Risk Of PCa Research Articles

Prostate volume index and prostatic chronic inflammation predicted low tumor load in 945 patients at baseline prostate biopsy.

To assess associations of prostate volume index (PVI), defined as the ratio of the volume of the central transition zone to the volume of the peripheral zone of the prostate and prostatic chronic inflammation (PCI) as predictors of tumor load by number of positive cores (PC) in patients undergoing baseline random biopsies. Parameters evaluated included age, PSA, total prostate volume, PSA density, digital rectal exam, PVI, and PCI. All patients underwent standard transperineal random biopsies. Tumor load was evaluated as absent (no PC), limited (1-3 PC), and extensive (more than 3 PC). The association of factors with the risk of tumor load was evaluated by the multinomial logistic regression model. The study evaluated 945 patients. Cancer PC were detected in 477 (507%) cases of whom 207 (43.4%) had limited tumor load and 270 (56.6%) had extensive tumor load. Among other factors, comparing patients with limited tumor load with negative cases, PVI [odds ratio, OR = 0.521, 95% confidence interval (CI) 0.330-0.824; p < 0.005] and PCI (OR = 0.289, 95% CI 0.180-0.466; p < 0.0001) were inversely associated with the PCA risk. Comparing patients with extensive tumor load with negative patients, PVI (OR = 0.579, 95% CI 0.356-0.944; p = 0.028), and PCI (OR = 0.150, 95% CI 0.085-0.265; p < 0.0001), predicted PCA risk. Comparing extensive tumor load with limited tumor load patients, PVI and PCI did not show any association with the tumor load. Increased PVI and the presence of PCI decreased the risk of increased tumor load and associated with less aggressive prostate cancer biology in patients at baseline random biopsies.

Germline Genetics of Prostate Cancer: Time to Incorporate Genetics into Early Detection Tools.

Prostate cancer (PCa) remains the most common solid malignancy in men, and its prevalence makes understanding its heritability of paramount importance. To date, the most common factors used to estimate a man's risk of developing PCa are age, race, and family history. Despite recent advances in its utility in multiple malignancies (e.g., breast and colon cancer), genetic testing is still relatively underutilized in PCa. Multiple highly penetrant genes (HPGs) and single-nucleotide polymorphisms (SNPs) have been show to increase a patient's risk of developing PCa. Mutations in the former, like DNA damage repair genes, can confer a 2- to 3-fold increased risk of developing PCa and can increase the risk of aggressive disease. Similarly, PCa-risk SNPs can be used to create risk scores (e.g., genetic or polygenic risk scores) that can be used to further stratify an individual's disease susceptibility. Specifically, these genetic risk scores can provide more specific estimates of a man's lifetime risk ranging up to >6-fold higher risk of PCa. It is becoming increasingly evident that in addition to the standard family history and race information, it is necessary to obtain genetic testing (including an assessment of HPG mutation status and genetic risk score) to provide a full risk assessment. The additional information derived thereby will improve current practices in PCa screening by risk-stratifying patients before initial prostate-specific antigen testing, determining a patient's frequency of visits, and even help identify potentially at-risk family members.

Genetic profiling in the diagnosis of hereditary prostate cancer: Where do we stand?

Prostate cancer has a heterogeneous genetic profile compared with other tumour entities. Accordingly, there are also various mutations that increase the risk of prostate cancer. Some genetic variants only have a mild impact, whereas other gene mutations (BRCA1 /2; HOXB13) may increase the risk significantly. All in all, a man with a negative family history is unlikely to be a carrier of mutations that are associated with an increased risk of PCa. However, this likelihood increases if the family history is positive for a known mutation or if there are relatives who were affected at an early age. In such cases, genetic counselling and testing should be considered, with a particular focus on BRCA1/2 mutations and HOXB13 mutations. However, genetic profiling has not had the potential to replace PSA testing, mpMRI of the prostate gland and/or prostate biopsies as part of cancer screening or the diagnostic algorithm in the general population. The presence of mutations associated with PCa merely allows patients to undergo screening earlier and in tighter intervals and possibly receive earlier definitive treatment.

