Circulating tumor DNA analysis in advanced urothelial carcinoma: insights from biological analysis and extended clinical follow-up

Abstract

AbstractPurposeTo investigate whether circulating-tumor DNA (ctDNA) assessment in patients with muscle-invasive bladder cancer predicts treatment response and provides early detection of metastatic disease.Experimental DesignWe present full follow-up results (median follow-up: 68 months) from a previously described cohort of 68 neoadjuvant chemotherapy (NAC)-treated patients who underwent longitudinal ctDNA testing (712 plasma samples). In addition, we performed ctDNA evaluation of 153 plasma samples collected before and after radical cystectomy (RC) in a separate cohort of 102 NAC-naïve patients (median follow-up: 72 months). Total RNA-sequencing of tumors was performed to investigate biological characteristics of ctDNA shedding tumors.ResultsAssessment of ctDNA after RC identified metastatic relapse with a sensitivity of 94% and specificity of 98% using the expanded follow-up data for the NAC-treated patients. ctDNA dynamics during NAC was independently associated with patient outcomes when adjusted for pathological downstaging (HR=4.7,p=0.029). For the NAC-naïve patients, ctDNA was a prognostic predictor before (HR=3.4,p=0.0005) and after RC (HR=17.8,p=0.0002). No statistically significant difference in recurrence-free survival for patients without detectable ctDNA at diagnosis was observed between the cohorts. Baseline ctDNA positivity was associated with the Ba/Sq subtype and enrichment of epithelial-to-mesenchymal transition and cell-cycle associated gene sets.ConclusionsctDNA is prognostic in NAC-treated and NAC-naïve patients with more than five years follow-up and outperforms pathological downstaging in predicting treatment efficacy. Patients without detectable ctDNA at diagnosis may benefit significantly less from NAC, but additional studies are needed.