Abstract: Objective To investigate ctDNA-driven gene mutations in patients with non-small cell lung cancer（NSCLC） based on circulating single-molecule amplification and resequencing technology（cSMART） and guide its treatment. Methods Totals of 107 patients with NSCLC were enrolled from July 2016 to December 2018 at the Department of Oncology Medical in Liaoning Cancer Hospital. The mutations of 9 ctDNA-driven genes such as EGFR，ALK，KRAS，BRAF，PIK3CA，ERBB2，ROS1，RET and MET were detected by cSMART. After each 2-4 treatment courses，the patient's 9 ctDNA-driven genes mutation distributions were evaluated，and the patients were guided to medication based on the NCCN guidelines and 9 genes test results. A total of 57 patients with NSCLC who completed the survival information and completed the follow-up treatment were divided into the standard treatment group（n=39） and the non-standard treatment group （n=18） according to whether they followed the guidelines，and compared the therapeutic effects. Results Based on cSMART，78 cases were positive mutation and 28 cases were negative mutation. Among the 78 patients who drived gene mutations，27 patients had single gene mutation，24 patients had double gene mutations，11 patients had three gene mutations，5 patients had four gene mutations，and 5 patients had five gene mutations. 106 patients with non-small　cell lung cancer had a total of 186 mutations, including 26 without mutations and 160 mutations. Among 160 mutations，there were 61　EGFR mutations，11 ALK mutations（including ALK fusion and point mutation），54 TP53 mutations，26 KRAS mutations，5 PIK3CA mutations，1  BRAF mutation，1  MET mutation and 1 ERBB2 mutation. The median progression-free survival（mPFS） of patients receiving standard treatment was longer than that of patients receiving non-standard treatment（10.0 months vs 5.5 months χ2=6.420，P=0.011）. Conclusions It is simple and non-invasive based on cSMART assay ctDNA to identify non-small cell lung cancer drive gene mutations. EGFR and ALK are common driving mutations，and their targeted therapy are better.

Key words: Non-small cell lung cancer, cSMART, Liquid biopsy, ctDNA, EGFR, Gradient lymphoma kinase