The Landscape of Actionable Genomic Alterations by Next-Generation Sequencing in Tumor Tissue Versus Circulating Tumor DNA in Chinese Patients With Non-Small Cell Lung Cancer

Background: Circulating tumor DNA (ctDNA) sequence analysis shows great potential in the management of non-small cell lung cancer (NSCLC) and the prediction of drug sensitivity or resistance in many cancers. Here, we drew and compared the somatic mutational profile using ctDNA and tumor tissue sequence analysis in lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), and assess its potential clinical value. Methods: In this study, 221 tumor tissues and 174 plasma samples from NSCLC patients were analyzed by hybridization capture-based next-generation sequencing (NGS) panel including 95 cancer-associated genes. Tumor response assessments were applied to 137 patients with advanced-stage (III and IV) NSCLC who first received targeted agents. Results: Twenty significantly mutated genes were identified such as TP53, EGFR, RB1, KRAS, PIK3CA, CD3EAP, CTNNB1, ERBB2, APC, BRAF, TERT, FBXW7, and HRAS. Among them, TP53 was the most frequently mutated gene and had a higher mutation probability in male (p = 0.00124) and smoking (p < 0.0001) patients. A total of 48.35% (191/395) of NSCLC patients possessed at least one actionable alteration according to the OncoKB database. Although the sensitivity of genomic profiling from ctDNA was lower than that from tumor tissue DNA, the mutational landscape of target genes from ctDNA is similar to that from tumor tissue DNA, which led to 61.22% (30/49) of mutational concordance in NSCLC. Additionally, the mutational concordance between tissue DNA and ctDNA in LUAD differs from that in LUSC, which is 63.83% versus 46.67%, indicating that NSCLC subtypes influence the specificity of mutation detection in plasma-derived ctDNA. Lastly, patients with EGFR and TP53 co-alterations showed similar responses to Gefitinib and Icotinib, and the co-occurring TP53 mutation was most likely to be a poor prognostic factor for patients receiving Gefitinib, indicating that the distributions and types of TP53 mutations may contribute to the efficacy and prognosis of molecular targeted therapy. Conclusions: As a promising alternative for tumor genomic profiling, ctDNA analysis is more credible in LUAD than in LUSC. Genomic subtyping has strong potential in prognostication and therapeutic decision-making for NSCLC patients, which indicated the necessity for the utility of target NGS in guiding clinical management.