Performance of the Bladder EpiCheck™ Methylation Test for Patients Under Surveillance for Non–muscle-invasive Bladder Cancer: Results of a Multicenter, Prospective, Blinded Clinical Trial

Background: The highly frequent strategy of surveillance for non–muscle-invasive bladder cancer (NMIBC) involves cystoscopy and cytology. Urine assays currently available have not shown performance sufficient to replace the current gold standard for follow-up, which would require a very high negative predictive value (NPV), especially for high-grade tumors. Bladder EpiCheck (BE) is a novel urine assay that uses 15 proprietary DNA methylation biomarkers to assess the presence of bladder cancer. Objective: To assess the performance of BE for NMIBC recurrence. Design, setting, and participants: This was a blinded, single-arm, prospective multicenter study. The inclusion criteria were age ≥22 yr, urothelial carcinoma (UC) being monitored cystoscopically at 3-mo intervals, all UC resected within 12 mo, able to produce 10 ml of urine, and able to consent. Outcome measurements and statistical analysis: The BE test characteristics were calculated and compared to cytology and cystoscopy results confirmed by pathology. Results and limitations: Out of 440 patients recruited, 353 were eligible for the performance analysis. Overall sensitivity, specificity, NPV, and positive predictive value were 68.2%, 88.0%, 95.1%, and 44.8%, respectively. Excluding low-grade (LG) Ta recurrences, the sensitivity was 91.7% and NPV was 99.3%. The area under receiver operating characteristic (ROC) curves with and without LG Ta lesions was 0.82 and 0.94, respectively. Conclusions: In follow-up of NMIBC patients, the BE test showed an overall high NPV of 95.1%, and 99.3% when excluding LG Ta recurrences. With high specificity of 88.0%, the test could be incorporated in NMIBC follow-up since high-grade recurrences would be instantly detected with high confidence. Thus, the current burden of repeat cystoscopies and cytology tests could be reduced. Patient summary: The Bladder EpiCheck urine test has a clinically relevant and high negative predictive value. Its use in clinical routine could reduce the number of follow-up cystoscopies, and thus associated patient and financial burdens. Bladder EpiCheck is a methylation-based urine assay for detection of bladder cancer. It might serve as a rule-out test for intermediate- and high-risk non–muscle-invasive bladder cancer. Thus, the test could avoid unnecessary procedures, reducing both the financial and patient burden of repeat cystoscopies.