147例肺腺癌EGFR基因19、21外显子突变与临床病理特征及预后的关系

摘 要：［目的］ 探讨肺腺癌患者表皮生长因子受体（epithelial growth factor receptor,EGFR）基因19外显子、21外显子突变,及其与临床病理特征和预后的关系。［方法］ 回顾性分析2016年1月至2017年10月我院收治的147例肺腺癌患者的临床资料,检测EGFR基因突变。采用单因素分析和多元Logistic回归模型分析肺腺癌患者EGFR基因19、21外显子突变与临床病理特征的关系。生存曲线分析肺腺癌患者EGFR基因19、21外显子突变与预后的关系。［结果］ 147例肺腺癌患者中发生EGFR基因突变68例（46.26%),其中19外显子突变35例（23.81%）,21外显子突变28例（19.05%）,其他类型突变5例（3.40%）。女性、无吸烟史、TNMⅠ~Ⅱ期、高分化者EGFR基因19、21外显子突变高于男性、有吸烟史,Ⅲ期~Ⅳ期和低分化患者。EGFR基因19、21外显子突变患者的中位生存时间为80周,高于19、21外显子未突变患者的中位生存时间66周（P<0.05）。EGFR基因19外显子突变患者的中位生存时间为82周,21外显子突变患者的中位生存时间为78周（P＞0.05）。 ［结论］ 肺腺癌EGFR基因19、21外显子突变发生率为46.26%。性别、吸烟史、肿瘤分化程度等临床病理特征均与EGFR基因19、21外显子突变有关。EGFR基因19、21外显子突变患者的预后好于19、21外显子未突变患者,EGFR基因19突变患者的预后与21外显子突变患者无明显差异。     

非小细胞肺癌EGFR基因靶向治疗研究进展

人表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitors, EGFR-TKIs）给EGFR基因敏感突变患者带来巨大的临床获益。随着临床和基础研究的不断深入,EGFR-TKI已经越来越受到关注。本综述旨在将2016年EGFR-TKI药物研究进展进行概述。     

不同基因分型晚期非小细胞肺癌患者的预后分析

背景与目的 非小细胞肺癌(non-small cell lung cancer,NSCLC)已由原来的组织分型指导下的治疗转变为基因分型指导治疗的模式,表皮生长因子受体(epidermal growth factor receptor,EGFR)和间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)是肺癌最重要的两个驱动基因.本研究旨在探讨不同基因分型的复发或转移晚期NSCLC患者的临床特点及预后影响因素.方法 回顾性分析北京胸科医院2004年7月-2015年12月间553例EGFR和ALK基因状态明确的晚期NSCLC患者的临床资料,采用Cox比例风险回归模型对患者预后的独立影响因素进行分析.结果 553例细胞学或组织学证实的晚期NSCLC患者,EGFR突变患者227例,ALK阳性患者58例,EGFR和ALK双突变患者2例,EGFR和ALK野生型患者266例.227例EGFR突变患者的中位生存期(overall survival,OS)为28.7个月(95%CI:22.160-35.240),体能状态(performance status,PS)评分为0分-1分(HR=4.451;95%CI:2.112-9.382;P<0.001)、接受EGFR-酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)靶向治疗(HR=2.785;95%CI:1.871-4.145;P<0.001)是EGFR突变患者生存的独立影响因素.58例ALK阳性患者的中位OS为15.5个月(95%CI:10.991-20.009),接受克唑替尼靶向治疗(P=0.022)是ALK阳性患者生存的独立影响因素.266例野生型患者的中位OS为12.1个月(95%CI:10.660-13.540),PS评分为0分-1分(HR=2.313;95%CI:1.380-3.877;P=0.001)、接受化疗(HR=1.911;95%CI:1.396-2.616;P<0.001)是野生型患者生存的独立影响因素.结论 不同基因型的晚期NSCLC患者的预后差异较大,靶向治疗可改善EGFR突变、ALK阳性患者生存.     

