Natural History and Molecular Characteristics of Lung Cancers Harboring EGFR Exon 20 Insertions

Oxnard, Geoffrey R.; Lo, Peter C.; Nishino, Mizuki; Dahlberg, Suzanne E.; Lindeman, Neal I.; Butaney, Mohit; Jackman, David M.; Johnson, Bruce E.; Jänne, Pasi A.

doi:10.1097/jto.0b013e3182779d18

Cited by 362Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchCancer Genomics and Diagnostics

Natural History and Molecular Characteristics of Lung Cancers Harboring EGFR Exon 20 Insertions

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Oxnard, Geoffrey R., Lo, Peter C., Nishino, Mizuki, Dahlberg, Suzanne E., Lindeman, Neal I., Butaney, Mohit, Jackman, David M., Johnson, Bruce E. +1 more·2013·Journal of Thoracic Oncology

DOI 10.1097/jto.0b013e3182779d18PMC PMC3549533

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Abstract

Introduction Exon 20 insertions are the third most common family of epidermal growth factor receptor (EGFR) mutations found in non-small-cell lung cancer (NSCLC). Little is known about cancers harboring these mutations aside from their lack of response to EGFR tyrosine kinase inhibitors, impairing the development of effective targeted therapies.Methods NSCLC patients with EGFR genotyping were studied using a mechanism approved by the Institutional Review Board. Cancers with exon 20 insertions were indentified, sequences were characterized, and effectiveness of different treatment regimens was reviewed retrospectively. Clinical characteristics and survival were compared with cancers harboring common EGFR mutations and cancers with wild-type EGFR.Results One thousand eighty-six patients underwent EGFR genotyping from 2004 to 2012. Twenty seven (2.5%) harbored exon 20 insertions, making up 9.2% of all cancers with documented EGFR mutations. Compared with wild-type cancers, those with exon 20 insertions were more commonly found in never-smokers and Asian patients. Insertion sequences were highly variable, with the most common variant (V769_D770insASV) making up only 22% of cases. Median survival of patients with exon 20 insertions was 16 months, similar to the survival of wild-type cancers and shorter than the survival of cancers with common EGFR mutations.Conclusions Patients with EGFR exon 20 insertions have similar clinical characteristics to those with common EGFR mutations but a poorer prognosis. The prevalence of this subset of NSCLC is similar to that of other genotype-defined subsets of lung adenocarcinoma (e.g. those with BRAF mutations, HER2 insertions, ROS1 rearrangements) and is a population of interest for trials of new targeted therapies.

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EGFR exon 20 insertions are typically unresponsive to first- and second-generation EGFR TKIs due to modified structures of their kinase domains.
“they are typically unresponsive to first and second-generation EGFR TKIs due to the modified structures of their kinase domains”
From Diverse EGFR Exon 20 Insertions and Co-Occurring Molecular Alterations Identified by Comprehensive Genomic Profiling of NSCLC (2018) · cites this paper as [6]
Patients with exon 20 insertions have a similar overall survival to EGFR wild type patients.
“and are associated with a similar overall survival of EGFR wild type patients [71].”
From Heterogeneous Responses to Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) in Patients with Uncommon EGFR Mutations: New Insights and Future Perspectives in this Complex Clinical Scenario (2019) · cites this paper as [71]
EGFR A763_Y764insFQEA accounts for 10-20% of all reported EGFR exon 20 insertions.
“This sequence alteration accounts for 10–20% of all reported EGFR exon 20 insertions 31,32,35.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [31]
The most common exon 20 insertions are post C-helix insertions of 1-4 amino acids, accounting for 80-90% of all exon 20 insertions.
“The most common EGFR exon 20 insertions that have been reported in NSCLC samples are post C-helix insertions of one to four amino-acids, which in aggregate account for 80–90% of all exon 20 insertions 31,32,35.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [31]
Patients with NSCLC harboring EGFR exon 20 insertion mutations present a shorter survival time compared to patients with classic EGFR mutations.
“Therefore, patients with NSCLC harboring EGFR exon 20 insertion mutations present a shorter survival time compared to patients with classic EGFR mutations [21].”
From In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer (2015) · cites this paper as [21]

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Abstract 5838: The landscape of EGFR exon 20 insertion mutations in Chinese patients with non-small cell lung cancer
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Authors: Oxnard, G. R., Lo, P. C., Nishino, M., Dahlberg, S. E., Lindeman, N. I., Butaney, M., Jackman, D. M., Johnson, B. E., & Jänne, P. A.
Affiliations: Brigham and Women's Hospital (US)
Dana-Farber Cancer Institute (US)
Corresponding author: Oxnard, Geoffrey R.
ORCID: Oxnard, Geoffrey R.
Nishino, Mizuki
Dahlberg, Suzanne E.
Lindeman, Neal I.
Butaney, Mohit
Johnson, Bruce E.
Venue: Journal of Thoracic Oncology
Publisher: Elsevier BV
Published: 2013-02
Volume: 8
Issue: 2
Pages: 179-184
ISSN: 1556-0864 (ISSN-L)
DOI: 10.1097/jto.0b013e3182779d18
PMC: PMC3549533
OpenAlex: W2075445339
Cited by: 360
References: 32
Citations by year: 2026: 17 · 2025: 30 · 2024: 33 · 2023: 41 · 2022: 50 · 2021: 36 · 2020: 31 · 2019: 26 · 2018: 24 · 2017: 19 · 2016: 16 · 2015: 15 · 2014: 15 · 2013: 7
FWCI: 14.35
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 1034 d)
Locations: Journal of Thoracic Oncology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (5k23ca157631-02)
National Cancer Institute (K23-CA157631, P50CA090578, R01CA135257)
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: EGFR exon 20 insertion, non-small cell lung cancer, lung adenocarcinoma, EGFR mutation, EGFR tyrosine kinase inhibitors, survival, never smokers, Asian patients, targeted therapy, molecular properties
MeSH terms: Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell, Exons, Female, Follow-Up Studies, Humans, Lung Neoplasms, Male, Middle Aged, Molecular Sequence Data, Mutation, Neoplasm Staging, Prognosis, Retrospective Studies, Survival Rate, Mutagenesis, Insertional, Sequence Homology, Amino Acid, Young Adult, ErbB Receptors

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Natural History and Molecular Characteristics of Lung Cancers Harboring EGFR Exon 20 Insertions

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