Retrospective analysis of acquired resistance during the treatment with gefitinib in non-small cell lung cancer patients with epidermal growth factor receptor mutations

Background. Gefitinib, a selective inhibitor of tyrosine kinase of the epidermal growth factor receptor (EGFR), can be effective in patients with non-small-cell lung cancer (NSCLC) harboring somatic mutations of EGFR. However, the clinical resistance to gefitinib is an unsolved problem. Methods. We analyzed patients with advanced NSCLC with EGFR mutations treated with gefitinib between June 2004 and June 2007 in our institution. The effectiveness of gefitinib, the pattern of relapse, progression-free survival (PFS), and overall survival were assessed retrospectively. EGFR mutations were all examined by DNA direct sequence or peptide nucleic acid-locked nucleic acid (PNA-LNA) polymerase chain reaction (PCR) clamp method by using the tumor specimen before treatment, and re-examination of EGFR mutations by using relapsed tumor sample was performed for some patients. Results. From June 2004 to June 2007, 51 patients with advanced NSCLC harboring EGFR mutations started treatment with gefitinib, and 36 had partial response and 8 had stable disease. The overall response rate and disease control rate were 71% and 86%, respectively. Among 44 responders to gefitinib, disease progression was observed in 33 patients by April 2008. The initial sites of relapse were thoracic (primary lung tumor, pleural effusion, etc) in 21 patients, and distant (brain, bone, etc) in 12 patients. There was no statistical difference in PFS among the initial sites of recurrence. T790M, a resistant mutation of EGFR, was detected in 3 specimens obtained after relapse. Interestingly, most of patients with initial relapse in the thorax had to change the treatment from gefitinib within 3 months, however, more than half of the patients with brain relapse could be managed by radiation therapy with gefitinib for over 3 months. The median survival time of patients with initial relapse in the brain was 28.2 months, which is quite better than that of general NSCLC patients with brain metastasis. Conclusion. Different patterns of relapse were observed in NSCLC patients treated with gefitinib. The new therapeutic strategy according to the mechanism of resistance to EGFR-TKI is warranted.