晚期肺腺癌EGFR基因突变状态检测及分析

目的分析晚期肺腺癌表皮生长因子受体（epidermal growth factor receptor,EGFR）基因突变率及其与临床特征的相关性。方法收集2010-09-07-2011-07-21首都医科大学附属北京胸科医院收治的晚期初治肺腺癌患者102例,有可供检测的肿瘤组织标本。利用扩增受阻突变系统（amplification refractory mutation system,ARMS）进行EGFR基因突变检测,统计分析EGFR基因突变状态和临床特征的相关性。结果 102例晚期肺腺癌组织中,共检测到EGFR基因突变55例（53.9%）,其中18外显子突变1例（1.0%）,19外显子突变25例（24.5%）,20外显子突变2例（2.0%）,21外显子突变26例（25.5%）,同时存在19和20外显子突变1例（1.0%）。Ⅳ期患者EGFR基因突变率为57.6%（53/92）,高于ⅢB期患者20.0%（1/10）,差异有统计学意义,P=0.041;女性患者EGFR基因突变率56.9%（33/58）高于男性患者的50.0%（22/44）,不吸烟患者EGFR基因突变率58.1%（36/62）高于吸烟患者的36.0%（9/25）,〈65岁患者EGFR基因突变率56.8%（42/74）高于≥65岁患者的46.4%（13/28）,但差异均无统计学意义,P〉0.05。不同取材部位及取材方法之间EGFR基因突变率差异无统计学意义,P〉0.05。结论晚期肺腺癌EGFR基因突变率以Ⅳ期、女性和不吸烟患者较高,但性别及吸烟状态之间的差异无统计学意义。不同的肿瘤活检部位及活检方法之间EGFR基因突变率并无差异。     

中国西北地区非小细胞肺癌EGFR、ALK、ROS1基因突变和临床病理特征分析

目的 探讨来自中国西北地区汉族人群的非小细胞肺癌(NSCLC)患者表皮生长因子受体(EGFR)、间变性淋巴瘤激酶(ALK)和C?ros原癌基因1?受体酪氨酸激酶(ROS1)基因突变特点及与临床病理特征的相关性.方法 收集2014年12月至2018年10月空军军医大学第二附属医院胸腔外科就诊的4580例NSCLC患者的肿...     

存在驱动基因突变肺鳞癌患者的临床病理特征及预后分析

背景与目的表皮生长因子受体（epidermal growth factor receptor, EGFR）、间变淋巴瘤激酶（anaplastic lymphoma kinase, ALK）以及KRAS基因是非小细胞肺癌（non-small cell lung cancer, NSCLC）常见的驱动基因。多项临床研究已证实,EGFR敏感突变及棘皮动物微管相关类蛋白4-间变淋巴瘤激酶（echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase,EML4-ALK）基因重排的晚期肺腺癌患者,一线治疗选择靶向药物优于化疗,其在总缓解率（overall response rate, ORR）、无进展生存期（progression-free survival, PFS）及生活质量方面均有明显优势。然而,在肺鳞癌患者中,目前尚无明确的基因检测位点及靶向药物来指导临床治疗。本研究旨在分析肺鳞癌患者EGFR、ALK以及KARS基因的突变状态,以及相关的临床病理特征,从而为今后的治疗提供相应指导。方法回顾性分析已行相关驱动基因检测的肺鳞癌患者90例,利用突变扩增阻滞系统（ampliifcation refractory mutation system, ARMS）的方法进行EGFR及KRAS基因检测,荧光原位杂交（fluorescencein situ hybridization, FISH）技术进行ALK基因融合检测。结果90例患者均进行了EGFR及KRAS基因检测,8例患者为EGFR基因突变（8.8%）;2例患者为KRAS基因突变（2.2%）;18例患者通过FISH方法进行了ALK基因融合检测,1例患者存在EML4-ALK基因融合（5.6%）。女性患者的EGFR基因突变率高于男性（P=0.022）。EGFR突变及野生型患者在病理分期（P=0.042）及分化程度（P=0.003）上均有差异。以胸膜为首发转移部位的EGFR突变患者比率高于EGFR野生型患者（P=0.013）。靶向治疗与化疗对EGFR突变患者的PFS无影响（P=0.607）。结论 ALK基因融合患者应用靶向治疗后可获得理想疗效。     

肺腺癌EGFR-TKI失败后的治疗策略

肺腺癌的治疗因表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitor, EGFR-TKI）的出现而率先步入靶向治疗时代,而一代可逆性EGFR—TKI的耐药成为不可避免的挑战。对EGFR信号通路内部和外部异常的深入研究是应对EGFR—TKI耐药的根本,在此基础上开发了二代不可逆性EGFR—TKI、多靶点TKI以及其他多种靶向药物。综合应用靶向药物、化疗和放疗等多种治疗方式,寻找最佳结合模式,对延长患者生存也有重要作用。     

