Comprehensive molecular profiling of advanced NSCLC using NGS: Prevalence of druggable mutations and clinical trial opportunities in the ATLAS study

Background: In Spain, next-generation sequencing (NGS) is currently available in a limited number of specialized centers and remains inaccessible to a significant proportion of patients. The ATLAS study aims to explore the tumor molecular profile beyond known EGFR mutations and ALK translocations us...

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Detalles Bibliográficos
Autores: Serna-Blasco, R, Mediavilla-Medel, P, Medinab, K, Sala, MA, Aguiar, D, Díaz-Serrano, A, Antonanzas, M, Ocaña, J, Mielgo, X, Fernández, I, López-Castroj, R, Cobo, M, Martínez, M, Villa, JC, Rosado, P, López, A, Guirado, M, Viteri, S, Rodríguez, D, García, F, Simón, S, Moreno, MA, Catot, S, Larriba, JLG, Salas, C, Calvo, V, Romero, A, Provencio, M
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
Repositorio:r-FISABIO. Repositorio Institucional de Producción Científica
OAI Identifier:oai:fisabio.fundanetsuite.com:p18930
Acceso en línea:https://fisabio.portalinvestigacion.com/publicaciones/18930
Access Level:acceso abierto
Palabra clave:Next-generation sequencing
NSCLC
Molecular profiling
Druggable mutations
Actionable mutations
Clinical trials
KRAS
Precision medicine
Biomarker identification
Target treatment
Descripción
Sumario:Background: In Spain, next-generation sequencing (NGS) is currently available in a limited number of specialized centers and remains inaccessible to a significant proportion of patients. The ATLAS study aims to explore the tumor molecular profile beyond known EGFR mutations and ALK translocations using NGS on tumor biopsy samples. Methods: Patients with EGFR-sensitizing mutations or ALK translocations were excluded. A total of 455 patients with advanced non-small cell lung cancer (NSCLC) were enrolled from 22 Spanish hospitals. DNA and RNA were extracted from formalin-fixed paraffin-embedded samples, and libraries were prepared using the Oncomine Focus Assay. The Trialing app was used to identify active clinical trials in Spain. Results: Mutations were detected in 65.7 % of the cases. Local pathology assessments detected druggable mutations in only 7.9 % of cases, while centralized NGS testing increased this detection rate to 25.9 %. The most prevalent druggable alteration was KRAS G12C (53.6 %), followed by MET amplification (8.1 %) and MET exon 14 skipping (7.3 %). Additionally, 34.5 % of patients had molecular alterations matching clinical trials, offering potential treatment opportunities. Women had a significantly higher probability of harbouring druggable mutations (36 % vs. 20.3 %, p < 0.001), including the KRAS G12C which was significantly more frequent in females (22.6 % vs. 10 %). KRAS mutations were more common in adenocarcinomas and increased with tumor differentiation grade (p < 0.001 and p = 0.049, respectively). Likewise, ALK translocations, EGFR mutations, BRAF V600E, MET exon 14 skipping, and RET/ROS1 fusions were mainly found in adenocarcinomas whereas copy number variations were more frequent in squamous carcinomas (28.6 % vs. 15.1 %; p = 0.003) and in men (22 % vs. 11.6 %; p = 0.008). Conclusion: The ATLAS study demonstrates the utility of comprehensive NGS testing, which detects clinically relevant mutations in more than one-third of patients and may extend therapy options.

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