Prostatectomy-based validation of combined urine and plasma test for predicting high grade prostate cancer.

BACKGROUND: Distinguishing between low- and high-grade prostate cancers (PCa) is important, but biopsy may underestimate the actual grade of cancer. We have previously shown that urine/plasma-based prostate-specific biomarkers can predict high grade PCa. Our objective was to determine the accuracy of a test using cell-free RNA levels of biomarkers in predicting prostatectomy results. METHODS: This multicenter community-based prospective study was conducted using urine/blood samples collected from 306 patients. All recruited patients were treatment-naïve, without metastases, and had been biopsied, designated a Gleason Score (GS) based on biopsy, and assigned to prostatectomy prior to participation in the study. The primary outcome measure was the urine/plasma test accuracy in predicting high grade PCa on prostatectomy compared with biopsy findings. Sensitivity and specificity were calculated using standard formulas, while comparisons between groups were performed using the Wilcoxon Rank Sum, Kruskal-Wallis, Chi-Square, and Fisher's exact test. RESULTS: GS as assigned by standard 10-12 core biopsies was 3 + 3 in 90 (29.4%), 3 + 4 in 122 (39.8%), 4 + 3 in 50 (16.3%), and > 4 + 3 in 44 (14.4%) patients. The urine/plasma assay confirmed a previous validation and was highly accurate in predicting the presence of high-grade PCa (Gleason ≥3 + 4) with sensitivity between 88% and 95% as verified by prostatectomy findings. GS was upgraded after prostatectomy in 27% of patients and downgraded in 12% of patients. CONCLUSIONS: This plasma/urine biomarker test accurately predicts high grade cancer as determined by prostatectomy with a sensitivity at 92-97%, while the sensitivity of core biopsies was 78%.

Specimen Provenance Testing Identifies Contamination That Affects Molecular Prognostic Assay Results in Prostate Cancer Biopsy Specimens.

OBJECTIVE: To determine if tissue contamination in histologic specimens can significantly affect the results of prognostic molecular markers that are routinely used as confirmatory tests to safely assign appropriate candidates to prostate cancer active surveillance protocols. MATERIALS AND METHODS: This study evaluates 2134 cases from a single, large urology practice that were successfully tested for DNA specimen provenance verification using short tandem repeat analysis for the presence of a significant level of contaminating DNA. After removal of the contamination, 5 of the samples were retested, and the results of the molecular diagnostic test were compared. RESULTS: Forty-nine of the 2134 cases (2.3%) sent for DNA provenance analysis were found to possess significant levels of contamination. Of these 49 cases, 7 were resent for a repeat molecular diagnostic test after being decontaminated. Five of these prostate cancer specimens had sufficient tissue and RNA to give a more accurate cell cycle progression (CCP) score. The average absolute change in these patients' CCP scores was 0.48, with a minimum of 0.1-unit and a maximum of 1.0-unit difference. These changes in CCP scores are significant enough to cause meaningful alterations in a patient's calculated 10-year mortality rate, as defined by their combined risk score. CONCLUSION: DNA contamination in unstained tissue sections sent for prognostic prostate cancer molecular diagnostic testing occurs in 2.3% of the cases, and can be of a magnitude that affects the results and subsequent clinical decision of appropriateness for active surveillance.

A Multi-Center Prospective Study to Validate an Algorithm Using Urine and Plasma Biomarkers for Predicting Gleason ≥3+4 Prostate Cancer on Biopsy.

Background: Unnecessary biopsies and overdiagnosis of prostate cancer (PCa) remain a serious healthcare problem. We have previously shown that urine- and plasma-based prostate-specific biomarkers when combined can predict high grade prostate cancer (PCa). To further validate this test, we performed a prospective multicenter study recruiting patients from community-based practices. Patients and Methods: Urine and plasma samples from 2528 men were tested prospectively. Results were correlated with biopsy findings, if a biopsy was performed as deemed necessary by the practicing urologist. Of the 2528 patients, biopsy was performed on only 524 (21%) patients. Results: Of the 524 patients, Gleason≥3+4 PCa was found in 161 (31%) and Gleason ≥4+3 was found in 62 (12%) of the patients. The urine/plasma biomarkers algorithm showed sensitivity and specificity of 75% and 69% for predicting Gleason ≥3+4. However, upon incorporating prostate size and prior history of biopsy in the algorithm, we achieved a sensitivity between 97% and 86% and a specificity between 36% and 57%, dependent on the used cut-off point. Sensitivity for predicting PCa Gleason ≥4+3 was between 96% and 99% and specificity between 59% and 37%, dependent on the cut-off point. Diagnosis of Gleason ≥3+4 was missed in 1% to 3% of tested patients and of Gleason ≥4+3 in 0.2% to 1%. Conclusion: This test when integrated with prostate volume and the prior prostate biopsy enhance the sensitivity and specificity for predicting the presence of high grade prostate cancer with negative predictive value (NPV) of 90% to 97% for Gleason ≥3+4 and between 98% to 99% for Gleason ≥4+3.