CAV1 polymorphisms rs1049334, rs1049337, rs7804372 might be the potential risk in tumorigenicity of urinary cancer: A systematic review and meta-analysis

Background As an integral membrane, Caveolin-1 (CAV1), is a pivotal component to make up the caveolae protein. It has been demonstrated to influence tumorigenicity, including bladder, colon, liver, stomach, breast and lung cancer. Several publications had illustrated the relationship of between CAV1 polymorphism and urinary cancer, but the results were not consistent. We performed a comprehensive meta-analysis to explore the associations and remove the fog.Material and methods Extensive retrieve was performed in PubMed, Embase, Medline, Web of Science, CNKI, and Wanfang database up to September, 2018. Odds ratios (ORs) and 95% confidence intervals (CIs) were conducted to evaluate the overall strength of the associations in five genetic models, as well as in subgroup analyses, stratified by ethnicity, cancer type or source of control. Q-test, Egger’s test and Begg’s funnel plot were applied to evaluate the heterogeneity and publication bias. In-silico analysis was managed to demonstrate the relationship of polymorphism and CAV1 mRNA expression level.Results 34 case-control studies with a total of 13,778 cancer cases and 20,581 healthy controls were enrolled into the meta-analysis. The polled result shown that an increased risk of rs1049334 polymorphism on urinary cancer were reveled in homozygote comparison model (MM vs. WW: OR = 1.240, 95% CI = 1.052–1.462, P = 0.011) and recessive comparison model (MM vs. MW + WW: OR = 1.198, 95% CI = 1.018–1.410, P = 0.030). What’s more, rs17878467 polymorphism may play a protect role in the tumorigenesis of urinary cancer, shown in heterozygote comparison model (MW vs. WW: OR = 0.882, 95% CI = 0.78–0.999, P = 0.048). For rs7804372, the overall pooled results revealed a reducing risk in allelic contrast model (M vs. W: OR = 0.734, 95%CI = 0.544-0.99, P = 0.043), homozygote comparison model (MM vs. WW: OR = 0.532, 95% CI = 0.313–0.905, P = 0.020) and recessive comparison model (MM vs. MW + WW: OR = 0.580, 95% CI = 0.437–0.77, P < 0.001). In the stratified analyses by cancer types, the risk of PCa is downgrade by rs7804372 in all five genetic models. The GTEx in-silico analysis index that the polymorphism of CAV1 influence its mRNA expression by a dose-dependent effective of its mutant allele.Conclusion rs1049334 polymorphismof CAV1 upgrade the risk of urinary cancer, while rs1049337 and rs7804372 polymorphisms may act as a protector of urinary cancer. Further large and well-designed studies in various populations are needed to confirm the results.

Comparing diagnostic and prognostic performance of two-gene promoter methylation panels in tissue biopsies and urines of prostate cancer patients

BackgroundProstate cancer (PCa) is one of the most common cancers among men worldwide. Current screening methods for PCa display limited sensitivity and specificity, not stratifying for disease aggressiveness. Hence, development and validation of new molecular markers is needed. Aberrant gene promoter methylation is common in PCa and has shown promise as clinical biomarker. Herein, we assessed and compared the diagnostic and prognostic performance of two-gene panel promoter methylation in the same sample sets.MethodsPromoter methylation of panel #1 (singleplex-miR-34b/c and miR-193b) and panel #2 (multiplex-APC, GSTP1, and RARβ2) was evaluated using MethyLight methodology in two different cohorts [prostate biopsy (#1) and urine sediment (#2)]. Biomarkers’ diagnostic (validity estimates) and prognostic (disease-specific survival, disease-free survival, and progression-free survival) performance was assessed.ResultsPromoter methylation levels of both panels showed the highest levels in PCa samples in both cohorts. In tissue samples, methylation panel #1 and panel #2 detected PCa with AUC of 0.9775 and 1.0, respectively, whereas in urine samples, panel #2 demonstrated superior performance although a combination of miR-34b/c, miR-193b, APC, and RARβ2 disclosed the best results (AUC = 0.9817). Furthermore, higher mir-34b/c and panel #2 methylation independently predicted for shorter DSS. Furthermore, time-dependent ROC curves showed that both miR-34b/c and GSTP1 methylation levels identify with impressive performance patients that relapse up to 15 years after diagnosis (AUC = 0.751 and AUC = 0.765, respectively).ConclusionsWe concluded that quantitative gene panel promoter methylation might be a clinically useful tool for PCa non-invasive detection and risk stratification for disease aggressiveness in both tissue biopsies and urines.

