Compound EGFR Mutations and Response to EGFR Tyrosine Kinase Inhibitors

Abstract

INTRODUCTION Non-small-cell lung cancers (NSCLCs) containing epidermal growth factor receptor (EGFR) mutations are exquisitely sensitive to EGFR tyrosine kinase inhibitors (TKIs). This is the case of the most common EGFR mutations affecting exon 18 (G719X), 19 (inframe deletions) and 21 (L858R and L861Q). However, the frequency of compound (i.e., double or complex) EGFR mutations - where an EGFR TKI sensitizing or other mutation is identified together with a mutation of unknown clinical significance – and their pattern of response/resistance to EGFR TKIs are less well described. METHODS We analyzed the EGFR mutation pattern of 79 cases of NSCLC harboring EGFR mutations, and compiled the genotype-response data for patients with NSCLCs with compound EGFR mutations treated with EGFR TKIs. RESULTS Out of the 79 EGFR mutated tumors identified, 11 (14%) had compound mutations. Most involved the EGFR TKI-sensitizing G719X (n=3, plus S768I or E709A), L858R (n=4, plus L747V, R776H, T790M or A871G), L861Q (n=1, plus E709V) and delL747_T751 (n=1, plus R776H). 8 patients received an EGFR TKI: 3 cases with G719X plus another mutation had partial responses (PR) to erlotinib; out of 3 cases with L858R plus another mutation, 2 displayed PRs and 1 (with EGFR-L858R+A871G) progressive disease to erlotinib; 1 NSCLC with EGFR-L861Q+E709A and 1 with delL747_T51+R776S had PRs to EGFR TKIs. CONCLUSIONS Compound EGFR mutations comprised 14% of all mutations identified during routine sequencing of exons 18–21 of EGFR in our cohort. Most patients with an EGFR TKI sensitizing mutation (G719X, exon 19 deletion, L858R and L861Q) in addition to an atypical mutation responded to EGFR TKIs. Reporting of the genotype-response pattern of NSCLCs with EGFR compound and other rare mutations, and the addition of this information to searchable databases will be helpful to select the appropriate therapy for EGFR mutated NSCLC.

Epidermal growth factor receptor exon 20 p.S768I mutation in non-small cell lung carcinoma: A case report combined with a review of the literature and investigation of clinical significance

“…By contrast, a positive clinical response to gefitinib in an NSCLC patient harboring the rare mutation p.S768I was observed by Masago et al (25). Additional previous studies have also reported partial responses to EGFR-TKIs in patients exhibiting p.S768I and other mutations (8,20,23,29,30). In addition, a number of retrospective analyses of EGFR mutations (Table I) have investigated the p.S768I mutation; however, the clinical responsiveness to EGFR-TKIs has not been reported (7,12,13,26,31).…”

Kinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements

“…These mutations encompass EGFR-exon 18 indels/E709X (<0.5% of EGFR mutations), exon 18 G719X (~3% of EGFR mutations), exon 19 insertions (<0.5% of EGFR mutations), exon 20 A763_ Y764insFQEA (<0.5% of EGFR mutations), exon 20 S768I (<1.5% of EGFR mutations) and the exon 21 L861Q (~3% of EGFR mutations); either alone or compound with other EGFR mutations (19). It is interesting to note that in preclinical models, the inhibitory concentrations of 1 (23) when compared to EGFR-exon 19 deletion mutants.…”

The Importance of EGFR Mutation Detection Method for the Correct Clinical Management of Patients with Non-Small Cell Lung Cancer: A Case Report

“…This E709A mutation, undetected in the first molecular diagnosis made by pyrosequencing procedure in another Italian Hospital Center, was then a naïve EGFR mutation of exon 18 of EGFR gene, together with G719A. The attenuated response or less sensitivity to TKIs and downstream effector phosphorylation profiles than the EGFR mutation of codon 719 alone were demonstrated only by two studies [11,12], in tumor simple and in vitro NSCLC patients, respectively, while the more attenuated response to TKIs due to naïve co-presence of the mutations at 719 and 709 codons of the same exon was found and/or described by few reports [8,9,[13][14][15]. In particular, Tam et al (2009), found that double mutant (E709A+G719C) of EGFR, showed a response profile intermediate between those of E709A and G719C, suggesting that the presence of the uncommon E709A, in addition to the activating G719C, would confer relative resistance to gefitinib treatment [12].…”