Prevalence and breakdown of EGFR exon 20 driver mutations in routine NHS lung cancer diagnostic testing

Abstract

INTRODUCTION In nonsmall cell lung cancer (NSCLC), oncogenic driver mutations in epidermal growth factor receptor (EGFR) typically occur in exons 18, 19, 20 and 21. Until recently, EGFRdriven tumours displaying sensitivity to EGFR tyrosine kinase inhibitors (TKIs) have almost exclusively comprised those with activating mutations in exons 18, 19 and 21, while tumours with primary activating mutations located within exon 20, and particularly those with insertions or deletion–insertions, largely appeared to be resistant to TKIs. For this reason, singlegene tests such as quantitative PCR (qPCR)based assays performed as part of standard clinical diagnostic testing have understandably focused predominantly on the most common driver mutations within exons 18, 19 and 21, which are known to confer TKI sensitivity. Novel therapeutic agents for patients with EGFR exon 20 insertions are currently in trials, and as such, determining the frequency and diversity of exon 20 mutations in the NSCLC population may be highly relevant to future clinical practice. Since data from most qPCRbased EGFR tests are unlikely to identify and will not classify the full spectrum of exon 20 activating mutations, nextgeneration sequencing (NGS)based NSCLC screening is best placed to determine their frequency within a cohort of these patients. While this has been reported in other populations, this has not been described in the UK from largescale standard of care testing centred within the National Health Service (NHS). Our laboratory has been performing targeted NGS as the standard of care test for NSCLCassociated mutations since 2014, as previously described, and this clinical sequencing data have been used to profile EGFR exon 20 mutations across a large representative cohort.