EGFR酪氨酸激酶区域基因变异与吉非替尼治疗非小细胞肺癌临床因素相关性研究进展

【指示性摘要】吉非替尼是表皮性生长因子受体（EGFR）酪氨酸激酶抑制剂，在非小细胞肺癌的治疗中受到普遍关注，而EGFR突变有助于筛选针对吉非替尼治疗的受益人群，本文回顾了近期国外对EGFR突变及其与病理类型、种族、性别、生存期等临床因素的相关性。     

Caveolin-1的表达与EGFR突变在NSCLC中的相关性及其临床意义的研究

目的 研究Caveolin-1在非小细胞肺癌(NSCLC)中的表达,探讨Caveolin-1的表达与肺癌表皮生长因子受体(EGFR)突变的关系。方法 运用免疫组织化学法检测哈尔滨医科大学附属肿瘤医院40例NSCLC组织中Caveolin-1表达,同时应用ARMS-qPCR方法检测EGFR突变情况,并结合患者的临床病理特征和相关性进行分析。结果 Caveolin-1在NSCLC组织中阳性表达率显著低于正常肺组织,NSCLC组织中Caveolin-1表达与组织学类型相关,同时与EGFR突变呈负相关,差异有统计学意义(P＜0.05)。结论 Caveolin-1表达与EGFR突变在NSCLC中呈负相关,与组织学类型密切相关,可能成为诊断和判定NSCLC临床预后的重要分子指标。     

PD-L1、MDM2在EGFR罕见突变NSCLC患者中的表达及其临床意义

目的:探讨PD-L1和MDM2在表皮生长因子受体（epidermal growth factor receptor,EGFR）罕见突变的非小细胞肺癌（non-small cell lung cancer,NSCLC）患者中的表达,分析其与临床病理特征及预后的关系,探寻EGFR罕见突变人群的预后预测因子及免疫治疗的应用前景。方法:收集并随访69例EGFR罕见突变的NSCLC患者完整的临床病理资料（最终随访到64例,失访率7.25%）,采用免疫组化法检测51例保存完整的EGFR罕见突变的NSCLC福尔马林固定石蜡包埋组织中PD-L1、MDM2的表达水平,同时选取9例癌旁组织和8例正常组织的蜡块切片作为对照组,分析其与患者临床病理特征和预后的关系。结果:64例EGFR罕见突变的NSCLC患者,突变类型包括单突变41例（64.06%）,复合突变（同时存在两种或两种以上的EGFR突变）23例（35.94%）。NLR中位数为2.63,PD-L1在EGFR罕见突变NSCLC癌组织的阳性表达率为29.41%,在癌旁组织及正常肺泡上皮细胞中阴性表达（P=0.039）。MDM2在癌组织、癌旁组织和正常组织中的阳性表达率分别为86.27%、33.33%、12.5%,差异有明显统计学意义（P=0.000）。I/II期患者PD-L1在肿瘤细胞中的表达高于III/IV期（P=0.013）,而III/IV期患者MDM2在肿瘤中的表达高于I/II期患者（P=0.001）。而年龄、性别、是否吸烟、NLR、突变类型、病理分级与EGFR罕见突变癌患者组织中PD-L1、MDM2的表达水平无统计学差异（P>0.05）。64例患者的mOS为22.31个月。年龄、性别、吸烟、EGFR突变类型、PD-L1、MDM2表达与预后无明显相关。NLR<2.63患者的mOS优于NLR≥2.63（46.16个月vs 12.58个月）的患者,差异具有显著统计学意义（χ2=9.72,P=0.002）。病理分级为1/2级患者mOS优于3级患者（41.46个月vs 15.97个月）,差异具有明显统计学意义（χ2=6.17,P=0.013）。I/II期患者mOS优于III/IV期患者（59.17个月vs 15.97个月）,差异具有明显统计学意义（χ2=18.89,P=0.000）。Cox多因素回归分析:NLR（HR=2.667,P=0.007）、分期（HR=8.778,P=0.000）是EGFR罕见突变NSCLC患者的独立预后因素。结论:NLR可考虑作为EGFR罕见突变NSCLC患者预后的疗效预测因子;PD-L1在EGFR罕见突变的NSCLC中阳性表达率较高,免疫治疗可能获益。     

非小细胞肺癌少见的EGFR外显子21 L858R复合突变与单一突变的分析研究

目的 比较了少见EGFR外显子21 L858R复合突变与单一突变的临床特征及研究两组对TKI治疗的反应.方法 回顾性分析799例非小细胞肺癌患者,接受EGFR突变测试,443例患者发现有EGFR突变,其中22例(4.97％)有复合突变,详细描述6例EGFR外显子21 L858R复合突变患者和18例单一L858R突变患者的临床特征.结果 疾病控制率和客观反应率L858R复合突变组和单一突变组之间没有差别.log-rank test发现,两组总生存或无疾病进展生存方面比较无显著性差异.结论 复合突变组和单一突变组对EGFRTKIs反应和患者预后无显著差异.     

