非小细胞肺癌EGFR基因第19外显子突变的特征分析

吉非替尼(gefitinib)是针对肺癌表皮生长因子受体(epiddermal growth factor receptor,EGFR)设计的肿瘤靶向药物,已使众多的非小细胞肺癌(NSCLC)患者获益,但其疗效与EGFR基因突变相关[1-3].通过EGFR基因第19外显子可筛选gefitinib药物的最适合患者进行个体化治疗,提高疗效,减少盲目用药.我们检测了62例NSCLC患者的EGFR基因第19外显子突变,并分析突变DNA特征及氨基酸变化规律.     

吉非替尼在非小细胞肺癌中的研究进展

随着非小细胞肺癌的发病率不断升高,传统的含铂双药联合化疗的疗效并没有取得令人满意的效果,以吉尼替尼为代表的分子靶向药物对 EGFR突变型NSCLC取得了较好的疗效,鉴于此,进一步研究EGFR基因的突变的情况,寻找与吉非替尼敏感性的其他因素,对于提高NSCLC患者治疗疗效具有重要意义。     

非小细胞肺癌个体化治疗的靶向分子检测

非小细胞肺癌(non-small cell lung cancer, NSCLC)的个体化治疗是目前肿瘤研究领域的热点之一.以EGFR体系突变活化和ALK重排为分子学特征的NSCLC对酪氨酸激酶抑制剂(tyrosine kinase inhibitors, TKIs)如吉非替尼(gefitinib)、埃洛替尼(erlotinib)以及可卓替尼(crizotinib)有良好的反应性,而EGFR突变和ALK重排也成为筛选TKIs治疗对象和预测治疗反应性的最有价值指标.近年来,欧洲、北美和亚洲地区先后公布EGFR突变检测的共识,我国也于2011年达成了EGFR突变检测的专家共识[1-4].     

非小细胞肺癌表皮生长因子受体基因突变检测的经验总结分析

肺癌是当今世界上对人类健康与生命危害严重的恶性肿瘤之一。研究表明，表皮生长因子受体(EGFR)在43％～89％的非小细胞肺癌(NSCLC)中表达上调，它在肿瘤的形成以及介导瘤细胞的生物学行为上发挥着重要的作用，是目前NSCLC治疗的重要靶点之一[1]。吉非替尼等治疗肺癌的靶向药物，为EGFR酪氨酸激酶抑制剂(TKI)，可通过对肿瘤细胞EGFR的特异性结合阻断细胞信号通路，抑制肿瘤细胞增殖并促其凋亡[2]。     

非小细胞肺癌表皮生长因子受体及其靶向治疗研究进展

非小细胞肺癌是目前全球最常见的恶性肿瘤之一,尽管手术治疗和化学治疗技术不断发展,但非小细胞肺癌患者生存率却没有明显改变。表皮生长因子受体 (epidermal growth factor receptor,EGFR)是一种受体型酪氨酸激酶,在非小细胞肺癌中有过表达,且与非小细胞肺癌的发生、发展、侵袭等方面密切相关,是最有前途的特异性肿瘤靶向治疗分子之一。此外,在非小细胞肺癌中常检测到EGFR基因突变,尤其是在女性、非吸烟者、肺腺癌和亚洲人种中,这与非小细胞肺癌患者对吉非替尼治疗的敏感性密切相关。     

盐酸厄洛替尼片的临床应用概况

<正>肺癌是世界范围内最常见的恶性肿瘤,其中80%的肺癌是非小细胞肺癌(non-small cell lung caner,NSCLC),手术治疗只适用于少数患者且术后复发甚至死亡的比率高达60%,虽然化疗、放疗技术在不断提高,但NSCLC患者的预后很差~([1-2])。厄洛替尼(erlotinib)是小分子酪氨酸激酶抑制剂,可直接作用于表皮生长因子受体(epidermal growth factor receptor,EGFR),通过抑制EGFR,切断细胞内的酪氨酸激酶磷酸化进程,进而达到抗肿瘤作用~([3])。临床主要用于治疗晚期非小细胞肺癌。本文就近年来厄洛替尼的临床应     

