@article{876ebbe6f42a498db2bd6eb8f53f577d,
title = "Circulating Tumor DNA Analysis for Detection of Minimal Residual Disease After Chemoradiotherapy for Localized Esophageal Cancer",
abstract = "Background & Aims: Biomarkers are needed to risk stratify after chemoradiotherapy for localized esophageal cancer. These could improve identification of patients at risk for cancer progression and selection of additional therapy. Methods: We performed deep sequencing (CAncer Personalized Profiling by deep Sequencing, [CAPP-Seq]) analyses of plasma cell-free DNA collected from 45 patients before and after chemoradiotherapy for esophageal cancer, as well as DNA from leukocytes and fixed esophageal tumor biopsy samples collected during esophagogastroduodenoscopy. Patients were treated from May 2010 through October 2015; 23 patients subsequently underwent esophagectomy, and 22 did not undergo surgery. We also sequenced DNA from blood samples from 40 healthy control individuals. We analyzed 802 regions of 607 genes for single-nucleotide variants previously associated with esophageal adenocarcinoma or squamous cell carcinoma. Patients underwent imaging analyses 6–8 weeks after chemoradiotherapy and were followed for 5 years. Our primary aim was to determine whether detection of circulating tumor DNA (ctDNA) after chemoradiotherapy is associated with risk of tumor progression (growth of local, regional, or distant tumors, detected by imaging or biopsy). Results: The median proportion of tumor-derived DNA in total cell-free DNA before treatment was 0.07%, indicating that ultrasensitive assays are needed for quantification and analysis of ctDNA from localized esophageal tumors. Detection of ctDNA after chemoradiotherapy was associated with tumor progression (hazard ratio, 18.7; P <. 0001), formation of distant metastases (hazard ratio, 32.1; P <. 0001), and shorter disease-specific survival times (hazard ratio, 23.1; P <. 0001). A higher proportion of patients with tumor progression had new mutations detected in plasma samples collected after chemoradiotherapy than patients without progression (P = .03). Detection of ctDNA after chemoradiotherapy preceded radiographic evidence of tumor progression by an average of 2.8 months. Among patients who received chemoradiotherapy without surgery, combined ctDNA and metabolic imaging analysis predicted progression in 100% of patients with tumor progression, compared with 71% for only ctDNA detection and 57% for only metabolic imaging analysis (P <. 001 for comparison of either technique to combined analysis). Conclusions: In an analysis of cell-free DNA in blood samples from patients who underwent chemoradiotherapy for esophageal cancer, detection of ctDNA was associated with tumor progression, metastasis, and disease-specific survival. Analysis of ctDNA might be used to identify patients at highest risk for tumor progression.",
keywords = "Chemoradiotherapy, Genetics, Polymorphism, SNP",
author = "Azad, {Tej D.} and Chaudhuri, {Aadel A.} and Penny Fang and Yawei Qiao and Esfahani, {Mohammad S.} and Chabon, {Jacob J.} and Hamilton, {Emily G.} and Yang, {Yi D.} and Alex Lovejoy and Newman, {Aaron M.} and Kurtz, {David M.} and Michael Jin and Joseph Schroers-Martin and Henning Stehr and Liu, {Chih Long} and Hui, {Angela Bik Yu} and Viren Patel and Dipen Maru and Lin, {Steven H.} and Alizadeh, {Ash A.} and Maximilian Diehn",
note = "Funding Information: Conflicts of interest The authors disclose the following: Aadel A. Chaudhuri reports honoraria and travel support from Roche Sequencing Solutions and Foundation Medicine and has received research funding from Roche Sequencing Solutions and served as a consultant for Oscar Health. Aaron M. Newman, Ash A. Alizadeh, and Maximilian Diehn are coinventors on patent applications related to cancer biomarkers. Aaron M. Newman reports consultancy with CiberMed. Ash A. Alizadeh, Maximilian Diehn, and David M. Kurtz are consultants for Roche Molecular Systems, and Alex Lovejoy is employed by Roche Molecular Systems. Jacob J. Chabon served as a consultant with Lexent Bio. Ash A. Alizadeh has served as a consultant for