@article{c8f434a5c5944c648ca6903e77fdc839,
title = "Genotype-Specific Differences in Circulating Tumor DNA Levels in Advanced NSCLC",
abstract = "Introduction: Plasma-based circulating tumor DNA (ctDNA) is an established biomarker for molecular profiling with emerging applications in disease monitoring in multiple tumor types, including, NSCLC. However, determinants of ctDNA shedding and correlation with tumor burden are incompletely understood, particularly in advanced-stage disease. Methods: We retrospectively analyzed ctDNA-based and tissue-based genomic data and imaging from 144 patients with NSCLC. Tumor burden was quantified with computed tomography (CT) and brain magnetic resonance imaging for the overall cohort and 18F-fludeoxyglucose positron emission tomography-CT in a subset of patients. Results: There was a moderate but statistically significant correlation between ctDNA variant allele frequency and multiple imaging measures of tumor burden such as CT volume (rho = 0.34, p ≤ 0.0001) and metabolic tumor volume (rho = 0.36, p = 0.003). This correlation was strongest in KRAS-mutant tumors (rho = 0.56, p ≤ 0.001), followed by TP53 mutants (rho = 0.43, p ≤ 0.0001), and weakest in EGFR-mutated (EGFR+) tumors (rho = 0.24, p = 0.077). EGFR+ tumors with EGFR copy number gain had significantly higher variant allele frequency than EGFR+ without copy number gain (p ≤ 0.00001). In multivariable analysis, TP53 and EGFR mutations, visceral metastasis, and tumor burden were independent predictors of increased ctDNA shedding. Conclusions: Levels of detectable ctDNA were affected not only by tumor burden but also by tumor genotype. The genotype-specific differences observed may be due to variations in DNA shedding and cellular turnover. These findings have implications for the emerging use of ctDNA in NSCLC disease monitoring and early detection.",
keywords = "Cancer detection, Genotype, Liquid biopsy, Lung cancer, PET/CT, Tumor volume, ctDNA",
author = "Lam, {Vincent K.} and Jianjun Zhang and Wu, {Carol C.} and Tran, {Hai T.} and Lerong Li and Lixia Diao and Jing Wang and Waree Rinsurongkawong and Raymond, {Victoria M.} and Lanman, {Richard B.} and Jeff Lewis and Roarty, {Emily B.} and Jack Roth and Stephen Swisher and Lee, {J. Jack} and Gibbons, {Don L.} and Papadimitrakopoulou, {Vassiliki A.} and Heymach, {John V.}",
note = "Funding Information: Disclosure: Dr. Lam reports receiving advisory role fees from Takeda , Seattle Genetics , and Bristol-Myers Squibb and research funding from Bristol-Myers Squibb. Dr. Raymond is an employee and stockholder of Guardant Health, Inc. Dr. Lanman reports receiving advisory role fees from Guardant Health, Inc ., and is a stockholder. Dr. Roth reports receiving ownership interest in and advisory role fees from Genprex. Dr. Gibbons reports receiving advisory role fees from AstraZeneca , GlaxoSmithKline , Sanofi , and Janssen and research funding from Janssen, Takeda, Ribon Therapeutics , Astellas , and AstraZeneca. Dr. Papadimitrakopoulou reports receiving honoraria from F. Hoffman-La Roche ; research funding from AstraZeneca, Bristol-Myers Squibb, Eli Lilly , Novartis , Merck , F. Hoffman-La Roche, Nektar Therapeutics , Janssen , Checkmate , and Incyte ; and advisory role fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Novartis, Merck, F. Hoffman-La Roche, Nektar Therapeutics, Janssen, AbbVie , Araxes , Arrys Therapeutics , Bolt Therapeutics , Clovis Oncology , Exelixis , G2 Innovation , Gritstone , Ideaya , Leeds Biolabs , Loxo Oncology , Takeda, Tesaro , and TRM Oncology . Dr. Zhang reports receiving research funding from Merck and Johnson and Johnson and consulting fees from Bristol-Myers Squibb, Johnson and Johnson, AstraZeneca, Geneplus , OrigMed , and Innovent . Dr. Heymach reports receiving advisory role fees from AstraZeneca, Boehringer Ingelheim , Bristol-Myers Squibb, Catalyst , EMD Serono , Foundation Medicine , Hengrui Therapeutics , Genentech , GlaxoSmithKline, Guardant Health, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, Seattle Genetics , Spectrum, and Takeda; research funding from AstraZeneca, GlaxoSmithKline, Spectrum, and royalties; and licensing fees from Spectrum. The remaining authors declare no conflict of interest. Funding Information: Disclosure: Dr. Lam reports receiving advisory