非小细胞肺癌中EGFR突变与临床病理特征的关系

目的 观察非小细胞肺癌(non-small cell lung cancers,NSCLC)患者肿瘤组织中表皮生长因子受体(epidermal growth factor receptor,EGFR)19号和21号外显子突变情况,探讨其与临床病理特征的关系.方法 应用显微切割技术及扩增阻滞突变系统检测108例石蜡包埋NSCLC组织中EGFR基因第19号和21号外显子突变情况.结果 108例NSCLC患者中,EGFR基因突变率为36.1%(39例),其中19号外显子突变率为13.0%(14例),21号外显子突变率为23.1%(25例);EGFR基因突变的患者多为不吸烟、肿瘤直径较小(<3 cm)、腺癌、无远处转移及临床分期较早(P<0.05),与患者性别、病理分级及淋巴结转移无显著相关性(P>0.05);所有鳞癌标本中均无EGFR基因突变;EGFR突变的患者应用吉非替尼靶向治疗后原发肿瘤和脑转移灶明显缩小.结论 EGFR基因19号和21号外显子突变作为有效的NSCLC靶向治疗的临床筛选指标,很可能参与NSCLC的发生、发展,与相关的临床病理指标结合可为NSCLC的靶向治疗提供更可靠的依据.     

中国人非小细胞肺癌EGFR和K-RAS基因突变情况的研究

目的研究中国人非小细胞肺癌表皮生长因子受体(epidermal growth factor receptor,EGFR)基因和K-RAS基因突变情况。方法通过PCR扩增和基因测序的方法检测了101例中国人非小细胞肺癌(non-small cell lung cancers,NSCLCs)EGFR第18、19和21外显子及K-RAS密码子12、13的突变情况,并观察分析了其突变与肺癌临床特征及吉非替尼(gefitinib,商品名:易瑞沙/Iressa)药物治疗肺癌的疗效间的关系。结果共检测到26例EGFR突变(25.7%),3例K-RAS突变(2.9%),并发现腺癌患者、非吸烟患者和女性患者EGFR突变率较高(分别为44.2%、65.7%和48.3%)。10例服用吉非替尼有效的患者9例伴有EGFR突变。结论中国人肺癌的EGFR突变率高于西方人,吉非替尼疗效与EGFR突变有关。     

中国间变性淋巴瘤激酶(ALK)阳性非小细胞肺癌诊断专家共识(2013版)

随着分子医学进展和靶向药物的不断涌现,晚期非小细胞肺癌(NSCLC)的治疗已进入到个体化治疗的时代.目前临床应用的个体化靶向治疗主要针对表皮生长因子受体(EGFR)基因突变性和间变性淋巴瘤激酶(ALK)融合基因阳性肺癌,这两种基因变异型肺癌均具有明确的分子靶点、靶点检测技术及上市的靶向药物,临床疗效得到明显提高.     

克唑替尼治疗非小细胞肺癌的研究

非小细胞肺癌（NSCLC）是肺癌常见类型,早期诊断难度较大,5年生存率低。克唑替尼作为抑制Met/ALK/ROS的ATP竞争性的多靶点蛋白激酶抑制剂,是治疗NSCLC的分子靶向药物,在控制变性淋巴瘤激酶（ALK）阳性NSCLC患者疾病发展中具有重要意义,可有效延长患者无进展生存期,且较化疗毒副反应更小,患者耐受性高,但克唑替尼的耐药性也是临床关注重点。本文主要对克唑替尼治疗NSCLC、克唑替尼药理作用及其临床效果、耐药后治疗等进行综述,旨在为更好的发挥该药治疗效果,为临床治疗NSCLC提供参考依据。     

Consistent mutation status within histologically heterogeneous lung cancer lesions

Mattsson J S M, Imgenberg‐Kreuz J, Edlund K, Botling J & Micke P
(2012) Histopathology  61, 744–748 Consistent mutation status within histologically heterogeneous lung cancer lesions Aims: Activating epidermal growth factor receptor (EGFR) and KRAS mutations characterize molecular subgroups of non‐small‐cell lung cancer (NSCLC) with a strong predictive value for response to EGFR inhibitor therapy. However, the temporal occurrence and clonal stability of these mutations during the course of cancer progression are debated. The aim of this study was to characterize the presence of EGFR and KRAS mutations in histologically different areas of primary NSCLC lesions. Methods and results: Formalin‐fixed paraffin‐embedded cancer specimens from six cases with EGFR mutations and five cases with KRAS mutations were selected from a pool of primary resected NSCLC patients. From each tumour, three morphologically distinct areas were manually microdissected and analysed for the presence of mutations. The results demonstrated consistent EGFR and KRAS mutation status in the different histological areas of all primary tumours. Conclusions: The results support the concept that activating EGFR and KRAS mutations are oncogenic events that are consistently present throughout the primary tumour independently of histological heterogeneity. Thus, for molecular diagnostics, any part of the tumour is likely to be representative for EGFR and KRAS mutation testing.     

