Abstract
Patients with advanced non-small-cell lung cancer (NSCLC) harboring sensitive epithelial growth factor receptor (EGFR) mutations invariably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Identification of actionable genetic alterations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. One of the major resistant mechanisms is secondary EGFR-T790M mutation. Other mechanisms, such as HER2 and MET amplifications, and PIK3CA mutations, were also reported. However, the mechanisms in the remaining patients are still unknown. In this study, we performed mutational profiling in a cohort of 83 NSCLC patients with TKI-sensitizing EGFR mutations at diagnosis and acquired resistance to three different first-generation EGFR TKIs using targeted next generation sequencing (NGS) of 416 cancer-related genes. In total, we identified 322 genetic alterations with a median of 3 mutations per patient. 61% of patients still exhibit TKI-sensitizing EGFR mutations, and 36% of patients acquired EGFR-T790M. Besides other known resistance mechanisms, we identified TET2 mutations in 12% of patients. Interestingly, we also observed SOX2 amplification in EGFR-T790M negative patients, which are restricted to Icotinib treatment resistance, a drug widely used in Chinese NSCLC patients. Our study uncovered mutational profiles of NSCLC patients with first-generation EGFR TKIs resistance with potential therapeutic implications.
Highlights
Lung cancer is the leading cause of cancer death in China as well as worldwide [1]
The epidermal growth factor receptor (EGFR) gene mutations are found in ~10% of lung adenocarcinomas in Caucasian population [3], but in 30% ~ 50% of Asian population [7, 8], which define a substantial population that can benefit from the use of EGFR tyrosine kinase inhibitors (TKIs)
The choice of collecting different tumor materials depends on clinical risks that would impose on the patients by the operation. 45 patients (54.2%) patients were undertaken blood withdrawing for testing circulating tumor DNAs (ctDNA), while in others tumor tissues or pleural effusions were obtained through biopsies
Summary
80% of lung cancers are non-small-cell lung carcinoma (NSCLC), and the overall 5-year relative survival rate for this cohort is less than 20% [2]. Patients with advanced NSCLC have an extremely high mortality rate. Several randomized phase III clinical trials have shown the superiority in the overall response rate (ORR) and median progression-free survival (PFS) of EGFR TKI treatment over chemotherapy as first-line therapy for patients with TKI-sensitizing EGFR mutations www.impactjournals.com/oncotarget [9, 10]. The vast majority of patients inevitably experienced acquired resistance in less than one year, limiting the overall survival advantage of EGFR TKI treatment over chemotherapy [11, 12]
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