表皮生长因子受体酪氨酸激酶抑制剂治疗晚期非小细胞肺癌研究进展

表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)已成为晚期非小细胞肺癌治疗的研究热点.在有EGFR突变的患者中,一线单药EGFR-TKI能显著延长患者无进展生存期;EGFR突变是EGFR-TKI治疗获益的有效预测指标.虽然EGFR-TKI与化疗同步联合未能显示出生存优势,但在序贯联合的研究中能延长无进展生存期.EG...     

吉非替尼治疗表皮生长因子受体基因突变的晚期非小细胞肺癌患者疗效的meta分析

目的非小细胞肺癌（NSCLC）是恶性程度和死亡率极高的肿瘤,吉非替尼（gefitinib）是近年来研发的一种新的分子靶向药物,本文旨在系统评价吉非替尼治疗表皮生长因子受体（EGFR）基因突变的晚期NSCLC的有效性。方法计算机检索维普数据库（2000-2011．06）、万方数据库（2000-2011．06）、CNKI（2000-2011．06）、OVID（2000-2011．06）、Karger Online Jounals（2000-2011．06）。两名评价者独立评价纳入研究的质量、提取资料并交叉核对,研究采用RevMan5．1软件进行rneta分析。结果共纳入10个研究,包括941例,meta分析结果显示,吉非替尼治疗晚期NSCLC患者,EGFR基因突变者相比较于非突变者而言,疾病总有效率明显增加（RR=4．42,95％CI：3．49-5．60）,疾病控制率明显增加（RR=1．79,95％CI：1．23-2．61）,疾病进展率明显降低（RR=0．24,95％CI：0．18-0．32）。结论吉非替尼治疗EGFR基因突变的晚期NSCLC有一定的优势,可作为治疗EGFR基因突变的晚期NSCLC患者的常规药物。     

表皮生长因子受体抑制剂在非小细胞肺癌治疗中的研究进展

化疗一直是晚期非小细胞肺癌(NSCLC)的主要治疗手段之一,但是治疗的有效率仅为30％左右,且具有较大的不良反应,耐药和血液学的不良反应是患者预后不良的主要原因之一.随着分子生物标记如表皮生长因子受体(EGFR)等的发现和相应靶向药物的研发与批准应用,肺癌的治疗正在发生重大变化.大量研究证实EGFR抑制剂靶向治疗能改善NSCLC患者的疾病无进展期和生活质量,而正确的选择合适的患者是靶向治疗成功的关键.本文将对EGFR的组成及活化、检测方法、EGFR靶向药物在NSCLC治疗中的作用以及获得性耐药患者的治疗进展进行综述.     

表皮生长因子受体基因突变在晚期非小细胞肺癌二线治疗中作用的研究

目的 探讨表皮生长因子受体(EGFR)基因突变在晚期非小细胞肺癌(NSCLC)二线治疗中的指导意义.方法 对2005年12月至2009年12月住我院的139例既往至少接受过1次含铂化疗且最近1次化疗后肿瘤进展或复发的NSCLC的病理组织行EGFR基因检测,根据检测的结果把患者分为EGFR突变型口服吉非替尼组(31例)和EGFR野生型口服吉非替尼组(50例)及EGFR野生型口服吉非替尼组(50例).对3组患者进行临床特征、病理、疗效、生存期、体力状况评分(PS)、毒副反应及生活质量的分析.结果 女性、腺癌、非吸烟者的EGFR突变率高于对应组;突变型吉非替尼组、野生型吉非替尼组(62.0%,31例)和野生型多烯紫杉醇组中位无进展生存期(分别为2.8、2.0和2.5个月)、中位生存时间(分别为8.9、7.1和7.8个月)比较,差异有统计学意义(H值分别为11.198、16.991,均P＜0.01).突变型吉非替尼组、野生型吉非替尼组PS评分的变化分别为96.8%(30例)和62.0%(31例),差异有统计学意义(x2=12.583,P＜0.01).野生型吉非替尼组(62.0%,31例)和野生型多烯紫杉醇组(66.0%,33例)化疗PS评分变化比较,差异无统计学意义(x2=0.878,P＞0.05).结论 表皮生长因子受体基因突变可作为指导晚期NSCLC二线治疗的重要指标.