158例肺癌表皮生长因子受体检测及其意义探讨

目的；探讨表皮生长因子受体（ＥＧＦＲ）在肺癌中的表达特征及其临床病理意义。方法：应用ＡＢＣ免疫组织化学法对１５８例肺癌组织进行ＥＧＦＲ检测。结果：非小细胞肺 ＥＧＦＲ阳性率为８０．６％，而小细胞肺癌的ＥＧＦＲ均为阴性，并发现非小细胞肺癌ＥＧＦＲ表达与癌的组织学类型、分化程度、生物行为、肿块大小和临床分期均无相关性。结论：检测肺癌的ＥＧＦＲ有助于鉴别小细胞肺癌和非小细胞肺癌，并认为关于ＥＧＦＲ可能是     

STAT5、VEGF和EGFR在非小细胞肺癌中表达的相关性研究

目的:检测信号转导与转录激活因子5(STAT5)、血管内皮生长因子(VEGF)和表皮生长因子受体(EGFR)在非小细胞肺癌(NSCLC)中的表达情况,探讨三者与NSCLC临床病理特征之间的关系及三者彼此的关系。方法:采用免疫组化(SP法)检测STAT5、VEGF和EGFR在68例NSCLC及26例癌旁正常对照组织中的表达情况。结果:(1)STAT5、VEGF及EGFR在NSCLC组织中的阳性表达明显高于肺正常组织(P<0.05);(2)STAT5的阳性表达与NSCLC组织学类型有关,在腺癌中的表达明显高于鳞癌,与组织分化程度、TNM分期及淋巴结转移无关;(3)VEGF的阳性表达与NSCLC的分化程度、淋巴结转移和TNM分期有关(P<0.01),与NSCLC的组织学类型无关(P>0.05);(4)EGFR的阳性表达与NSCLC的TNM分期和淋巴结转移有关(P<0.01),与NSCLC的组织学类型和分化程度无关(P>0.05);(5)Spearman相关分析显示STAT5、VEGF和EGFR在NSCLC中的阳性表达两两比较(秩和检验方法)均呈正相关。结论:STAT5、VEGF、EGFR可能在肺癌的发生、侵袭和转移中起重要的作用,抑制STAT5信号通路可望成为非小细胞肺癌的治疗靶点。     

Epidermal growth factor receptor (EGFR) gene copy number detection in non-small-cell lung cancer; a comparison of fluorescence in situ hybridization and chromogenic in situ hybridization

AIMS: The epidermal growth factor receptor (EGFR) is an important target for anticancer therapy. In non-small-cell lung cancer (NSCLC), mutations in the tyrosine kinase domain of EGFR and EGFR gene copy number have been demonstrated to identify patients most likely to benefit from EGFR tyrosine kinase inhibitors. EGFR gene copy number has been assessed mainly by fluorescence in situ hybridization (FISH), a method requiring the use of a fluorescence microscope and often hampered by the rapid fading of the fluorescent signal. These limitations of FISH can be overcome by using chromogenic in situ hybridization (CISH). To test the applicability of CISH for EGFR gene copy number testing in NSCLC, a comparison of CISH and FISH was performed. METHODS AND RESULTS: A total of 58 formalin-fixed, frozen NSCLC tissue samples were collected on which both CISH and FISH were performed. High concordance was found in the assessment of EGFR copy number between observers and between techniques (kappa coefficient = 0.64-0.76). CISH seemed the ideal technique for paraffin sections, whereas FISH was favourable for frozen material. CONCLUSIONS: CISH is a suitable alternative strategy to FISH in determining EGFR gene copy number in NSCLC patients.     

Comparison detection methods for EGFR in formalin-fixed paraffin-embedded tissues of patients with NSCLC

Epidermal growth factor receptor (EGFR) is an important gene in the development of lung cancer. Non-small cell lung cancer (NSCLC) is the most common lung cancer. In the present study, the expression of EGFR in 717 patients with NSCLC was detected by Ventana automatic immunohistochemical technique, and the samples was verified by Real-time PCR, and then the results were compared with the data acquired by next-generation sequencing technology (NGS), which is the high throughput, multiple sites for EGFR gene mutation testing. The expression of Ventana EGFR in 717 cases of NSCLC was detected by immunohistochemistry, and the positive rate was 60.70 % (435 / 717). The mutation rate of EGFR was 57.60 % (413/717). The coincidence rate of Ventana EGFR immunohistochemical assay and Real-time PCR assay reached 94.94 %, and the two had high consistency. The coincidence rate of Ventana EGFR immunohistochemical assay and NGS were high correlation. Based on these results, Ventana EGFR automatic immunohistochemical detection has high accuracy, simple operation process, low price and easy interpretation. It can be used as the preferred method for EGFR detection.     

