Published on August 12, 2026, in European Urology Focus, a retrospective study at Mount Sinai Hospital evaluated perioperative circulating tumor DNA in 159 muscle-invasive bladder cancer patients. Researchers found that detectable ctDNA strongly correlated with decreased disease-free survival across both pure urothelial carcinoma and histological subtypes.
Evaluating ctDNA Across Bladder Cancer Histologies at Mount Sinai Hospital
Circulating tumor DNA is emerging as a promising biomarker for risk stratification in muscle-invasive bladder cancer, but its prognostic performance in tumors with histological subtypes has remained less clear. On August 12, 2026, European Urology Focus published the study titled Prognostic Value of Perioperative Circulating Tumor DNA in Pure Urothelial Carcinoma and Histological Subtypes of Bladder Cancer.
The research team analyzed a prospectively maintained database of consecutive patients with nonmetastatic muscle-invasive bladder cancer who underwent robot-assisted radical cystectomy at Mount Sinai Hospital between November 2021 and May 2025.
All patients had at least one perioperative tumor-informed ctDNA assessment performed as part of routine clinical practice using the Signatera 16-plex multiplex PCR next-generation sequencing assay. Histology was classified as either pure urothelial carcinoma or a histological subtype. A histological subtype was defined by the presence of a nonurothelial component representing at least 5% of the tumor in the cystectomy specimen. Overall, 159 patients were included, of whom 92 had pure urothelial carcinoma and 67 had histological subtypes.
Pathological Differences and Higher Aggressiveness in Histological Subtypes
Preoperative ctDNA data were available for 138 patients and postoperative ctDNA data for 144 patients. Preoperative samples were obtained within 1 month before or on the day of radical cystectomy, at a median of 1 day before surgery. Postoperative ctDNA was assessed using the first sample collected within 90 days after surgery, at a median of 32 days. Patients were evaluated according to both histology and ctDNA detectability, with disease-free survival as the outcome.
Patients with histological subtypes were more likely to have detectable preoperative ctDNA than those with pure urothelial carcinoma, at 61% versus 40%, respectively. They also displayed more advanced pathological features. Pathological stage ≥pT2 was observed in 90% of patients with histological subtypes compared with 57% of those with pure urothelial carcinoma, while lymph node involvement was present in 39% versus 23%, respectively. Adjuvant therapy was also used more frequently in patients with histological subtypes, at 33% compared with 19% in the pure urothelial carcinoma group. The histological subtype cohort included micropapillary, squamous, glandular, plasmacytoid, sarcomatoid, nested, small cell, and other less common tumor subtypes.
Preoperative ctDNA Impact on Disease-Free Survival
Among the 138 patients with available preoperative ctDNA results, 45 had undetectable ctDNA and pure urothelial carcinoma, 37 had detectable ctDNA and pure urothelial carcinoma, 15 had undetectable ctDNA and histological subtypes, and 41 had detectable ctDNA and histological subtypes. After a median follow-up of 21 months, 46 patients experienced disease recurrence or death. In patients with pure urothelial carcinoma, 24-month disease-free survival was 89% among those with undetectable preoperative ctDNA compared with 49% among those with detectable ctDNA. A similar pattern was observed in patients with histological subtypes, where 24-month disease-free survival was 79% with undetectable ctDNA versus 43% with detectable ctDNA.
After multivariable adjustment, detectable preoperative ctDNA remained independently associated with recurrence or death in both histological groups. For patients with pure urothelial carcinoma, the hazard ratio was 4.07. For patients with histological subtypes, the hazard ratio was 3.99. There were no significant differences in disease-free survival between pure urothelial carcinoma and histological subtypes among either the ctDNA-detectable or ctDNA-undetectable populations.
Postoperative ctDNA Outcomes and Broader National Context
Postoperative ctDNA results were available for 144 patients. Among them, 66 had undetectable ctDNA and pure urothelial carcinoma, 15 had detectable ctDNA and pure urothelial carcinoma, 43 had undetectable ctDNA and histological subtypes, and 20 had detectable ctDNA and histological subtypes. After a median follow-up of 22 months, 49 patients had experienced disease recurrence or death. In the pure urothelial carcinoma group, 24-month disease-free survival was 81% in patients with undetectable postoperative ctDNA compared with 30% in those with detectable ctDNA. Among patients with histological subtypes, the corresponding rates were 66% and 29%. Detectable postoperative ctDNA remained independently associated with disease recurrence or death after multivariable adjustment, yielding a hazard ratio of 4.38.
According to federal cancer data, bladder cancer remains the sixth most common cancer in the United States, with estimated new cases reaching 84,870 and deaths totaling 17,420 in 2025. The identification of reliable prognostic markers like ctDNA across diverse histological variants addresses a critical stratification gap for a disease where muscle-invasive cases are traditionally treated by either removing the bladder or treating the bladder with radiation and chemotherapy.
