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

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)...

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Bibliographic Details
Published in:Clinical cancer research 2020-04, Vol.26 (8), p.1924-1931
Main Authors: Pairawan, Seyed, Hess, Kenneth R, Janku, Filip, Sanchez, Nora S, Mills Shaw, Kenna R, Eng, Cathy, Damodaran, Senthilkumar, Javle, Milind, Kaseb, Ahmed O, Hong, David S, Subbiah, Vivek, Fu, Siqing, Fogelman, David R, Raymond, Victoria M, Lanman, Richard B, Meric-Bernstam, Funda
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Aged, 80 and over
Biomarkers, Tumor - blood
Biomarkers, Tumor - genetics
Cell-Free Nucleic Acids - blood
Cell-Free Nucleic Acids - genetics
Child
Female
Gene Frequency
High-Throughput Nucleotide Sequencing - methods
Humans
Male
Middle Aged
Mutation
Neoplasm Metastasis
Neoplasms - blood
Neoplasms - genetics
Neoplasms - mortality
Neoplasms - pathology
Prognosis
Retrospective Studies
Survival Rate
Young Adult
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Summary: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. 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. cfDNA mutations were detected in 240 patients (80.5%). 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; < 0.0001). VAF was classified by quartiles, Q1 lowest, Q4 highest VAF. Higher VAF levels were associated with a significantly worse overall survival (VAF Q3 HR 2.3, = 0.0069; VAF Q4 HR = 3.8, < 0.0001) on univariate analysis. On multivariate analysis, VAF Q4, male sex, albumin level 0 and number of prior therapies >4 were independent predictors of worse OS. Higher levels of cfDNA VAF and a higher number of NSMs 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.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-19-0306