EGFR-TKI治疗肺腺癌的疗效与血清肿瘤标志物的相关性

目的探讨表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinaseinhibitor,EGFR-TKI)对肺腺癌的疗效和血清肿瘤标志物间的关系。方法 回顾分析48例应用EGFR-TKI治疗的晚期肺腺癌患者的临床特征、生存时间和治疗前血清肿瘤标志物水平的相关性。结果 EGFR-TKI治疗后有效率为58.3%,控制率为65.6%;中位生存时间为13.2月。统计学分析显示:吸烟史、血清CEA和CA19-9水平与EGFR-TKI的疗效相关(P<0.05);治疗前血清CEA,CA19-9水平高者有着更高的治疗有效率、控制率和更长的生存期(P<0.05)。结论 EGFR-TKI治疗前血清CA19-9和CEA的水平对预测EGFR-TRI对肺腺癌患者的疗效有参考价值。     

EGFR突变IIIa期肺腺癌术后靶向治疗疗效分析

目的:探索第一代EGFR酪氨酸激酶抑制剂用于EGFR突变IIIa期肺腺癌患者术后辅助治疗的疗效。方法:回顾性纳入2014年1月至2018年7月期间本中心符合纳入标准的、接受第一代EGFR-TKI治疗的IIIa期肺腺癌患者,获取其一般临床数据、无病生存期（disease-free survival,DFS）和不良事件等信息,分析其对预后的影响。结果:研究纳入了80例IIIa期EGFR敏感突变患者,其中以T3N1分期（43/80）和19外显子缺失突变（49/80）患者为主。EGFR-TKI平均治疗时间为18.7月。全部患者总体DFS为26.8（24.5~29.1）月,不同的TNM分期之间无统计学差异（P=0.74）。总体III-IV级不良事件发生率为11.25%。结论:IIIa期EGFR突变阳性的患者术后采用EGFR-TKI辅助治疗可显著延长DFS,该治疗安全可靠。     

Personalizing therapy with targeted agents in non-small cell lung cancer

In the last 6 years, since the first reports of an association between somatic mutations in epidermal growth factor receptor (EGFR) exons 19 and 21 and response to EGFR tyrosine kinase inhibitors (TKIs), treatment of non-small cell lung cancer (NSCLC) has changed dramatically. Based on laboratory and clinical observations, investigators have anticipated that these mutations could be predictive of response to EGFR TKIs and numerous studies have confirmed that the presence of mutation was associated with longer survival in patients receiving targeted therapy. Prospective trials comparing standard platinum-based chemotherapy with EGFR TKIs in patients with and without activating EGFR mutations validated the predictive value of molecular selection of patients for first-line treatment of advanced NSCLC. Recently, preclinical and first-in-human studies have demonstrated impressive activity of ALK TKI in tumors harboring ALK rearrangement. In this article, we review current data on molecular biology of lung cancer and evidence-based patient selection for targeted therapy.     

Mutation abundance affects the therapeutic efficacy of EGFR-TKI in patients with advanced lung adenocarcinoma: A retrospective analysis

Purpose: To investigate the influence of mutation abundance and sites of epidermal growth factor receptor (EGFR) on therapeutic efficacies of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) treatments of patients with advanced non-small cell lung carcinoma (NSCLC).

Methods: EGFR mutational sites and mutation abundance were analyzed by amplification refractory mutation system (ARMS) in paraffin-embedded tissue sections taken from primary or metastatic tumors of 194 NSCLC patients.

Results: The median progression-free survival (PFS) time of the enrolled patients was 9.3 months (95% CI, 8.2–10.8 months). The PFS was significantly different with EGFR gene mutation abundance after EGFR-TKI therapy (P = 0.014). The median PFS was significantly longer when the cut-off value of EGFR mutation abundance of exon 19 or exon 21, and solely exon 19 was > 26.7% and 61.8%, respectively. For patients who received EGFR-TKI as first-line treatment, the median PFS was significantly longer in the high mutation abundance group than in the low mutation abundance group (12.7 vs 8.7 months, P = 0.002).

Conclusion: The PFS benefits were greater in patients with a higher abundance of exon 19 deletion mutations in the EGFR gene after EGFR-TKI treatment and first line EGFR-TKI treatment led to improved PFS in high mutation abundance patients.     