Somatic mutations of the epidermal growth factor receptor and non-small-cell lung cancer

Frequent overexpression of epidermal growth factor receptor (EGFR) in non-small-cell lung cancer (NSCLC) makes EGFR a new therapeutic target. Two specific EGFR tyrosine kinase inhibitors, gefitinib (ZD1839, Iressa) and erlotinib (OSI-774, Tarceva), have been developed and approved by the US Food and Drug Administration for second-line and third-line treatment of advanced NSCLC. Clinical trials have shown considerable variability in the response rate between different patients with NSCLC, which led to the discovery of somatic EGFR-activating mutations. This brief review summarises the discovery and functional consequences of the mutations, their clinicopathological features and significant implications in the treatment and prognosis of NSCLC.     

Detection of low-level EGFR T790M mutation in lung cancer tissues

Epidermal growth factor receptor (EGFR) gene mutation status is critical to predicting responsiveness to EGFR tyrosine kinase inhibitor (TKI) therapies in non-small cell lung cancer (NSCLC) patients. However, a vast majority of the patients experience recurrence of the cancers by a secondary mutation of EGFR (T790M). Earlier studies suggested evidence that subclones bearing EGFR T790M mutation pre-exist in NSCLCs even prior to the therapies. However, to date, the status of T790M mutation in primary NSCLC is largely known. In this study, we developed an assay using peptide nucleic acid (PNA)-clamping PCR for detection of low-level EGFR T790M mutation. We found that the assay showed the highest sensitivity (0.01% mutation detection) in the clamping condition. We analyzed 147 NSCLC tissues [70 adenocarcinomas (AD), 62 squamous cell carcinomas (SQ), 12 large cell carcinomas (LC), and three adenosquamous carcinomas] that had not been exposed to the TKI therapies, and found 12 (8.2%; 12/147) EGFR T790M mutation in eight AD (11.4%), three SQ (4.8%), and one LC (8.3%) by the PNA-clamping PCR. However, this mutation was not detected by conventional DNA sequencing. Our data indicate that EGFR T790M exists in pretreatment NSCLC at low levels irrespective of histologic types. This study provides a basis for developing an applicable protocol for detecting low-level EGFR T790M mutation in primary NSCLC, which might contribute to predicting recurrence of the tumor in response to the TKI therapies.     

The role of Axl in drug resistance and epithelial-to-mesenchymal transition of non-small cell lung carcinoma

Axl, a member of receptor tyrosine kinases (RTKs), has been established as a strong candidate for targeted therapy of cancer. Some reports showed that Axl is a promising therapeutic target to enhance EGFR TKI response in selected EGFR WT NSCLC patients. The present study was aimed to investigate the role of Axl in non-small cell lung carcinoma (NSCLC) drug resistance and the progress of epithelial-to-mesenchymal transition (EMT). MTT was used to detect the cytotoxicity of chemotherapeutic drugs in NSCLC cells, and Western blot to detect the expression of Axl in EGFR wild type NSCLC cell lines. The EMT markers were also determined by Western blot. We found that when downregulating Axl in EGFR WT NSCLC cells, the cells showed a more sensitive response to erlotinib than those overexpressed Axl. The further study showed that when downregulating Axl, the EMT markers E-cadherin was increased while N-cadherin and vimentin were decreased. Those data showed that the inhibition of Axl could reverse the EMT. Combined therapeutic strategies of the inhibitor of Axl and EGFR TKI could be more effective in the treatment of NSCLC drug resistance patients. The EMT signature and Axl might be predictive biomarkers of drug response and therapeutic targets in patients with NSCLC.     

The Role of Monoclonal Antibody in Combination with First-Line Chemotherapy in Asian Patients with Advanced Non-Small Cell Lung Cancer

The strategies of incorporating monoclonal antibodies (MoABs) have now proved efficacy in the first-line treatment of advanced non-small cell lung cancer (NSCLC). These include targeting the vascular endothelial growth factor (VEGF) or epidermal growth factor receptor (EGFR). Bevacizumab is a MoAB targeting the vascular endothelial growth factor (VEGF), an important mediator of new blood vessel formation. Cetuximab is a MoAB directed at EGFR. Binding cetuximab to EGFR blocks signal transduction and promotes receptor internalization and degradation. In this review, we present current data of bevacizumab and cetuximab for the first line treatment of advanced NSCLC. We also refer to their potential for Asian patients with advanced NSCLC in the first-line setting.