Genomic Profile of Non-Small Cell Lung Cancer in a Spanish Cohort: A 2-Year Descriptive Study Using Next-Generation Sequencing

Background/Objectives: Next-generation sequencing (NGS) has become the standard of care for identifying actionable genomic alterations in non-small cell lung cancer (NSCLC). This study aims to describe the clinicopathological characteristics and genomic landscape of a non-selected cohort of NSCLC patients from the Canary Islands (Spain), analyzed during the first two years of our Molecular Diagnosis Unit’s operation. Methods: We conducted an observational, retrospective study including 448 tumors from 446 patients diagnosed between March 2023 and March 2025. Genomic profiling was performed using amplicon-based NGS panels (Oncomine™ Focus and Precision Assays) on semiconductor sequencing platforms to detect single-nucleotide variants (SNVs), indels, copy number alterations (CNAs), and gene fusions from DNA and RNA. Results: Actionable alterations were identified in 55.1% of tumors. The most prevalent alterations were found in TP53 (29.5%), KRAS (27.2%), and EGFR (14.1%), with KRAS G12C being the most frequent variant. Stratified analysis revealed a high prevalence of ALK fusions in patients < 50 years (33.3%). Crucially, and in stark contrast with traditional exclusion criteria, 54.0% of EGFR mutations and 50.0% of ALK fusions were detected in patients with a history of smoking. Concomitant alterations were observed in 34.8% of cases, with TP53 being the most common co-mutation partner. Conclusions: Our real-world data confirm the feasibility and clinical value of routine NGS testing for NSCLC. The findings highlight specific genomic patterns in this population and demonstrate that smoking status should not preclude comprehensive molecular testing for canonical drivers.