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. 2024 Oct 1;8(1):217.
doi: 10.1038/s41698-024-00720-9.

Molecular landscape of ERBB2 alterations in 3000 advanced NSCLC patients

Lingzhi Hong  1   2 , Sonia Patel  1 , Leylah M Drusbosky  3 , Yuanyuan Xiong  4 , Rongrong Chen  4 , Ruixuan Geng  5 , Simon Heeke  1 , Monique Nilsson  1 , Jia Wu  1   2 , John V Heymach  1 , Yingyi Wang  6 , Jianjun Zhang  7   8 , Xiuning Le  9
Affiliations

Molecular landscape of ERBB2 alterations in 3000 advanced NSCLC patients

Lingzhi Hong et al. NPJ Precis Oncol. .

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.

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Conflict of interest statement

L.M.D. is employee and stockholder of Guardant Health. Y.X. and R.C. are employee of Geneplus-Beijing. S.H. received consulting fees from Guardant health and AstraZeneca. M.N. receives royalties and licensing fees from Spectrum Pharmaceuticals. J.V.H. reports receiving advisory/consulting fees from AstraZeneca, Boehringer-Ingeheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation Medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, Sanofi, Takeda Pharmaceuticals, Mirati Therapeutics, Bristiol-Myers Squibb, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, EMD Serono, Pneuma Respiratory, Kairos Venture Investments, Leads Biolabs, RefleXion, and research funding from GlaxoSmithKline, AstraZeneca, Spectrum, all outside of the submitted work. J.Z. reports grants from Merck, grants and personal fees from Johnson and Johnson and Novartis, and personal fees from Bristol Myers Squibb, AstraZeneca, GenePlus, Innovent, and Hengrui outside the submitted work. X.L. receives consulting/advisory fees from EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Novartis, Eli Lilly, Boehringer Ingelheim, Hengrui Therapeutics, Janssen, Blueprint Medicines, Regeneron, Sensei Biotherapeutics, Abion, Pinetree Therapeutics and Abbvie, and Research Funding from Eli Lilly, EMD Serono, ArriVent, Teligene, Regeneron, Blackdiamond, and Boehringer Ingelheim. The other authors declare no competing interests in the submitted work.

Figures

Fig. 1
Fig. 1. ERBB2 mutational profile in newly diagnosed NSCLC patients.
ERBB2 oncogenic mutations and proportion reported by OncoKB and COSMIC in Geneplus (a, c) and Guardant360 (b, d). e Proportion of ERBB2 oncogenic mutations for 70 patients with co-occurring ERBB2 amplification in Geneplus cohort. f ERBB2 mutational profile of the 70 patients with co-occurring ERBB2 amplification in Geneplus cohort.
Fig. 2
Fig. 2. Differential co-mutated genes between patients with ERBB2 oncogenic mutations and with ERBB2 amplifications in Geneplus cohort.
a Co-mutation plot showing co-occurring alterations between ERBB2 oncogenic mutations and amplifications. Enrichment analysis of co-altered genes between patients with ERBB2 oncogenic mutations and amplifications: (b) gene SNVs/Indels; (c) gene CNVs. d Map of chromosome 17 (Chr17) showing the location of ERBB2 and co-amplified genes on the same chromosome.
Fig. 3
Fig. 3. Difference between EGFR and ERBB2 exon 20 insertions (ex20 ins) in NSCLC.
ERBB2 ex20 ins in Geneplus (a) and Guardant360 (b). EGFR ex20 ins in Geneplus (c) and Guardant360 (d). Bubble plots of ex20 ins comparison between ERBB2 and EGFR in NSCLC patients in Geneplus (e) and Guardant360 (f).
Fig. 4
Fig. 4. Differential co-mutated genes between patients with EGFR and ERBB2 exon 20 insertions (ex20 ins) in Geneplus cohort.
Co-mutation plots of ERBB2 (a) and EGFR (b). Enrichment analysis of co-altered genes between patients with ERBB2 ex20 ins and EGFR ex20 ins: (c) gene SNVs/Indels; (d) gene CNVs.
See this image and copyright information in PMC

References

    1. Wee, P. & Wang, Z. Epidermal growth factor receptor cell proliferation signaling pathways. Cancers9, 52 (2017). - PMC - PubMed
    1. Friedlaender, A. et al. EGFR and HER2 exon 20 insertions in solid tumours: from biology to treatment. Nat. Rev. Clin. Oncol.19, 51–69 (2022). - PubMed
    1. Arcila, M. E. et al. Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin. Cancer Res. 18, 4910–8, (2012). - PMC - PubMed
    1. Shigematsu, H. et al. Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res. 65, 1642–6, (2005). - PubMed
    1. Tomizawa, K. et al. Prognostic and predictive implications of HER2/ERBB2/neu gene mutations in lung cancers. Lung Cancer74, 139–44, (2011). - PubMed

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