Genentech, Roche, Chugai, Gilead, and Celgene and reports ownership interest in CiberMed and FortySeven. Maximilian Diehn has served as a consultant for Roche, AstraZeneca, and BioNTech. Maximilian Diehn and Aadel A. Chaudhuri have received research funding from Varian Medical Systems. Maximilian Diehn also reports ownership interest in CiberMed. Steven H. Lin has received research funding from Genentech, New River Labs, BeyondSpring Pharmaceuticals, Hitachi Chemical Diagnostics, and Elekta. Steven H. Lin serves on an advisory board of AstraZeneca. The remaining authors disclose no conflicts. Funding Information: Funding This work was supported by grants from the National Cancer Institute (Maximilian Diehn, Ash A. Alizadeh, R01CA188298), the US National Institutes of Health Director's New Innovator Award Program (Maximilian Diehn, 1-DP2-CA186569), a Stanford Cancer Institute?Developmental Cancer Research Award (Maximilian Diehn and Ash A. Alizadeh), Doris Duke Charitable Foundation Clinical Research Mentorship Fellowship (Tej D. Azad), the Stanford Medical Scholars Program (Tej D. Azad), the Ludwig Institute for Cancer Research (Maximilian Diehn, Ash A. Alizadeh), and the CRK Faculty Scholar Fund (Maximilian Diehn), a Stanford Society for Physician Scholars Grant (Tej D. Azad, Aadel A. Chaudhuri), a Radiological Society of North America Resident/Fellow Grant (Aadel A. Chaudhuri), the American Society of Clinical Oncology Young Investigator Award (Aadel A. Chaudhuri), the Mabuchi Research Fund (Steven H. Lin), and the R. Lee Clark Clinical Innovator Award (Steven H. Lin). Conflicts of interest The authors disclose the following: Aadel A. Chaudhuri reports honoraria and travel support from Roche Sequencing Solutions and Foundation Medicine and has received research funding from Roche Sequencing Solutions and served as a consultant for Oscar Health. Aaron M. Newman, Ash A. Alizadeh, and Maximilian Diehn are coinventors on patent applications related to cancer biomarkers. Aaron M. Newman reports consultancy with CiberMed. Ash A. Alizadeh, Maximilian Diehn, and David M. Kurtz are consultants for Roche Molecular Systems, and Alex Lovejoy is employed by Roche Molecular Systems. Jacob J. Chabon served as a consultant with Lexent Bio. Ash A. Alizadeh has served as a consultant for Genentech, Roche, Chugai, Gilead, and Celgene and reports ownership interest in CiberMed and FortySeven. Maximilian Diehn has served as a consultant for Roche, AstraZeneca, and BioNTech. Maximilian Diehn and Aadel A. Chaudhuri have received research funding from Varian Medical Systems. Maximilian Diehn also reports ownership interest in CiberMed. Steven H. Lin has received research funding from Genentech, New River Labs, BeyondSpring Pharmaceuticals, Hitachi Chemical Diagnostics, and Elekta. Steven H. Lin serves on an advisory board of AstraZeneca. The remaining authors disclose no conflicts. Funding Information: Funding This work was supported by grants from the National Cancer Institute (Maximilian Diehn, Ash A. Alizadeh, R01CA188298), the US National Institutes of Health Director{\textquoteright}s New Innovator Award Program (Maximilian Diehn, 1-DP2-CA186569), a Stanford Cancer Institute–Developmental Cancer Research Award (Maximilian Diehn and Ash A. Alizadeh), Doris Duke Charitable Foundation Clinical Research Mentorship Fellowship (Tej D. Azad), the Stanford Medical Scholars Program (Tej D. Azad), the Ludwig Institute for Cancer Research (Maximilian Diehn, Ash A. Alizadeh), and the CRK Faculty Scholar Fund (Maximilian Diehn), a Stanford Society for Physician Scholars Grant (Tej D. Azad, Aadel A. Chaudhuri), a Radiological Society of North America Resident/Fellow Grant (Aadel A. Chaudhuri), the American Society of Clinical Oncology Young Investigator Award (Aadel A. Chaudhuri), the Mabuchi Research Fund (Steven H. Lin), and the R. Lee Clark Clinical Innovator Award (Steven H. Lin). Publisher Copyright: {\textcopyright} 2020 AGA Institute",
year = "2020",
month = feb,
doi = "10.1053/j.gastro.2019.10.039",
language = "English",
volume = "158",
pages = "494--505.e6",
journal = "Gastroenterology",
issn = "0016-5085",
number = "3",
}