Tumor Gene Expression Profiling in Prostate Cancer (PCa) Identifies Molecular Taxonomies Associated with Node Positivity and Quantitative Imaging Features on Multiparametric MRI (mpMRI)

Genomic classifiers based on tumor gene expression add to the predictive power of clinicopathologic features in contemporary PCa risk stratification. Increasingly, mpMRI is utilized to identify occult high grade disease as well as to aid in pre-treatment staging of localized disease. We undertook a study to examine the association of tumor gene expression profiles following radical prostatectomy (RP) with radiographic features on pre-prostatectomy mpMRI. We queried an institutional review board-approved research registry of PCa patients who had preoperative 3T mpMRI followed by post-prostatectomy tumor molecular testing performed in the course of clinical care. Genomic testing was not geographically matched to mpMRI detected lesions. Our analysis focused on correlative findings between clinical information, a genomic classifier score, and MRI features. Statistical software was used for statistical modeling of associations between gene signatures, clinicopathologic variables and imaging characteristics. Forty-eight patients met criteria for this analysis. Median age was 67 years (range 45-78) and average pre-op PSA was 11.72. Pathologic findings after RP were: 28 (58%) Gleason Score (GS) 7 (17 were 3+4, 11 were 4+3), 5 (10%) GS 8, 15 (31%) GS 9, 42 (87.5%) had EPE, 15 (31.3%) had SVI, 30 (62.5%) had positive surgical margins (SM), and 13 (27%) were node positive. A majority of patients had pre-op PI-RADS 5 lesions (n=38) detected on mpMRI. No patients had clinically or radiographically suspicious lymph nodes prior to RP. The number of patients with Decipher low, intermediate, and high risk scores were 11 (23%), 11 (23%), and 26 (54%), respectively. Non-parametric testing demonstrated a significant association between Decipher score and PI-RADS score on mpMRI (Kruskal-Wallis Test, p<0.050). Similarly, mean apparent diffusion coefficients (ADC) were directly correlated with Decipher score (Kruskal-Wallis Test, p<0.05). mpMRI features alone did not correlate with positive SM and accounting for Decipher score in univariate or multivariate models did not improve the ability of mpMRI features to predict SM status. Higher post-operative decipher score was, however, associated with likelihood of pathologic node positivity (ANOVA p=0.009). A significant correlation was observed between Decipher scores and PI-RADS classification as well as mean tumor ADC values on mpMRI. A high risk Decipher score was associated with higher rates of pathologic LN positivity otherwise undetected on mpMRI. These data support further validation of genomic classifiers in combination with mpMRI for risk stratifying PCa patients.

The effect of 3-month finasteride challenge on biomarkers for predicting cancer outcome on biopsy: Results of a randomized trial.

BackgroundFinasteride, a 5-alpha reductase inhibitor may have effects on biomarkers such as prostate-specific antigen (PSA) that could be leveraged to improve screening.ObjectiveTo determine the predictive characteristics of biomarkers for prostate cancer for cancer on biopsy following 3 months of finasteride use compared with placebo.Design, setting and participants383 men from multiple clinical sites with intermediate prostate cancer risk, without history of prostate cancer, were randomly allocated in a double-blinded manner, 4:1, to receive either finasteride or placebo for 90 days at which time a prostate biopsy was performed.Outcome measurements and statistical analysisThe primary outcomes were associations of biomarkers with prostate cancer that were tested using multiple logistic regression and area under the receiver operating curves (AUC). Biomarkers for PCA risk (PCA3, TMPRSS2:ERG (T2:ERG) gene product, and PSA) were measured at baseline and at biopsy in a blinded fashion to assess the predictive performance of baseline levels, 90-day levels, and measures of change relative to standard predictors.Results and limitationsA total of 292 (233 finasteride; 59 placebo) randomized patients underwent biopsy and were analyzed. On finasteride, baseline and 90-day measures of PCA3 and T2:ERG had similar moderate discrimination capacity with AUCs 62 to 65% (p-values < 0.001 and 0.001, respectively), but their rates of change had no discrimination ability (AUC 51%, (95% CI 43 to 60% p = 0.72) and 48% (95% CI 44 to 60%, p = 0.62), respectively).) Relative to baseline, the 90-day PCA3 and PSA decreased in the finasteride group by 25% and 50%, respectively (both p<0.001). T2:ERG had a smaller, non-significant change post finasteride treatment (p = 0.08).ConclusionsShort-term finasteride therapy did not improve performance of the most commonly-employed prostate cancer biomarkers. Threshold values for new biomarkers of prostate cancer should be interpreted with caution in patients receiving finasteride until formal validation of test performance in these patients is conducted.Patient summaryThree months of finasteride treatment did not increase the accuracy for predicting the outcome on prostate biopsy but did have a significant effect on biomarker values. Adjustments to thresholds for biopsy for men on finasteride are proposed.Trial registrationClinicalTrials.gov, NCT01296672.

