HER2 amplification and HER2 mutation are distinct molecular targets in lung cancers

Li, Bob T.; Ross, Dara S.; Aisner, Dara L.; Chaft, Jamie E.; Hsu, Meier; Kako, Severine L.; Kris, Mark G.; Varella-Garcia, Marileila; Arcila, Maria E.

doi:10.1016/j.jtho.2015.10.025

Cited by 288Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchLung Cancer Research Studies

HER2 amplification and HER2 mutation are distinct molecular targets in lung cancers

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Li, Bob T., Ross, Dara S., Aisner, Dara L., Chaft, Jamie E., Hsu, Meier, Kako, Severine L., Kris, Mark G., Varella-Garcia, Marileila +1 more·2016·Journal of Thoracic Oncology

DOI 10.1016/j.jtho.2015.10.025PMC PMC4698879

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Abstract

Introduction Human epidermal growth factor receptor 2 gene (HER2 [also known as ERBB2]) alterations have been identified as oncogenic drivers and potential therapeutic targets in lung cancers. The molecular associations of HER2 gene amplification, mutation, and HER2 protein overexpression in lung cancers have not been distinctly defined. To explore these associations, Memorial Sloan Kettering Cancer Center and the University of Colorado combined their data on HER2 alterations in lung cancers.Methods Tumor specimens from 175 patients with lung adenocarcinomas and no prior targeted therapy were evaluated for the presence of HER2 amplification and mutation and HER2 protein overexpression. Amplification was assessed by fluorescence in situ hybridization (FISH) and defined as an HER2-to-chromosome enumeration probe 17 ratio of at least 2.0. Mutation was assessed by fragment analysis, mass spectrometry genotyping, and Sanger sequencing. Overexpression was assessed by immunohistochemical (IHC) staining. The frequencies of HER2 amplification and mutation and HER2 overexpression were calculated and their overlap examined.Results HER2 amplification was detected by FISH in 5 of 175 cases (3%). HER2 mutation was detected in 4 of 148 specimens (3%), including three identical 12-base pair insertions (p.A775_G776insYVMA) and a 9-base pair insertion, all in exon 20. None of the HER2-mutant cases was amplified. HER2 overexpression (2+ or 3+) on IHC staining was not detected in the 25 specimens available for testing, and negative IHC staining correlated with the negative results according to FISH.Conclusions HER2 mutations are not associated with HER2 amplification, thus suggesting a distinct entity and therapeutic target. HER2-positive lung cancer may not be an adequate term, and patient cohorts for the study of HER2-targeted agents should be defined by the specific HER2 alteration present.

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ERBB2 exon 20 insertions confer sensitivity to ERBB2-targeted therapies.
“Ten ERBB2 mutations were detected, including 5 exon 20 insertions shown to confer sensitivity to ERBB2-targeted therapies (36).”
From Detection of Therapeutically Targetable Driver and Resistance Mutations in Lung Cancer Patients by Next-Generation Sequencing of Cell-Free Circulating Tumor DNA (2016) · cites this paper as [36]

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Authors: Li, B. T., Ross, D. S., Aisner, D. L., Chaft, J. E., Hsu, M., Kako, S. L., Kris, M. G., Varella-Garcia, M., & Arcila, M. E.
Affiliations: The University of Sydney (AU)
Memorial Sloan Kettering Cancer Center (US)
University of Colorado Anschutz (US)
Corresponding author: Li, Bob T.
ORCID: Li, Bob T.
Ross, Dara S.
Aisner, Dara L.
Chaft, Jamie E.
Hsu, Meier
Kris, Mark G.
Arcila, Maria E.
Venue: Journal of Thoracic Oncology
Publisher: Elsevier BV
Published: 2016-03
Volume: 11
Issue: 3
Pages: 414-419
ISSN: 1556-0864 (ISSN-L)
DOI: 10.1016/j.jtho.2015.10.025
PMC: PMC4698879
OpenAlex: W2262992387
Cited by: 286
References: 16
Citations by year: 2026: 20 · 2025: 33 · 2024: 23 · 2023: 31 · 2022: 32 · 2021: 42 · 2020: 39 · 2019: 23 · 2018: 23 · 2017: 12 · 2016: 7
FWCI: 11.09
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, 365 d)
Locations: Journal of Thoracic Oncology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (1RC2 CA148394, P50CA058187, P30 CA046934, P30 CA008748)
Boehringer Ingelheim
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
Keywords: HER2, HER2 amplification, HER2 mutation, HER2 overexpression, lung adenocarcinoma, HER2 exon 20 insertion, HER2-targeted therapy, molecular subtyping
MeSH terms: Adenocarcinoma of Lung, Adenocarcinoma, Aged, Female, Gene Amplification, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, In Situ Hybridization, Fluorescence, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Genes, erbB-2, Molecular Targeted Therapy

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HER2 amplification and HER2 mutation are distinct molecular targets in lung cancers

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