Bladder cancer is the tenth-most common cancer in the world with 82,000 new cases diagnosed in the United States in 2023.¹ Given the high risk of progression and recurrence, patients with bladder cancer undergo routine surveillance with cystoscopy and urine cytology. A positive cytology often triggers additional testing with the goal of identifying disease recurrence early to minimize chance of progression.¹Despite its widespread use, urine cytology is not perfect. Studies have shown cytology has a moderately high sensitivity and positive predictive value in patients with carcinoma in situ high-grade tumors but performs poorly in patients with low-grade disease. A study of 1375 patients found cytology had a sensitivity of only 54% for high-grade disease, which has potentially significant consequences for patients.¹ Furthermore, cytology results are subjectively interpreted by pathologists with variability in report labeling. There has been great interest and progress in the development of urine biomarkers that may help clinicians determine when management intensification or deintensification is appropriate.

There are several urine biomarkers that have been developed in recent years, and many are commercially available and/or approved by the FDA. Maas et al recently published a comprehensive review on available biomarkers.³ Since bladder cancer arises in the mucosa, which is in proximity to urine, there are differences in biomarkers in the urine of patients with and without cancers with respect to cells and cellular components (proteins, DNA, RNA). There is considerable variability in the studies related to these markers, with some being evaluated in few studies, while others having undergone more extensive evaluation and validation. The majority of urine markers have superior overall sensitivity relative to cytology, mostly driven by improved sensitivity for low-grade disease.³ However, urine markers have a lower specificity than cytology, yielding more false positives and limiting their role in routine practice. AUA guidelines do not currently recommend the use of urinary biomarkers to replace cystoscopy, but they do provide two clinical scenarios where biomarkers may be useful: (1) to adjudicate equivocal cytology or indeterminate cystoscopic findings and (2) to assess response to bacillus Calmette-Guérin (BCG).

Many patients who undergo repeat instrumentation or receive intravesical therapies have atypical cytology or indeterminate findings on cystoscopy, such as red patches. These findings raise concern about the presence of malignancy, especially carcinoma in situ, but often are benign findings caused by inflammation. To avoid unnecessary biopsies, urine-based tumor markers may help differentiate patients with disease from those with benign changes. Several markers have been studied in this setting. Urovysion^® FISH has demonstrated a high positive predictive value for detecting cancer in patients with equivocal cytology results, especially in those with a previous diagnosis of high-grade disease.⁴ More recently, Cxbladder™ was found to have accurate adjudication of inconclusive cytology and cystoscopy,⁵ demonstrating even higher specificity when including DNA markers.⁶ Data also suggest urine markers have clinical utility in assessing response to BCG. A study from MD Anderson in 2012 found patients with a positive UroVysion^® FISH test during BCG treatment are at higher risk for recurrence and progression.⁷ These findings were validated in a multicenter prospective study of patients initiating BCG, which found a 3.3-fold increased risk of recurrence in those with a positive UroVysion^® FISH test after BCG.⁸ These studies suggest urine markers may hold a prognostic role but do not predict response to therapy or support changing therapies from standard of care yet. Furthermore, markers may help identify patients who could benefit from clinical trials or combination therapies. If studies investigating BCG combination regimens, such as combining immunotherapy with BCG (NCT03711032), demonstrate a marginal benefit with increased toxicity, then urine markers may help select which patients could have greater benefit from treatment intensification.

Another promising role of biomarkers is in bladder cancer surveillance, specifically in frequency of cystoscopy. Office cystoscopy is uncomfortable and affects quality of life for patients undergoing bladder cancer surveillance. There is currently no biomarker that tells a physician whose cystoscopy to perform and whose cystoscopy to defer, and current AUA guidelines do not recommend the use of urinary biomarkers in place of cystoscopy for nonmuscle-invasive bladder cancer surveillance.¹ However, this may be an appropriate future use of these biomarkers. For patients with low-grade bladder cancer, there is a low risk of progression, and strategies to reduce cystoscopy by alternating cystoscopy with a urine marker are being studied such as NCT05796375. A recent study assessed the feasibility of high frequency versus low frequency cystoscopy surveillance in 45 patients with low-risk and low intermediate–risk bladder cancer and found a low-grade recurrence rate of 14% and 20.8% in the high frequency and low frequency group, respectively.⁹ They found zero high-grade recurrences or progressions and higher costs in the higher frequency group, with a third of invited patients refusing to participate, as they preferred a high frequency regimen. Patients conveyed similar procedure related discomfort and quality-of-life measures regardless of surveillance regimen. These results raise important considerations regarding feasibility and effects of decreasing routine cystoscopies for bladder cancer surveillance, but larger prospective randomized trials are needed. Importantly, future studies should continue to consider quality-of-life and cost-effectiveness factors.

A new next-generation sequencing urine marker called UroAmp MRD has demonstrated potential in predicting treatment response in muscle invasive disease, with additional studies showing promise in nonmuscle-invasive bladder cancer cohorts.¹⁰ Indeed, an exciting role for markers may lie in the high-risk population, not only to assess treatment response but also to identify missed diagnoses in the setting of a negative cystoscopy and negative cytology. Prospective studies are needed to demonstrate a sufficiently high positive predictive value so that the cancer yield can justify the risk of anesthesia and biopsies.

There is significant interest in urine markers that may help personalize clinical care by improving detection and surveillance of disease with appropriate identification of high-risk patients who need treatment intensification and by reducing the burden of disease for those at low risk. The research focus should be on clinical utility studies to help guide use of these valuable tools.