肺腺癌患者表皮生长因子受体基因突变与肿瘤标志物关系研究

目的  探讨肺腺癌患者表皮生长因子受体（EGFR）基因突变与血清肿瘤标志物之间的关系。 方法  选择2015年1月至2017年12月,中国医科大学附属第四医院胸外科肺腺癌患者资料97例。采用化学发光免疫法检测患者血清各肿瘤标志物水平,并对检测结果进行统计学分析。 结果  女性患者EGFR基因突变率高于男性患者,非吸烟患者高于吸烟患者,差异有统计学意义（均P＜0001）。而年龄、肿瘤分期对EGFR基因突变率无影响,差异无统计学意义（P＞005）。血清癌胚抗原（CEA）水平异常组EGFR基因突变率高于正常组,差异有统计学意义（P＜005）;当50 μg／L＜CEA＜100 μg／L时,EGFR基因突变率最高（77％）。血清细胞角蛋白19片段（CYFRA21 1）浓度,正常组患者EGFR基因突变发生率高于异常组,差异有统计学意义（P＜005）,而神经元特异性烯醇化酶（NSE）、CA125、CA153和CA19 9正常组与对应的异常组EGFR基因突变率差异无统计学意义（P＞005）。ROC曲线显示,血清CEA、CYFRA21 1水平预测EGFR基因突变的曲线下面积分别为0740、0609。 结论  肺腺癌患者女性、非吸烟患者更容易发生EGFR基因突变,血清肿瘤标志物CEA 、CYFRA21 1水平对预测EGFR基因突变有一定价值。     

肺腺癌患者EGFR和KRAS基因突变与预后的相关性研究

目的 探讨肺腺癌患者表皮生长因子受体(EGFR)和KRAS基因突变与预后的相关性.方法 选取134例肺腺癌患者的肺腺癌组织标本,应用探针扩增阻滞突变系统在PCR仪上进行EGFR和KRAS基因突变检测,分析EGFR和KRAS基因突变与肺腺癌患者临床病理特征及预后的关系.结果 134例患者中,EGFR基因突变53例,突变率为39.55%,KRAS基因突变6例,突变率为4.48%.肺腺癌患者EGFR基因突变率与年龄、吸烟史有关(P﹤0.01).EGFR基因突变型患者的KRAS基因突变率低于EGFR基因野生型患者(P﹤0.05).EGFR基因突变型患者的无进展生存期(PFS)长于EGFR基因野生型患者(P﹤0.05),KRAS基因野生型患者的PFS长于KRAS基因突变型患者(P﹤0.05).结论 EGFR基因突变的肺腺癌患者KRAS基因更倾向于野生型,EGFR基因突变型或KRAS基因野生型的肺腺癌患者PFS更长.     

The EGFR mutation and its correlation with response of gefitinib in previously treated Chinese patients with advanced non-small-cell lung cancer.

BACKGROUND: The aim of the study was to evaluate the efficacy of gefitinib and the epidermal growth factor receptor (EGFR) mutation to gefitinib response in a series of Chinese patients with pretreated advanced non-small-cell lung cancer (NSCLC). METHODS: A total of 98 patients who had failed at least one platinum-based regimen received gefitinib 250 mg once daily. The mutation analysis of the EGFR kinase domain was performed for 30 patients using paraffin-embedded tumor tissue. RESULTS: The response rate was 31.6% and the disease control rate was 67.3%. Objective response was correlated with adenocarcinoma, female gender and non-smokers. Median progress free survival (PFS) was 7.0 months, median overall survival (OS) was 12.0 months and 1-year survival was 53.1%. The median PFS and OS were improved among patients with adenocarcinoma, gefitinib responders and non-smokers. Active gene mutation was detected in 12 patients. Mutation rates were higher among gefitinib responders, non-smokers, patients with adenocarcinoma and female patients. OS was longer for patients with gene mutation than for patients without mutation. CONCLUSION: Gefitinib demonstrated significant antitumor activity with a favorable toxicity profile for pretreated Chinese patients with advanced NSCLC. The active mutation of the EGFR kinase domain was strongly associated with response to gefitinib and prolonged overall survival.     

