EGFR突变阴性NSCLC患者分子靶向治疗的研究现状

<正>随着医学分子生物学的发展,分子靶向治疗日益受到临床重视,作为肺癌驱动基因之一表皮生长因子受体(EGFR)突变体的发现开启了非小细胞性肺癌(NSCLC)靶向治疗之门,随后一系列以IPASS为代表的8项临床研究一致证实,与化疗相比,一线使用第1、2代EGFR-酪氨酸激酶抑制剂(TKI)能显著延长EGFR基因突变阳性晚期NSCLC患者的无进展生存期(PFS),提高总缓解率(ORR)和生活质量〔1〕。目前,EGFR基因     

EGFR基因突变在非小细胞肺癌中进展

EGFR表达异常见于多种恶性肿瘤,与肿瘤的生物学行为以及患者的预后有着密切联系.本文就EGFR基因突变在非小细胞肺癌(NSCLC)中的发生机制和分子靶向治疗的情况作一综述.一、EGFR基因突变EGFR为erbB家族成员之一,具有酪氨酸激酶活性,与HER2、HER3及HER4一起组成erbB家族.EGFR是一种跨膜糖蛋白受体,具有酪氨酸激酶活性,过度表达于45％～70的NSCLC中[1].EGFR作用于细胞信号传导通路,激活时,可导致肿瘤细胞的酪氨酸蛋白激酶活化及受体自身磷酸化,促进细胞的分化增生、肿瘤内的血管生成、凋亡抑制及肿瘤转移[2].     

EGFR 20外显子插入突变的非小细胞肺癌治疗研究进展

非小细胞肺癌(NSCLC)是肺癌最常见的亚型,常伴有表皮生长因子受体(EGFR)突变.EGFR 20外显子插入突变(EGFR ex20ins)是一种罕见的EGFR基因突变,其结构不同于经典EGFR基因突变,对传统治疗方法如表皮生长因子受体—酪氨酸激酶抑制剂(EGFR-TKIs)可产生耐药,治疗相对困难.对于携带EGFR...     

EGFR-TKIs治疗非小细胞肺癌并发相关间质性肺病的诊治

近年来,分子靶向药物表皮生长因子受体（epidermal growth factor receptor,EGFR）酪氨酸激酶抑制剂（tyrosine kinase inhibitors,TKIs）对EGFR敏感突变晚期非小细胞肺癌（non—small cell lung cancer,NSCLC）的疗效已经获得肯定。随着应用的深入,     

EGFR基因突变与肺癌EGFR—TKI获得性耐药的研究进展

随着肺癌分子发病机制的研究，针对这些机制的靶向治疗药物逐渐进入临床，其中表皮生长因子受体（epidermal growth factor receptor，EGFR）是目前研究最多的肺癌治疗靶点。然而多中心研究显示，EGFR酪氨酸激酶抑制剂（tyrosine kinase inhibitor，TKI）只对部分患者有效，且经过一定时间的治疗后出现疾病进展，即发生了获得性耐药，这种耐药可能与EGFR基因的二次突变有关，     

EGFR TKIs在EGFR突变型非小细胞肺癌一线治疗中的研究现况

<正>肺癌目前位于全世界癌症死亡原因的首位,严重威胁人类的生命和健康。近年来与肿瘤形成和发展相关的分子机制逐渐明确,导致了靶向抑制不同生长因子及其受体家族药物的不断发展。其中研究最普遍的是靶向作用于表皮生长因子受体(epidermal growth factor receptor EGFR)的药物,包括抑制表皮生长因子受体细胞内酪氨酸激酶活性的表皮生长因子受体酪氨酸激酶抑制剂(EGFR tyrosine ki-     

晚期非小细胞肺癌TKI耐药后治疗进展

<正>在非小细胞肺癌(NSCLC)中约15%白种人患者存在表皮生长因子受体(EGFR)突变〔1〕,而亚裔人种的EGFR突变率较高,约为30%〔2〕。多项大型临床资料显示以EGFR-酪氨酸激酶抑制剂(TKI)为代表的分子靶向药物治疗晚期NSCLC可提高患者的生活质量,延长患者的生存期,已成为临床治疗肺癌的手段之一。IPASS、NEJ002、WJTOG3405、EURTAC等研究已证     

