Evaluation of epidermal growth factor receptor (EGFR) mutations and gene copy numbers as predictors of clinical outcomes in Japanese patients with recurrent non-small-cell lung cancer (NSCLC) receiving gefitinib

Abstract

7032 Background: Recent reports have suggested that somatic mutations in the EGFR tyrosine kinase domain and EGFR gene amplifications are associated with gefitinib sensitivity in patients (pts) with NSCLC. To evaluate the predictive values of these factors, we studied consecutive pts with NSCLC who relapsed after surgery and received gefitinib in our hospital. Methods: Surgical specimens were analyzed in 66 pts who had been treated with gefitinib (250 mg/day) between July 2002 and May 2004. Direct sequencing of exons 18–24 of EGFR was performed to detect mutations, and quantitative real-time PCR was performed to analyze the EGFR gene copy number using DNA extracted from laser-captured tumor cells. Results: All the pts were Japanese; median age: 65 (32–80) years; female/male: 26/40; adenocarcinoma (Ad)/others: 62/4; never/former/current smokers: 31/12/23; prior chemotherapy (yes/no): 29/37. Thirty-nine pts (59%) had EGFR somatic mutations; 20 pts had deletions in exon 19, 17 pts had point mutations (L858R) in exon 21 and 2 pts had point mutations (G719S or G719C) in exon 18. Four pts had minor secondary mutations in exons 18 or 20. EGFR mutations were seen in 69%/53% of the female/male pts, 68%/83%/35% of never/former/current smokers, 73%/50% of Ad pts with/without predominant papillary growth, and 72%/27% of Ad pts with/without BAC feature. EGFR gene amplification (≥3/cell) was observed more frequently in pts with EGFR mutations than in pts with wild-type EGFR (56% vs. 26%), and high-level amplification (≥6/cell) was observed only in pts with EGFR mutations (33% vs. 0%). CR/PR/SD/PD were observed in 2/29/4/1 pts with EGFR mutations and in 0/3/5/14 pts with wild-type EGFR. The response rate was higher (84% vs. 11%), the time to progression (TTP) was longer (median TTP: 12.6 vs. 1.7 months), and the overall survival (OS) was longer (1-y OS: 80% vs. 47%) in pts with EGFR mutations. Other factors, including the EGFR gene copy number, were not independent predictors of clinical outcomes. Conclusions: EGFR mutations are frequently detected in Japanese patients with NSCLC and strongly predict gefitinib sensitivity. No significant financial relationships to disclose.