放疗、化疗及放化疗治疗非小细胞肺癌对 EGFR 基因突变状态的影响

目的：研究放疗、化疗和放化疗三种临床非小细胞肺癌（non - small cell lung cancer,NSCLC）治疗方式对 EGFR 基因突变状态的影响。方法：采用 ARMS 血浆 EGFR 基因突变分析方法,分别对393例晚期NSCLC 患者放疗、化疗和放化疗治疗前、治疗后获得的外周血标本进行 EGFR 基因突变检测。结果：放疗、化疗和放化疗三种治疗手段均影响 EGFR 基因突变状态。单纯放疗组放疗前的 EGFR 基因突变率为31.78%,放疗后的 EGFR 基因突变率为20.16%,放疗显著影响 EGFR 基因突变状态（P <0.016）。单纯化疗组化疗前的 EGFR 基因突变率为34.56%,化疗后的 EGFR 基因突变率为22.06%,化疗显著影响 EGFR 基因突变状态（P <0.013）。放化疗组放化疗前的 EGFR 基因突变率为33.59%,放化疗后 EGFR 基因突变率为17.19%,放化疗显著影响 EGFR 基因突变状态（P <0.001）。结论：放疗、化疗和放化疗均可降低 NSCLC 患者外周血中EGFR 基因突变率,提示放疗、化疗和放化疗治疗会对外周血中 EGFR 基因突变状态发生影响,采用外周血检测 NSCLC 的 EGFR 基因状态能够在治疗过程中动态观察患者的变化,进一步指导临床治疗。     

表皮生长因子受体突变细胞系H1650耐药机制探讨

背景与目的 表皮生长因子受体(epidermal growth factor receptor,EGFR)高表达和突变与40％左右的肺癌有关,已成为靶向治疗药物研究热点;随着Gefitinib和Erlotinib作为EGFR酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)代表药物应用于临床,继而产生的耐药现象亦成为临床一大难题,部分耐药机制仍不清楚.本研究探讨非小细胞肺癌(non-small cell lung cancer,NSCLC)细胞系H1650耐药机制.方法 选用real-time RT-PCR检测EGFR野生型NSCLC细胞系中EGFR mRNA表达水平;MTT检测癌细胞对Erlotinib的药物敏感性;Western blot检测EGFR突变NSCLC细胞系突变情况和Erlotinib及PI3K抑制剂(LY294002)对EGFR突变型NSCLC细胞下游信号蛋白磷酸化水平的影响.结果 EGFR野生型细胞系中,EGFR mRNA表达水平高低不一,但均对Erlotinib耐药;EGFR突变型细胞系中,HCC827和H1650为同种突变类型,HCC827对Erlotinib敏感,H1650则相对耐药;检测显示,H1650细胞中PTEN表达缺失,给予Erlotinib和LY294002处理后,HCC827中P-AKT明显被抑制,但H1650中p-AKT下调不明显.结论 在NSCLC细胞系中,Erlotinib药物敏感性与EGFR的mRNA表达高低无关,但与EGFR的突变类型有关;H1650对Erlotinib相对耐药可能与PTEN缺失导致的P-AKT持续活化有关.     

表皮生长因子受体与酪氨酸激酶抑制剂在肿瘤防治中的应用进展

表皮生长因子受体(epidermal growth factor receptor,EGFR)信号传递系统可调控细胞周期，调节细胞生长与分化，促进损伤修复。EGFR在包括非小细胞肺癌(non-small-cell lung cancer,NSCLC)在内的多种上皮源性肿瘤中过表达预示存活率低、预后差、转移可能性大，可作为肿瘤基因治疗的靶位。酪氨酸激酶抑制剂(tyrosine kinase inhibitors，TKIs)可选择性抑制EGFR酪氨酸激酶活性，抑制肿瘤生长，增加放化疗敏感性。     

