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Decoding the Evolutionary Response to Ensartinib in ALK-Positive Non-Small-Cell Lung Cancer Patients by Dynamic Circulating Tumor DNA Sequencing.

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收录情况： ◇ SCIE

作者：
Yunpeng Yang[1] * ; Jie Huang[1] * ; Tao Wang[2] * ; Jianya Zhou[3] * ; Jing Zheng[3] ; Jifeng Feng[4] ; Wu Zhuang[5] ; Jianhua Chen[6] ; Jun Zhao[7] ; Wei Zhong[8] ; Yanqiu Zhao[9] ; Yiping Zhang[10] ; Yong Song[11] ; Yi Hu[12] ; Zhuang Yu[13] ; Youling Gong[14] ; Yuan Chen[15] ; Feng Ye[16] ; Shucai Zhang[17] ; Lejie Cao[18] ; Yun Fan[10] ; Gang Wu[19] ; Yubiao Guo[20] ; Chengzhi Zhou[21] ; Kewei Ma[22] ; Jian Fang[7] ; Weineng Feng[23] ; Yunpeng Liu[24] ; Zhendong Zheng[25] ; Gaofeng Li[26] ; Huijie Wang[27] ; Shundong Cang[28] ; Ning Wu[29] ; Wei Song[30] ; Xiaoqing Liu[31] ; Shijun Zhao[32] ; Lieming Ding[33] ; Li Mao[33] ; Giovanni Selvaggi[34] ; Larry Zhu[33] ; Shanshan Xiao[2] ; Xiaobin Yan[33] ; Zhilin Shen[33] ; Li Zhang[1,*1] ;
机构： [1]Department of Medical Oncology, Sun Yat-sen University Cancer Center, State KeyLaboratory of Oncology in South China, Collaborative Innovation Center for CancerMedicine, Guangzhou, China [2]Hangzhou Repugene Technology, Hangzhou, China [3]Department of Respiratory Disease, Thoracic Disease Center, The First AffiliatedHospital, College of Medicine, Zhejiang University, Hangzhou, China [4]Department of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute ofCancer Research, The Affiliated Cancer Hospital of Nanjing Medical University,Nanjing, China [5]Department of Thoracic Oncology, Fujian Provincial Cancer Hospital, Fujian MedicalUniversity Cancer Hospital, Fuzhou, China [6]Department of Medical Oncology-Chest, Hunan Cancer Hospital, Changsha, China [7]Department of Thoracic Oncology, Beijing Cancer Hospital, Beijing, China [8]Department of Pulmonary Medicine, Peking Union Medical College Hospital,Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing,China [9]Respiratory Department of Internal Medicine, Henan Provincial Cancer Hospital,Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China [10]Thoracic Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China [11]Division of Respiratory Medicine, Jinling Hospital, Nanjing University School ofMedicine, Nanjing, China [12]Department of Oncology, Chinese PLA General Hospital, Beijing, China [13]Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao,China [14]Department of Thoracic Oncology, Cancer Center, West China Hospital, SichuanUniversity, Chengdu, China [15]Department of Oncology, Tongji Hospital, Tongji Medical College, HuazhongUniversity of Science and Technology, Wuhan, China [16]Department of Medical Oncology, Cancer Hospital, The First Affiliated Hospital ofXiamen University, School of Medicine, Xiamen University, Teaching Hospital ofFujian Medical University, Xiamen, China [17]Department of Medical Oncology, Beijing Chest Hospital, Capital Medical 45 University,Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China [18]Respiratory Medicine, The First Affiliated Hospital of the University of Science andTechnology of China, Anhui Provincial Hospital, Hefei, China [19]Cancer Center, Union Hospital, Tongji Medical College, Huazhong University ofScience and Technology, Wuhan, China [20]Pulmonary & Critical Care Medicine, The First Affiliated Hospital, Sun Yat-senUniversity, Guangzhou, China [21]Respiratory Medicine Department, State Key Laboratory of Respiratory Disease,National Clinical Research Center for Respiratory Disease, Guangzhou Institute ofRespiratory Health, The First Affiliated Hospital of Guangzhou Medical University,Guangzhou, China [22]Cancer Center, The First Hospital of Jilin University, Changchun, China [23]Department of Head and Neck and Thoracic Medical Oncology, The First People’sHospital Of Foshan, Foshan, China [24]Oncology Medicine, The First Hospital of China Medical University, Shenyang,China [25]Oncology Department, General Hospital of Northern Theater Command, Shenyang,China [262]nd Department of Thoracic Surgery, Yunnan Cancer Hospital, Kunming, China [27]Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China [28]Medical oncology, Henan Provincial People's Hospital, Henan, China [29]PET-CT Center & Department of Diagnostic Radiology, National Cancer Center,National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy ofMedical Sciences, Peking Union Medical College, Beijing, China [30]Department of Radiology, Peking Union Medical College Hospital, ChineseAcademy of Medical Sciences, Peking Union Medical College, Beijing, China [31]Department of Pulmonary Oncology, The Fifth Medical Centre Chinese PLA GeneralHospital, Beijing, China [32]Department of Diagnostic Radiology, National Cancer Center, National ClinicalResearch Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences,Peking Union Medical College, Beijing, China [33]Betta Pharmaceuticals Co., Ltd, Hangzhou, China [34]X-covery Holdings, Palm Beach Gardens, FL, USA
出处：
DOI： 10.1016/j.jtho.2021.01.1615
ISSN：

