Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M. EGFR R108K (C.323G>A) is a rare missense mutation in Exon 3. In a study of 1006 lung carcinomas, R108K mutation was found concomitantly with other EGFR mutations - most notably p.L858R (Illei et.al). However, its prognostic and therapeutic significance remains to be fully elucidated.
Illei PB, Belchis D, Tseng LH, et al. Clinical mutational profiling of 1006 lung cancers by next generation sequencing. Oncotarget. 2017;8(57):96684-96696. Published 2017 May 20. doi:10.18632/oncotarget.18042
Sequist LV, et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol 2008;26(15):2442-9
Pao W, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004;101(36):13306-11
Pirker R Third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer. Curr Opin Oncol 2016;28(2):115-21
Ma C, et al. T790M and acquired resistance of EGFR TKI: a literature review of clinical reports. J Thorac Dis 2011;3(1):10-8
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