (5382insC, 4153delA, C61G), four alleles in CHEK2 (1100delC, IVS2+1G>A, del5395, I157T), one allele in NBS1 (657del5), one allele in HOXB13 (G84E), and for nine SNPs which have previously been shown to be associated with prostate cancer risk. A founder mutation in CHEK2 (I157T) predicted prostate cancer in unscreened men.

Current prospects for the chemoprevention of prostate cancer

AbstractUnlike other areas of medicine, such as cardiology and diabetology, urology has often been slow to embrace strategies for risk reduction. Currently, urologists prefer to treat the disease at the stage they encounter it, rather than approaching the problem with a preventative frame of mind. However, a recent publication evaluating the effect of dutasteride on prostate cancer calls this view into question. The current lifetime risk of prostate cancer in the USA is estimated at 16.7 per cent. As the disease is both extremely common and generally slow to progress, potentially it provides a prime target for chemoprevention.

CURRENT PROSPECTS FOR THE CHEMOPREVENTION OF PROSTATE CANCER

Unlike other areas of medicine, such as cardiology and diabetology, urology has often been slow to embrace strategies for risk reduction. Currently, urologists prefer to treat the disease at the stage they encounter it, rather than approaching the problem with a preventative frame of mind. However, a recent publication evaluating the effect of dutasteride on prostate cancer calls this view into question. The current lifetime risk of prostate cancer in the USA is estimated at 16.7 per cent. As the disease is both extremely common and generally slow to progress, potentially it provides a prime target for chemoprevention.

Chemoprevention of prostate cancer: lessons learned

A challenge to the prevention of prostate cancer is its fundamental basis; a man who is disease-free must take an agent that might have side-effects to reduce his risk of disease. Although the lifetime risk of prostate cancer in the USA is 18% [3], the converse is that the use of preventive agents in the USA is unnecessary in at least 82% of men. With this in mind, before the PCPT it was not certain whether chemoprevention studies could be completed, given that a healthy, asymptomatic population was required to be enrolled. Other challenges include the need for regular dosing, regular follow-up, and even prostate biopsy in some designs. Despite these challenges, three phase III studies and one relatively large phase IIB study were successfully completed, i.e. the PCPT (finasteride) [4], the REDUCE trial (dutasteride) [5], the SELECT trial (selenium, α -tocopherol) [6] and the GTX-006-211 (toremifene) [7].