Abstract IA08: Early detection of high-risk localized prostate cancer

Abstract Despite prostate cancer being the second leading cause of cancer death amongst U.S. men and prevalent use of serum prostate specific antigen (PSA) as an FDA-approved biomarker, PCa screening and early detection is highly controversial. Widespread PSA screening and prostate biopsy led to a profound stage migration, with the majority of newly diagnosed cases being clinically localized and low grade. Thus PSA-screening programs, typically using a threshold of 4.0ng/mL for biopsy referral, result in substantial overdiagnosis, estimated at 15-84%. Additionally, although active surveillance (AS) is an emerging management option for men with presumed indolent, low-grade (Gleason score 6, grade group I) PCa, most U.S. men with such disease still undergo curative treatment via radical prostatectomy (RP) or radiation therapy (RT), which have well-documented side effects that substantially impact quality of life. Hence, serum PSA-based screening has also led to PCa overtreatment, where screening-detected tumors that never would have caused clinical symptoms are treated definitively. Lastly, as a result of PSA screening, an estimated ~1,000,000 prostate biopsies are performed annually, which are associated with infection requiring antibiotics in ~6% of patients and hospitalization in ~1% of biopsied patients. Despite appeals to lower the commonly used cutoff for biopsy in the U.S. or the development of multivariate models that incorporate PSA and other clinical factors to provide individualized PCa risk estimates, PSA is still commonly used as a dichotomous test, with referral for biopsy if PSA is &amp;gt; 4.0ng/mL. Several modifications of serum PSA, including free PSA, PSA velocity, various PSA isoforms, and related proteins including KLK2, have been proposed as biomarkers and show clinical utility to further define an individual’s risk for PCa. More recently, urine-based biomarkers, such as the long noncoding RNA (lncRNA) transcript PCA3, as well as germline single-nucleotide polymorphisms (SNPs) that are associated with increased PCa risk, have also been proposed as biomarkers. Likewise, advances in multiparametric MRI are also enabling the noninvasive detection and targeted biopsy of prostate cancer. Lastly, numerous tissue-based prognostic assays are available to identify undersampled or unsampled aggressive prostate cancer from diagnostic material. Here, I will review the underlying challenges inherent in the early detection of aggressive, high-risk localized prostate cancer, focusing on both the high prevalence of disease as well as multifocality. In addition, I will review the clinical utility of available approaches, as well as implementation issues. Importantly, enormous advances have been made in our understanding of the prostate cancer genome and transcriptome, which have been incompletely leveraged in early detection strategies. These findings will be discussed in the context of improved detection of high-risk localized prostate cancer, which has the potential to dramatically impact the lives of millions of U.S. men. Citation Format: Scott A. Tomlins. Early detection of high-risk localized prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr IA08.

Human methionine synthase A2756G polymorphism increases susceptibility to prostate cancer.

Background/Aims: Previous results on the association between MTR gene A2756G polymorphism and PCa risk are inconclusive.Methods: We used odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) to evaluate the correlation between MTR A2756G polymorphism and risk of PCa in meta-analysis. Serum expression of MTR was detected by ELISA and in-silico tools were utilized to assess this variant.Results: Our study included 2,921 PCa patients and 3,095 control subjects. The results indicated that the MTR A2756G polymorphism is linked with an increased risk of PCa using three genetic models (G-allele vs. A-allele: OR = 1.16, 95%CI = 1.04 - 1.30; GA vs. AA: OR = 1.17, 95%CI = 1.02 - 1.33; GG+GA vs. AA: OR = 1.18, 95%CI = 1.04 - 1.34). Stratified analysis produced similar results. A significant association was also indicated in advanced PCa from the meta-analysis. Finally, our experiments showed evidence that serum MTR levels in PCa patients with AA genotypes were statistically higher than in those with GG/GA genotypes.Conclusions: Our present study suggests that the MTR A2756G polymorphism may contribute to the risk of developing PCa, particularly in Asian and hospital-based studies. Moreover, serum MTR might be utilized in diagnosis of PCa.