晚期非小细胞肺癌中老年患者胸水表皮生长因子受体基因突变及其酪氨酸激酶抑制剂靶向治疗效果

目的分析晚期非小细胞性肺癌(NSCLC)中老年患者胸水表皮生长因子受体(EGFR)基因突变及EGFR-酪氨酸激酶抑制剂(EGFR-TKIs)靶向治疗的临床效果。方法共纳入NSCLC患者74例,均为一线化疗方案无效,行EGFR 19和21位点检测,对EGFR野生型41例(对照组)更改化疗方案,对EGFR突变型33例(观察组)采用靶向药物吉非替尼250 mg/d,疗程为3个月,对比临床效果。结果 EGFR突变与患者性别、年龄、肿瘤分期及直径无相关性(P0. 05)。观察组的无进展生存时间延长,客观有效率和疾病控制率高于对照组,差异有统计学意义(P0. 05)。两组化疗严重不良反应发生率比较无显著差异(P0. 05)。结论 EGFR基因突变的靶向治疗可改善晚期NSCLC患者的生存预后。     

EGFR基因突变与酪氨酸激酶抑制剂疗效及预后之间的关系

背景与目的表皮生长因子受体（epidermal growth factor receptor，EGFR）信号通路在非小细胞肺癌的发生和发展中起重要作用。EGFR酪氟酸激酶抑制剂（EGFR tyrosine kinase inhibitors，EGFR-TKIs）是目前非小细胞肺癌（NSCLC）治疗的热点。研究表明，EGFR基因突变与TKIs的疗效及预后相关。本研究旨在了解EGFR基因突变与两种酪氨酸激酶抑制剂疗效及预后的相关性。方法共收集了34例接受gefitinib单药治疗和25例接受erlotinib单药治疗的晚期NSCLC患者的病理组织蜡块及相关临床资料。用PCR-PAGE检测EGFR199b显子突变，PCR＊RFLP检测EGFR21外显子突变，均用直接测序进行验证。结合临床进行分析。结果59例NSCLC标本中共检测出22例标本中有EGFR基因突变，突变率为37．3％。EGFR基因突变率在女性、腺癌、不吸烟患者中高（P〈0．05）。有EGFR基因突变的患者接受酪氨酸激酶抑制剂治疗的有效率高于无突变患者（50％vs18．9％，P〈0．05），疾病控制率高于无突变患者（86．4％vs54．1％，P〈0．05）。有EGFR基因突变的患者的疾病进展时间和总生存期均高于无突变患者，但是没有统计学差异（P〉0.05）。结论EGFR基因突变在女性、腺癌和不吸烟者中发生率高。有EGFR基因突变的晚期NSCLC接受EGFR酪氨酸激酶抑制剂治疗的有效率和疾病控制率高于无EGFR基因突变者。     

S768I及其相关联合突变在非小细胞肺癌治疗中的研究进展

非小细胞肺癌为肺癌最常见的分类.针对非小细胞肺癌患者的分子靶向治疗已发展十余年,现今其已逐渐成为拥有敏感基因突变患者的一线治疗.在研究中发现,除常见经典突变以外,某些罕见突变及其相关联合突变仍可能与对表皮生长因子受体-酪氨酸激酶抑制剂的敏感性相关.文中主要综述了近年S768I突变及其相关联合突变在非小细胞肺癌治疗中的研究进展.     

Targeted therapy: An evolving world of lung cancer

Lung cancer remains one of the most fatal illnesses. Recent development in cancer genomics and molecular targeted therapy leads to a paradigm shift in management of advanced‐stage non‐small cell lung cancer. Patients with activated mutation of epidermal growth factor receptor (EGFR) responded dramatically to EGFR tyrosine kinase inhibitor such as gefitinib or erlotinib. Multiple randomized studies have showed EGFR tyrosine kinase inhibitor to be superior to standard first‐line chemotherapy in this biomarker‐selected population. As the vasculature is considered to be the ‘Achillus heel’ of the tumour, anti‐angiogenic treatment is considered to be a suitable target. Inhibition of vascular endothelial growth factor may improve the efficacy of chemotherapy, although a practical biomarker has not been identified. We have entered an era of personalized therapy for lung cancer and this evolvement holds great promises for better treatment in future.     