role fees from Takeda, Seattle Genetics, and Bristol-Myers Squibb and research funding from Bristol-Myers Squibb. Dr. Raymond is an employee and stockholder of Guardant Health, Inc. Dr. Lanman reports receiving advisory role fees from Guardant Health, Inc., and is a stockholder. Dr. Roth reports receiving ownership interest in and advisory role fees from Genprex. Dr. Gibbons reports receiving advisory role fees from AstraZeneca, GlaxoSmithKline, Sanofi, and Janssen and research funding from Janssen, Takeda, Ribon Therapeutics, Astellas, and AstraZeneca. Dr. Papadimitrakopoulou reports receiving honoraria from F. Hoffman-La Roche; research funding from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Novartis, Merck, F. Hoffman-La Roche, Nektar Therapeutics, Janssen, Checkmate, and Incyte; and advisory role fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Novartis, Merck, F. Hoffman-La Roche, Nektar Therapeutics, Janssen, AbbVie, Araxes, Arrys Therapeutics, Bolt Therapeutics, Clovis Oncology, Exelixis, G2 Innovation, Gritstone, Ideaya, Leeds Biolabs, Loxo Oncology, Takeda, Tesaro, and TRM Oncology. Dr. Zhang reports receiving research funding from Merck and Johnson and Johnson and consulting fees from Bristol-Myers Squibb, Johnson and Johnson, AstraZeneca, Geneplus, OrigMed, and Innovent. Dr. Heymach reports receiving advisory role fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Catalyst, EMD Serono, Foundation Medicine, Hengrui Therapeutics, Genentech, GlaxoSmithKline, Guardant Health, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, Seattle Genetics, Spectrum, and Takeda; research funding from AstraZeneca, GlaxoSmithKline, Spectrum, and royalties; and licensing fees from Spectrum. The remaining authors declare no conflict of interest.This study was funded by Lung SPORE P50CA07907 (The University of Texas Southwestern Medical Center and The University of Texas MD Anderson Cancer Center), National Institutes of Health CCSG CA016672, and the Gil and Dody Weaver Foundation. The authors acknowledge the generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Moon Shots Program. The authors thank the GEMINI team for their research support. Drs. Lam, Zhang, and Heymach contributed to conception and design; Drs. Lam, Wu, Zhang, and Heymach contributed to development of methodology; Drs. Lam, Wu, Tran, Rinsurongkawong, Lewis, Roarty, Roth, Swisher, Lee, and Gibbons contributed to data acquisition; Drs. Lam, Wu, Li, Diao, Wang, Lee, Zhang, and Heymach contributed to analysis and interpretation of data; Drs. Lam, Wu, Tran, Li, Diao, Wang, Rinsurongkawong, Raymond, Lanman, Lewis, Roarty, Roth, Swisher, Lee, Gibbons, Papadimitrakopoulou, Zhang, and Heymach contributed to writing, review, and revision of the manuscript; Drs. Lam, Zhang, and Heymach contributed to study supervision of the manuscript. Funding Information: This study was funded by Lung SPORE P50CA07907 (The University of Texas Southwestern Medical Center and The University of Texas MD Anderson Cancer Center), National Institutes of Health CCSG CA016672 , and the Gil and Dody Weaver Foundation . The authors acknowledge the generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Moon Shots Program. The authors thank the GEMINI team for their research support. Drs. Lam, Zhang, and Heymach contributed to conception and design; Drs. Lam, Wu, Zhang, and Heymach contributed to development of methodology; Drs. Lam, Wu, Tran, Rinsurongkawong, Lewis, Roarty, Roth, Swisher, Lee, and Gibbons contributed to data acquisition; Drs. Lam, Wu, Li, Diao, Wang, Lee, Zhang, and Heymach contributed to analysis and interpretation of data; Drs. Lam, Wu, Tran, Li, Diao, Wang, Rinsurongkawong, Raymond, Lanman, Lewis, Roarty, Roth, Swisher, Lee, Gibbons, Papadimitrakopoulou, Zhang, and Heymach contributed to writing, review, and revision of the manuscript; Drs. Lam, Zhang, and Heymach contributed to study supervision of the manuscript. Publisher Copyright: {\textcopyright} 2021 International Association for the Study of Lung Cancer",
year = "2021",
month = apr,
doi = "10.1016/j.jtho.2020.12.011",
language = "English (US)",
volume = "16",
pages = "601--609",
journal = "Journal of Thoracic Oncology",
issn = "1556-0864",
publisher = "International Association for the Study of Lung Cancer",
number = "4",
}