PO-060 Association between RS10993994 polymorphism in MSMB gene with early-onset prostate cancer in mexican men

IntroductionProstate cancer (PCa) is a public health problem worldwide, which has been related to sexually transmitted infections (STIs). The risk allele (T) of rs10993994 (C>T) polymorphism in the MSMB gene encodes for a prostate secretory protein of 94 amino acids (PSP94), conferring susceptibility to STIs development. This allele has also been associated with an increment (~35%) of PCa risk. Nonetheless, the genetic contribution of this polymorphism has not been evaluated in the Mexican men yet as well as neither whether the STIs history modifies this association.Material and methodsSocio-demographic characteristics, sexual, and reproductive history of incident PCa cases (n=322) and 628 healthy population controls matched by age (±5 years) were analysed as well as the genotyping of rs10993994 polymorphism in Mexico City males. Unconditional logistic regression models were used to estimate the odds ratios for PCa, PCa aggressiveness and age of onset. The interaction between STI history and MSMB polymorphism were evaluated including an interaction term between both variables.Results and discussionsNo frequency differences were found between cases and controls. Nevertheless, when adjusting by age, PCa family history in first-degree relatives, residence place and the STIs history were done, TT genotype carriers had almost three-fold higher odds (OR 2.61; IC 95% 1.06, 6.44; p=0.04) of early-onset PCa (age at diagnosis <60 years). No interaction between STIs history and rs10993994 with early-onset PCa (OR 1.78; IC 95% 0.27, 11.92; p=0.55) was observed.ConclusionTo our knowledge, this is the first study that explores the role of rs10993994 as a risk factor for PCa in Mexican men. Our findings are partially consistent with a previous study that reported association between T allele in MSMB gene and early-onset PCa. Because all STIs were considered together, we do not reject a possible interaction between a specific STI (mainly fungal aetiology) and rs10993994 polymorphism.

223 Impact of time from diagnosis to treatment on erectile function outcomes after radical prostatectomy

To test the impact of time from diagnosis to treatment on erectile function (EF) outcomes after radical prostatectomy (RP). Data were available for 827 patients submitted to RP at a single academic center in 2002-2017. Time from diagnosis to treatment was defined as the interval between biopsy and RP. Preoperative risk-groups were defined according to the D’Amico’s risk. EF after surgery was assessed with the International Index of Erectile Function-EF domain (IIEF-EF) (EF recovery defined as an IIEF-EF>=22). Cox regression analyses tested the impact of time-to-surgery on the probability of post-RP EF recovery. Kaplan-Meier analysis compared the cumulative incidence of EF recovery according to times from diagnosis to RP. As a second aim, the impact of time-to-surgery on EF outcomes was tested in a sub-cohort of patients eligible for active surveillance (AS). Overall, 306 (37%), 422 (51%) and 99 (12%) patients were diagnosed with low, intermediate and high risk PCa, respectively. Of all, 148 (17.9%) were eligible for AS but eventually preferred surgical treatment. Patients were surgically treated at a median (IQR) time of 3.5 (2.1,5.5) months from biopsy; a total of 152 (18%) and 22 (2.7%) patients were treated after 6 and 12 months from biopsy. Median (IQR) follow-up was 24 (12,48) months. The overall probability of EF recovery was 32% (95%CI: 29-36) at 24 months post-RP. At Cox-regression analysis, time from biopsy to surgery was not associated with the chance of post-RP EF recovery (HR:1.01; p=0.6) after accounting for age, baseline IIEF-EF, comorbidities, type of surgery (open vs. robotic) and PCa risk category. At Kaplan-Meier analysis, the cumulative incidence of EF recovery after RP did not differ among patients treated within 6, from 6 to 12 and after 12 months from biopsy (p=0.3). Similar results were obtained in the sub-cohort of patients eligible for AS.

Mono Institutional Retrospective Analysis of Local Relapse after Brachytherapy Ldr with Seeds Implantation in Prostate Cancer

We retrospectively analyzed the clinical records of 510 consecutive patients with diagnosis of low-intermediate risk of PCa, according to NCCN risk group and ASTRO-EAU- EORTC guidelines treated from Sept 1999 to Dec 2016 with I 125 BT LDR as monotherapy, using a real time approach at our Institution. As the nadir PSA value is a time-dependent variable, a landmark analysis method was used, and this demonstrated that lower nadir values at 3 years (fixed time point) after BT translated into improved long-term biochemical outcomes.

