TY - JOUR
T1 - Cell-free circulating tumor DNA variant allele frequency associates with survival in metastatic cancer
AU - Pairawan, Seyed
AU - Hess, Kenneth R.
AU - Janku, Filip
AU - Sanchez, Nora S.
AU - Shaw, Kenna R.Mills
AU - Eng, Cathy
AU - Damodaran, Senthilkumar
AU - Javle, Milind
AU - Kaseb, Ahmed O.
AU - Hong, David S.
AU - Subbiah, Vivek
AU - Fu, Siqing
AU - Fogelman, David R.
AU - Raymond, Victoria M.
AU - Lanman, Richard B.
AU - Meric-Bernstam, Funda
N1 - Funding Information:
F. Janku reports receiving commercial research grants from Novartis, Gen-entech, BioMed Valley Discoveries, Plexxikon, Deciphera, Piqur, Symphogen, Bayer, Fujifilm Corporation and Upsher-Smith Laboratories, Astex, Asana, Astellas, Agois, Proximagen, and Bristol-Myers Squibb; holds ownership interest (including patents) in Tovagene; and is an advisory board member/unpaid consultant for Deciphera, IFM Therapeutics, Synlogic, Guardant Health, Ideaya, PureTechHealth, Jazz Pharmaceuticals, Primmune Therapeutics, Sotio, Trova-gene, and Immunomet. S. Damodaran reports receiving commercial research grants from Guardant Health and is an advisory board member/unpaid consultant for Taiho and Tempus. D.S. Hong is an employee/paid consultant for Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, and Trieza Therapeutics; reports receiving commercial research grants from AbbVie, Adaptimmune, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, MiRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, and Takeda; reports receiving speakers bureau honoraria from LOXO, MiRNA, ASCO, AACR, SITC, GENMAB; and reports receiving other remuneration from Molecular Match, OncoResponse, and Presagia Inc. V. Subbiah reports receiving other commercial research support from Novartis, Bayer, Nanocarrier, NOXO Oncology, Blueprint Medicines, Vegenics, Amgen, Takeda, Roche/Genentech, and Incyte. R.B. Lanman is an employee/paid consultant for Guardant Health Inc. and Biolase; holds ownership interest (including patents) in Guardant Health, Inc., Biolase, Inc. and Forward Medical, Inc.; and is an advisory board member/ unpaid consultant for Forward Medical, Inc. F. Meric-Bernstam reports receiving commercial research grants from Novartis, AstraZeneca, Taiho, Genentech, Calithera, Debiopharm, Bayer, Aileron, PUMA, CytoMx, Zymeworks, Curis, Pfizer, eFFECTOR, Abbvie, Guardant Health, Daiichi Sankyo, and GlaxoSmithKline; reports receiving speakers bureau honoraria from Sumitomo Dainippon and Dialectica; and is an advisory board member/unpaid consultant for Genentech, Pieris, Samsung Bioepis, Aduro, OrigMed, Debiopharm, Xencor, Jackson Laboratory, Zymeworks, Kolon Life Sciences, Parexel International, Inflection Biosciences, Darwin Health, Spectrum, Mersana, and Seattle Genetics. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
This work was supported by the T32 (CA009599, to S. Pairawan and F. Meric-Bernstam), Guardant Health (to N.S. Sanchez and F. Meric-Bernstam), Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy (to N.S. Sanchez, K.R. Mills Shaw, and F. Meric-Bernstam), Cancer Prevention
Funding Information:
mThis work was supported by the T32 (CA009599, to S. Pairawan and F. Meric- Bernstam), Guardant Health (to N.S. Sanchez and F. Meric-Bernstam), Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy (to N.S. Sanchez, K.R. Mills Shaw, and F. Meric-Bernstam), Cancer Prevention Research Institutive of Texas (CPRIT) Precision Oncology Decision Support Core RP150535 (to N.S. Sanchez, K.R. Mills Shaw, and F. Meric-Bernstam), and the MD Anderson Cancer Support Grant (P30 CA016672).
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/4/15
Y1 - 2020/4/15
N2 - 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 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; P < 0.0001).VAFwas 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 nonvisceral metastatic sites >0 and number of prior therapies >4 were independent predictors of worse OS. Conclusions: 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.
AB - 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 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; P < 0.0001).VAFwas 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 nonvisceral metastatic sites >0 and number of prior therapies >4 were independent predictors of worse OS. Conclusions: 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.
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U2 - 10.1158/1078-0432.CCR-19-0306
DO - 10.1158/1078-0432.CCR-19-0306
M3 - Article
C2 - 31852833
AN - SCOPUS:85083487252
SN - 1078-0432
VL - 26
SP - 1924
EP - 1931
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 8
ER -