Genomic landscape of stage 0-IA lung adenocarcinoma identified by on-site reflex targeted NGS

Early molecular profiling in non-squamous non-small cell lung carcinoma (NSCLC), particularly lung adenocarcinoma (LUAD), is critical for guiding individualized treatment strategies. Limited data exist on the genomic landscape of Stage 0-IA LUAD. This study assessed the feasibility and clinical relevance of reflex targeted next-generation sequencing (NGS) performed on-site at diagnosis in resected early-stage LUAD.

We retrospectively analyzed 239 consecutive Stage 0-IA LUAD cases diagnosed between 2022 and 2024 at a single institution. Ultra-fast reflex DNA- and RNA-based NGS was performed on resected specimens using a 50-gene targeted panel. Alterations were classified according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). Associations between genomic alterations, histologic subtypes, and tumor grades were evaluated.

Stage IA1 was the most frequent diagnosis (46%). High-quality sequencing data were obtained in all cases, with a median turnaround time of 102 h. At least one genomic alteration was detected in 80% of tumors. KRAS mutations were most frequent (35.8%), including KRAS G12C in 16%. EGFR mutations were present in 27.2%, primarily classical sensitizing alterations. Other actionable findings included ALK fusions (3.3%), RET rearrangements (1.2%), MET exon 14 skipping (2.4%), HER2 mutations (3.7%), and BRAF V600E (0.8%). ESCAT Level I alterations were found in 34% of tumors; 20% of these co-occurred with TP53 mutations. Significant associations were observed between genomic alterations, histologic subtypes, and tumor grades.

Reflex NGS at diagnosis in resected Stage 0-IA LUAD is feasible, rapid, and reveals a high rate of actionable alterations, which may support its integration in the future into early-stage diagnostic workflows.