Abstract：

Objective To explore the effect of gene mutations of epidermal growth factor receptor ( EGFR) on targeting therapy of advanced non-small cell lung cancer (NSCLC). Methods The 139 hospitalized patients who had been treated at least once with platinum-based chemotherapy and had tumor progression or recurrence after the last chemotherapy between December 2005 and December 2009, underwent EGFR gene test extracted from the pathological tissues. Based on the results of the test, the patients were divided into three groups: EGFR mutation per os (p.o.)Gefitinib (MPG) group, wild-type EGFR per os (p. o. ) Gefitinib (WpG) group and wild-type EGFR post-docetaxel chemotherapy (WpD) group. Clinical characteristics, pathology, treatment efficacy,survival time, performance status (PS) score, adverse reaction and quality of life of patients in the three groups were assessed. Results The EGFR mutation rate were higher in female, patients with adenocarcinoma and non-smokers than in male, smokers and those without adenocarcinoma. There were significant differences in median progression-free survival and median survival time among the three groups, which were 2.8 and 8. 9 months in MpG group, 2.0 and 7.1 months in WpG group,2.5 and 7. 8 months in WpD group(H=11. 198, 16. 991 ,all P＜0.01). The changes of PS score were significantly different between MpG group and WpG group (96. 8% vs. 62. 0%, x2 = 12. 583 ,P＜0. 01 ). However, there was no difference in changes of PS score between WpG group and WpD group (62. 0% vs. 66. 0%, x2 =0. 878,P＞0. 05). Conclusions The gene mutation of epidermal growth factor receptor may be served as an important indicator of advanced non-small cell cancer therapy.     

Inhibition of epidermal growth factor receptor and symptom improvement in advanced non-small cell lung cancer

The majority of patients with non-small cell lung cancer (NSCLC) are not candidates for curative resection because of advanced disease at the time of diagnosis. Systemic chemotherapy has been employed with modest success to provide symptom relief and prolonged survival for patients with this incurable disease. Any benefit derived from chemotherapy in this palliative setting must be balanced against the substantial toxicity associated with cytotoxic drugs. A novel approach to anticancer treatment based on specific targeting molecular processes has recently demonstrated efficacy. ZD1839 is a low-molecular-weight molecule that is capable of inhibiting epidermal growth factor receptor (EGFR)-associated tyrosine kinase activity. Consequently, ZD1839 interrupts EGFR-mediated activities such as tumor cellular proliferation, motility, survival, and invasiveness. In vitro and in vivo studies have shown that ZD1839 has activity against NSCLC. The results of ZD1839 in randomized clinical trials of patients with advanced NSCLC are reported in this review. In addition to evaluating response rates and clinical endpoints, these trials prospectively evaluated symptom improvement and quality of life.     

Clinical outcomes of advanced non-small cell lung cancer patients screened for epidermal growth factor receptor gene mutations

Purpose  

To evaluate the relationship between the epidermal growth factor receptor (EGFR) mutation status and the effectiveness of gefitinib monotherapy or chemotherapy in patients with advanced non-small cell lung cancer (NSCLC).     

晚期非小细胞肺癌患者体液标本表皮生长因子受体突变基因检测的进展

尽管肺癌的诊断、分期、治疗日趋规范化,但由于缺乏有效的早期筛查制度和方法,加之传统化疗的疗效出现平台期,导致肺癌患者总体预后依然很差,5年生存率仅为16％。随着分子肿瘤学的发展,发现表皮生长因子受体（epidermalgrowthfactorreceptor,EGFR）是原癌基因c—erbBl的表达产物,其突变参与了肿瘤的生长、侵袭等过程。     

The role of epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of advanced stage non-small cell lung cancer

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) like erlotinib and gefitinib have been extensively studied. Multiple randomized trials have evaluated the role of EGFR TKIs in advanced stage non-small cell lung cancer (NSCLC) as a monotherapy in the first line, or subsequent lines of therapy, and in the first line in the maintenance setting or in combination with chemotherapy. Most of these trials showed positive results in particular for selected patients with specific clinical characteristic and somatic activating mutation of EGFR. A further understanding of the mechanism of primary and secondary resistance has led to the development of promising novel agents designed to overcome resistance to EGFR.     

