April 28, 2026
As evidence continues to grow supporting the use of circulating tumor DNA (ctDNA) to monitor minimal residual disease in solid tumors, experts at Mayo Clinic who specialize in treating urothelial carcinoma are increasingly adopting tumor-informed ctDNA testing across a broad range of clinical applications.
Parminder Singh, M.D., a hematologist-oncologist at Mayo Clinic Comprehensive Cancer Center in Arizona, and his colleagues recently published a review in JCO Oncology Practice describing ctDNA's value as both a predictive and prognostic biomarker of minimal residual disease.
"We are at an inflection point with this tool," he says. "It's become extremely important in decision-making in bladder cancer treatment."
Why tumor-informed ctDNA matters
Specialists have long struggled with both overtreatment and undertreatment in bladder cancer, particularly after definitive therapy. Historically, clinicians relied on imaging or pathologic-molecular risk features to guide treatment decisions, with testing limited to a small set of commonly observed mutations.
Studies evaluating ctDNA have since shown that many solid tumor types, including urothelial carcinoma, tend to shed detectable ctDNA, which also seems to correlate with biologic aggressiveness. These findings suggest that tumor histology and genomic instability strongly influence ctDNA kinetics. With the advent of next-generation sequencing, researchers can now design personalized assays to identify and track tumor-informed mutations in the bloodstream.
This approach enables detection of low concentrations of ctDNA in heterogeneous tumors and allows for greater precision, Dr. Singh says. "Before, we were looking at the anatomy. Now, we're looking at the biology, and ctDNA offers a level of sensitivity and specificity we didn't previously have. That makes it a more robust marker for predicting both treatment benefit and prognosis."
"These predictive benefits have really surfaced over the past year with new data," he adds.
In their clinical practice today, Dr. Singh and his colleagues frequently use ctDNA testing, in conjunction with imaging, to guide clinical decision-making. They use it in two settings: after definitive therapy to stratify recurrence risk and discuss adjuvant strategies, and in patients with advanced disease who are receiving systemic therapy.
Using ctDNA as a predictive biomarker in urothelial cancer
By using ctDNA as a prognostic biomarker, Dr. Singh and his colleagues can determine whether a patient is likely to experience a recurrence in the coming months and may benefit from additional therapy. They can also identify patients with low recurrence risk who might be harmed by overtreatment.
"That distinction not only complements the data we had before in terms of anatomy, but it also helps us tailor the treatment in a more precise fashion for the patient who's sitting right in front of us," Dr. Singh says.
Evidence from recent phase 3 trials has helped clarify how ctDNA can inform treatment decisions in urothelial carcinoma. In the IMvigor010 study, for example, tumor-informed ctDNA testing identified molecular relapse months before disease progression was detected on imaging. And ctDNA positivity after cystectomy was strongly associated with worse overall survival. The predictive benefit of ctDNA was observed in patients who were ctDNA-positive demonstrating increased likelihood of clinical benefit from adjuvant immunotherapy supporting the use of ctDNA. The IMvigor101 study results were published in The Lancet.
Findings from the NIAGARA trial, published in the New England Journal of Medicine, further reinforce this approach. In that study, patients who were ctDNA-negative after neoadjuvant therapy had better event-free survival, and clearance of ctDNA over time was associated with improved outcomes regardless of pathologic response.
Together, these data support ctDNA as a clinically meaningful complement to imaging, offering a more precise way to stratify recurrence risk and tailor systemic therapy decisions.
What's next for ctDNA in urothelial carcinoma
Ongoing clinical trials are evaluating treatment intensification and de-escalation strategies in patients with metastatic urothelial disease. Predictive biomarkers face a higher bar for validation and clinical acceptance, underscoring the importance of continued prospective study.
Trials using ctDNA as a predictive tool in metastatic disease are expected to be reported either this year or next, Dr. Singh says, providing additional clarity on ctDNA's role in advanced disease settings.
"I think this is a very exciting time for patients with bladder cancer," he adds. "Mayo Clinic is already working to improve upon this test — to develop a next-generation test that will use whole-genome sequencing at each time point to inform patient decision-making."
For more information
Mittal K, et al. Circulating tumor DNA in urothelial cancer: Practical applications in oncology clinic. JCO Oncology Practice. 2025;00:1.
Bellmunt J, et al. Adjuvant atezolizumab versus observation in muscle invasive urothelial carcinoma (IMvigor010): A multicentre, open label, randomised, phase 3 trial. The Lancet Oncology. 2021;22(4):525.
Powles T, et al. Perioperative durvalumab with neoadjuvant chemotherapy in operable bladder cancer. The New England Journal of Medicine. 2024;391:507.
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