Carbohydrate intake and the risk of prostate cancer

BackgroundProstate cancer (PCa) is one of the leading cause cancer among men worldwide. Many epidemiologic studies have reported an association between carbohydrate intake and PCa. However, the evidence from epidemiologic studies is inconsistent. We conducted a comprehensive meta-analysis to explore the associations between carbohydrate intake and PCa risk and to investigate potential dose–response relationships. MethodsWe searched PubMed and EMBASE for studies published from 1980 to 2018. 21 studies were included with 98,739 participants and 11,573 cases. Multivariate-adjusted odds ratios (ORs) were pooled using random-effect models. Potential dose–response relationships were evaluated for PCa risk. ResultsWe did not detect an association about higher carbohydrate intake and PCa risk (OR:1.11, 95% confidence interval [CI]: 0.98–1. 26, I2 = 62.7%), nor association was detected about higher carbohydrate intake with advanced PCa risk (OR:0.95, 95% CI: 0.78–1.16, I2 = 14.1%) or non-advanced Pca risk (OR:1.01, 95% CI: 0.79–1.29, I2 = 64.4%). There was not a significant dose–response association observed for carbohydrate intake with PCa risk and advanced PCa risk. ConclusionsOur meta-analysis shows no association between carbohydrate intake and prostate cancer risk. Nor is association detected about carbohydrate intake with advanced or non-advanced Pca risk. More studies are needed for a further dose-response meta-analysis.

Family history of breast cancer increases the risk of prostate cancer: results from the EPICAP study.

IntroductionFamilial aggregation is now well established with an increased risk of prostate cancer in patients with a family history of prostate cancer in first degree relatives. The aim of this paper was to investigate the role of family history of cancer in first degree relatives in prostate cancer risk.ResultsAs expected, a family history of prostate cancer in first-degree relatives was more frequent in cases than in controls (OR 3.10, 95% CI 2.32–4.15). A family history of early BCa (before age 50) in first-degree relatives was more frequent in cases than in controls (OR 1.79, 95% CI 1.09–2.94) with higher risk of aggressive PCa. The association was more pronounced for BCa in daughters (OR 15.26 95% CI 1.95–120).ConclusionsIn summary, a family history of BCa in first degree relatives before age 50 may increases the risk of PCa with higher Gleason score. This finding could suggest a specific prostate surveillance and/or genetic counselling for men who present such familial history.MethodsEPIdemiological study of Prostate CAncer (EPICAP) is a population-based case-control study specifically designed to investigate the role of environmental and genetic factors in prostate cancer. Detailed information on family history of cancer in first degree relatives (parents, brothers and sisters, children) was collected as well as the age of occurrence and the localization of each cancer. Overall, 819 cases and 879 controls have been included.

A case-control study of lower urinary-tract infections, associated antibiotics and the risk of developing prostate cancer using PCBaSe 3.0.

ObjectivesTo investigate the association between lower urinary-tract infections, their associated antibiotics and the subsequent risk of developing PCa.Subjects/Patients (or materials) and methodsUsing data from the Swedish PCBaSe 3.0, we performed a matched case-control study (8762 cases and 43806 controls). Conditional logistic regression analysis was used to assess the association between lower urinary-tract infections, related antibiotics and PCa, whilst adjusting for civil status, education, Charlson Comorbidity Index and time between lower urinary-tract infection and PCa diagnosis.ResultsIt was found that lower urinary-tract infections did not affect PCa risk, however, having a lower urinary-tract infection or a first antibiotic prescription 6–12 months before PCa were both associated with an increased risk of PCa (OR: 1.50, 95% CI: 1.23–1.82 and 1.96, 1.71–2.25, respectively), as compared to men without lower urinary-tract infections. Compared to men with no prescriptions for antibiotics, men who were prescribed ≥10 antibiotics, were 15% less likely to develop PCa (OR: 0.85, 95% CI: 0.78–0.91).ConclusionPCa was not found to be associated with diagnosis of a urinary-tract infection or frequency, but was positively associated with short time since diagnoses of lower urinary-tract infection or receiving prescriptions for antibiotics. These observations can likely be explained by detection bias, which highlights the importance of data on the diagnostic work-up when studying potential risk factors for PCa.

Status of TMPRSS2-ERG fusion in prostate cancer patients from India: correlation with clinico-pathological details and TMPRSS2 Met160Val polymorphism.

