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

Abstract:

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. (Summary); Romero, A; Provencio, M (corresponding author), Inst Invest Biomd Puerta de Hierro Segovia de Aran, Liquid biopsy Lab, Calle Manuel de Falla 1, Majadahonda 28222, Madrid, Spain. (Author of contact); Serna-Blasco, Roberto, Department of Medical Oncology, Instituto de Investigación Sanitaria Puerta de Hierro–Segovia de Arana, Madrid, Madrid, Spain; Mediavilla-Medel, Pilar, Department of Medical Oncology, Instituto de Investigación Sanitaria Puerta de Hierro–Segovia de Arana, Madrid, Madrid, Spain; Medina, Karla, Department of Oncology, Hospital Universitario Nuestra Senora de Candelaria, Santa Cruz de Tenerife, Santa Cruz de Tenerife, Spain; Sala, Maria Ángeles, Department of Oncology, Osakidetza, Basurto University Hospital, Bilbao, Biscay, Spain; Aguiar-Bujanda, David, Department of Oncology, Hospital de Gran Canaria Dr. Negrin, Las Palmas de Gran Canaria, Las Palmas, Spain; Díaz-Serrano, Asuncion, Hospital Virgen de la Concha, Zamora, Zamora, Spain; Antoñanzas-Basa, Monica, Department of Oncology, Hospital Clínico San Carlos, Madrid, Madrid, Spain; Ocaña, Julio, Department of Oncology, Hospital CIMA-Sanitas, Barcelona, Catalonia, Spain; Mielgo-Rubio, Xabier, Department of Oncology, Hospital Universitario Fundación Alcorcón, Alcorcon, Madrid, Spain; Fernández, Inmaculada, Department of Oncology, Hospital Universitario Virgen Macarena, Sevilla, Spain; López-Castro, Rafael, Department of Oncology, Hospital Clínico Universitario de Valladolid, Valladolid, Valladolid, Spain; Cobo, Manuel Angel, Department of Oncology, Hospital Regional Universitario Carlos Haya, Malaga, Malaga, Spain; Martínez, Mireia, Department of Oncology, Hospital Universitario Araba, Vitoria-Gasteiz, Alava, Spain; Villa-Guzmán, José Carlos, Department of Oncology, Hospital General de Ciudad Real, Ciudad Real, Ciudad Real, Spain; Rosado, Petra, Department of Oncology, Hospital Universitario de Puerto Real, Cadiz, Cadiz, Spain; López, Ana, Department of Oncology, Hospital Universitario Severo Ochoa, Leganes, Madrid, Spain; Guirado, María, Department of Oncology, Hospital General Universitario de Elche, Elche, Spain; Viteri, Santiago, UOMI Cancer Center, Barcelona, Spain; Rodríguez, Delvys, Department of Oncology, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Las Palmas, Spain; García, Florencia, Department of Oncology, Hospital Quironsalud Barcelona, Barcelona, Catalonia, Spain; Simon, Soraya, Department of Oncology, Hospital Virgen de La Luz de Cuenca, Cuenca, Azuay, Spain; Moreno, María Ángeles Esteban, Department of Oncology, Hospital Universitario De Jerez, Andalucía, Spain; Catot, Sílvia, Althaia Xarxa Assistencial de Manresa, Manresa, Spain; González-Larriba, José Luís González, Department of Oncology, Hospital Clínico San Carlos, Madrid, Madrid, Spain; Salas Antón, Clara L., Department of Pathology, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain; Calvo de Juan, Virginia Engels, Department of Oncology Hospital, Clínica Puerta de Hierro, Majadahonda, Madrid, Spain; Romero, Atocha, Department of Medical Oncology, Instituto de Investigación Sanitaria Puerta de Hierro–Segovia de Arana, Madrid, Madrid, Spain, Department of Oncology Hospital, Clínica Puerta de Hierro, Majadahonda, Madrid, Spain; Provencio Pulla, M., Department of Oncology Hospital, Clínica Puerta de Hierro, Majadahonda, Madrid, Spain (Authors with Filk); This study was funded by the Spanish Lung Cancer Group, the nextGenerationEU/PRTR program (CPP2022-009545) and the following ISCIII grants (PI24/01725, PI21/01500, PI22/01223, DTS21/00124), cofunded by the European Regional Development Fund. Additional support came from the Ministerio de Educaci\u00F3n y Formaci\u00F3n Profesional; Fellowships: FI22/00321 (Mediavilla-Medel P). (Notes)