KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer
KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer
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DOI：
10.1158/1078-0432.ccr-06-3043
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发表时间：
2007-05-15
影响因子：
11.5
通讯作者：
Wistuba, Ignacio I.
中科院分区：
文献类型：
--
作者：
Massarelli, Erminia;Varella-Garcia, Marileila;Wistuba, Ignacio I.
目的：EGFR基因突变和EGFR拷贝数增加与非小细胞肺癌（NSCLC）患者对表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（EGFR-TKI）的良好应答相关。相比之下，KRAS突变已被证明预测对此类治疗的不良反应。我们测试了这三种标志物的组合在预测EGFR-TKIs.Experimental Design治疗的NSCLC患者的反应和生存中的效用：包括用EGFR-TKI治疗的晚期NSCLC患者和可用的存档组织标本。使用基于PCR的测序分析EGFR和KRAS突变。EGFR的拷贝数进行了分析，使用荧光原位杂交。结果：这项研究包括73例，其中59人成功地分析了所有三个潜在的标志物。71例患者中有7例（9.8%）检测到EGFR突变，59例患者中有32例（54.2%）检测到EGFR拷贝数增加，70例患者中有16例（22.8%）检测到KRAS突变。EGFR突变（P < 0.0001）而不是EGFR拷贝数增加（P = 0.48）与良好的反应相关。在具有这些特征的患者中没有检测到生存益处。KRAS突变与疾病进展（P = 0.04）和较短的中位进展时间（P = 0.0025）相关，但与生存期无关。EGFR突变和EGFR拷贝数增加的患者有> 99.7%的客观缓解机会，而KRAS突变伴或不伴EGFR拷贝数增加的患者有> 96.5%的疾病进展机会。
Purpose: EGFR gene mutations and increased EGFR copy number have been associated with favorable response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) in patients with non - small-cell lung cancer (NSCLC). In contrast, KRAS mutation has been shown to predict poor response to such therapy. We tested the utility of combinations of these three markers in predicting response and survival in patients with NSCLC treated with EGFR-TKIs.Experimental Design: Patients with advanced NSCLC treated with EGFR-TKI with available archival tissue specimens were included. EGFR and KRAS mutations were analyzed using PCR-based sequencing. EGFR copy number was analyzed using fluorescence in situ hybridization.Results: The study included 73 patients, 59 of whom had all three potential markers successfully analyzed. EGFR mutation was detected in 7 of 71 patients (9.8%), increased EGFR copy number in 32 of 59 (54.2%), and KRAS mutation in 16 of 70 (22.8%). EGFR mutation (P < 0.0001) but not increased EGFR copy number (P = 0.48) correlated with favorable response. No survival benefit was detected in patients with either of these features. KRAS mutation correlated with progressive disease (P = 0.04) and shorter median time to progression (P = 0.0025) but not with survival. Patients with both EGFR mutation and increased EGFR copy number had a > 99.7% chance of objective response, whereas patients with KRAS mutation with or without increased EGFR copy number had a > 96.5% chance of disease progression.Conclusion: KRAS mutation should be included as indicator of resistance in the panel of markers used to predict response to EGFR-TKIs in NSCLC.