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Clin Cancer Res. 2019 Dec 18. pii: clincanres.0306.2019. doi: 10.1158/1078-0432.CCR-19-0306. [Epub ahead of print]

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

Author information

1
Surgical Oncology, University of Texas MD Anderson Cancer Center.
2
Biostatistics, University of Texas MD Anderson Cancer Center.
3
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center.
4
Genomic Medicine, The University of Texas MD Anderson Cancer Center.
5
The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center.
6
Co-Director, GI Oncology, Vanderbilt-Ingram Cancer Center.
7
Division Of Medical Oncology, Department of Internal Medicine, Ohio State University.
8
Department of Gastrointestinal Oncology, University of Texas MD Anderson Cancer Center.
9
GI Medical Oncology, University of Texas MD Anderson Cancer Center.
10
Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center.
11
Center for Cancer Research, University of Texas MD Anderson Cancer Center.
12
Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center.
13
Medical Affairs, Guardant Health, Inc.
14
Department of Medical Affairs, Guardant Health, Inc.
15
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center fmeric@mdanderson.org.

Abstract

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 < 0.0001). 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, p = 0.0069: VAF Q4 HR = 3.8, p < 0.0001) on univariate analysis. On multivariate analysis, VAF Q4, male sex, albumin level < 3.5 g/dL, number of non-visceral metastatic sites > 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.

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