EGFR Exon 19 Insertions: A New Family of Sensitizing EGFR Mutations in Lung Adenocarcinoma
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Abstract
Purpose: Epidermal growth factor receptor (EGFR) genotyping is now standard in the management of advanced lung adenocarcinoma, as this biomarker predicts marked benefit from treatment with EGFR tyrosine kinase inhibitors (TKI). EGFR exon 19 insertions are a poorly described family of EGFR mutations, and their association with EGFR-TKI sensitivity in lung adenocarcinoma is uncertain. Experimental Design: Patients with lung cancers harboring EGFR exon 19 insertions were studied. The predicted effects of the insertions on the structure of the EGFR protein were examined, and EGFR exon 19 insertions were introduced into Ba/F3 cells to assess oncogenicity and in vitro sensitivity to EGFR-TKIs. In patients receiving TKI, response magnitude was assessed with serial computed tomographic (CT) measurement. Results: Twelve tumors harboring EGFR exon 19 insertions were identified; patients were predominately female (92%) and never-smokers (75%). The 11 specimens available for full sequencing all showed an 18-bp insertion that resulted in the substitution of a Pro for Leu at residue 747. The mutant EGFR transformed the Ba/F3 cells, which were then sensitive to EGFR-TKI. Six patients with measurable disease received TKI and five had a response on serial CT. Conclusions: EGFR exon 19 insertions are a newly appreciated family of EGFR-TKI–sensitizing mutations, and patients with tumors harboring these mutations should be treated with EGFR-TKI. While these mutations may be missed through the use of some mutation-specific assays, the addition of PCR product size analysis to multigene assays allows sensitive detection of both exon 19 insertion and deletion mutations. Clin Cancer Res; 18(6); 1790–7. ©2011 AACR.
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A763_Y764insFQEA must alter the structure of the β3-αC loop, like exon 19 deletion and insertion mutants.
“like both exon 19 deletion and insertion mutants 25, A763_Y764insFQEA must alter the structure of the β3-αC loop.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [25]
One patient with a K745_E746insIPVAIK tumor achieved partial response to afatinib.
“One patient with K745_E746insIPVAIK tumor achieved partial response to afatinib.28”
From Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy (2016) · cites this paper as [28]
Ins19 accounts for 0.6% (26/4519) of EGFR mutations.
“Ins19 is a subset accounting for 0.6% (26/4519).28, 48, 82, 83”
From Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy (2016) · cites this paper as [28]
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- Authors
- He, M., Capelletti, M., Nafa, K., Yun, C.-H., Arcila, M. E., Miller, V. A., Ginsberg, M. S., Zhao, B., Kris, M. G., Eck, M. J., Jänne, P. A., Ladanyi, M., & Oxnard, G. R.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Authors' Affiliations: 1Molecular Diagnostics Service, Department of Pathology, 2Thoracic Oncology Service, Department of Medicine, Departments of 3Radiology and 4Medical Physics, 5Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center; 6Weill-Cornell Medical College, New York, New York; 7Lowe Center for Thoracic Oncology, Department of Medical Oncology, 8Department of Cancer Biology, Dana-Farber Cancer Institute; and Departments of 9Biological Chemistry and 10Medicine, Harvard Medical School, Boston, Massachusetts
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2012-03-14
- Volume
- 18
- Issue
- 6
- Pages
- 1790-1797
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC3306520
- OpenAlex
- W2098674632
- Cited by
- 149
- References
- 44
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 3 · 2023: 7 · 2022: 7 · 2021: 4 · 2020: 6 · 2019: 11 · 2018: 16 · 2017: 10 · 2016: 5 · 2015: 16 · 2014: 22 · 2013: 25 · 2012: 5
- FWCI
- 14.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA116020, P01CA129243, R01CA114465, P50CA090578)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- lung adenocarcinoma, EGFR tyrosine kinase inhibitors, EGFR mutation, drug sensitivity, never smokers, mutation detection
- MeSH terms
- Gefitinib, Adenocarcinoma of Lung, Afatinib, Adenocarcinoma, Adult, Aged, Antineoplastic Agents, Exons, Female, Humans, Lung Neoplasms, Male, Middle Aged, Quinazolines, Mutagenesis, Insertional, Sequence Deletion, Cell Line, Tumor, Protein Kinase Inhibitors, ErbB Receptors
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