Relationship of tumor fraction in circulating tumor DNA with prognosis in patients with advanced urothelial cancer

•ctDNA TF is assessed in real-world data in urothelial carcinoma.•ctDNA TF in UC is associated with important clinical and pathological features.•ctDNA TF is associated with rwPFS.•ctDNA TF is prognostic across a range of TF cut points.•More work is needed to optimize and validate a specific cut point for prognosis. BackgroundAdvanced urothelial cancer (aUC) is often characterized by rapid symptomatic disease progression, making early disease control of particular importance. Circulating tumor DNA (ctDNA) is a promising prognostic biomarker and emerging evidence shows that a single time point/measurement of ctDNA tumor fraction (TF) is prognostic in several other tumor types but has not yet been investigated in aUC. This study aimed to evaluate the prognostic value of ctDNA TF in aUC.Patients and methodsThis study used a cohort of patients from a de-identified nationwide (US-based) urothelial clinico-genomic database who underwent ctDNA testing using FoundationOne®Liquid or FoundationOne®Liquid CDx as part of routine care. Patient/disease characteristics and laboratory and treatment data were captured from the electronic health record. Real-world progression-free survival (rwPFS) and overall survival (rwOS) were evaluated by ctDNA TF while controlling for relevant covariates.ResultsEighty-three patients with aUC were included. High ctDNA TF (≥1%) was associated with poor prognostic clinical features. High ctDNA TF also correlated with significantly reduced rwPFS in univariable analysis [hazard ratio (HR) 2.01, 95% CI (1.14-3.56), P = 0.01] and after correction for covariates [HR 2.37, 95% CI (0.99-5.66), P = 0.05]. There was a trend toward shorter rwOS in univariable [HR 1.71, 95% CI (0.87-3.36)] and multivariable [HR 1.55, (0.57-4.23)] analysis.ConclusionsctDNA TF is a prognostic biomarker in aUC with potential to inform expected longevity of patients. Uniform cohorts, with regard to treatments given and line of therapy, would help further evaluate the ability of ctDNA TF to identify patients with aggressive disease and inform the design of future studies to personalize therapeutic decision making. Advanced urothelial cancer (aUC) is often characterized by rapid symptomatic disease progression, making early disease control of particular importance. Circulating tumor DNA (ctDNA) is a promising prognostic biomarker and emerging evidence shows that a single time point/measurement of ctDNA tumor fraction (TF) is prognostic in several other tumor types but has not yet been investigated in aUC. This study aimed to evaluate the prognostic value of ctDNA TF in aUC. This study used a cohort of patients from a de-identified nationwide (US-based) urothelial clinico-genomic database who underwent ctDNA testing using FoundationOne®Liquid or FoundationOne®Liquid CDx as part of routine care. Patient/disease characteristics and laboratory and treatment data were captured from the electronic health record. Real-world progression-free survival (rwPFS) and overall survival (rwOS) were evaluated by ctDNA TF while controlling for relevant covariates. Eighty-three patients with aUC were included. High ctDNA TF (≥1%) was associated with poor prognostic clinical features. High ctDNA TF also correlated with significantly reduced rwPFS in univariable analysis [hazard ratio (HR) 2.01, 95% CI (1.14-3.56), P = 0.01] and after correction for covariates [HR 2.37, 95% CI (0.99-5.66), P = 0.05]. There was a trend toward shorter rwOS in univariable [HR 1.71, 95% CI (0.87-3.36)] and multivariable [HR 1.55, (0.57-4.23)] analysis. ctDNA TF is a prognostic biomarker in aUC with potential to inform expected longevity of patients. Uniform cohorts, with regard to treatments given and line of therapy, would help further evaluate the ability of ctDNA TF to identify patients with aggressive disease and inform the design of future studies to personalize therapeutic decision making.