吉非替尼治疗表皮生长因子受体突变型非小细胞肺癌患者的效果及影响因素分析

目的 观察吉非替尼治疗表皮生长因子受体(EGFR)突变型非小细胞肺癌(NSCLC)患者的疗效并探讨影响因素.方法 选取150例EGFR突变型NSCLC患者的临床资料,所有患者均给予吉非替尼口服治疗,连续治疗6个疗程,评估其临床疗效,并对可能影响EGFR突变型NSCLC患者临床疗效的相关因素进行单因素和多因素分析.结果 150例患者中,总缓解患者48例(32.00％)设为缓解组,剩余102例患者设为对照组.缓解组和对照组患者性别、肿瘤分期、病理类型和肿瘤直径比较,差异均有统计学意义(P﹤0.05).Logistic回归分析结果显示,性别、肿瘤分期、病理类型和肿瘤直径均为EGFR突变型NSCLC患者临床疗效的影响因素(P﹤0.05).治疗期间,150例患者药物不良反应总发生率为28.67％.结论 吉非替尼治疗EGFR突变型NSCLC患者有一定的临床疗效,性别、肿瘤分期、病理类型和肿瘤直径均为EGFR突变型NSCLC患者临床疗效的影响因素.     

表皮生长因子受体及β-连环素在非小细胞肺癌组织中的表达及相关性研究

目的　探讨表皮生长因子受体(EGFR )和β-连环素(βcatenin)在非小细胞肺癌(NSCLC)中的表达及其相关性。方法　应用SABC免疫组化技术检测了5 3例NSCLC中EGFR和βcatenin的表达情况。结果　在5 3例非小细胞肺癌病理组织中,EGFR和βcatenin阳性表达率分别为67.9% (3 6/5 3 )和5 4.7% (2 9/5 3 )。在不同临床分期,有无淋巴结转移的NSCLC比较中EGFR表达有显著差异(P <0 .0 5 ) ;在不同分化程度、有无淋巴结转移的NSCLC中βcatenin表达有显著差异(P <0 .0 5 ) ,EGFR和βcatenin表达呈负相关(γ=-0 .843 6,P =0 .0 0 1)。结论　在NSCLC中,EGFR及βcatenin的表达与淋巴结转移密切相关,两者表达呈负相关,βcatenin低表达提示预后不良。     

基因突变检测可指导非小细胞肺癌的个体化治疗

<正>据《中国科学报》2013年12月31日消息报道,肺癌是全球排名第一位的恶性肿瘤,分为非小细胞肺癌(NSCLC)和小细胞肺癌(SCLC)。NSCLC约占肺癌总数的80.0%⁸5.0%,患者早期手术后复发转移率较高,中晚期对放化疗治疗不敏感,死亡率高,临床迫切需要更有效的方法来支持NSCLC的诊断和治疗。随着分子生物学研究的不断深入,近10年来,国际医学界在NSCLC的发生、维持和进展的关键驱动分子和细胞机制研究等方面取得多项重大进展,发现了间变性淋巴瘤激酶(ALK)、表皮生长因子受体(EGFR)和K-ras     

局部晚期非小细胞肺癌表皮生长因子受体基因状态对同步放化疗疗效和预后的影响

目的 探讨表皮生长因子受体(EGFR)基因突变状态对局部晚期非小细胞肺癌(NSCLC)患者同步放化疗疗效和预后的影响。方法 收集武警河南省总队医院2012年1月至2021年3月收治的经病理学和影像学确诊为不能手术切除的局部晚期NSCLC且间变性淋巴瘤激酶(ALK)、鼠类肉瘤病毒癌基因(KRAS)等驱动基因阴性一线行同步放化疗的216例患者的完整临床病理资料。结果 216例局部晚期NSCLC患者中EGFR基因突变型占44.9%(97/216)、EGFR基因野生型占55.1%(119/216)。女性、腺癌和无吸烟史患者EGFR基因突变发生率高于有男性、鳞癌和吸烟史的患者,差异均有统计学意义(χ²=5.981,P=0.016;χ²=5.780,P=0.036;χ²=4.623,P=0.041)。216例患者客观缓解率(ORR)、疾病控制率(DCR)和中位疾病无进展生存期(PFS)分别为77.8%(168/216)、82.4%(178/216)和11.7个月。EGFR突变型ORR、DCR、中位PFS分别为84.5%(82/97)...     

吉非替尼靶向治疗非小细胞肺癌

吉非替尼(gefitinib)是用于靶向治疗非小细胞肺癌(NSCLC)的二线或三线药物,是表皮生长因子受体(EGFR)酪氨酸激酶(PTK)抑制剂,能选择性阻断EGFR的PTK,有效地"切断"EGFR向细胞内发出信号.gefitinib具有减慢和降低癌细胞增殖的作用,虽不能完全治愈NSCLC,但可以长期使用,能有效延缓病情恶化,减少并发症,改善患者的生活质量,延长患者生存期,为NSCLC患者提供了一种重要的新型治疗方法.现综述gefitinib的作用机制及其临床应用.     

