Analysis of EGFR inhibitor and/or COX-2 inhibitor sensitivity for clinical application in lung cancer.

我们对EGFR基因的外显子19缺失和L858R点突变进行了突变分析。外显子19缺失采用共片段分析，L858R突变采用环切实时定量PCR技术检测。使用这种方法，我们前瞻性地评估了吉非替尼单药治疗晚期或未经治疗的表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）患者的疗效。66例患者中有27例（41%）检测到EGFR基因突变。10例外显子19缺失，17例L858R缺失。21名携带EGFR突变的患者接受吉非替尼治疗，其反应和不良事件被认为是可评估的。19例EGFR突变患者获得客观缓解（3例完全缓解，16例部分缓解），总缓解率为90.5%（95%置信区间（CI）， 69.6%-98.8%）。中位无进展生存期为7.7个月（95% CI， 6.0个月至未达到）。我们还研究了14个在EGFR酪氨酸激酶结构域发生继发性突变的对吉非替尼获得性耐药的肿瘤。14例肿瘤中有7例继发性T790M突变。由于我们目前的研究也表明同时阻断EGFR和COX-2介导的途径具有协同抑制作用，因此EGFR抑制剂和COX-2抑制剂联合使用可能为肺癌治疗提供一种有前景的策略。

We performed mutational analyses of exon 19 deletion and the L858R point mutation of the EGFR gene. Exon 19 deletion was determined by common fragment analysis, and L858R mutation was detected by the cycleave real-time quantitative PCR technique. Using this method, we evaluated the efficacy of gefitinib monotherapy prospectively in patients with advanced or pretreated non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Mutations of the EGFR gene were detected in 27 (41%) of 66 patients. Ten had exon 19 deletion and 17 had L858R. Twenty-one patients harboring EGFR mutations were treated with gefitinib and were considered assessable for responses and adverse events. Nineteen patients with EGFR mutations achieved objective responses (three complete responses and 16 partial responses) resulting in an overall response rate of 90.5% (95% confidence interval (CI), 69.6%-98.8%). The median progression-free survival was 7.7 months (95% CI, 6.0 months to not reached). We also studied 14 tumors with acquired resistance to gefitinib for secondary mutations occurring in the EGFR tyrosine kinase domain. Seven of the 14 tumors had a secondary T790M mutation. Because our present study also indicated the cooperative inhibitory effect by simultaneously blocking EGFR-and COX-2-mediated pathways, combination of EGFR inhibitor and COX-2 inhibitor may provide a promising strategy for lung cancer therapy.