Epidermal growth factor receptor gene mutation,amplification and protein expression in malignant pleural mesothelioma

Epidermal growth factor receptor (EGFR) is overexpressed in a variety of epithelial malignancies. In lung cancer cases, EGFR gene mutation at the kinase domain and EGFR gene amplification are reported to be predictors of the response to EGFR tyrosine kinase inhibitors. In malignant pleural mesothelioma (MPM), the role of EGFR is less clear. We studied EGFR gene mutation, amplification and protein expression in 25 Japanese patients with MPM. None had previously reported EGFR mutations detected by the TaqMan PCR assay. Using immunohistochemistry, 8/25 (32%) cases were positive for the EGFR protein. The cases of sarcomatous type and desmoplastic type were all negative. Fluorescence in situ hybridization analysis revealed three low polysomy cases and one high polysomy case. The low polysomy cases included one biphasic type and two epithelial types, and the high polysomy case was epithelial type. These four cases expressed EGFR protein. In MPM, EGFR seems to play a role in a limited subset of patients. To identify possible candidates for EGFR tyrosine kinase in inhibitor therapy, the information on the EGFR gene status may be valuable.     

非小细胞肺癌表皮生长因子受体20外显子插入突变四例报道并文献复习

肺癌占恶性肿瘤发病率第一位,在亚裔非吸烟肺腺癌女性中,表皮生长因子受体(EGFR)是最常见的突变基因,其中约90％的EGFR突变是19外显子典型框内突变或21外显子L858R点突变,其次为20外显子插入突变.不同突变患者的治疗方法及其从酪氨酸激酶抑制剂(TKI)治疗中的获益不同.本文报道4例非小细胞肺癌EGFR 20外...     

Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors

The tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) have shown anti-tumor activity in the treatment of non-small cell lung cancer (NSCLC). Dramatic and durable responses have occurred in NSCLC tumors with mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). In contrast, these inhibitors have shown limited efficacy in glioblastoma, where a distinct EGFR mutation, the variant III (vIII) in-frame deletion of exons 2-7, is commonly found. In this study, we determined that EGFRvIII mutation was present in 5% (3/56) of analyzed human lung squamous cell carcinoma (SCC) but was not present in human lung adenocarcinoma (0/123). We analyzed the role of the EGFRvIII mutation in lung tumorigenesis and its response to tyrosine kinase inhibition. Tissue-specific expression of EGFRvIII in the murine lung led to the development of NSCLC. Most importantly, these lung tumors depend on EGFRvIII expression for maintenance. Treatment with an irreversible EGFR inhibitor, HKI-272, dramatically reduced the size of these EGFRvIII-driven murine tumors in 1 week. Similarly, Ba/F3 cells transformed with the EGFRvIII mutant were relatively resistant to gefitinib and erlotinib in vitro but proved sensitive to HKI-272. These findings suggest a therapeutic strategy for cancers harboring the EGFRvIII mutation.     

Lack of EGFR gene mutations in exons 19 and 21 in esophageal (Barrett's) adenocarcinomas

SUMMARY.  Epidermal growth factor receptor is over-expressed in several tumors and is the target for the tyrosine kinase inhibitor gefitinib. This receptor is also over-expressed in esophageal adenocarcinomas. In non-small cell lung cancer, specific somatic mutations residing in the epidermal growth factor receptor tyrosine kinase in the activation loop and the glycine-rich P-loop, are responsible for an enhanced sensitivity toward gefitinib. We analyzed exons 19 and 21 coding for the receptor tyrosine kinase of the epidermal growth factor gene in 105 samples of esophageal (Barrett's) adenocarcinoma by denaturing high-pressure liquid chromatography. We found only one silent mutation in exon 19 of adenine to guanine in codon 754 leading to a substitution of K to K, the rest of the sample being wild-type genotype. In conclusion, mutations within the tyrosine kinase domain of EGFR associated with sensitivity of non-small cell lung cancer patients to gefitinib are not present in esophageal (Barrett's) adenocarcinoma.     

