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Updated: Mar 28, 2026
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
HER2 Amplification and HER2 Mutation Are Distinct Molecular Targets in Lung Cancers
Bob T Li1, Dara S Ross2, Dara L Aisner3
1Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA; Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
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.
Insights
Human epidermal growth factor receptor 2 (HER2) mutations in lung cancer are distinct from amplification and may represent a separate therapeutic target. Defining patient cohorts by specific HER2 alterations is crucial for targeted therapy studies.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Alterations in the Human Epidermal Growth Factor Receptor 2 (HER2) gene (also known as ERBB2) are key drivers in lung cancers.
- Understanding the distinct molecular associations of HER2 amplification, mutation, and protein overexpression is critical for targeted therapies.
Purpose of the Study:
- To investigate the molecular associations between HER2 gene amplification, mutation, and protein overexpression in lung adenocarcinomas.
- To clarify the distinct roles of different HER2 alterations in lung cancer.
Main Methods:
- Evaluated 175 lung adenocarcinoma specimens for HER2 amplification (FISH), mutation (fragment analysis, mass spectrometry, Sanger sequencing), and protein overexpression (IHC).
- Calculated frequencies of HER2 alterations and examined their overlap.
- Defined HER2 amplification by an HER2-to-chromosome 17 ratio ≥ 2.0.
Main Results:
- HER2 amplification detected in 3% (5/175) of cases.
- HER2 mutations (exon 20 insertions) found in 3% (4/148) of cases; no overlap with amplification.
- No HER2 protein overexpression detected; negative IHC correlated with negative FISH results.
Conclusions:
- HER2 mutations and amplification represent distinct entities in lung cancer.
- HER2 mutations suggest a unique therapeutic target.
- Patient cohorts for HER2-targeted therapies should be stratified by specific HER2 alterations, not just 'HER2-positive' status.
