Integrated Urine and Plasma DNA Analysis for Molecular Staging of Upper Tract Urothelial Carcinoma.

BACKGROUND AND OBJECTIVE: Current clinical risk stratification for determining neoadjuvant chemotherapy (NAC) usage in nonmetastatic upper tract urothelial carcinoma (UTUC) is frequently inaccurate. This uncertainty leads to suboptimal patient selection, often resulting in either overtreatment of low-stage disease or missed opportunities for NAC in advanced cases. This study evaluates the prognostic performance of urine tumor DNA (utDNA) and plasma circulating tumor DNA (ctDNA) testing as a tool for improving the diagnostic staging and clinical management of UTUC. METHODS: A total of 41 patients who underwent surgical extirpation for localized UTUC were evaluated using utDNA and ctDNA. Prognostic performance of utDNA and ctDNA testing was compared to standard-of-care (SOC) risk assessment and pathology at surgery. The primary analysis was validation of utDNA TP53 mutation and ctDNA status as predictors of muscle-invasive UTUC. KEY FINDINGS AND LIMITATIONS: A total of 21 (51%) patients had muscle-invasive UTUC. Univariable logistic regression identified molecular staging (utDNA TP53 and ctDNA status) as a strong predictor of muscle-invasive disease (odds ratio [OR] 9.6, p = 0.002) and the only significant predictor by multivariable analysis (OR 8.5, p = 0.004). When combined with SOC diagnostic staging (biopsy and imaging), molecular staging had significantly better specificity (70% vs 25%) and postive predictive value (74% vs 53%) compared to SOC risk factors (high-grade biopsy and cytology) for identifying muscle-invasive disease, with equivalent sensitivity (81% vs 81%) and negative predictive value (78% vs 56%, p = 0.15). CONCLUSIONS AND CLINICAL IMPLICATIONS: Composite liquid biopsy testing can significantly enhance noninvasive staging of UTUC. Improved staging and prognostic classification can improve personalized risk assessment and treatment intensification.