血清miRNA-1296联合表皮生长因子受体检测对非小细胞肺癌患者预后评估价值的分析

目的 研究血清miRNA-1296联合表皮生长因子受体(EGFR)检测对非小细胞肺癌(NSCLC)患者的预后评估价值.方法 选取61例NSCLC患者为NSCLC组,选取同期61例健康体检者为对照组.检测血清miRNA-1296、EGFR水平,分析两者在NSCLC患者中的相关性,观察两者对NSCLC患者预后的评估价值.结...     

BRCA1:一种新的非小细胞肺癌放化疗疗效的预测基因

非小细胞肺癌(non-small celllung cancer,NSCLC)是世界范围内最常见的恶性肿瘤之一。放化疗是其治疗的主要方法 ,研究和确定临床上NSCLC放化疗敏感性预测和诊断的靶向分子和指标将有利于NSCLC患者的个体化治疗,以获得最佳治疗效果。本文就BRCA1作为NSCLC放化疗疗效的重要指标的研究现状做一综述,以期为临床NSCLC患者个体化放化疗提供参考。     

Epidermal growth factor receptor as a target to improve treatment of lung cancer

Despite considerable efforts to reduce tobacco use, lung cancer remains the most common cancer in both men and women. Recent advances in radiation therapy and chemotherapy for lung cancer have yielded encouraging results, but survival in patients with locally advanced non-small-cell lung cancer (NSCLC) remains poor. As more and more molecular changes and their importance in malignant tissues continue to be characterized, approaches to target those aberrant pathways are being actively explored. The epidermal growth factor receptor (EGFR) is commonly overexpressed in NSCLC, particularly squamous cell carcinoma, and has been implicated in the development and progression of this disease, although a clear correlation with prognosis has not been established. Several different strategies have been developed to target and block the EGFR and its downstream effects, and some of them have been intensively studied in preclinical and clinical studies as a single-agent approach or in combination with radiation therapy or chemotherapy. In this article, we review the role of EGFR in lung cancer, as well as preclinical and clinical data on strategies to interfere with EGFR signaling alone or in combination with chemotherapy, radiation, or both.     

化疗对晚期非小细胞肺癌患者表皮生长因子受体基因突变状态的影响

目的 探讨化疗对晚期非小细胞肺癌(NSCLC)患者表皮生长因子受体(EGFR)基因突变状态的影响.方法 选取85例晚期NSCLC患者作为研究对象.化疗前、化疗4~6个周期后均采集所有研究对象的外周血,采用酶切富集联合变性高效液相色谱法(REDE-DHPLC)检测EGFR-19外显子、EGFR-21外显子的突变状态.结果 85例晚期NSCLC患者化疗前EGFR突变阳性率为55.29%(47/85),化疗4~6个周期后EGFR突变阳性率为35.29%(30/85),化疗前后EGFR突变阳性率比较差异有统计学意义(P<0.05).化疗前后共有37例晚期NSCLC患者发生EGFR突变,其中27例从EGFR突变阳性转为EGFR突变阴性,10例患者从EGFR突变阴性转为EGFR突变阳性,两种突变模式发生率比较差异有统计学意义(P<0.05).结论 晚期NSCLC患者化疗过程中EGFR突变状态可能会发生改变,因此在给予其靶向治疗前应重新对其进行EGFR突变检查.     

非小细胞肺癌脑转移治疗进展

非小细胞肺癌(NSCLC)脑转移的治疗方法包括激素、抗惊厥药物治疗、手术、放疗、化疗.近年来分子靶向治疗如表皮生长因子(EGFR)酪氨酸激酶抑制剂(TKI)成为NSCLC脑转移的新的治疗选择.     

