Cell-Free Circulating Tumor DNA Variant Allele Frequency Associates with Survival in Metastatic Cancer

Purpose: Physicians are expected to assess prognosis both for patient counseling and for determining suitability for clinical trials. Increasingly, cell-free circulating tumor DNA (cfDNA) sequencing is being performed for clinical decision-making. We sought to determine whether variant allele frequency (VAF) in cfDNA is associated with prognosis. Experimental Design: We performed a retrospective analysis of 298 patients with metastatic disease who underwent clinical comprehensive cfDNA analysis and assessed association between VAF and overall survival. Results: cfDNA mutations were detected in 240 (80.5%) patients. Median overall survival (OS) was 11.5 months. cfDNA mutation detection and number of nonsynonymous mutations (NSM) significantly differed between tumor types; being lowest in appendiceal cancer and highest in colon cancer. Having more than one NSM detected was associated with significantly worse OS (HR = 2.3, p 0 and number of prior therapies >4 were independent predictors of worse OS. Conclusions: Higher levels of cfDNA VAF and higher number of NSM were associated with worse OS in patients with metastatic disease. Further study is needed to determine optimal VAF thresholds for clinical decision-making and the utility of cfDNA VAF as a prognostic marker in different tumor types.