Urine Biomarkers for Bladder Cancer Diagnosis and Screening

Flexible cystoscopy is the mainstay of bladder cancer detection but is an imperfect test which is resource-intensive and invasive for patients. A focus of bladder cancer research has been to develop non-invasive tests to reliably detect urothelial cancers without the need for cystoscopy. Bladder cancer is unique in that tumor cells are in prolonged contact with a plentiful and easily-collected liquid biopsy, urine; hence, non-invasive alternatives to cystoscopy have been sought for over 30 years. Despite considerable progress in recent years in identifying and commercializing diagnostic urinary biomarkers (some of which rival the sensitivity and specificity of cystoscopy), none are yet being used routinely at the clinical front line as a replacement for cystoscopy, nor are any recommended for this purpose by international guideline committees. It is recognized that there are challenges to overcome, such as false-negative tests due to low rates of shedding by some tumors, false positives caused by hematuria, urothelial field changes or inflammatory conditions, and clinical study design. In this chapter, we outline the relevant clinical settings, the molecular changes associated with bladder cancer that can be detected in urine, the mechanisms of release of these biomolecules into urine, and important considerations for their detection, measurement, and validity. Furthermore, we provide an overview of all classes of diagnostic urinary biomarkers, highlighting a new generation of urine tests that have been enabled by the expansion of our understanding of bladder cancer genomics during the course of the last 10 years. Finally, in order to realize the full potential and clinical impact of these biomarkers and to progress beyond simple descriptions of test accuracy, we encourage investigators to conduct randomized interventional studies to assess how such tests can change clinical pathways for the better. Consequently, there is a realistic expectation that the latest nucleic acid-based tests will be in routine clinical use within 5 years.