Somatic mutation profiling by NGS-based liquid biopsy in advanced non-small cell lung cancer: frequency, clinical correlates, and prognostic significance.

Liquid biopsy-based next-generation sequencing (NGS) of plasma cell-free DNA (cfDNA) - including its tumour-derived fraction known as circulating tumor DNA (ctDNA) - enables non-invasive, comprehensive mutational profiling in advanced non-small cell lung cancer (NSCLC). However, data on multi-gene plasma NGS panels in Turkish populations remain limited. One hundred consecutive stage IV NSCLC patients (42 newly diagnosed, 58 with progression/recurrence) who underwent plasma cfDNA/ctDNA-based NGS analysis between January and November 2019 were retrospectively analyzed. Somatic mutations across 19 genes were assessed using the GeneRead QIAact Lung DNA UMI Panel (Qiagen) on the GeneReader platform. Pathogenic mutations were detected in 25 patients (25%), yielding 34 PMs across seven genes. EGFR was most frequently mutated (52.9%), followed by KRAS (20.5%) and PIK3CA (14.5%). Multimetastatic patients had significantly higher cfDNA levels (10.0 ± 3.9 vs. 3.8 ± 1.0 ng; p = 0.01) and shorter OS (17.2 ± 5.5 vs. 49.5 ± 5.7 months; p < 0.001). Among EGFR wild-type patients with progression, resistance mutation carriers had markedly shorter OS (16.5 ± 0.5 vs. 48.7 ± 6.6 months; p = 0.001). KRAS G12C was the predominant KRAS variant (71%). NGS-based liquid biopsy identified actionable and resistance-associated mutations in 25% of advanced NSCLC patients in this Turkish Black Sea cohort. Total cfDNA concentration correlated with metastatic burden. The detection of KRAS G12C and EGFR T790M variants supports the complementary clinical utility of multi-gene plasma ctDNA panels alongside tissue genotyping in personalized treatment decisions, although confirmation in larger prospective cohorts with paired tissue analysis is warranted.