EGFR Exon 20 Insertion Mutations in Sinonasal Squamous Cell Carcinoma.

Laura Pacini,Mario A Hermsen,Paul H Huang,Virginia N Cabal

doi:10.3390/cancers14020394

Abstract

Simple SummaryThe majority of patients with sinonasal squamous cell carcinoma (SNSCC) associated with inverted sinonasal papilloma carry an exon 20 insertion activating mutation in the epidermal growth factor receptor (EGFR). The aim of this review is to document the various features of EGFR mutations in SNSCC and other cancers, and to assess what we can learn from the study of these mutations in lung cancer, with a special focus on new therapeutic opportunities for SNSCC patients carrying EGFR exon 20 insertions mutations.Recurrent epidermal growth factor receptor (EGFR)-activating mutations have been identified in a rare form of head and neck cancer known as sinonasal squamous cell carcinoma (SNSCC), a malignant disease with a 5-year mortality rate of ~40%. Interestingly, the majority of EGFR mutations identified in patients with primary SNSCC are exon 20 insertions (Ex20ins), which is in contrast to non-small-cell lung cancer (NSCLC), where the EGFR exon 19 deletion and L858R mutations predominate. These studies demonstrate that EGFR Ex20ins mutations are not exclusive to lung cancer as previously believed, but are also involved in driving SNSCC pathogenesis. Here we review the landscape of EGFR mutations in SNSCC, with a particular focus on SNSCC associated with inverted sinonasal papilloma (ISP), a benign epithelial neoplasm. Taking lessons from NSCLC, we also discuss potential new treatment options for ISP-associated SNSCC harbouring EGFR Ex20ins in the context of targeted therapies, drug resistance and precision cancer medicine. Moving forward, further basic and translational work is needed to delineate the biology of EGFR Ex20ins in SNSCC in order to develop more effective treatments for patients with this rare disease.

Highlights

Introduction published maps and institutional affilSinonasal squamous cell carcinoma (SNSCC) is a rare malignancy accounting for 3–5%of head and neck cancer cases and 75% of all sinonasal tumours [1,2,3]
Given that epidermal growth factor receptor (EGFR) activates signalling networks associated with promoting cell survival, vival, growth, invasion and proliferation, it is unsurprising that aberrations that result in growth, invasion and proliferation, it is unsurprising that aberrations that result in hyperachyperactivation of EGFR are common in many cancers
In the phase II, open-label, multi-cohort, multicentre ZENITH20 trial (NSCT03318939), a cohort of 115 non-small-cell lung cancer (NSCLC) patients that have progressed after previous treatment with a proven EGFR or HER2 exon 20 insertions (Ex20ins) mutation who were treated with 16 mg poziotinib once daily achieved an overall response rate (ORR) of 14.8% and a disease control rate (DCR) of 68.7% with a median

Summary

EGFR Mutations in Cancer

Given that EGFR activates signalling networks associated with promoting cell sur‐. Given that EGFR activates signalling networks associated with promoting cell survival, vival, growth, invasion and proliferation, it is unsurprising that aberrations that result in growth, invasion and proliferation, it is unsurprising that aberrations that result in hyperachyperactivation of EGFR are common in many cancers. EGFR tyrosine kinase inhibitor (TKI) therapy, especially the ATP-irreversible second- and ical trials are currently ongoing neratinib to evaluateand the osimertinib, activity of these inhibitors on GBM patients third-generation inhibitors, respectively. The two most common mutations, in-frame deletions in exon 19 (Ex19del) affecting the amino acid motif LREA (E746–750del) and substitution of arginine for leucine at position 858 (L858R) in exon 21, are referred to as “classical” EGFR mutations and together account for approximately 85% of EGFR mutations in patients with NSCLC [40] These mutations can result in the constitutive activation of signal transduction pathways, leading to cell proliferation and survival regardless of the presence of extracellular ligands. A new generation of compounds capable of selectively targeting EGFR Ex20ins have been evaluated in a number of clinical trials involving NSCLC patients and two new targeted therapies have recently been approved by the US Food and Drug Administration (FDA) for the treatment of this previously undruggable molecular subtype of NSCLC

EGFR Mutations in SNSCC

EGFR Ex20ins Targeted Therapies

Lessons from Lung Cancer That Could Be Applied to the Treatment of SNSCC

Findings

Conclusions