Researchers have reported findings that may help redefine treatment for patients with muscle-invasive bladder cancer, a potentially aggressive form of the disease that is traditionally treated with surgical removal of the bladder. The study, published by Matthew D. Galsky, MD, and colleagues in the Proceedings of the National Academy of Sciences, demonstrates that ultrasensitive testing of tumor-derived DNA in blood and urine may help identify patients who can safely forgo radical cystectomy without compromising cancer outcomes.
Muscle-invasive bladder cancer is commonly treated with chemotherapy followed by radical cystectomy, a procedure that significantly affects quality of life. However, decades of clinical observations have shown that a substantial percentage of patients have no detectable cancer remaining at the time of surgery, raising critical questions about whether all patients require such aggressive treatment.
Matthew D. Galsky, MD
“Our goal is to move beyond a one-size-fits-all approach,” said Dr. Galsky, Professor of Medicine (Hematology and Medical Oncology) at the Icahn School of Medicine, Deputy Director of the Mount Sinai Tisch Cancer Center, and first author of the study. “We are working toward a future where treatment decisions are guided by precise molecular tools that tell us which patients truly need surgery, and which patients may be cured without losing their bladder.”
Using highly sensitive assays, researchers can detect circulating tumor DNA (ctDNA) in blood and urine tumor DNA (utDNA) in urine to identify traces of residual cancer that may be invisible on scans or biopsies.
Study Findings
In this study, investigators analyzed plasma ctDNA and urine utDNA from patients enrolled in a clinical trial evaluating a bladder-sparing treatment strategy. The approach allowed patients who achieved a complete clinical response after tumor biopsy and systemic therapy to forgo immediate bladder removal. The ctDNA and utDNA assays were performed in close collaboration with Bert Vogelstein, MD, and Yuxuan Wang, MD, PhD, and their team at Johns Hopkins University; Dr. Vogelstein and team are among the pioneering researchers who first showed that ctDNA could be used as a measure of measurable residual disease (MRD) in solid tumors.
The study revealed several clinically important results:
- Among patients who achieved a complete clinical response following systemic therapy, 3-year bladder-intact survival reached 69%, underscoring the potential durability of bladder-sparing treatment strategies in carefully selected individuals.
- Researchers also found that molecular testing could help predict metastatic risk. Patients with detectable ctDNA prior to systemic therapy faced a significantly higher likelihood of developing metastatic disease. In contrast, only 4.5% of patients with undetectable baseline ctDNA went on to develop metastases, suggesting that ctDNA may serve as a powerful indicator of prognosis.
- Importantly, patients with undetectable ctDNA either before or after treatment demonstrated an exceptionally low risk of metastatic recurrence. This finding highlights the potential role of ctDNA monitoring as a tool for identifying patients who may safely avoid radical bladder removal.
The study also showed that plasma and urine DNA testing provide complementary insights. utDNA proved more sensitive than blood-based ctDNA for detecting residual disease confined to the bladder. Detectable utDNA in patients who otherwise appeared to have no evidence of cancer was associated with shorter bladder-intact survival, suggesting that urine-based testing may help uncover hidden cancer not captured by conventional assessments.
“These findings show that blood and urine DNA testing provide complementary information,” Dr. Galsky explained. “Together, they offer a powerful new way to identify patients most likely to benefit from bladder preservation.”
Radical cystectomy, while often curative, requires urinary diversion and can profoundly affect daily functioning and quality of life. More precise tools to assess residual disease could help spare some patients from unnecessary surgery while maintaining excellent cancer control.
“This research represents an important step toward personalized care in muscle-invasive bladder cancer,” said Dr. Galsky. “As therapies and diagnostics improve, we must ensure we are not overtreating patients who may already be cured.”
The researchers emphasized that these results establish a scientific foundation for how ctDNA and utDNA monitoring might be incorporated into clinical decision-making. However, ongoing studies are underway to validate the approach in additional patient cohorts.
DISCLOSURE: For full disclosures of the study authors, visit pnas.org.
