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Updated: Jun 11, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Molecular landscape of ERBB2 alterations in 3000 advanced NSCLC patients
Lingzhi Hong1,2, Sonia Patel1, Leylah M Drusbosky3
1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract:
ERBB2 (HER2) represents a newly recognized actionable oncogenic driver in non-small cell lung cancer (NSCLC), with approved targeted therapy available. Understanding the landscape of ERBB2 alterations and co-occurring mutations is essential for guiding treatment decisions. We conducted an analysis involving 3000 NSCLC patients with all types of ERBB2 alterations, drawn from two extensive retrospective cohorts: 1281 from Geneplus (Chinese) and 1719 from Guardant360 (the United States, US). The incidence of all types of ERBB2 alterations was found to be 5.6% in the Chinese group and 5.2% in the US group. In both cohorts, among oncogenic alterations of ERBB2, exon 20 insertion Y772_A775dupYVMA was the most frequent alteration (58% vs 41.6% in the Chinese vs the US), followed by G776delinsVC/LC/VV/IC (10.7% vs 9.7%), and S310X (10.5% vs 15.4%). EGFR ex20 insertions were identified in the A767-V774 region, whereas ERBB2 ex20 insertions were observed in the Y772-P780 region. Notably, EGFR ex20 insertions exhibited greater insertion diversity. Clinical characteristics of EGFR and ERBB2 ex20 NSCLC were similar, characterized by low tumor mutation burden (TMB), a predominant never-smoker population, and a majority of lung adenocarcinoma cases.
Insights
ERBB2 (HER2) alterations occur in over 5% of non-small cell lung cancer (NSCLC) patients. Exon 20 insertions are the most common ERBB2 alteration, guiding targeted therapy in NSCLC.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- ERBB2 (HER2) is an actionable oncogenic driver in non-small cell lung cancer (NSCLC).
- Understanding ERBB2 alterations and co-mutations is crucial for effective treatment strategies.
- Targeted therapies for ERBB2-altered NSCLC are becoming available.
Purpose of the Study:
- To analyze the landscape of ERBB2 alterations in NSCLC across different populations.
- To identify the most frequent ERBB2 alterations and their co-occurring mutations.
- To compare ERBB2 alterations with EGFR exon 20 insertions in NSCLC.
Main Methods:
- Retrospective analysis of 3000 NSCLC patients from Chinese (Geneplus) and US (Guardant360) cohorts.
- Comprehensive genomic profiling to identify ERBB2 alterations and co-mutations.
- Comparison of mutation frequencies, types, and clinical characteristics between cohorts.
Main Results:
- ERBB2 alterations were found in 5.6% (Chinese) and 5.2% (US) of NSCLC patients.
- The most frequent ERBB2 alteration was exon 20 insertion Y772_A775dupYVMA (58% vs 41.6%).
- EGFR and ERBB2 exon 20 insertions share similar clinical features, including low tumor mutation burden and a non-smoker predominance.
Conclusions:
- ERBB2 alterations represent a significant actionable target in NSCLC.
- Exon 20 insertions are the predominant oncogenic alteration in ERBB2-driven NSCLC.
- ERBB2-altered NSCLC shares clinical characteristics with EGFR exon 20 insertion NSCLC, suggesting potential therapeutic parallels.
