A high number of co-occurring genomic alterations detected by NGS is associated with worse clinical outcomes in advanced EGFR-mutant lung adenocarcinoma: Data from LATAM population

• Published in: Lung cancer (Amsterdam, Netherlands) Netherlands), 2022-12, Vol.174, p.133-140
• Main Authors: Heredia, David, Mas, Luis, Cardona, Andres F., Oyervides, Víctor, Motta Guerrero, Rodrigo, Galvez-Nino, Marco, Lara-Mejía, Luis, Aliaga-Macha, Carlos, Carracedo, Carlos, Varela-Santoyo, Edgar, Ramos-Ramírez, Maritza, Davila-Dupont, David, Martínez, Juan, Cruz-Rico, Graciela, Remon, Jordi, Arrieta, Oscar
• Format: Article
• Language: English
• Subjects: Adenocarcinoma of Lung - drug therapy; Adenocarcinoma of Lung - genetics; Carcinoma, Non-Small-Cell Lung - drug therapy; EGFR mutation; ErbB Receptors - genetics; High-Throughput Nucleotide Sequencing; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Mutation; Next-generation sequencing; Non-small cell lung cancer; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; TP53; Tumor Suppressor Protein p53 - genetics
• ISSN: 0169-5002; 1872-8332
• DOI: 10.1016/j.lungcan.2022.11.002

•Co-occurring genomic alterations at diagnosis might represent de novo and primary resistance mechanisms to tyrosine kinase inhibitors (TKIs) in advanced EGFR-mutant (EGFRm) non-small lung cancer (NSCLC).•In this study, we assessed the prognostic role of co-occurring genomic alterations in advanced EGFRm NSCLC.•TP53 mutations are the most frequent alteration associated in LATAM patients with EGFRm NSCLC and are associated with a worse overall prognosis.•Our study demonstrates that EGFRm NSCLC is not a single oncogene-driven disease, and an increased number of co-occurring genetic alterations negatively impact the PFS in the LATAM population. Co-occurring genomic alterations identified downstream main oncogenic drivers have become more evident since the introduction of next-generation sequencing (NGS) analyses at diagnosis and progression. Emerging evidence has stated that co-occurring genomic alterations at diagnosis might represent de novo and primary resistance mechanisms to tyrosine kinase inhibitors (TKIs) in advanced EGFR-mutant (EGFRm) non-small lung cancer (NSCLC). In this study, we assessed the prognostic role of co-occurring genomic alterations in advanced EGFRm NSCLC. A cohort of 111 patients with advanced NSCLC harboring EGFR-sensitive mutations detected by PCR was analyzed in 5 Latin American oncological centers from January 2019 to December 2020. All eligible patients received upfront therapy with EGFR-TKI. Co-occurring genomic alterations were determined at diagnosis in every patient by the NGS (FoundationOneCDx) comprehensive platform, which evaluates 324 known cancer-related genes. EGFR exon19 deletion was the most frequent oncogenic driver mutation (60.4 %) detected by NGS. According to the NGS assay, 31 % and 68.3 % of patients had 1–2 and ≥ 3 co-occurring genomic alterations, respectively. The most frequent co-occurring genomic alterations were TP53 mutations (64.9 %) followed by CDKN2AB alterations (13.6 %), BRCA2 (13.6 %), and PTEN (12.7 %) mutations. Baseline central nervous system disease was present in 42.7 % of patients. First- or second-generation EGFR TKIs (gefitinib, afatinib, or erlotinib) were the most common treatment in 67.5 % of patients, while osimertinib was administered in 27.9 % of cases. The median PFS in all evaluated patients was 13.63 months (95 %CI: 11.79–15.52). Using ≥ 3 co-occurring alterations as the cut-off point, patients with ≥ 3 co-occurring genomic alterations showed a median PFS, of 12.7 months (95 %CI: 9