Landscape of Chinese Lung Cancer Patients With Compound Mutations and Acquired Resistance Alterations: A Retrospective Study.

Epidermal growth factor receptor (EGFR) mutations are key oncogenic drivers in non-small cell lung cancer (NSCLC). Rare and compound EGFR mutation-mediated resistance to tyrosine-kinase inhibitors (TKIs) is a major hurdle for NSCLC treatment. Here, we characterized compound EGFR mutations and elucidated mechanisms of acquired resistance to EGFR TKIs in Chinese NSCLC patients. Using next-generation sequencing (NGS) data, the mutation spectrum of 10 lung cancer-related genes was analyzed in 8849 patients. From this cohort, 7081 NSCLC tissue samples were assessed, revealing common EGFR mutations (19-Del, exon 21 p.L858R), rare EGFR mutations, variants of uncertain significance (VUSs), and compound EGFR mutations. Acquired resistance mutations were further evaluated in 77 paired baseline and post-progression samples. Among the 8849 patients, 4320 (48.82%) harbored common EGFR mutations, 973 (11.00%) carried Kirsten rat sarcoma viral oncogene (KRAS) hotspot mutations, 357 (4.03%) had phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, 246 (2.78%) had Erb-B2 receptor tyrosine kinase 2 (ERBB2) mutations, 102 (1.15%) had B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutations, and 95 (1.07%) had mesenchymal epithelial transition factor (MET) mutations. Compound EGFR mutations were identified in 7.99% of NSCLC patients, comprising 7.50% dual mutations and 0.49% multiple (> 2) mutations. Compared to single EGFR mutations, compound EGFR mutations were more frequently associated with EGFR exon 21 p.L858R and EGFR rare mutations, but not with EGFR 19-Del or VUSs (p < 0.001). Compared to patients with EGFR 19-Del, patients with EGFR exon 21 p.L858R mutation had significantly more rare point mutations in EGFR exon 7, 18, and 21, and fewer EGFR exon 20 p.T790M mutations. Additionally, EGFR exon 20 p.T790M-mediated acquired resistance was the most common mechanism (71.43%), followed by mutations in the RAS/RAF/MEK pathway (18.18%). These resistance-associated mutations frequently co-occurred with tumor protein p53 (TP53) variants (15.58%). Notably, the mean duration of disease progression following EGFR-TKI initiation did not differ significantly between patients with EGFR exon 21 p.L858R mutation and those with EGFR 19-Del. Our study reveals the heterogeneity of compound EGFR mutations, and characterizes the spectrum of acquired resistance mutations to EGFR TKIs.