Expanding the search for significant EGFR mutations in NSCLC outside of the tyrosine kinase domain with next-generation sequencing.

While conventional organization of EGFR mutations in non-small cell lung cancer (NSCLC) includes classic lesions sensitive to tyrosine kinase inhibitors (TKI) and variants localized to the tyrosine kinase domain (TKD) in exons 18-21, next-generation sequencing (NGS) raises the prospect of identifying clinically relevant variants in extra-TKD regulatory regions. NSCLC patients at our institution who received tumor profiling with NGS from 2013 to 2015 were identified. EGFR mutations were arranged based upon their distribution relative to the TKD. In silico analysis was performed to predict non-synonymous single nucleotide polymorphism (nsSNP) pathogenicity. Of 247 patients, 43 EGFR variants were seen in 39 patients (16%). While 32 had TKD lesions demonstrable through standard testing, 7 had extra-TKD nsSNPs (7/43), of which 5 were extracellular domain (ECD), 1 juxtamembrane (JM) and 1 carboxy-terminal (CT). Aside from known pathogenic ECD mutation G598V, 5/6 extra-TKD nsSNPs were predicted damaging with in silico analysis. Seven of 7 extra-TKD nsSNP+ patients smoked and were stage IV; 5/7 were adenocarcinoma. An adenocarcinoma patient with JM R675Q had erlotinib, 150 mg daily, added following progression of disease on carboplatin and paclitaxel and had a partial response for 4 months. No other extra-TKD nsSNP+ patient received EGFR-directed therapy. >2% NSCLC cases in our cohort had EGFR nsSNPs located outside of the TKD, representing >16% of all EGFR mutations. Extra-TKD variants should be characterized collaboratively to determine TKI sensitivity and additional therapeutic targets.