While promising, circulating tumor DNA (ctDNA) from plasma is not yet ready for guiding local treatment decisions in bladder cancer. Data from studies like RETAIN show it is insufficient for identifying patients with residual disease confined to the bladder, limiting its utility in bladder-sparing protocols.

Data from trials like Niagara suggests a powerful new paradigm for assessing treatment success. Combining urine tumor DNA (uTDNA) for local disease and circulating tumor DNA (ctDNA) for systemic relapse offers a more dynamic view than traditional pathology and is poised to become the superior surrogate endpoint in bladder cancer trials.

Circulating tumor DNA is a powerful tool for detecting systemic minimal residual disease but is not sensitive enough for local, non-muscle invasive recurrences. This limitation means traditional surveillance like cystoscopy remains indispensable, as a negative ctDNA test can provide a false sense of security about local control.

Professor Powles highlights a critical limitation of ctDNA in bladder cancer management. While excellent for assessing systemic risk, ctDNA may remain negative during a local, non-muscle invasive relapse (e.g., T1 cancer). This necessitates continued local surveillance like cystoscopy, even in ctDNA-negative patients pursuing bladder-sparing approaches.

The future of bladder cancer surveillance may involve using two types of liquid biopsies in tandem. A patient who is utDNA-positive but ctDNA-negative likely has a local, primary bladder issue. Conversely, a utDNA-negative but ctDNA-positive result suggests the cancer has already spread systemically, providing crucial information for treatment planning.

While circulating tumor DNA (ctDNA) is a powerful prognostic marker, it is not yet part of the formal "clinical complete response" definition for bladder-sparing trials. Experts lack data on its ability to predict the superficial, non-muscle invasive relapses common in this setting.

Professor Powles predicts that urinary tumor DNA (utDNA) will become the key biomarker for detecting local relapse in bladder-sparing strategies. He notes that blood-based ctDNA is poor at identifying non-muscle invasive disease, creating a clear and necessary role for utDNA to assess local risk and guide interventions more accurately.

Experts suggest urinary tumor DNA (utDNA) may better reflect local disease in the bladder, while circulating tumor DNA (ctDNA) indicates systemic disease. Using both tests in parallel could provide a more complete picture, with dual-negative results potentially becoming a key criterion for safely pursuing bladder-sparing approaches.

A positive ctDNA (blood) but negative utDNA (urine) test suggests systemic, metastatic disease. Conversely, a positive utDNA with negative ctDNA points to a tumor confined to the bladder. This integrated biomarker approach can help determine whether systemic therapy or local treatment like surgery is the priority.