非小细胞肺癌表皮生长因子受体基因突变与分子靶向治疗

肺癌分子靶向治疗近年来取得较大进展.特别是针对表皮生长因子受体(EGFR)分子靶向药物表现出确定的临床效果.临床应用表明,EGFR基因酪氨酸激酶域体细胞突变与非小细胞肺癌患者对酪氨酸激酶抑制剂吉非替尼的敏感性相关.本文就EGFR生物学特点、EGFR在肺癌中的表达、EGFR基因突变率、EGFR基因突变与EGFR酪氨酸激酶抑制剂疗效的关系作一综述.     

晚期非小细胞肺癌表皮生长因子受体敏感突变类型与表皮细胞生长因子受体酪氨酸激酶抑制剂疗效的回顾性研究

目的探讨晚期非小细胞肺癌(NSCLC)不同的表皮生长因子受体(EGFR)敏感突变类型对表皮细胞生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)疗效的相关性。方法回顾分析2012年1月至2015年12月第三军医大学三所附属医院经EGFR基因检测为19外显子缺失或21外显子L858突变、并且接受一线EGFR酪氨酸激酶抑制剂(EGFR-TKI)治疗的NSCLC患者临床资料,分析两组EGFR突变状态人群客观缓解率(ORR)、中位无进展生存时间(m PFS)、中位总生存时间(m OS)和不良反应等临床指标的差异。结果共收集108例患者,19外显子缺失组59例,21外显子L858R突变组49例。两组患者的临床资料基线水平一致(P0.05),ORR分别为52.5%和44.9%(P=0.429),m PFS分别为12.3个月和9.1个月(P=0.000),m OS分别为25.7个月和20.3个月(P=0.051),1年生存率分别为93.2%和83.1%(P=0.042),2年生存率分别为56.8%和40.0%(P=0.030),不良反应相似,主要为皮疹。结论与21外显子L858突变相比,EGFR 19外显子缺失患者,一线使用EGFR-TKI时,PFS显著优势,OS有获益趋势。     

KRAS和表皮生长因子受体突变基因与原发性非小细胞肺癌的相关性

目的 研究KRAS和表皮生长因子受体(EGFR)基因在原发性非小细胞肺癌(NSCLC)中的突变状态以及其与靶向治疗效果的相关性。方法 收集郑州大学第一附属医院收治的150例经病理证实的NSCLC患者原发肿瘤及受累的淋巴结标本,进行KRAS和EGFR突变基因序列分析。150例中12例患者纵隔淋巴结转移灶经DNA序列分析发现EGFR基因突变后给予吉非替尼进行术前辅助治疗。结果150对（分别为原发灶和受累淋巴结）标本中,2例原发肿瘤和10例淋巴结转移灶中检测到KRAS突变基因,35例原发肿瘤和44例淋巴结转移灶中检测到EGFR突变基因。KRAS和EGFR基因在原发灶和转移灶中不一致的比率分别为6.7％ (10/150)和8.7％ (13/150)。1例原发肿瘤无EGFR突变的患者接受吉非替尼治疗后效果不佳。结论 NSCLC患者原发灶和转移灶中KRAS和EGFR基因突变状态不一致,这对于应用酪氨酸激酶抑制剂靶向治疗NSCLC具有重要的参考意义。     

Rationale for investigation of epidermal growth factor receptor inhibitors in definitive treatment of locally advanced non-small cell lung cancer and head and neck cancer

Designing targeted therapies has become an important field in cancer therapeutics. The epidermal growth factor receptor (EGFR) is a molecular target that has gained immense attention as preclinical and clinical studies have supported its potential role for therapy of a variety of cancers, including non-small cell lung cancer (NSCLC) and head and neck (HN) cancer. Several compounds that specifically inhibit EGFR have been developed, including ZD1839, C225, and OSI-774. Interestingly, studies suggesting a potential role for EGFR inhibitors as an adjunct to the current combined-modality approach for therapy of NSCLC and HN cancer have been performed in the preclinical and clinical setting. Therefore, determining the potential of EGFR inhibitors to improve the efficacy of standard combined-modality regimens (chemotherapy/radiation therapy +/- surgery) for NSCLC and HN cancer patients is of the utmost importance. An overview of the rationale and the ongoing/proposed studies aimed at determining the role for EGFR inhibitors in combination with radiation therapy for NSCLC and HN cancer patients will be presented.     

