Circulating tumor DNA clearance predicts prognosis across treatment regimen in a large real-world longitudinally monitored advanced non-small cell lung cancer cohort

Yong Song; Chengping Hu; Zhanhong Xie; Lin Wu; Zhengfei Zhu; Chuangzhou Rao; Li Liu; Yuan Chen; Naixin Liang; Jun Chen; Chunhong Hu; Nong Yang; Jie Hu; Weixin Zhao; Gangling Tong; Xiaorong Dong; Di Zheng; Meiling Jin; Jianhua Chen; Meijuan Huang; Yong He; Rafael Rosell; Giuseppe Lippi; Mari Mino-Kenudson; Han Han-Zhang; Xinru Mao; Lu Zhang; Hao Liu; John K Field; Shannon Chuai; Junyi Ye; Yusheng Han; Shun Lu; Written on behalf of AME Lung Cancer Collaborative Group

doi:10.21037/tlcr.2020.03.17

Circulating tumor DNA clearance predicts prognosis across treatment regimen in a large real-world longitudinally monitored advanced non-small cell lung cancer cohort

Transl Lung Cancer Res. 2020 Apr;9(2):269-279. doi: 10.21037/tlcr.2020.03.17.

Authors

Yong Song¹, Chengping Hu², Zhanhong Xie³, Lin Wu⁴, Zhengfei Zhu⁵, Chuangzhou Rao⁶, Li Liu⁷, Yuan Chen⁸, Naixin Liang⁹, Jun Chen¹⁰, Chunhong Hu¹¹, Nong Yang⁴, Jie Hu¹², Weixin Zhao⁵, Gangling Tong¹³, Xiaorong Dong⁷, Di Zheng¹⁴, Meiling Jin¹², Jianhua Chen⁴, Meijuan Huang¹⁵, Yong He¹⁶, Rafael Rosell¹⁷, Giuseppe Lippi¹⁸, Mari Mino-Kenudson¹⁹, Han Han-Zhang²⁰, Xinru Mao²⁰, Lu Zhang²⁰, Hao Liu²⁰, John K Field²¹, Shannon Chuai²⁰, Junyi Ye²⁰, Yusheng Han²⁰, Shun Lu²²; Written on behalf of AME Lung Cancer Collaborative Group

Affiliations

¹ Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of the Medicine, Nanjing 210002, China.
² Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha 410008, China.
³ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
⁴ Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China.
⁵ Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
⁶ Department of Radiotherapy and Chemotherapy, Hwamei Hospital, University of Chinese Academy of Sciences, Ningbo 315010, China.
⁷ Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
⁸ Department of Medical Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
⁹ Department of Thoracic Surgery, Peking Union Medical College Hospital Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
¹⁰ Department of Lung Cancer Surgery, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
¹¹ Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha 410008, China.
¹² Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
¹³ Department of Oncology, Peking University Shenzhen Hospital, Shenzhen 518036, China.
¹⁴ Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
¹⁵ Department of Oncology, West China Hospital, Chengdu 610041, China.
¹⁶ Department of Respiratory Medicine, Daping Hospital, Army Medical University, Chongqing 400042, China.
¹⁷ Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Germans Trias I Pujol Health Sciences Institute and Hospital Badalona, Barcelona, Spain.
¹⁸ Section of Clinical Biochemistry, University of Verona, Verona, Italy.
¹⁹ Department of Pathology, Massachusetts General Hospital, Boston, USA.
²⁰ Burning Rock Biotech, Guangzhou 510300, China.
²¹ Roy Castle Lung Cancer Research Program, The University of Liverpool, Department of Molecular and Clinical Cancer Medicine, Liverpool, UK.
²² Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.

Abstract

Background: Although growth advantage of certain clones would ultimately translate into a clinically visible disease progression, radiological imaging does not reflect clonal evolution at molecular level. Circulating tumor DNA (ctDNA), validated as a tool for mutation detection in lung cancer, could reflect dynamic molecular changes. We evaluated the utility of ctDNA as a predictive and a prognostic marker in disease monitoring of advanced non-small cell lung cancer (NSCLC) patients.

Methods: This is a multicenter prospective cohort study. We performed capture-based ultra-deep sequencing on longitudinal plasma samples utilizing a panel consisting of 168 NSCLC-related genes on 949 advanced NSCLC patients with driver mutations to monitor treatment responses and disease progression. The correlations between ctDNA and progression-free survival (PFS)/overall survival (OS) were performed on 248 patients undergoing various treatments with the minimum of 2 ctDNA tests.

Results: The results of this study revealed that higher ctDNA abundance (P=0.012) and mutation count (P=8.5×10^-4) at baseline are associated with shorter OS. We also found that patients with ctDNA clearance, not just driver mutation clearance, at any point during the course of treatment were associated with longer PFS (P=2.2×10^-16, HR 0.28) and OS (P=4.5×10^-6, HR 0.19) regardless of type of treatment and evaluation schedule.

Conclusions: This prospective real-world study shows that ctDNA clearance during treatment may serve as predictive and prognostic marker across a wide spectrum of treatment regimens.

Keywords: Circulating tumor DNA (ctDNA); circulating tumor DNA clearance (ctDNA clearance); liquid biopsy; non-small cell lung cancer (NSCLC).