Discrepancy between plasma cell-free DNA and tissue-based analysis for detection of gene amplifications in non–small cell lung cancer.

Abstract

8537 Background: Therapeutic strategies have been developed in patients with non-small cell lung cancer (NSCLC) harboring gene amplifications (amp) such as MET and HER2 . Although both plasma cell-free DNA (cfDNA) and tissue-based next-generation sequencing (NGS) are available for the detection of gene amp, the concordance between plasma cfDNA and tissue-based analysis for the detection of gene amp remains unclear. Methods: We investigated plasma cfDNA and tissue-based NGS concordance for detection of gene amp in NSCLC using a large-scale screening cohort (LC-SCRUM-Liquid). Paired blood samples were prospectively collected within 4 weeks of corresponding tumor tissue sampling from patients with advanced NSCLC. Guardant360 panel or Oncomine Precision Assay panel was used for plasma cfDNA NGS. Oncomine Comprehensive Assay panel or Oncomine Precision Assay was used for tissue-based NGS. The concordance of EGFR , MET and HER2 gene amp were evaluated. Results: A total of 1,133 pairs of blood and tissue samples were successfully analyzed between December 2017 and December 2024. The median age of the patients was 69 years (range 25-91), 60% were male, 68% were ever smokers, and 79% had a histopathological diagnosis of adenocarcinoma. The positive percent agreement (PPA) and positive predictive value (PPV) of plasma cfDNA analysis relative to tissue-based analysis are shown in the table. For detecting MET amp, the PPA of plasma cfDNA analysis relative to tissue-based analysis tended to be lower in the patients with metastases involving fewer than two organs compared to those with metastases involving two or more organs (25% vs. 63%, P = 0.07). Among the patients with EGFR , MET , or HER2 amp detected by either tissue-based or plasma cfDNA analysis, the correlation of the copy number variants between tissue-based and plasma cfDNA analysis was very weak (r = 0.20). Conclusions: The concordance between plasma cfDNA and tissue-based analysis for detecting gene amp is markedly low, particularly in patients with a low tumor burden. Detection of gene amp using plasma cfDNA analysis may be insufficient for accurately evaluating the efficacy of targeted therapies for patients with lung cancer harboring gene amp. Concordance of gene amp between plasma cell-free DNA and tissue-based analysis. Tissue PPA PPV + - cfDNA EGFR amp + 9 37 13% 20% - 60 1027 MET amp + 9 7 38% 56% - 15 1102 HER2 amp + 0 4 0% 0% - 3 1126