老年非小细胞肺癌患者表皮生长因子受体基因19-21外显子突变研究

目的 研究老年非小细胞肺癌(NSCLC)患者表皮生长因子受体(epidermal growth factor receptor,EGFR)基因酪氨酸激酶区19-21外显子的突变状态,并对其临床特征进行初步分析.方法 选取46例病理确诊的老年非小细胞肺癌患者,提取肺癌组织或胸腔积液及心包积液肿瘤细胞基因组DNA,通过巢式PCR基因扩增和直接测序的方法 .分析19、20、21外显子的突变情况,并与其临床特征及应用酪氨酸激酶抑制剂(TKI)疗效的关系进行了初步分析. 结果 46例中,26例检测出带有基因突变(56.5%),其中非沉默突变者为19例(41.3%).19号外显子突变6例(13.0%),20号外显子突变13例(28.2%),21号外显子突变14例(30.4%).其中7例带有2处突变,其余均为单处突变.不吸烟者的突变发生率显著高于吸烟者(P＜0.01).应用酪氨酸激酶抑制剂(TKI)临床获益的患者带有EGFR 19、20、21外显子的基因突变的几率显著高于未获益者(P＜0.05).60～69岁与70～85岁年龄组基因突变状态差异无统计学意义. 结论 老年NSCLC患者EGFR基因酪氨酸激酶区19-21外显子突变特征与肺癌患者总体类似,与年龄关系不大,老年NSCLC患者同样可以通过基因检测获得TKI治疗预测信息.     

Targeted therapy in advanced non-small-cell lung cancer

Molecularly targeted therapies have recently expanded the options available for patients with advanced non-small-cell lung cancer (NSCLC). Two cancer cell pathways in particular have been exploited, the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathway. The former has emerged as a key regulator of cancer cell proliferation and invasion, and several EGFR inhibitors have been developed. Erlotinib, a small-molecule inhibitor of the EGFR intracellular tyrosine kinase, has been found to improve survival compared with placebo in previously treated patients with advanced NSCLC and is Food and Drug Administration (FDA)-approved in this setting. Clinical and molecular predictors of response to erlotinib, such as a history of never smoking and EGFR gene mutation or amplification, are presently being evaluated to select patients for earlier therapy with erlotinib. Additional EGFR inhibitors are also being examined in randomized trials. The VEGF pathway, a key mediator of angiogenesis, has become an attractive target in multiple malignancies, including lung cancer. Bevacizumab, a monoclonal antibody to VEGF, received FDA approval for use in advanced non-squamous-cell NSCLC in 2006 after a phase III trial reported a significant survival advantage when bevacizumab was added to standard first-line chemotherapy. Small-molecule inhibitors of the VEGF receptor tyrosine kinase, such as sunitinib and sorafenib, have also shown promise in phase II trials and are being further investigated in phase III studies. Because preclinical data suggest a synergistic effect when VEGF and EGFR inhibitors are combined, the concurrent use of erlotinib and bevacizumab has additionally been evaluated in a phase II trial, with encouraging early results suggesting at least equivalent activity to standard salvage chemotherapy, with less toxicity. Several other novel agents are being examined, including inhibitors of histone deacteylases and the 26S proteosome. Research efforts are currently focusing on tailoring such therapies according to predictive clinical and molecular markers.     

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...     

Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1

Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease progression using EGFR-mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS/RAF/MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS, KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR-mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment.     

Detection of response-predicting mutations in the kinase domain of the epidermal growth factor receptor gene in cholangiocarcinomas

Purpose: Epidermal growth factor receptor (EGFR) signalings have recently been implicated in the genesis and progression of cholangiocarcinomas. Thus, the EGFR kinase inhibitor appears to be promising in the treatment of this cancer. The response-predicting mutations in the tyrosine kinase domain of EGFR gene have recently been detected in non-small cell lung cancers. This study was, therefore, to investigate if these mutations are also found in cholangiocarcinomas. Methods: Twenty-two consecutive cholangiocarcinoma patients who underwent surgical resection were enrolled. Their resected paraffin-embedded cholangiocarcinoma specimens were used for mutation analysis, which was performed by DNA sequencing of exons 18, 19 and 21 in the EGFR gene. Clinical characteristics were compared between each group according to the presence or absence of mutations. Results: Three patients (13.6%) harbored EGFR mutations. All the mutations found were deletions in exon 19. Mutations were more common in intra-hepatic or poorly differentiated tumors. Differences in age, sex, stage at diagnosis and survival were not observed between mutation-positive and -negative patients. Conclusions: This study, for the first time, demonstrates that a subset of cholangiocarcinoma patients has response-predicting EGFR mutations. Therefore, a highly selected application of the EGFR kinase inhibitor would be therapeutically effective in these patients. Grant Support: supported by grant No. 03-2005-024 from the Seoul National University Hospital Research Fund.