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EGFR
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Interpretation 278
Tier 1
EGFR
Variants
EGFR E709_T710delinsD
EGFR exon(s) 18 indel
EGFR exon(s) 18 deletion
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Non-Small Cell Lung Carcinoma
Interpretation

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 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 exon 18 mutations account for 3.6% of all the EGFR mutations in lung adenocarcinomas. Of these, G719 mutations account for the majority of them and are sensitive to anti-EGFR inhibitors. Exon 18 deletions are rare (<0.1%) and but they are potentially responsive to anti-EGFR TKIs in some small clinical case studies. Of note, they appeared to be more sensitive to second-generation TKIs, especially afatinib and neratinib, than to first- and third-generation TKIs based on in vitro experiments.

Citations
  1. Ackerman A, et al. EGFR delE709_T710insD: a rare but potentially EGFR inhibitor responsive mutation in non-small-cell lung cancer. J Thorac Oncol 2012;7(10):e19-20
  2. Kobayashi Y, et al. EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs. Clin Cancer Res 2015;21(23):5305-13
  3. 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
  4. 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
  5. 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
  6. 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
Last updated: 2016-06-01 20:16:47 UTC
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When using PMKB, please cite: Huang et al., JAMIA 2017


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