非小细胞肺癌组织化疗前后表皮生长因子受体基因的突变

目的:探讨非小细胞肺癌(non-small cell lung cancer,NSCLC)患者化疗前、后肿瘤组织中表皮生长因子受体(epidermal growth factor receptor,EGFR)基因外显子19和21的突变状况。方法:提取31例NSCLC患者化疗前、后肿瘤组织标本中的基因组DNA,采用巢式PCR技术扩增EGFR基因外显子19和21,并进行测序分析。结果:6例患者化疗前、后EGFR基因发生突变,其中4例为19号外显子发生缺失突变,2例为2l号外显子发生替代突变,且化疗前、后的突变状况一致。女性患者突变率(2/3)高于男性(4/28)(P=0.029),非吸烟者的突变率(4/9)高于吸烟者(2/22)(P=0.043)。结论:NSCLC组织EGFR基因外显子19和21突变在化疗前、后无明显改变。     

Pharmacodynamic separation of epidermal growth factor receptor tyrosine kinase inhibitors and chemotherapy in non-small-cell lung cancer

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) given concurrently with chemotherapy do not improve patient outcomes compared with chemotherapy alone in advanced-stage non-small-cell lung cancer (NSCLC). One potential explanation for this lack of benefit is a negative interaction or antagonism between chemotherapy and EGFR TKIs when delivered concomitantly. Support for this line of reasoning is provided by preclinical data demonstrating that EGFR TKIs induce primarily a cytostatic effect resulting from a G1 cell cycle arrest in cell lines with wild-type EGFR, reducing cell cycle phase-dependent activity of chemotherapy, whereas they induce apoptotic cell death in tumors with EGFR-activating mutations. Because the great majority of NSCLC tumors consist of wild-type EGFR, sequence-specific interactions of EGFR TKI/chemotherapy combinations might negatively influence the efficacy of these regimens in patients with NSCLC. Further evidence is provided by EGFR mutational analysis in patient tumor specimens from the TRIBUTE study. Herein we provide the preclinical and clinical rationale for studies examining the concept of pharmacodynamic separation as a means for overcoming hypothesized antagonism of EGFR TKIs and chemotherapy.     

Prospective study of second-line chemotherapy for non-small cell lung cancer selected according to EGFR gene status

We prospectively investigated the outcome of personalized second-line treatment based on epidermal growth factor receptor (EGFR) gene status in previously treated patients with advanced non-small cell lung cancer (NSCLC). EGFR gene status was evaluable by LH-mobility shift assay in registered patients. Gefitinib (Gef) treatment was recommended if the patients had EGFR mutation (mEGFR). EGFR gene status was evaluable in 146 patients. Seventy-four of the patients were female, 82 were smokers, and 122 had adenocarcinoma. Overall, 67 patients had mEGFR and received Gef. Forty-nine of 79 patients with wild-type EGFR (wEGFR) received other chemotherapies or radiation but 30 selected best supportive care only as a second-line treatment. Patients with mEGFR survived significantly longer than patients with wEGFR (p < 0.0001). However, the survival of patients who received other forms of chemotherapy was not different from that of patients who received best supportive care only as a second-line treatment in patients with wEGFR. Examination of the association between overall survival after first-line chemotherapy and prognostic factors using multivariate regression analysis showed that mEGFR and response to first-line chemotherapy were independent factors (p = 0.003 and p = 0.003, respectively). Selection of second-line treatment according to EGFR gene status may be useful for patients with NSCLC.     

EGFR突变状态对Ⅲ期非鳞非小细胞肺癌患者放化疗近期疗效和长期生存的预测价值

背景与目的表皮生长因子受体(epidermal growth factor receptor,EGFR)突变状态与III期非小细胞肺癌放化疗近期疗效和生存的关系是目前临床研究热点。本研究旨在探讨EGFR突变状态与III期非鳞非小细胞肺癌放化疗疗效的关系。方法本研究共计入组187例III期非鳞非小细胞肺癌患者,其中87例能够评估放化疗近期疗效和2年生存率,128例患者适合评估一线化疗疗效。采用变性高效液相色谱法检测EGFR基因突变状态。结果 EGFR突变阳性患者对联合放化疗的客观缓解率为84.6%(33/39),明显高于EGFR突变阴性患者56.3%(27/48)(P=0.004)。2年生存率EGFR突变阳性患者为53.8%(21/39),EGFR突变阴性患者为50%(24/48),两组在长期生存方面无统计学差异(P=0.871)。结论在III期非鳞非小细胞肺癌中,EGFR突变预示更高的放化疗近期疗效,与生存期无关。     

Modulation of epidermal growth factor receptor status by chemotherapy in patients with locally advanced non-small-cell lung cancer is rare.

