Detection of rare and novel EGFR mutations in NSCLC patients: Implications for treatment-decision

Objectives: Mutations 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 (R) EGFR Mutation Test, and the Idylla (TM) EGFR Mutation Assay. Methods: A total of 1228 NSCLC patients were screened for mutations in exons 18-21 of the EGFR gene using Sanger sequencing. Results: We observed that 252 patients (similar to 20%) had at least one mutation in the EGFR gene, and 38 (similar to 3%) carried uncommon genetic alterations that would not be identified by the cobas (R) or the Idylla (TM) tests. We further found six new single mutations and seven previously unreported compound mutations. Clinical information and patient outcome are presented for these cases. Conclusions: This 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.