晚期非小细胞肺癌EGFR蛋白磷酸化、基因突变与EGFR-TKI疗效相关性的研究  

Relationship between EGFR protein phosphorylation,EGFR mutation and EGFR-TKI efficacy in advanced non-small cell lung cancer

作　　者：王芬[1] 王洁 白桦 王书航 王树滨[1] 申东兰[1] 

机构地区：[1]北京大学深圳医院肿瘤科,广东深圳518036 [2]北京肿瘤医院胸部肿瘤内科,北京100036

出　　处：《中国癌症杂志》2014年第9期657-668,共12页China Oncology

摘　　要：背景与目的：近年来以吉非替尼和厄洛替尼为代表的表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitors，EGFR-TKI），因其在晚期非小细胞肺癌（advanced non-small cell lung cancer，NSCLC）治疗中独特的临床疗效和较低的不良反应而备受关注。尽管EGFR基因突变是目前认为最确切的预测EGFR-TKI疗效的指标，但与临床疗效间并非“全或无”的关系，提示仍有其他机制参与其中。本研究旨在探讨晚期NSCLC组织标本中EGFR磷酸化酪氨酸1068（EGFR-pTyr1068）、1173（EGFR-pTyr1173）表达与EGFR基因突变的关系，及其在EGFR-TKI治疗中的疗效预测价值。方法：采用变性高效液相色谱法（denaturing high performance liquid chromatography，DHPLC）检测205例晚期NSCLC患者组织中EGFR基因突变（19、21外显子突变）情况；并采用免疫组化方法检测其EGFR-pTyr1068、EGFR-pTyr1173表达。结果：晚期NSCLC患者组织中EGFR-pTyr1068和1173表达阳性率分别为80.0%（164/205）、57.6%（95/165）；其表达与临床病理特征（年龄、性别、病理类型、吸烟状态、疾病分期）无相关性。全组EGFR基因突变率为44.9%（92/205），与吸烟状态有关（P=0.024），而与其他临床病理特征（性别、年龄、病理类型、疾病分期）无关。EGFR基因突变与EGFR-pTyr1068表达呈弱相关性（P〈0.001），与EGFR-pTyr1173无相关性（P=0.297）。EGFR基因突变型患者EGFR-TKI治疗的客观缓解率（objective response rate，ORR）、疾病控制率（disease control rate，DCR）和中位无进展生存期（progress free survival，PFS）分别为48.3%（43/89）、80.9%（72/89）和8.8个月（95%CI：6.11～11.42），均明显高于EGFR基因野生型患者[16.2%（17/105）、56.2%（59/105）和2.1个月，95%CI：0.89～3.24]，差异有统计学意义（P〈0.001，P〈0.001，P=0.024）；EGFR-pTyr1068表达阳性患者ORR和DCR分别为37.7%（58/Background and purpose：EGFR-TKI （EGFR-tyrosine kinase inhibitors）, represented by geiftinib and erlotinib, have exhibited signiifcant antiproliferative effects against non-small cell lung cancer （NSCLC） with low toxicity.EGFR gene mutation was discovered to be a predictive biomarker for EGFR-TKI treatment. Although the efifcacy of EGFR-TKI is limited toEGFR wild-type patients, it is still noticeable suggesting that some other mechanisms are responsible for it. The current study is aimed at evaluating the expression of phosphorylated EGFR in advanced NSCLC, investigating its relationship withEGFR mutations and EGFR-TKI efifcacy.Methods：EGFR gene mutations were detected by denaturing high performance liquid chromatography （DHPLC） in 205 stageⅢB-ⅣNSCLC patients. The expressions of phosphorylated tyrosine 1068 （pTyr1068） and 1173 （pTyr1173） were detected by immunohistochemistry.Results：The positive expressions of pTyr1068 and pTyr1173 were 80.0% （164/205） and 57.6% （95/165） respectively. None of them were related to clinical pathological characteristics （age, gender, pathological type, smoking status, disease stage）.EGFR gene mutation rate was 44.9% （92/205）, which was only related to smoking status （P=0.024） compared to other clinical pathological characteristics.EGFR gene mutations were poorly related to pTyr1068 expression （P〈0.001） and not related to pTyr1173 expression （P=0.297）. The objective response rate （ORR）,disease control rate （DCR）, and progressive free survival （PFS） of EGFR-TKI treatment in patients withEGFR mutations were 48.3% （43/89）, 80.9% （72/89） and 8 months （95%CI： 6.11-11.42） respectively, which were signiifcantly higher than that ofEGFR wild-type patients [ORR=16.2% （17/105,P〈0.001）; DCR=56.2%（59/105,P〈0.001）; Median PFS： 2.1 months, （95%CI： 0.89-3.24;P=0.001）]. Superior ORR： DCR and PFS appeared in patients with pTyr1068 positive expression compared to negative [ORR： 37.7% （58/154�

关 键 词：晚期非小细胞肺癌 表皮生长因子受体磷酸化酪氨酸 表皮生长因子受体基因突变 表皮生长因子受体酪氨酸激酶抑制剂 预测因子 

分 类 号：R734.2[医药卫生—肿瘤]