PURPOSE: To determine whether epidermal growth factor receptor (EGFR) expression in non-small-cell lung cancer (NSCLC) is modulated by chemotherapy and to assess the agreement of EGFR status between mediastinal nodes and the primary tumor after chemotherapy. PATIENTS AND METHODS: Patients with NSCLC stage IIIa/b pN2/3 confirmed by mediastinoscopy or mediastinostomy were treated with at least three cycles of chemotherapy before undergoing surgery. EGFR expression was evaluated on mediastinal nodes at the time of initial diagnosis and on both the primary tumor and residual metastatic nodes after treatment. RESULTS: EGFR expression determined on 138 of 164 patients who underwent mediastinoscopy or mediastinostomy was 0 (22 patients), 1+ (27 patients), 2+ (28 patients), and 3+ (61 patients). Fifty-four patients of 164 received chemotherapy followed by surgery. Of the 89 of 138 patients with EGFR score of 2+/3+ at the time of diagnosis, 34 patients underwent surgery after induction chemotherapy. None changed to zero EGFR immunoreactivity, with 29 patients (88%) maintaining a score of 2+/3+. Of the 22 of 138 patients with no EGFR expression at the time of diagnosis, six underwent surgical resection after induction chemotherapy. Of these six patients, four changed their EGFR expression from an EGFR score of 0 to 2+/3+. After treatment, the agreement of EGFR status between tumor and nodes in the subgroup of patients with EGFR score 2+/3+ was 89% to 92%. CONCLUSION: Our data suggest a very good agreement of EGFR status before and after chemotherapy in EGFR-positive NSCLC. Induction chemotherapy can induce EGFR expression in occasional EGFR-negative tumors.     

Dual targeting of the vascular endothelial growth factor and epidermal growth factor receptor pathways: rationale and clinical applications for non-small-cell lung cancer

The vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways represent 2 clinically validated targets for non-small-cell lung cancer (NSCLC), and there is strong biologic rationale for therapeutic approaches targeting both pathways in NSCLC and other diseases. These 2 pathways are interrelated, as VEGF is known to be downregulated by EGFR inhibition through hypoxia-inducible factor 1alpha-dependent and hypoxia-inducible factor 1alpha-independent mechanisms. Furthermore, acquired resistance to EGFR inhibitors is associated with increased levels of VEGF, and dual VEGF/EGFR inhibition has demonstrated activity in the presence of EGFR tyrosine kinase inhibitor-resistant disease. This approach is being investigated clinically using combinations of drugs that target the pathways separately, such as erlotinib and bevacizumab, or individual drugs that target both pathways, such as vandetanib. Randomized phase II studies in previously treated patients with NSCLC suggest that dual VEGF/EGFR inhibition might be more active than targeting either pathway alone and that the combination could also enhance the efficacy of chemotherapy. Phase III clinical trials are currently in progress to determine whether dual VEGF/EGFR inhibition, alone or in combination with chemotherapy, should become a standard therapeutic option for patients with NSCLC.     

晚期肺腺癌患者化疗前后血清EGFR基因突变状态的比较

背景与目的 存在表皮生长因子受体(epidermal growth factor receptor,EGFR)基因突变的非小细胞肺癌(non-small cell lung cancer,NSCLC)作为NSCLC的一个特殊亚群,对于表皮生长因子酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitor,EGFR-TKI)的治疗显示出良好的疗效.本研究旨在检测晚期肺腺癌患者化疗前后血清EGFR基因外显子19和外显子21的突变状态,并分析化疗是否对EGFR基因突变状态产生影响.方法 磁珠法提取血清游离DNA后,使用酶切富集巢式PCR分别对血清游离DNA中EGFR外显子19和外显子21进行特异性扩增,应用直接测序法对EGFR基因突变状态进行榆测.结果 33例肺腺癌患者化疗前EGFR基凶突变率为39.4%(13/33),化疗后为54.5%(18/33),化疗前后EGFR基因突变状态的一致率为54.5%(18/33);在不一致的15例患者中,10例由化疗前EGFR基因突变阴性变为阳性,5例由化疗前阳性变为阴性.结论 化疗可能导致血清EGFR基因突变状态的改变.