EGFR-TKI一线治疗不同EGFR突变状态晚期非小细胞肺癌疗效分析

目的：分析表皮生长因子受体酪氨酸酶抑制剂（EGFR-TKI）一线治疗不同EGFR突变状态（外显子19缺失、21突变）晚期非小细胞肺癌（NSCLC）的疗效。方法收集徐州市肿瘤医院经组织病理学证实的EGFR突变阳性晚期NSCLC患者72例,分析两种不同EGFR突变状态与一线EGFR-TKI治疗的客观缓解率（ORR）、疾病控制率（DCR）、无进展生存期（PFS）以及总生存期（OS）之间的关系。结果72例患者均进行EGFR基因检测,其中37例为EGFR19外显子缺失,35例为EGFR21外显子突变。72例患者均可评价疗效,其中EGFR19外显子缺失的患者ORR 75．7％,DCR 89．2％;EGFR21外显子突变的患者ORR 51．4％,DCR 68．6％,差异均有统计学意义（χ2＝4．583,P＝0．032;χ2＝4．636,P＝0．031）。EGFR19外显子缺失和21外显子突变的患者校正后的中位PFS分别为13．2个月、10．8个月,差异有统计学意义（χ2＝4．700,P＝0．030）;中位OS分别为30．2个月、25．6个月,差异有统计学意义（χ2＝4．686,P＝0．030）。两组间不良反应无明显差别,皮疹最为常见,两组差异无统计学意义（48．7％∶48．6％,χ2＝0．000,P＝0．995）。结论 EGFR突变状态是晚期NSCLC患者一线EGFR-TKI治疗疗效和OS的预测因素,EGFR19外显子缺失患者的疗效优于EGFR21外显子突变患者。     

鄂尔多斯地区晚期肺腺癌患者EGFR敏感基因突变状态与一般临床特征的关系

目的:分析鄂尔多斯市中心医院晚期肺腺癌患者表皮生长因子受体(epidermal growth factor receptor,EGFR)突变状态与一般临床特征的关系。方法:分析自2012年6月开始收治的Ⅲb-Ⅳ期肺腺癌患者接受EGFR 19、21外显子突变情况与患者一般临床特征、转移部位、治疗情况的关系。结果:选取123例晚期肺腺癌患者纳入分析,46.34%（57/123）的晚期肺腺癌患者接受了EGFR 19、21外显子检测, EGFR基因突变率为49.12%（28/57）,其中19外显子突变率为39.29%（11/28）,21外显子突变率为46.43%（13/28）,19、21外显子同时突变率为14.29%（4/28）。EGFR基因突变状态在患者性别、年龄、吸烟状态、分期、体力评分和转移部位间比较未见显著性差异,19或21外显子突变在患者性别、年龄、吸烟状态、分期、体力评分和转移部位间比较未见显著性差异,根据EGFR基因突变状态选择一线治疗模有统计学意义（P＜0.05）。结论:鄂尔多斯地区晚期肺腺癌接受EGFR敏感基因检测率为46.34%,突变率为49.12%,突变状态在一般临床特征和转移部位间未见显著性差异,根据EGFR基因突变状态患者选择一线治疗方式差异有显著意义。     

Brain metastases in lung adenocarcinoma: impact of EGFR mutation status on incidence and survival

Background

The brain represents a frequent progression site in lung adenocarcinoma. This study was designed to analyse the association between the epidermal growth factor receptor (EGFR) mutation status and the frequency of brain metastases (BM) and survival in routine clinical practice.

Patients and methods

We retrospectively analysed the medical records of 629 patients with adenocarcinoma in Slovenia who were tested for EGFR mutations in order to analyse the cumulative incidence of BM, the time from the diagnosis to the development of BM (TDBM), the time from BM to death (TTD) and the median survival.

Results

Out of 629 patients, 168 (27%) had BM, 90 patients already at the time of diagnosis. Additional 78 patients developed BM after a median interval of 14.3 months; 25.8 months in EGFR positive and 11.8 months in EGFR negative patients, respectively (p = 0.002). EGFR mutations were present in 47 (28%) patients with BM. The curves for cumulative incidence of BM in EGFR positive and negative patients demonstrate a trend for a higher incidence of BM in EGFR mutant patients at diagnosis (19% vs. 13%, p = 0.078), but no difference later during the course of the disease. The patients with BM at diagnosis had a statistically longer TTD (7.3 months) than patients who developed BM later (3.1 months). The TTD in EGFR positive patients with BM at diagnosis was longer than in EGFR negative patients (12.6 vs. 6.8, p = 0.005), while there was no impact of EGFR status on the TTD of patients who developed BM later.

Conclusions

Except for a non-significant increase of frequency of BM at diagnosis in EGFR positive patients, EGFR status had no influence upon the cumulative incidence of BM. EGFR positive patients had a longer time to CNS progression. While EGFR positive patients with BM at diagnosis had a longer survival, EGFR status had no influence on TTD in patients who developed BM later during the course of disease.