A large scale prospective concordance study of oncogene driver detection between plasma- and tissue-based NGS analysis in advanced non-small cell lung cancer (NSCLC)

Abstract

Background: Liquid biopsy-based next-generation sequencing (NGS) is clinically useful as a less invasive multi-gene analysis for precision cancer medicine. However, performance of NGS using plasma cell-free DNA (cfDNA) compared to tumor tissue has not been evaluated in a large-scale sample. Methods: A liquid biopsy study is additionally conducted in the nation-wide lung cancer genome screening project (LC-SCRUM-Japan), targeting 2000 NSCLC patients. Tumor genetic alterations are evaluated by cfDNA-and tissue-based NGS tests. Plasma is collected within 4 weeks of the corresponding tissue biopsy. cfDNA is analyzed using Guardant360sR(investigational device exemption version, Guardant Health); tumor tissue is analyzed by Oncomine Comprehensive AssaysRversion 3 (Thermo Fisher Scientific). We assessed the detectability of 8 oncogene drivers: mutations of EGFR, KRAS, BRAF, ERBB2 and MET, and fusions of ALK, RET and ROS1. Results: As of March 2019, 270 advanced NSCLC patients were enrolled. Median age was 67 (range, 30-87) years, 169 patients (63%) were men, 86 (32%) were nonsmokers, 215 (80%) had adenocarcinoma, 206 (76%) were stage IV, and 224 (83%) received no prior chemotherapy. An oncogene driver was detected in 156 patients (58%) by at least one NGS method, including 138 (51%) in tissue and 107 (40%) in cfDNA. Using the tissue assay as a control, the positive percent agreement (PPA) of gene mutations in the cfDNA assay was 75% (91 of 121), including 74% (53 of 72) for EGFR, 78% (31 of 40) for KRAS, 100% (3 of 3) for BRAF, 75% (3 of 4) for ERBB2 and 50% (1 of 2) for MET. The PPA of gene fusions in the cfDNA assay was 24% (4 of 17), including 33% (2 of 6) for ALK, 33% (2 of 6) for RET and 0% (0 of 5) for ROS1. of 132 patients in whom no oncogene driver was detected by the tissue assay, 17 had the drivers detected in cfDNA: 8 EGFR, 5 KRAS, 1 BRAF, 1 ERBB2, 1 MET and 1 ALK. Conclusions: In the cfDNA-based NGS, the detectability of gene mutations was comparable with the previously reported single-gene tests using cfDNA, whereas that of gene fusions was low. The cfDNA-based assay may be useful for patients in whom oncogene driver detection was failed by the tissue-based assay. This study is now ongoing and we will present updated results.