Abstract
ObjectivesMutations in the gene that encodes epidermal growth factor receptor (EGFR) are biomarkers that predict how non-small cell lung cancer (NSCLC) patients respond to EGFR-targeted therapies collectively known as tyrosine kinase inhibitors (TKIs). Thus, EGFR genotyping provides crucial information for treatment decision. Both Sanger sequencing and real-time PCR methodologies are used for EGFR genotyping. However, methods based on real-time PCR have limitations, as they may not detect rare or novel mutations. The aim of this study was to determine the prevalence of rare mutations in the tyrosine kinase domain (exons 18–21) of the EGFR gene not targeted by the most frequently used real-time PCR approaches, i.e., the cobas® EGFR Mutation Test, and the Idylla™ EGFR Mutation Assay. MethodsA total of 1228 NSCLC patients were screened for mutations in exons 18–21 of the EGFR gene using Sanger sequencing. ResultsWe observed that 252 patients (∼20%) had at least one mutation in the EGFR gene, and 38 (∼3%) carried uncommon genetic alterations that would not be identified by the cobas® or the Idylla™ tests. We further found six new single mutations and seven previously unreported compound mutations. Clinical information and patient outcome are presented for these cases. ConclusionsThis study highlights the value of sequencing-based approaches to identify rare mutations. Our results add to the inventory of known EGFR mutations, thus contributing to improved lung cancer precision treatment.
Highlights
Every year, almost 2 million people receive a diagnosis of lung cancer [1]
We observed that 252 patients (∼20%) had at least one mutation in the epidermal growth factor receptor (EGFR) gene, and 38 (∼3%) carried uncommon genetic alterations that would not be identified by the cobas® or the IdyllaTM tests
This prevalence of mutations is higher than previously reported in unselected European patients [5], and the discrepancy is probably caused by the clinical selection bias of patients referred for EGFR genotyping
Summary
85% have non–small cell lung cancer (NSCLC) [2]. Mutations in exons 18–21 of the EGFR gene are often detected in tumor samples of NSCLC patients. Mutations in these exons, which encode the tyrosine kinase domain of the Epidermal Growth Factor Receptor (EGFR), result in a gain in function, leaving the intracellular signaling pathway of EGFR constitutively active. About 10–30% of NSCLC samples harbor somatic mutations in exons 18, 19, 20 and / or 21 of the EGFR gene kinase domain [5]. Novel drugs known as EGFR-targeted therapies, or EGFR-tyrosine kinase inhibitors (TKIs), namely gefitinib, erlotinib, afatinib and osimertinib, have been successful in delaying disease progression in a subgroup of NSCLC patients [6]
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