Gefitinib therapy in patients with advanced non-small cell lung cancer with or without testing for epidermal growth factor receptor (EGFR) mutations

Gefitinib is effective in treating advanced non-small cell lung cancer (NSCLC), especially in Asian patients in whom the prevalence of epidermal growth factor receptor (EGFR) mutation was high. We analyzed our gefitinib treatment use in patients for advanced NSCLC to study the influence of clinical factors on the treatment outcomes in a tertiary referral medical center in Taiwan. Clinical data and EGFR mutational status of the tumors were collected. A total of 907 patients received gefitinib for advanced NSCLC: 466 patients (51.4%) underwent testing for EGFR mutations, and the other 441 patients did not. In the 466 patients who were tested for EGFR mutations, 272 (58.4%) had EGFR mutations, and an EGFR mutation was a prominent factor for objective response to gefitinib (67.3% vs. 18.3% in wildtype EGFR, p < 0.001). In the 441 patients who did not receive EGFR mutation sequencing, nonsmoker status, female sex, and adenocarcinoma cell type were predictors for better gefitinib response (p < 0.005). We found that testing for EGFR mutations was helpful in NSCLC patients in Taiwan to guide the use of gefitinib. In patients with positive activating EGFR mutations, gefitinib efficacy was prominent and significant. Therefore, analysis for EGFR mutation should be advocated. In those patients who have unknown EGFR mutation status, demographic and histopathology characteristics can be relied on to judge the potential efficacy of gefitinib use.     

非小细胞肺癌表皮生长因子受体基因突变的临床意义

表皮生长因子受体(epidermal growth factor receptor,EGFR)是一种具有酪氨酸激酶活性的跨膜糖蛋白,可介导细胞的增殖、分化、凋亡抑制及血管生成等多种细胞过程.在多种人类恶性肿瘤中.均存在EGFR表达上调的现象,其中约70%的非小细胞肺癌(non-small cell lung cancer,NSCLC)患者表现为EGFR过表达.另外,在亚洲非吸烟的女性肺腺癌患者中,EGFR的基因突变率达40%以上,表明EGFR的异常表达与NSCLC的发生及发展有密切关系.本文主要就近年来关于EGFR过表达和基因突变与NSCLC发生及转移关系的研究作一综述.     

Acquired resistance of non-small cell lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors

Activation of epidermal growth factor receptor (EGFR) triggers anti-apoptotic signaling, proliferation, angiogenesis, invasion, metastasis, and drug resistance, which leads to development and progression of human epithelial cancers, including non-small cell lung cancer (NSCLC). Inhibition of EGFR by tyrosine kinase inhibitors such as gefitinib and erlotinib has provided a new hope for the cure of NSCLC patients. However, acquired resistance to gefitinib and erlotinib via EGFR-mutant NSCLC has occurred through various molecular mechanisms such as T790M secondary mutation, MET amplification, hepatocyte growth factor (HGF) overexpression, PTEN downregulation, epithelial-mesenchymal transition (EMT), and other mechanisms. This review will discuss the biology of receptor tyrosine kinase inhibition and focus on the molecular mechanisms of acquired resistance to tyrosine kinase inhibitors of EGFR-mutant NSCLC.     

Prediction of epidermal growth factor receptor mutations in the plasma/pleural effusion to efficacy of gefitinib treatment in advanced non-small cell lung cancer

Purpose  

Recently, mutations in the epidermal growth factor receptor (EGFR) gene were reported to correlate with EGFR tyrosine kinase inhibitor response in advanced non-small cell lung cancer (NSCLC). In this study, we attempted to detect EGFR mutations in plasma and pleural effusion samples and to make clear its correlations with gefitinib response and survival in NSCLC patients.     

