Revealing the Invisible: Circulating and Urinary Tumor DNA in Bladder Cancer

Muscle-invasive bladder cancer (MIBC) carries a high risk of recurrence and metastatic progression despite aggressive treatment with radical cystectomy or trimodality therapy. Current surveillance methods, including imaging and cystoscopy, have limited sensitivity for detecting molecular residual disease (MRD) and early recurrence, highlighting the need for reliable biomarkers to guide treatment selection. Circulating tumor DNA (ctDNA) is a promising non-invasive biomarker that can provide real-time insights into tumor burden, treatment response, and recurrence risk. In this narrative review, we synthesize evidence on ctDNA’s potential in monitoring and guiding MIBC treatment. We discuss ctDNA detection methods and applications in genomic profiling, perioperative risk stratification, MRD detection, treatment selection, response monitoring, and post-treatment surveillance. Postoperative ctDNA positivity has been associated with significantly shorter disease-free survival (HR 6.93, 95% CI 2.40–20.05), and patients who failed to achieve ctDNA clearance during neoadjuvant chemotherapy had worse recurrence-free survival (HR 4.7, 95% CI 1.2–18.8). With further prospective validation, serial ctDNA monitoring may enable earlier detection of molecular recurrence and inform the timing and use of adjuvant therapy. The recent FDA approval of adjuvant atezolizumab for MIBC patients with ctDNA-detected MRD following cystectomy marks an important milestone in ctDNA-guided treatment selection. Given ctDNA’s limited sensitivity in detecting localized bladder recurrence, urinary tumor DNA (utDNA) may serve as a complementary biomarker to detect intravesical disease. Broader clinical implementation of these liquid biopsy strategies will require further validation, standardization, and efforts to reduce false-positive and false-negative results.