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Sci Rep. 2017 Nov 6;7(1):14605. doi: 10.1038/s41598-017-14962-0.

Discovery of targetable genetic alterations in advanced non-small cell lung cancer using a next-generation sequencing-based circulating tumor DNA assay.

Author information

1
Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, 16 Jiangsu Road, Qingdao, 266005, China.
2
BGI-Qingdao Institute, Qingdao SINO-GERMAN Ecopark, 2877 Tuanjie Road, Qingdao, 266555, China.
3
Department of Experimental Therapeutics, University of Texas, South Campus Research Building 4 (4SCR), Room 4SCR3.2085, 1901 East Road, Houston, Texas, 77054, USA.
4
Department of Thoracic Surgery, Qingdao Municipal Hospital, 1 Jiaozhou Road, Qingdao, 266011, China.
5
Department of Medical Oncology, Qingdao Municipal Hospital, 5 Donghai Middle Road, Qingdao, 266071, China.
6
BGI-Shenzhen, Shenzhen, 518083, China.
7
Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao University, 16 Jiangsu Road, Qingdao, 266005, China.
8
Binhai Genomics Institute, BGI-Tianjin, BGI-Shenzhen, Tianjin, 300308, China.
9
Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, 16 Jiangsu Road, Qingdao, 266005, China. zhangxiaochun9670@126.com.

Abstract

Next-generation sequencing (NGS)-based circulating tumor DNA (ctDNA) assays have provided a new method of identifying tumor-driving genes in patients with advanced non-small cell lung carcinoma (NSCLC), especially in those whose cancer tissues are unavailable or in those that have acquired treatment resistance. Here, we describe a total of 119 patients with advanced EGFR-TKI-naive NSCLC and 15 EGFR-TKI-resistant patients to identify somatic SNVs, small indels, CNVs and gene fusions in 508 tumor-related genes. Somatic ctDNA mutations were detected in 82.8% (111/134) of patients in the total cohort. Of the 119 patients with advanced NSCLC, 27.7% (33/119) were suitable for treatment with National Comprehensive Cancer Network (NCCN) guideline-approved targeted drugs. Actionable genetic alterations included 25 EGFR mutations, 5 BRAF mutations, and 1 MET mutation, as well as 1 EML4-ALK gene fusion and 1 KIF5B-RET gene fusion. In 19.3% (23/119) of the patients, we also identified genomic alterations with that could be targeted by agents that are in clinical trials, such as mTOR inhibitors, PARP inhibitors, and CDK4/6 inhibitors. Additionally, the EGFR T790M mutation was found in 46.7% (7/15) of the patients with EGFR-TKI-resistant NSCLC, suggesting that the NGS-based ctDNA assay might be an optional method to monitor EGFR-TKI resistance and to discover mechanisms of drug resistance.

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