Longitudinal Tumor-informed Circulating Tumor DNA Status Predicts Disease Upstaging and Poor Prognosis for Patients Undergoing Radical Cystectomy

Abstract

Background and objective: Decision-making on the use of neoadjuvant and adjuvant treatment for patients with bladder cancer undergoing radical cystectomy (RC) currently depends on assessment of clinical and pathological features, which lack sensitivity. Circulating tumor DNA (ctDNA) has emerged as a possible novel prognostic biomarker in the field. Our aim was to assess whether ctDNA status before RC is predictive of pathological and oncological outcomes. We also evaluated the dynamic changes in ctDNA status after RC in relation to recurrence-free survival (RFS).

Methods: We analyzed data for patients who underwent RC during 2021-2023 for whom prospective tumor-informed ctDNA analyses were conducted before and after RC. RFS was evaluated using the Kaplan-Meier method. Predictors for disease recurrence were assessed using Cox proportional-hazards models. Pathological outcomes associated with detectable ctDNA before RC were assessed in univariable and multivariable regression analyses.

Key findings and limitations: We included 112 patients in the analysis. Median follow-up was 8 mo (interquartile range 4-13). ctDNA was detected before RC in 59 patients (53%) and was associated with poor RFS (log-rank p < 0.0001). Detectable ctDNA before RC was associated with poor outcomes regardless of clinical stage (<cT2 vs ≥cT2) and receipt of neoadjuvant therapy. Multivariable analyses revealed that detectable ctDNA before RC was associated with a higher risk of nodal disease (odds ratio 5.4, 95% confidence interval [CI] 1.9-18.2; p = 0.003) and locally advanced disease (odds ratio 3.6, 95% CI 1.5-9; p = 0.005). Cox regression analyses showed that detectable ctDNA before RC (hazard ratio 4.5, 95% CI 1-19; p = 0.04) and detectable ctDNA at the minimal residual disease window (hazard ratio 9.9, 95% CI 2.6-37; p < 0.001) were predictive of disease recurrence.

Conclusions and clinical implications: Detectable ctDNA before definitive therapy with RC is predictive of nodal involvement, locally advanced disease, and disease recurrence in patients with bladder cancer. ctDNA status holds promise for improving clinical staging and augmenting current decision-making tools.

Patient summary: We found that for patients with bladder cancer undergoing radical cystectomy, a test to show the presence of tumor DNA in blood before surgery was able to predict the risk of disease relapse and adverse pathology. Use of this assay could help in decision-making by clinicians and patients for optimal personalized treatment of this disease.

Keywords: Circulating tumor DNA; Non–muscle-invasive bladder neoplasms; Tumor biomarkers; Urinary bladder neoplasms.