BackgroundProstate cancer (PCa) shows considerable clinical heterogeneity that has been primarily attributed to variable molecular alterations. TMPRSS2–ERG fusion is one such molecular subtype that has been associated with predominantly poor prognosis. More recently, a single nucleotide polymorphism (SNP) in the TMPRSS2 gene rs12329760 C>T (Met160Val) has been shown to positively correlate with the fusion status and also to be associated with increased risk for PCa. The aim of the present study is to determine the frequency of TMPRSS2–ERG fusion and association of rs12329760 in Indian PCa patients with fusion status.MethodsTMPRSS2–ERG fusion by fluorescence in situ hybridization was determined in 102 of 150 PCa biopsy-proven cases. Genotyping for rs12329760 was performed on the entire cohort of 150 cases by Sanger sequencing.ResultsTMPRSS2–ERG fusion was seen in 27 of 102 (26%) cases. Fusion-positive patterns in this study showed fusion by translocation in nine of 27 cases (33.5%), by deletion in six of 27 (22%) cases, and by insertion in 12 of 27 cases (44.5%). No association of the fusion status with Gleason Score, pattern, or perineural invasion was seen. The TMPRSS2 SNP rs12329760 ‘T’ allele was prevalent with a frequency of 0.27 in the PCa patients. The SNP was significantly associated with fusion [odds ratio (OR) = 2.176, 95% confidence interval (CI) = 1.012–4.684, P = 0.04], more specifically fusion by deletion (P = 0.04).ConclusionThe results provided here determine the frequency of TMPRSS2–ERG fusions (26%) in a fairly large cohort of Indian PCa cases and also the association of rs12329760 SNP with TMPRSS2–ERG fusion. No association with other clinico-pathological features was observed. Future studies with clinical outcomes are warranted in this population.

Comparison of a low-cost immunohistochemistry marker panel with a cell-cycle progression assay for the prediction of outcome after radical prostatectomy.

118 Background: Gene expression assays appear to stratify prostate cancer risk, however tests involving amplification techniques are expensive and may strain payment systems. We aimed to compare the prognostic utility of a low-cost immunohistochemistry (IHC) panel consisting of three validated markers with an RNA expression based cell-cycle progression (CCP) score. Methods: Among 5,748 patients with PCa within an institutional database, we identified 424 with localized PCa treated with radical prostatectomy (RP). IHC analysis was performed using tissue microarrays to examine the expression status of PTEN, Ki67, and ERG compared with previously calculated CCP scores derived from 31 genes normalized to 15 housekeeper genes. Associations of IHC status, CCP scores, adjusted for clinical and pathologic characteristics (Cancer of the Prostate Risk Assessment Score, CAPRA-S) were performed using Cox proportional hazards regression to examine risk of biochemical recurrence (BCR), and metastasis or PCa- specific mortality (PCSM). We compared models using concordance index (c-index) testing. Results: Median age at treatment was 59 years and patients were followed for a median of 114 months post RP. By 10 years after RP, 27% experienced BCR and 4% developed metastasis or PCSM. Adjusted for CAPRA-S, the triad of PTEN loss, high Ki67, and positive ERG expression was independently associated with risk of BCR (HR 2.3, 95% CI 1.1-4.7) and metastasis/PCSM (HR 8.3, 95% CI 3.3-21.2). In a model including CAPRA-S, IHC panel, and CCP, the CCP score was independently associated with both recurrence and metastasis/PCSM (HR 1.9, 95% CI 1.5-2.5 and HR 2.5, 95% CI 1.5-4.1, respectively), but IHC expression status of PTEN/Ki67/ERG remained an independent predictor of both endpoints. The addition of the CCP assay marginally improved the c-index of a combined IHC and CAPRA-S model from 0.78 to 0.81 for the prediction of metastasis/PCSM. Conclusions: A low-cost three-marker IHC panel examining PTEN, Ki67, and ERG expression was independently associated with downstream PCa endpoints following RP. Efforts are warranted to reduce the cost of PCa prognostic tools in order to expand access.

Identification of fluorescence in situ hybridization assay markers for prediction of disease progression in prostate cancer patients on active surveillance