关键词： ALK-positive NSCLC circulating tumor DNA analysis TP53 mutation status resistance mechanism

摘要：
By implementing dynamic circulating tumor DNA (ctDNA) analysis, we explored impact of TP53 mutations on tumor evolution and resistance mechanisms to ensartinib in ALK-positive non-small-cell lung cancer (NSCLC) patients. In a multicenter phase 2 trial, ALK-positive NSCLC patients who progressed on crizotinib were treated with ensartinib. Blood samples for ctDNA analysis were collected at baseline, cycle 3 day 1 (C3D1) and disease progression (PD) and analyzed with a 212-gene panel. 440 samples were collected from 168 patients. Baseline TP53 mutations (20.2%) significantly correlated with inferior PFS (4.2 months vs 11.7 months, p < 0.0001). Patients with TP53 mutations had higher mutation load than those without TP53 mutations at baseline (13.79 ± 3.72 vs 4.67 ± 0.39, p < 0.001). Although there was no significant difference in mutation load between these groups at C3D1 (5.89 ± 2.25 vs 3.72 ± 0.62, p = 0.425), patients with mutated TP53 developed more mutations at PD (7.07 ± 1.25 vs 3.20 ± 0.33, p = 0.003). Frequency and abundance of secondary ALK mutations G1269A, G1202R and E1210K increased significantly at PD than baseline. In patients without secondary ALK mutations, we identified ALK-independent resistance mechanisms including bypass signaling activation, downstream effector protein reactivation, epithelial-mesenchymal transformation and epigenetic dysregulation. Our study highlighted the advantage of ctDNA analysis for monitoring tumor evolution. TP53 mutations promoted genetic evolution and accelerated occurrence of resistance. We also unveiled ALK-dependent resistance mechanisms, mainly by G1269A, G1202R and E1210K mutations, and ALK-independent resistance mechanisms to ensartinib. Copyright © 2021. Published by Elsevier Inc.

基金：
the National Key R&D Program of China(Grant No. 2016YFC0905500, 2016YFC0905503) and Betta Pharmaceuticals Co.Ltd.
语种：
外文
被引次数：
WOS：
PubmedID：
中科院(CAS)分区：
出版当年[2021]版：
大类 | 1 区 医学
小类 | 1 区 肿瘤学 1 区 呼吸系统
最新[2023]版：
大类 | 1 区 医学
小类 | 1 区 肿瘤学 1 区 呼吸系统
JCR分区：
出版当年[2020]版：
Q1 RESPIRATORY SYSTEM Q1 ONCOLOGY
最新[2023]版：
Q1 ONCOLOGY Q1 RESPIRATORY SYSTEM

影响因子： 最新[2023版] 最新五年平均 出版当年[2020版] 出版当年五年平均 出版前一年[2019版] 出版后一年[2021版]

第一作者：
第一作者机构： [1]Department of Medical Oncology, Sun Yat-sen University Cancer Center, State KeyLaboratory of Oncology in South China, Collaborative Innovation Center for CancerMedicine, Guangzhou, China
共同第一作者：
通讯作者：
通讯机构： [1]Department of Medical Oncology, Sun Yat-sen University Cancer Center, State KeyLaboratory of Oncology in South China, Collaborative Innovation Center for CancerMedicine, Guangzhou, China [*1]Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center No.651 East Dongfeng Road, Guangzhou, 510060，China
推荐引用方式(GB/T 7714)：
Yunpeng Yang,Jie Huang,Tao Wang,et al.Decoding the Evolutionary Response to Ensartinib in ALK-Positive Non-Small-Cell Lung Cancer Patients by Dynamic Circulating Tumor DNA Sequencing.[J].JOURNAL OF THORACIC ONCOLOGY.2021,16(5):827-839.doi:10.1016/j.jtho.2021.01.1615.
APA：
Yunpeng Yang,Jie Huang,Tao Wang,Jianya Zhou,Jing Zheng...&Li Zhang.(2021).Decoding the Evolutionary Response to Ensartinib in ALK-Positive Non-Small-Cell Lung Cancer Patients by Dynamic Circulating Tumor DNA Sequencing..JOURNAL OF THORACIC ONCOLOGY,16,(5)
MLA：
Yunpeng Yang,et al."Decoding the Evolutionary Response to Ensartinib in ALK-Positive Non-Small-Cell Lung Cancer Patients by Dynamic Circulating Tumor DNA Sequencing.".JOURNAL OF THORACIC ONCOLOGY 16..5(2021):827-839

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