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Primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer harboring TKI-sensitive EGFR mutations: an exploratory study

Cited 83 time in Web of Science Cited 94 time in Scopus
Authors
Lee, J. K.; Shin, J. -Y.; Kim, S.; Lee, S.; Park, C.; Kim, J. -Y.; Koh, Y.; Keam, B.; Min, H. S.; Kim, T. M.; Jeon, Y. -K.; Kim, Dong-Wan; Chung, Doo Hyun; Heo, Dae Seog; Lee, S. -H.; Kim, Jong-Il
Issue Date
2013-08
Citation
Annals of Oncology, Vol.24 No.8, pp.2080-2087
Keywords
epidermal growth factor receptor mutationerlotinibgefitinibprimary resistance
Abstract
The mechanism of primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC) has not been clearly understood. Eleven patients exhibiting primary resistance (disease progression < 3 months) were identified among 197 consecutive NSCLC patients with TKI-sensitive EGFR mutations who received EGFR TKIs at Seoul National University Hospital. Treatment-naive tumors were examined for concurrent genetic alterations using fluorescence in situ hybridization and targeted deep sequencing of cancer-related genes. Deletion polymorphism of Bcl-2-interacting mediator of cell death (BIM) gene was examined to validate its predictive role for TKI outcome. The median progression-free survival (PFS) for patients receiving EGFR TKIs was 11.9 months, and the response rate 78.8%. Among the 11 patients exhibiting primary resistance, a de novo T790M mutation was identified in one patient, and two exhibited mesenchymal-epithelial transition amplification and anaplastic lymphoma kinase fusion. Targeted deep sequencing identified no recurrent, coexistent drivers of NSCLC. Survival analysis revealed that patients with recurrent disease after surgery had a longer PFS than those with initial stage IV disease. However, BIM deletion polymorphism, line of treatment, EGFR genotype, and smoking were not predictive of PFS for EGFR TKIs. We identified coexistent genetic alterations of cancer-related genes that could explain primary resistance in a small proportion of patients. Our result suggests that the mechanism of primary resistance might be heterogeneous.
ISSN
0923-7534
URI
https://hdl.handle.net/10371/165462
DOI
https://doi.org/10.1093/annonc/mdt127
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College of Medicine/School of Medicine (의과대학/대학원)Cancer Research Institute (암연구소)Journal Papers (저널논문_암연구소)
College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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