BackgroundProstate Cancer (PCa) is the second most prevalent cancer among U.S. males. In recent decades many men with low risk PCa have been over diagnosed and over treated. Given significant co-morbidities associated with definitive treatments, maximizing patient quality of life while recognizing early signs of aggressive disease is essential. There remains a need to better stratify newly diagnosed men according to the risk of disease progression, identifying, with high sensitivity and specificity, candidates for active surveillance versus intervention therapy. The objective of this study was to select fluorescence in situ hybridization (FISH) panels that differentiate non-progressive from progressive disease in patients with low and intermediate risk PCa.MethodsWe performed a retrospective case-control study to evaluate FISH biomarkers on specimens from PCa patients with clinically localised disease (T1c-T2c) enrolled in Watchful waiting (WW)/Active Surveillance (AS). The patients were classified into cases (progressed to clinical intervention within 10 years), and controls (did not progress in 10 years). Receiver Operating Characteristic (ROC) curve analysis was performed to identify the best 3–5 probe combinations. FISH parameters were then combined with the clinical parameters ─ National Comprehensive Cancer Network (NNCN) risk categories ─ in the logistic regression model.ResultsSeven combinations of FISH parameters with the highest sensitivity and specificity for discriminating cases from controls were selected based on the ROC curve analysis. In the logistic regression model, these combinations contributed significantly to the prediction of PCa outcome. The combination of NCCN risk categories and FISH was additive to the clinical parameters or FISH alone in the final model, with odds ratios of 5.1 to 7.0 for the likelihood of the FISH-positive patients in the intended population to develop disease progression, as compared to the FISH-negative group.ConclusionsCombinations of FISH parameters discriminating progressive from non-progressive PCa were selected based on ROC curve analysis. The combination of clinical parameters and FISH outperformed clinical parameters alone, and was complimentary to clinical parameters in the final model, demonstrating potential utility of multi-colour FISH panels as an auxiliary tool for PCa risk stratification. Further studies with larger cohorts are planned to confirm these findings.

Prostate cancer small non-coding RNA transcriptome in Arabs

BackgroundProstate cancer (PCa) is a complex disorder resulting from the combined effects of multiple environmental and genetic factors. Small non-coding RNAs (sRNAs), particularly microRNAs (miRNAs), regulate several cellular processes and have an important role in many human malignancies including PCa. We assessed the sRNA profiles associated with PCa in Arabs, a population that has rarely been studied.MethodsWe used next generation sequencing technology to obtain the entire sRNA transcriptome of primary prostate tumor formalin-fixed paraffin-embedded tissues, and their paired non-tumor tissues, collected from Bedouin patients (Qatari and Saudi). The miRNA and the target gene expression were evaluated by real-time quantitative PCR. miRNA KEGG pathway and miRNA target genes were subsequently analyzed by starBase and TargetScan software.ResultsDifferent expression patterns of several sRNA and miRNA editing were revealed between PCa tumor and their paired non-tumor tissues. Our study identified four miRNAs that are strongly associated with prostate cancer, which have not been reported previously. Differentially expressed miRNAs significantly affect various biological pathways, such as cell cycle, endocytosis, adherence junction and pathways involved in cancer. Prediction of potential targets for the identified miRNAs indicates the overexpression of KRAS, BCL2 and down-regulation of PTEN in PCa tumor tissues.ConclusionThese miRNAs, newly associated with prostate cancer, may represent not only markers for the increased risk of PCa in Arabs, but may also reflect the clinical and pathological diversity as well as the ethno-specific heterogeneity of prostate cancer.

Abstract 2261: Synergistic effect and VEGF/HSP70-hom haplotype analysis: Relationship to prostate cancer risk and clinical outcome

Abstract Prostate cancer (PCa) is a complex disorder resulting from the combined effects of multiple environmental and genetic factors. Our previous single-locus analysis showed that VEGF and HSP70-hom polymorphisms were significantly associated with PCa susceptibility and prognosis. Both genes encoding these proteins were located on chromosome 6p21, and combining the neighboring single nucleotide polymorphisms (SNPs) into haplotypes may increase the association with the disease. Three tagging polymorphisms, the HSP70-hom 2437 T/C, the VEGF-1154 G/A, and the VEGF-634 G/C SNPs were genotyped in 101 cases and 80 controls. For the combined analysis of VEGF and HSP70-hom, we found a positive gradient in the odds ratios (ORs) related to the number of high-risk genotypes with a 3.53-fold increase of prostate carcinoma risk (OR= 3.53; p= 0.015). Furthermore, the TAG and CAG haplotypes at positions HSP70-hom, VEGF-1154 and VEGF -634 exhibited a two-fold (OR= 0.46; p= 0.014) and a seven-fold (OR= 0.14; p= 0.00005) reduction in PCa risk, respectively. Regarding PCa prognosis, the TAG haplotype had a negative association with the aggressive phenotype as defined by the histopathological grade (OR= 0.28; p= 0.006). Our findings confirm the role of at-risk haplotype across the HSP70-hom/VEGF gene cluster in determining susceptibility to PCa. Note: This abstract was not presented at the meeting. Citation Format: Sana Sfar, Hamadi Saad, Faouzi Mosbah, Lotfi Chouchane. Synergistic effect and VEGF/HSP70-hom haplotype analysis: Relationship to prostate cancer risk and clinical outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2261. doi:10.1158/1538-7445.AM2017-2261