Mutations in the epidermal growth factor receptor gene and effects of EGFR-tyrosine kinase inhibitors on lung cancers

Abstract

Epidermal growth factor receptor (EGFR) gene mutations are frequent in lung cancer arising in patients of Asian ethnicity, female sex, nonsmokers, and adenocarcinoma histology. About 70% of the patients with EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib and erlotinib, whereas only 10% of those without the mutations do so. Therefore, EGFR mutation is being recognized as one of the most reliable predictive factors for treatment using EGFR-TKIs. Another important issue in clinical practice is the fatal interstitial lung disease (ILD) that can develop in patients with gefitinib treatment, especially Asian patients. A nested case-control study recently conducted in Japan identified some risk factors that cause ILD, including age > or = 55 years, a history of smoking, preexisting ILD, poor performance status, short duration since diagnosis of lung cancer, reduced extent of normal lung on computed tomography, and concurrent cardiac disease. About half of the acquired resistance to EGFR-TKIs that almost always occurs during the course of treatment is caused by a secondary mutation at codon 790 (T790M). EGFR-TKIs are not universally effective for treating lung cancers but are effective in patients with particular genotypes. Therefore, patients who would benefit from EGFR-TKIs therapy should be concentrated in clinical trials. Based on this concept, Phase III clinical trials comparing gefitinib monotherapy with standard platinum-based chemotherapy are currently ongoing for patients with EGFR mutations and lung cancer.