The impact of EGFR mutations on gefitinib sensitivity in non-small cell lung cancer

Gefitinib (ZD1839, Iressa^®; AstraZeneca) has produced objective tumor responses and symptom improvement in some patients with non-small cell lung cancer. In clinical trials, 12-18.4% of patients had a rapid and often dramatic clinical response, and a subset analysis of the Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL)-1 and -2 trials demonstrated that female gender and adenocarcinoma were associated with a higher response to gefitinib. However, analysis from clinical trials have not found a relationship between epidermal growth factor receptor (EGFR) expression and response in patients receiving gefitinib. Recently, three studies have identified mutations affecting the EGFR in lung cancer from patients who respond to gefitinib. EGFR gene mutations were common in lung cancer from 'never smokers' and were associated with sensitivity of tumors to gefitinib. Furthermore, it has been reported that the phosphatidylinositol 3-kinase/Akt signaling pathway plays a critical role in the antitumor effects of gefitinib. Although EGFR mutations do not fully explain the clinical benefit, the data regarding EGFR mutations may help to define the patient population that will most likely benefit from EGFR tyrosine-kinase-targeted therapies.