Fortgeschrittenes NSCLC: NGS-Diagnostik aus Gewebe- oder Flüssigbiopsie

Background: Liquid biopsies (LB) are used increasingly to detect actionable mutations in patients newly diagnosed with advanced non-small cell lung cancer (aNSCLC), though tissue biopsies (TB) still remain the gold standard. The value of systematically combining LB and TB next-generation sequencing (NGS) for genomic profiling in these patients remains controversial. Methods: This single-centre retrospective study included 102 matched TB and LB samples collected from aNSCLC patients at diagnosis. Four circulating free DNA (cfDNA)-based NGS assays (1–4) were compared on site for performance and concordance with TB to detect ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) I/ II. Additionally, cfDNA droplet digital PCR methylation (ddPCR-met) testing estimated the tumour fraction to refine the interpretation of wild-type (WT) results. Results: Out of 102 patients, 13% had stage IIIB disease, and 11% presented with brain-only metastases. Adenocarcinoma was the predominant subtype (84%). Ninety LB samples yielded interpretable results across the four assays. Positive percent agreement with TB ranged from 56% (assay 2) to 79% (assay 4), with high concordance, particularly for single-nucleotide variants (SNVs). Hybrid capture-based assays (3 and 4) detected eight and seven gene fusions, respectively, while amplicon-based assays (1 and 2) detected only two each. Assay 3 only identified 12 MET amplifications, five of which were confirmed by fluorescence in situ hybridisation (FISH) but were missed by TB-based NGS. Five out of six negative cfDNA samples with ddPCR-met testing were WT across all assays. The plasma-first approach added incremental value, up to 21% (assay 3). Amplicon-based assays were faster and required less input of DNA for analysis. Patients with stage IIIB or brain-only metastases were significantly more likely to have negative/low levels of cfDNA ddPCR-met.