Clinical Validation of the Proenkephalin () Methylation Urine Test for Monitoring Recurrence of Non-muscle-invasive Bladder Cancer.

Background And Objective: To assess the effectiveness of a urine-based proenkephalin ( methylation test using linear target enrichment-quantitative methylation-specific polymerase chain reaction (me test) for detection of non-muscle-invasive bladder cancer (NMIBC) recurrence compared to cytology and the NMP22 test.

Methods: We first conducted a retrospective case-control study involving 54 patients with primary BC and 29 healthy individuals. We then prospectively enrolled 186 patients (January to December 2022) undergoing cystoscopy surveillance after transurethral resection of bladder tumor, of whom 59 had recurrent tumors. We analyzed voided urine samples for methylation levels in urinary DNA. Cystoscopy with histology was used as the reference standard for assessing the diagnostic accuracy of the me test in detecting BC recurrence. We calculated the sensitivity and specificity using receiver operating characteristic curve analysis. Survival differences were determined using the Kaplan-Meier method and Cox proportional-hazards model. A < 0.05 was considered statistically significant.

Key Findings And Limitations: In the case-control study, the test had sensitivity of 83.3% and specificity of 100%. For NMIBC patients undergoing cystoscopy surveillance, the sensitivity was 76.3% (95% confidence interval [CI] 63.4-86.4%) and the specificity was 85% (95% CI 77.6-90.7%), outperforming cytology (sensitivity: 28.8%, 95% CI 17.8-42.1%; < 0.001; specificity: 97.6%, 95% CI 93.2-99.5%) and the NMP22 test (sensitivity: 54.2%, 95% CI 40.7-67.2%; = 0.016; specificity 81.9%, 95% CI 74.1-88.2%). In the high-risk group, the me test had sensitivity of 89.7% (95% CI 75.8-97.1%) and a negative predictive value of 96.9%. For the group with low/intermediate risk, the sensitivity was 41.7%. In the group with negative cystoscopy, recurrence-free survival was shorter for patients with positive than for those with negative me results (245 vs 503 d), with a hazard ratio of 9.4 ( < 0.001). The main study limitation is the small sample size.

Conclusions And Clinical Implications: The me test showed good performance for detection of NMIBC recurrence and has potential for use for prognosis and prediction.

Patient Summary: We found that a test used to analyze urine samples showed good performance in detecting recurrence of NMIBC. This noninvasive me test may help in personalized follow-up care for patients with NMIBC.