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Ramakrishna R Sompallae1, Bilge Dundar1, Natalya V Guseva1

  • 1Department of Pathology, University of Iowa Hospitals & Clinics, Iowa City, IA, United States.

Frontiers in Oncology
|June 7, 2023
PubMed
Summary

Epidermal growth factor receptor (EGFR) and ERBB2 exon 20 insertions/duplications are rare in non-small cell lung cancer (NSCLC). These mutations are linked to poor prognosis and resistance to standard treatments, necessitating further research into targeted therapies.

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Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Exon 20 (ex20) in-frame insertions or duplications (ins/dup) in epidermal growth factor receptor (EGFR) and ERBB2 are found in 1.5% of non-small cell lung cancer (NSCLC).
  • These mutations confer resistance to classic EGFR inhibitors and immune checkpoint inhibitors, leading to poor prognosis.
  • Despite FDA approval of targeted therapies like mobocertinib and amivantamab, comprehensive studies on ex20 ins/dup NSCLC remain limited.

Purpose of the Study:

  • To identify and characterize non-small cell lung cancer (NSCLC) cases with epidermal growth factor receptor (EGFR) or ERBB2 exon 20 insertions/duplications (ex20 ins/dup).
  • To correlate these genetic alterations with clinical, morphological, and programmed death-ligand 1 (PD-L1) expression findings.
  • To understand the unique characteristics and potential therapeutic implications of EGFR/ERBB2 ex20 ins/dup NSCLC.
Keywords:
EGFR/ERBB2 exon20 insertion/duplicationERBB2PD-L1clinicopathologic featuresnon-small cell lung cancer

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Main Methods:

  • Retrospective review of 536 NSCLC cases tested between 2014 and 2023.
  • Utilized a custom 214-gene next-generation sequencing panel for DNA variants and the FusionPlex CTL panel for fusion transcripts.
  • Performed immunohistochemistry (IHC) for PD-L1 expression using 22C3 or E1L3N clones.

Main Results:

  • Identified 18 cases (9 EGFR, 9 ERBB2) with ex20 ins/dup, predominantly in non- or light smokers with stage IV adenocarcinoma.
  • Ex20 ins/dup variants were heterogeneous, clustered in the loop following the C-helix and α C-helix.
  • Co-existing TP53 variants were found in 67% of cases; PD-L1 expression was predominantly negative.

Conclusions:

  • NSCLCs with EGFR/ERBB2 ex20 ins/dup are rare, often acinar predominant, PD-L1 negative, and more common in non- or light smokers.
  • These mutations appear mutually exclusive with other common driver mutations in NSCLC.
  • Further investigation is warranted to correlate specific variants and co-mutations with treatment response and resistance mechanisms, particularly after mobocertinib therapy.