Unveiling the clinical impact of plasma-only mutations in non-small cell lung cancer: a Korean multicenter experience.

Background: Plasma-based circulating tumor DNA (ctDNA) analysis has emerged as a promising tool to complement tissue genotyping in non-small cell lung cancer (NSCLC), particularly when tissue acquisition is limited. We investigated the clinical applicability of ctDNA analysis in Korean patients with recurrent or metastatic NSCLC. Methods: We retrospectively analyzed 132 patients with NSCLC who underwent plasma ctDNA testing between June 2017 and December 2021 in the K-MASTER project. Mutation detection rates, concordance between tissue and plasma results, and survival outcomes according to targeted therapy administration were evaluated. Clinical characteristics of plasma-only mutations were further examined. Results: Actionable mutations were identified in 43.2% of patients through combined tissue and plasma analyses. Plasma ctDNA testing revealed actionable mutations in 11.4% of patients not detected by tissue genotyping, seven of whom received targeted therapy based on plasma results. Rare co-occurring actionable alterations were found in three patients, including concurrent EGFR and KRAS or ALK and EGFR mutations, suggesting intratumoral heterogeneity or possible multiple primary cancers. Among the three cases with plasma-positive but tissue-negative results, one had biopsies from bone and one from liver, suggesting possible effects of sampling bias or clonal evolution. Patients who received targeted therapy-guided by either tissue or plasma results-demonstrated significantly improved survival compared with those who did not (P=0.03). Conclusions: Plasma-based ctDNA analysis broadens detection of actionable genomic alterations and facilitates access to targeted therapies in NSCLC, particularly when tissue biopsy is limited. These findings support integrating liquid biopsy into routine practice to optimize patient outcomes.