Urinary Biomarkers in Bladder Cancer: Where Do We Stand?

Abhishek Bhat; Chad R. Ritch


Curr Opin Urol. 2019;29(3):203-209. 

In This Article

Where are we Going?: Commercially Available (Not FDA Approved) Urinary Biomarkers for Bladder Cancer

Though they may not be FDA approved, several urinary biomarkers are commercially available as laboratory-developed tests that meet the regulatory standards of the Clinical Laboratory Improvement Amendments. These urinary biomarkers are therefore available under the auspices of Clinical Laboratory Improvement Amendments.


Cxbladder (Pacific Edge Diagnostics, Dunedin, New Zealand) employs the reverse transcriptase - polymerase chain reaction (RT-PCR) detection of five mRNA's that are expressed in urine in bladder cancer patients: IGFBP5, HOXA13, MDK, CDK1, and CXCR2.[5] Studies have described a sensitivity of 82% in patients with hematuria and no history of bladder cancer and an ability to distinguish low grade noninvasive cancer with other type of cancers with a high specificity of 90%.[16] A recent study evaluating Cxbladder in bladder cancer surveillance demonstrated a sensitivity of 92% and negative predictive value (NPV) of 96%.[17] A large study of 803 patients compared Cxbladder with FDA approved urinary biomarkers. It was demonstrated that the sensitivity of Cxbladder (0.91) outperformed cytology (0.22), NMP22 ELISA (0.26), and NMP22 BladderChek (0.11). The NPV of CxBladder (0.96) was also superior to cytology (0.87), NMP22 ELISA (0.87), and NMP22 BladderChek (0.86). This supported the use of CxBladder as a confirmatory negative adjunct to cystoscopy, although further studies are required to assert this further.[18]

Assure MDx. Assure MDx (MDx Health, Irvine, California, USA) is a DNA-based urine assay that detects mutations in three genes: FGFR3, TERT, and HRAS in combination with methylation analysis of three other genes: OTX1, ONECUT2, and TWIST1. In an exploratory study of patients with hematuria, a model utilizing the Assure MDx assay combined with age, predicted the presence of bladder cancer with 97% sensitivity, 83% specificity, and an AUC of 0.93.[19] A follow-up validation study in an international multicenter cohort demonstrated 93% sensitivity and 86% specificity, with AUC of 0.96 [95% confidence interval (CI) 0.92–0.99].[20] This assay may therefore hold promise as a predictive urine test to help triage patients with hematuria and avoid cystoscopy in those who are not likely to have bladder cancer.

XPert BC. XPert BC (Cepheid, Sunnyvale, California, USA) is a mRNA-based assay that measures the expression of five[5] genes in the urine: UPK1B, IGF2, CRH, ANXA10, and ABL1 in a model to predict the presence of bladder cancer.[21] In a study of 230 NMIBC patients, the sensitivity of Xpert BC for detection of bladder cancer was 46.2% and the NPV was 83%. However, the specificity compared to urine cytology was lower at 77 versus 97.2%, respectively.[21] The predictive ability of Xpert BC versus cytology to detect recurrence in patients with NMIBC undergoing surveillance was recently evaluated in 140 patients. The test had 84% sensitivity and a 93% NPV, whereas cytology had a 33% sensitivity and 76% NPV; P < 0.001.[22] The heterogeneity among studies and lack of validation are limitations to the results supporting utility of Xpert BC at the current time. The relatively low specificity of Xpert BC also undermines the potential role as a replacement for urine cytology in NMIBC surveillance.

Urinary bladder cancer Rapid test. Urinary bladder cancer (UBC) is a urine-based assay that probes the qualitative or quantitative expression of cytokeratin 8 and 18. Hakenberg et al.[23] studied 112 patients before trans urethral resection of bladder tumor, 40 patients before secondary surgical treatment, and 2 groups of control study participants comprising 29 healthy study participants and 10 women with acute urinary tract infection with UBC Rapid test, UBC II ELISA (point of care) test, and urine cytology for the diagnosis of bladder cancer. The UBC Rapid, UBC II ELISA, and urine cytology confirmed sensitivity and specificity of 64.4, 46.6, and 70.5 and 63.6, 86.3, and 79.5%, respectively.[23] Comparisons with other commercial biomarker assays showed inferiority of the UBC Rapid test;[24] hence, its future utility as a urinary biomarker remains to be determined.