Preoperative Tumor-Informed ctDNA for Prediction of Nodal Metastases at Radical Cystectomy in Bladder Cancer

Background This study aimed to evaluate whether pre-surgical tumor-informed circulating tumor DNA (ctDNA) predicts pathologic nodal status at radical cystectomy and its potential role in risk stratification for future biomarker-guided surgical strategies. Methods The study prospectively analyzed 40 patients with non–muscle-invasive and muscle-invasive bladder cancer who underwent radical cystectomy with pelvic lymph node dissection (LND) and pre-surgical tumor-informed ctDNA testing. Compared with pathologic nodal findings, ctDNA status was classified as positive or negative. Diagnostic performance metrics with 95 % confidence intervals (CIs) were calculated. To assess reproducibility, data from a published cohort meeting comparable inclusion criteria were integrated for pooled descriptive analysis. Results Of 40 patients, 27 (68 %) were ctDNA-negative and 13 (32 %) were ctDNA-positive before cystectomy. Pathologic nodal metastases were identified in seven patients (18 %). For nodal metastases, ctDNA demonstrated a sensitivity of 86 % (95 % CI, 49–97 %), a specificity of 79 % (95 % CI, 62–89 %), and negative predictive value of 96 % (95 % CI, 82–99 %). In pooled descriptive analysis including 149 patients, the negative predictive value remained high at 92 % (95 % CI, 84–97 %). A simulated ctDNA-guided omission strategy may have avoided LND for 27 patients (68 %), with one false-negative case (3.7 %) that subsequently had recurrence. Conclusion Pre-surgical tumor-informed ctDNA showed high negative predictive value for nodal metastases at radical cystectomy. These findings supported prospective validation of ctDNA as a biomarker to identify patients at low risk of nodal metastases and inform future trials of biomarker-guided surgical strategies.