安罗替尼治疗表皮生长因子受体野生型老年晚期非小细胞肺癌病人的临床疗效

目的观察盐酸安罗替尼治疗表皮生长因子受体(EGFR)野生型老年晚期非小细胞肺癌(NSCLC)病人的疗效和安全性。方法选择2018年6月至2019年3月我院肿瘤科就诊的EGFR野生型老年晚期NSCLC病人,常规给予安罗替尼12 mg/次,1次/d,连续服药2周,停药1周,即3周为1个疗程。记录病人无进展生存期(PFS)、客观缓解率(ORR)、疾病控制率(DCR)及不良反应发生情况。结果共纳入26例病人,年龄66~85岁,中位年龄74.5岁;一线治疗21例,二线治疗3例,三线治疗2例。截至2019年10月10日,26例病人ORR为11.54%、DCR为76.92%、PFS为5.1个月。常见的不良反应为高血压、手足综合征、疲劳乏力、咯血、甲状腺功能异常等,不良反应经对症处理及安罗替尼暂停、减量后均可控制,未出现药物相关的死亡。结论安罗替尼在EGFR野生型晚期老年NSCLC病人的治疗中,病人的PFS有延长趋势,ORR及DCR较高,不良反应可控。     

BIM与EGFR突变非小细胞肺癌吉非替尼耐药的关系

BIM是Bcl-2中含BH3碱基亚家族的成员,是一种重要促凋亡调节蛋白.表皮生长因子受体(epidermal growth factor receptor,EGFR)突变的非小细胞肺癌(non-small cell lung cancer,NSCLC)患者对EGFR-酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)治疗敏感、疗效显著,但无论近期疗效如何,最终患者都不可避免地产生耐药及病情进展.BIM参与许多癌细胞(乳腺癌、肺癌、骨肉瘤、黑色素瘤)凋亡.近年来,有研究发现BIM表达与EGFR突变NSCLC吉非替尼耐药有关.因此,了解BIM与EGFR-TKIs耐药关系有利于临床指导.本文综述了近年来BIM与EGFR突变NSCLC吉非替尼耐药的关系.     

Detection of epidermal growth factor receptor mutation in transbronchial needle aspirates of non-small cell lung cancer

BACKGROUND: Somatic mutations of epidermal growth factor receptor (EGFR) are closely associated with an objective response to EGFR tyrosine kinase inhibitors. However, it is difficult to obtain sufficient tumor samples from patients with non-small cell lung cancer (NSCLC), so these diagnoses are often made using cytology procedures alone. The aim of this study was to detect EGFR mutations in transbronchial needle aspiration (TBNA) samples using both direct sequencing and a highly sensitive assay (Scorpions Amplified Refractory Mutation System; DxS; Manchester, UK) [ARMS], and to compare the sensitivity of these methods. METHODS: We enrolled 94 patients (63 men and 31 women) with NSCLC in this study. Cytologic diagnoses were adenocarcinoma (n = 58), squamous cell carcinoma (n = 24), and other types of NSCLC (n = 12). We extracted DNA from the TBNA samples, and EGFR mutations were analyzed using both direct sequencing (exons 19 and 21) and the Scorpions ARMS method (E746 A750del and L858R). RESULTS: Mutations were detected in 31 patients (33%; 14 women and 17 men). Of these, 23 patients had adenocarcinoma, 4 had squamous cell carcinoma, and 4 had other types of NSCLC. Direct sequencing detected 13 mutations (14%) in 13 patients (E746-A750del, n = 6; L858R, n = 7), and the Scorpions ARMS method detected 27 mutations (29%) in 27 patients (E746 A750del, n = 16; L858R, n = 11 patients). CONCLUSIONS: Both methods detected EGFR mutations in TBNA samples, but Scorpions ARMS is more sensitive than direct sequencing.     

肺癌分子靶向药物耐药机制的研究进展

随着肺癌分子发病机制的阐明，针对这些分子机制的靶向治疗逐步进入临床，其中表皮生长因子受体（EGFR）是目前研究最多、公认有效的肺癌治疗靶点。然而，EGFR酪氨酸激酶（TK）抑制剂（TKI）只对部分患者有效。因此了解肺癌耐受分子靶向药物的机制有助于指导临床用药，并为将来开发新的靶向治疗措施提供依据。现将EGFR—TKI的耐药机制综述如下。