EGFR and KRAS mutations in metastatic lung adenocarcinomas

In primary lung adenocarcinoma, EGFR and KRAS mutations are found in approximately 10% to 20% and 20% to 30%, respectively. Few studies have investigated these mutations in metastases. Patients with EGFR mutations have a 70% to 80% response rate to tyrosine-kinase inhibitors therapy and a longer progression-free survival rate in contrast to patients with KRAS mutations that are associated with virtually no response tyrosine-kinase inhibitors. In this study, we have investigated EGFR and KRAS mutations in metastatic lung adenocarcinoma. Using Johns Hopkins Hospital archives, 1966 lung adenocarcinomas were found from January 2007 to May 2010. A total of 60 metastatic adenocarcinomas (28 cytologic and 32 surgical cases) with EGFR and KRAS studies were identified. In addition, 18 cases of primary and matched metastases were also included. Exons 18 to 21 of EGFR and exon 2 of KRAS (codons 12 and 13) were sequenced. In our study, EGFR and KRAS mutations were found in 21.7% (13 of 60 cases) and 28.3% (17 of 60 cases), respectively, and occurred more often with advanced stage of primary tumors. KRAS mutations were associated with poor prognosis and occurred exclusively in smokers in comparison with EGFR mutation. Of 9 pairs, mutations were concordant in 77.8%; 1 pair displayed acquisition of KRAS mutation, whereas 1 pair showed loss of EGFR mutation in the corresponding metastasis. Our findings suggest that EGFR and KRAS status should be tested in metastasis regardless of known mutations of the primary tumor. Additional studies are needed to further investigate the mechanisms of discordances in metastatic tumors.     

两种突变特异性抗体用于肺腺癌EGFR基因突变的评价

目的：验证EGFR 19delE746-A750和21L858R突变抗体的灵敏度和特异性以及免疫组织化学与RT-PCR方法的一致性,并探讨免疫组化在肺腺癌EGFR基因突变状态评价中的应用。方法：采用免疫组织化学方法对139例经过RT-PCR验证EGFR基因突变状态的病例进行检测。并采用SPSS19.0软件对两种方法的检测结果进行一致性分析。结果：与RT-PCR结果相比,EGFR delE746-A750和L858R突变抗体的总体敏感性为78.5%,特异性为93%。分别分析EGFR delE746-A750和L858R特异抗体,前者的敏感性和特异性分别是64.3%和97.8%,后者为90.3%和95.2%。采用SPSS19.0软件进行Kappa检验显示免疫组化和RT-PCR的结果高度一致。结论：EGFR delE746-A750和L858R突变抗体具有良好的灵敏度和特异性,结合全自动免疫组化仪进行EGFR基因突变检测是一种经济便捷可靠的方法。     

非小细胞肺癌患者ALK,EGFR及KRAS基因的检测及临床病理特征

目的:研究汉族非小细胞肺癌患者中间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)、表皮生长因子受体(epidermal growth factor receptor,EGFR)及Kirsten鼠肉瘤基因(Kirstenrat sarcoma,KRAS)突变的阳性率及其与临床病理特征的关系.方法:采用免疫组织化学(immunohistochemistry,IHC)的方法检测ALK融合基因异常表达,采用PCR检测EGFR基因和KRAS基因突变,采用x2检验及Fisher精确概率法进行数据分析.结果:共2 267例进行了ALK融合基因检测,其中1 655例同时进行了EGFR突变检测,951例同时进行了KRAS检测.ALK融合基因、EGFR基因及KRAS基因突变阳性率分别为7.28％(165/2 267)、48.58％(804/1 655)、11.40％(108/947).ALK基因突变多见于年轻、腺癌患者;EGFR基因突变多见于女性、腺癌患者;KRAS基因突变多见于老年、男性、腺癌患者.1 655例同时进行了ALK与EGFR检测的病例中,共6例存在双基因突变(0.36％);947例同时进行了ALK与KRAS检测,共4例存在双基因突变(0.42％);943例同时进行了EGFR与KRAS突变检测,未发现双突变病例.结论:非小细胞肺癌患者ALK,EGFR和KRAS基因的突变与患者的年龄、性别、组织学类型均存在相应的联系,个别病例可以出现ALK融合基因与EGFR或KRAS突变共存.     

Monitoring of cyclooxygenase-2 levels can predict EGFR mutations and the efficacy of EGFR-TKI in patients with lung adenocarcinoma

Background: Epidermal growth factor receptor (EGFR) mutation detection has become a routine molecular test with significant implications for prognosis and therapeutic options of EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, acquiring sufficient amounts of tissue for analyzing EGFR mutations is not often feasible, and not all the patients with sensitive EGFR mutations have benefit from EGFR-TKI treatment. Method: EGFR mutations were detected by amplification refractory mutation system (ARMS) in 44 patients of newly diagnosed lung adenocarcinoma, and patients with EGFR-positive mutations received EGFR-TKI treatment. The serum cyclooxygenase-2 (COX-2) levels were tested before EGFR-TKI treatment and on the 30th days after EGFR-TKI treatment. Results: Twenty-nine cases were detected EGFR mutations. EGFR mutation rate of serum COX-2 high-level group was significantly higher than low-level group (92.9% vs. 53.3%, P = 0.025). Multivariate analysis showed that serum COX-2 level was independently associated with EGFR mutation (P = 0.033, OR = 12.385, 95%CI, 1.231-124.567). Analysis of the correlation between clinical characteristics and the response of EGFR-TKI showed that the serum COX-2 high-level group had a better efficacy than low-level group (P = 0.000), and multivariate logistic regression analysis showed that the serum COX-2 level was the independently influencing factor (P = 0.004). Kaplan-Meier analysis showed that patients of COX-2 high-level group have longer progression-free survival (PFS, P = 0.013), and the Cox regression analysis showed that the same result (P = 0.003; OR = 0.980, 95% CI, 0.967-0.993). Conclusion: The serum COX-2 level seems to be closely associated with EGFR mutations in patients with Lung adenocarcinoma. The serum COX-2 level could help us to predict the responses of EGFR-TKI and the PFS in patients harboring EGFR mutation.