Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy

Abstract

Somatic mutations in the epidermal growth factor receptor (EGFR) gene are present in approximately 20% (in Caucasians) to 40% (in East Asians) of adenocarcinomas of the lung. Targeted therapy for these lung cancers has been established based on evidence regarding mainly common mutations; that is, exon 19 deletions (Del19) and L858R. EGFR-tyrosine kinase inhibitors (TKI), gefitinib, erlotinib or afatinib showed high objective response rates (ORR) of approximately 60%. Several studies suggested that Del19 might be more sensitive to EGFR-TKI than L858R. On the other hand, it has been difficult to establish evidence for other less common mutations, accounting for 12% of all EGFR mutations, because there are many variants and many studies have excluded patients with these uncommon mutations. However, recent studies revealed that these rare genotypes could be targetable if appropriate TKI are selected. For example, G719X (X denotes A, S, C and so on), Del18, E709K, insertions in exon 19 (Ins19), S768I or L861Q showed moderate sensitivities to gefitinib or erlotinb with ORR of 30%-50%. However, afatinib appeared to be especially effective for these tumors. Although Ins20s (except for insFQEA) have been regarded as resistant mutations, osimertinib may be effective for rare subtypes of them and nazartinib (EGF816) is promising for the majority of them. For the further development of targeted therapy in all EGFR mutations, it is important to precisely detect targetable mutations, to select the most appropriate TKI for each mutation, and to continue investigating in vitro studies and collecting clinical data on even rare mutations.

Keywords: Adenocarcinoma; epidermal growth factor receptor; molecular targeted therapy; precision medicine; tyrosine kinase inhibitor.

Figure 1

Structure of the epidermal growth factor receptor (EGFR) protein and frequency of EGFR mutations in lung cancer by a compilation of recent large studies. Each codon of representative mutations was mapped on the protein sequence of the EGFR kinase domain. Codons in exon 18, 19, 20 and 21 are shown in blue, yellow, red and green, respectively. Spiral structures represent alpha‐helixes. Thick arrows indicate beta‐sheet. Figures were drawn using the PyMOL Molecular Graphics System (Version 1.7.4 Schrodinger, LLC) based on the crystal structure information from PDB ID 4R3P.