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New screening methods that can add predictive diagnostic value for aggressive (high-grade, Gleason score ≥7) prostate cancer (PCa) are needed to reduce unnecessary biopsies for patients with non-aggressive PCa. This is particularly important for men presenting for an initial biopsy with an equivocal PSA in the 2–10 ng ml−1 range. PCA3 and ERG are biomarkers that can add predictive value for PCa in urine; however, with a limited utility as a digital rectal exam (DRE) is required.First-catch urine samples were collected at six sites from men scheduled to undergo a prostate biopsy. Exosomal RNA was extracted, RNA copy numbers of ERG and PCA3 were measured by reverse transcription-quantitative PCR (RT-qPCR), and the EXO106 score (the sum of normalized PCA3 and ERG RNA levels) was computed. Performance was compared with standard of care (SOC; PSA, age, race or family history) parameters. Contingency table, logistic regression, receiver operating characteristics curve and box-plot analyses were performed.In this cohort (N = 195), a dichotomous EXO106 score demonstrated good clinical performance in predicting biopsy result for both any cancer and high-grade disease. For high-grade disease, the negative and positive predictive values were 97.5% and 34.5%, respectively. The discrimination between high-grade and Gleason score ≤6 (including benign) biopsy results by a combination of EXO106 and SOC (area under the curve (AUC) = 0.803) was significantly improved compared with SOC without EXO106 (AUC = 0.6723, P = 0.0009). The median EXO106 score correlated (P<0.001; Spearman's rank order) with histologic grade.A novel molecular signature (EXO106 score) derived from non-DRE urine demonstrated independent, negative predictive value for the diagnosis of high-grade PCa from initial biopsy for men with ‘gray zone’ serum PSA levels. Its use in the biopsy decision process could result in fewer prostate biopsies for clinically insignificant disease.