DNA Methylation Urine Biomarkers Test in the Diagnosis of Upper Tract Urothelial Carcinoma: Results from a Single-Center Prospective Clinical Trial

Abstract

Study Need and Importance: The correct risk categorization and staging of upper tract urothelial cancer (UTUC) is key for disease management. Computerized tomography urography and urinary cytology have limited accuracy for risk stratification of UTUC. Ureteroscopy (URS) may increase the risk of bladder cancer recurrence. Recently, Bladder EpiCheck TM (EpiCheck) showed a high accuracy in the detection of bladder cancer. The aim of the study is to investigate the diagnostic accuracy of EpiCheck in the clinical management of UTUC and to compare it with urinary cytology. What We Found: EpiCheck resulted diagnostic in 83/86 (97%) and 73/75 (97%) of upper urinary tract and bladder samples, respectively. Histology was positive in 47/83 (57%) and 42/73 (58%) cases, respectively. In upper urinary tract samples, Epi-Check yielded a sensitivity/specificity/negative predictive value (NPV)/positive predictive value of 83%/ 79%/77%/84% vs 59%/88%/61%/87% of cytology. The sensitivity/NPV for high-grade tumors was 96%/97% for EpiCheck vs 71%/86% for cytology. EpiCheck indicated URS in 45/80 (56%) patients, missing 17%/4% of all/high-grade UTUC with 9% of unnecessary URS. In bladder samples, the sensitivity/NPV for high-grade tumors was 71%/ 88% for EpiCheck and 59%/87% for cytology. Limitations: As no previous studies analyzed biomarker performances in UTUC, we included a heterogeneous population of patients. The diagnostic accuracy of EpiCheck might vary in first observation vs followup setting. Furthermore, no cost-effectiveness analysis was performed. Interpretation for Patient Care: Epicheck may be an important tool to decrease the number of unnecessary URSs. The clinical implementation of Epi-Check in UTUC warrants further investigation in multicentric prospective randomized trials.

A Urine-based DNA Methylation Marker Test to Detect Upper Tract Urothelial Carcinoma: A Prospective Cohort Study

“…The same epigenetic test was used in a prospective study by Territo et al, who reported a sensitivity, specificity, NPV, and PPV of 83%, 79%, 77%, and 84%, respectively, for selective samples obtained from the upper tract. 24 However, “bladder” samples from the same cohort demonstrated lower values, with sensitivity, specificity, NPV, and PPV of 51%, 79%, 77%, and 55%, respectively. Despite these advances, none of the aforementioned methylation panels and urine biomarkers has been validated for use in patients with UTUC.…”

“…Recently, a few studies have reported the clinical implementation of DNA methylation biomarkers in urine-based UTUC biospecimens. 16,22-24 Monteiro-Reis et al, using the methylation levels of 3 methylation biomarkers (GDF15, TMEFF2, and VIM) in urine samples of 22 UTUCs and 20 controls, reported a sensitivity of 91% and a specificity of 100% for the detection of UTUC. 16 A study of larger combinations of selected genes (CDH1, HSPA2, RASSF1A, TMEFF2, VIM, and GDF15) in the urine samples of 98 UTUC patients and 113 controls identified UTUC with a sensitivity of 82% and a specificity of 68%.…”

“…EpiCheck is a commercially available urine test that measures 15 methylation biomarkers mainly designed for UBC. 23,24 Using this test, Pierconti et al evaluated urine samples from 82 patients with clinically localized high-grade UTUC. 23 In this retrospective study, urine samples were obtained using selective ureteral catheterization, and the results showed a sensitivity of 97.4% for the detection of high-grade UTUC.…”

“…It has low sensitivity, especially when obtained from voided urine, with reported sensitivities ranging from 11% to 83% for voided urine compared to 33% to 100% for URS specimens. 24 Moreover, urinary cytology has poor performance in the detection of low-grade UTUCs, regardless of tumor location. 19 Similar results were observed in this study.…”

Epigenetic liquid biopsies for minimal residual disease, what’s around the corner?

“…Another PCR test is Bladder EpiCheck offered by Nucleix. This multiplex DNA methylation-based PCR assay is for monitoring of tumor recurrence in conjunction with cystoscopy in patients previously diagnosed with bladder cancer ( 53 , 54 ). Also in development, Singlera Genomics is recruiting colorectal cancer patients to run clinical trials on their ColonAiQ six-plex methylation PCR test for MRD and cancer recurrence ( 55 ).…”