Large-scale Prospective Validation Study of a Multiplex RNA Urine Test for Noninvasive Detection of Upper Tract Urothelial Carcinoma.

Abstract

Background: Current approaches for diagnosis and monitoring of upper tract urothelial carcinoma (UTUC) are often invasive, costly, and not efficient for early-stage and low-grade tumors.

Objective: To validate a noninvasive urine-based RNA test for accurate UTUC diagnosis.

Design, setting, and participants: Urine samples were prospectively collected from 61 patients with UTUC and 99 controls without urothelial carcinomas, in five clinical centers between October 2022 and August 2023 prior to any invasive test (cystoscope or ureteroscope) or treatment. All samples were analyzed with a urine-based RNA test composed of eight genes (CA9, CCL18, ERBB2, IGF2, MMP12, PPP1R14D, SGK2, and SWINGN). The test results were presented with a risk score for each participant, which was applied to categorize patients into low- or high-risk groups.

Outcome measurements and statistical analysis: The diagnosis of UTUC was based mainly on preoperative radiological examination criteria and confirmed by postoperative pathological results. The recursive feature elimination and support vector machine algorithms, χ², and Student t test were used.

Results and limitations: The eight-gene urine test accurately detected UTUC patients and controls with an area under the curve (AUC) of 0.901 in a single-center testing cohort (n = 93) and an AUC of 0.926 in a multicenter clinical validation cohort (n = 66). In the merged validation cohort, the eight-gene urine test achieved high sensitivity of 90.16%, specificity of 88.89%, and overall accuracy of 89.38%. Remarkably, excellent performance was achieved in 11 low-grade UTUC patients with accuracy of 100%. However, this study collected the urine of UTUC patients only at a single preoperative time point and did not perform continuous tests during the pathological process of UTUC in the surveillance population.

Conclusions: Our results demonstrated that the eight-gene urine test can differentiate accurately between UTUC and other urological diseases with high sensitivity and specificity. In clinical practice, it may be used for identifying UTUC patients effectively, leading to reduced reliance on ureteroscopy and blind surgery.

Patient summary: In this study, we investigated a multiplex RNA urine test for noninvasive upper tract urothelial carcinoma (UTUC) diagnosis before treatment. We found that the risk scores derived from the multiplex RNA urine test differed significantly between UTUC patients and corresponding controls.