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Potential impact of adding genetic markers to clinical parameters in predicting prostate biopsy outcomes in men following an initial negative biopsy: findings from the REDUCE trial.

ABSTRACT: Several germline single nucleotide polymorphisms (SNPs) have been consistently associated with prostate cancer (PCa) risk.To determine whether there is an improvement in PCa risk prediction by adding these SNPs to existing predictors of PCa.Subjects included men in the placebo arm of the randomized Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial in whom germline DNA was available. All men had an initial negative prostate biopsy and underwent study-mandated biopsies at 2 yr and 4 yr. Predictive performance of baseline clinical parameters and/or a genetic score based on 33 established PCa risk-associated SNPs was evaluated.Area under the receiver operating characteristic curves (AUC) were used to compare different models with different predictors. Net reclassification improvement (NRI) and decision curve analysis (DCA) were used to assess changes in risk prediction by adding genetic markers.Among 1654 men, genetic score was a significant predictor of positive biopsy, even after adjusting for known clinical variables and family history (p = 3.41 × 10(-8)). The AUC for the genetic score exceeded that of any other PCa predictor at 0.59. Adding the genetic score to the best clinical model improved the AUC from 0.62 to 0.66 (p<0.001), reclassified PCa risk in 33% of men (NRI: 0.10; p=0.002), resulted in higher net benefit from DCA, and decreased the number of biopsies needed to detect the same number of PCa instances. The benefit of adding the genetic score was greatest among men at intermediate risk (25th percentile to 75th percentile). Similar results were found for high-grade (Gleason score ? 7) PCa. A major limitation of this study was its focus on white patients only.Adding genetic markers to current clinical parameters may improve PCa risk prediction. The improvement is modest but may be helpful for better determining the need for repeat prostate biopsy. The clinical impact of these results requires further study.

SUBMITTER: Kader AK

PROVIDER: S-EPMC3568765 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Potential impact of adding genetic markers to clinical parameters in predicting prostate biopsy outcomes in men following an initial negative biopsy: findings from the REDUCE trial.

Kader A Karim AK Sun Jielin J Reck Brian H BH Newcombe Paul J PJ Kim Seong-Tae ST Hsu Fang-Chi FC D'Agostino Ralph B RB Tao Sha S Zhang Zheng Z Turner Aubrey R AR Platek Greg T GT Spraggs Colin F CF Whittaker John C JC Lane Brian R BR Isaacs William B WB Meyers Deborah A DA Bleecker Eugene R ER Torti Frank M FM Trent Jeffery M JM McConnell John D JD Zheng S Lilly SL Condreay Lynn D LD Rittmaster Roger S RS Xu Jianfeng J

European urology 20120512 6

<h4>Background</h4>Several germline single nucleotide polymorphisms (SNPs) have been consistently associated with prostate cancer (PCa) risk.<h4>Objective</h4>To determine whether there is an improvement in PCa risk prediction by adding these SNPs to existing predictors of PCa.<h4>Design, setting, and participants</h4>Subjects included men in the placebo arm of the randomized Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial in whom germline DNA was available. All men had an init ...[more]

PMID: 22652152

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Project description:UnlabelledStudy Type - Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Hypermethylation of genes such as glutathione-S-transferase P1 (GSTP1) and adenomatous polyposis coli (APC) occurs with high frequency in prostate tumour tissue but is much less common in the benign prostate; however, the potential value of gene methylation biomarkers as an adjunct to biopsy histopathology has had little study. When measured in histologically benign prostate biopsy tissue, APC gene hypermethylation was found to have high negative predictive value and high sensitivity. GSTP1 hypermethylation was found to have lower performance than APC.ObjectiveTo evaluate the performance of DNA methylation biomarkers in the setting of repeat biopsy in men with an initially negative prostate biopsy but a high index of suspicion for missed prostate cancer.Patients and methodsWe prospectively evaluated 86 men with an initial histologically negative prostate biopsy and high-risk features. All men underwent repeat 12-core ultrasonography-guided biopsy. DNA methylation of glutathione-S-transferase P1 (GSTP1) and adenomatous polyposis coli (APC) was determined using tissue from the initially negative biopsy and compared with histology of the repeat biopsy. The primary outcome was the relative negative predictive value (NPV) of APC compared with GSTP1, and its 95% confidence interval (CI).ResultsOn repeat biopsy, 21/86 (24%) men had prostate cancer. APC and GSTP1 methylation ratios below the threshold (predicting no cancer) produced a NPV of 0.96 and 0.80, respectively. The relative NPV was 1.2 (95% CI: 1.06-1.36), indicating APC has significantly higher NPV. Methylation ratios above the threshold yielded a sensitivity of 0.95 for APC and 0.43 for GSTP1. Combining both methylation markers produced a performance similar to that of APC alone. APC methylation patterns were consistent with a possible field effect or occurrence early in carcinogenesis.ConclusionsAPC methylation provided a very high NPV with a low percentage of false-negatives, in the first prospective study to evaluate performance of DNA methylation markers in a clinical cohort of men undergoing repeat biopsy. The potential of APC methylation to reduce unnecessary repeat biopsies warrants validation in a larger prospective cohort.

Project description:INTRODUCTION: There is no consensus on how to investigate men with negative transrectal ultrasound guided prostate biopsy (TRUS-B) but ongoing suspicion of cancer. Three strategies used are transperineal (TP-B), transrectal saturation (TS-B) and MRI-guided biopsy (MRI-B). We compared cancer yields of these strategies. METHODS: Papers were identified by search of Pubmed, Embase and Ovid Medline. Included studies investigated biopsy diagnostic yield in men with at least one negative TRUS-B and ongoing suspicion of prostate cancer. Data including age, PSA, number of previous biopsy episodes, number of cores at re-biopsy, cancer yield, and Gleason score of detected cancers were extracted. Meta-regression analyses were used to analyse the data. RESULTS: Forty-six studies were included; 12 of TS-B, 14 of TP-B, and 20 of MRI-B, representing 4,657 patients. Mean patient age, PSA and number of previous biopsy episodes were similar between the strategies. The mean number of biopsy cores obtained by TP-B and TS-B were greater than MRI-B. Cancer detection rates were 30·0%, 36·8%, and 37·6% for TS-B, TP-B, and MRI-B respectively. Meta-regression analysis showed that MRI-B had significantly higher cancer detection than TS-B. There were no significant differences however between MRI-B and TP-B, or TP-B and TS-B. In a sensitivity analysis incorporating number of previous biopsy episodes (36 studies) the difference between MRI-B and TP-B was not maintained resulting in no significant difference in cancer detection between the groups. There were no significant differences in median Gleason scores detected comparing the three strategies. CONCLUSIONS: In the re-biopsy setting, it is unclear which strategy offers the highest cancer detection rate. MRI-B may potentially detect more prostate cancers than other modalities and can achieve this with fewer biopsy cores. However, well-designed prospective studies with standardised outcome measures are needed to accurately compare modalities and define an optimum re-biopsy approach.

Dataset Information

Potential impact of adding genetic markers to clinical parameters in predicting prostate biopsy outcomes in men following an initial negative biopsy: findings from the REDUCE trial.

Publications

Potential impact of adding genetic markers to clinical parameters in predicting prostate biopsy outcomes in men following an initial negative biopsy: findings from the REDUCE trial.

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