非小细胞肺癌EGFR突变检测的研究和应用进展

近年来,靶向小分子酪氨酸激酶抑制剂（TKI）在表皮生长因子受体（EGFR）突变的晚期非小细胞肺癌（NSCLC）患者的治疗中得到了广泛应用。对EGFR突变情况进行检测成为晚期NSCLC个体化治疗的重要前提。目前,EGFR突变的检测方法仍以组织检查为金标准,同时,细胞学及外周血EGFR突变检测亦得到良好发展。对EGFR突变水平进行定性及定量测定,可较为方便地预测EGFR-TKI的疗效,监测疾病的进展,并可较早地发现EGFR-TKI获得性耐药。本文对EGFR突变的定性及定量检测技术的应用进展作一综述。     

EGFR突变晚期非小细胞肺癌的一线治疗进展

表皮生长因子受体(EGFR)突变在非小细胞肺癌中发生率高,酪氨酸激酶抑制剂(TKI)对EGFR突变患者有效率高、不良反应低,是EGFR突变晚期NSCLC患者的一线标准治疗。但EGFR-TKI应用一段时间后不可避免地会出现耐药。研究者在EGFR-TKI和化疗、抗血管生成治疗、放疗及免疫治疗等的联合应用领域进行了诸多尝试,显著延缓了疾病进展或耐药的发生,并转化为具有临床意义的生存获益。本文就EGFR突变晚期NSCLC患者一线治疗进展作一综述。     

肿瘤标志物预测NSCLC患者EGFR突变概率数学模型的建立与评价

目的:利用血清肿瘤标志物建立预测非小细胞肺癌（NSCLC）患者表皮生长因子受体（EGFR）基因突变概率的数学模型,并评价其临床应用价值。方法:回顾性分析我院经病理学确诊的NSCLC患者107例,对组织标本采用扩增阻滞突变系统实时荧光定量PCR（ARMS-PCR）技术检测EGFR基因突变,采集外周静脉血用化学发光法检测血清肿瘤标志物水平。多因素回归分析筛选出EGFR突变的独立预测因子,建立Logistic回归模型。绘制受试者工作特征曲线（ROC）并计算曲线下面积（AUC）,以评价模型准确性和临床价值。结果:107例NSCLC患者中43.9%为EGFR突变型,56.1%为EGFR野生型。Logistic回归分析显示吸烟史、CEA、CA199和CYFRA21-1在EGFR突变型和野生型组间差异有统计学意义,是EGFR突变的独立预测因子。由此建立预测模型:P=ex/(1+ex),X=-3.664+（3.246×吸烟史）+（2.441×CEA）+（1.866×CA199）-（1.918×CYFRA21-1）,e为自然对数;当截点P为0.478时,模型的敏感度为85.1%,特异性为65.0%。该模型的AUC为0.734（95%CI:0.637～0.830）。结论:非吸烟、CEA和CA199高表达及CYFRA21-1低表达是NSCLC患者EGFR基因突变的独立预测因子。由此建立的数学预测模型准确度较高,可为EGFR基因突变的预测提供有利帮助。     

EGFR 基因状态对晚期非小细胞肺癌一线化疗的影响

目的：评价 EGFR 突变状态对晚期非小细胞肺癌（NSCLC）一线化疗近期疗效、无疾病进展时间（PFS）的影响。方法：同期非随机对照研究,依照入选标准,入组67例初治晚期 NSCLC EGFR 野生型患者及51例初治晚期 NSCLC EGFR 敏感突变型患者,分别观察客观有效率（RR）、疾病控制率（DCR）及无疾病进展时间（PFS）。结果：EGFR 野生型与 EGFR 敏感突变型的晚期 NSCLC 一线化疗的近期有效率分别为16．4％和28．6％,差异无统计学意义（P ＞0．05）,疾病控制率分别为61．2％和81．6％,差异有统计学意义（P ＜0．05）。PFS 分别为3个月与5个月,差异有统计学意义（P ＜0．05）。结论：化疗仍然是 EGFR 敏感突变型的晚期NSCLC 一线治疗的重要选择,在 DCR 及 PFS 方面,明显优于 EGFR 野生型晚期 NSCLC。     

EGFR的多态性与鼻咽癌放射敏感性的初步研究

目的：探讨表皮生长因子受体（epidermal growth factor receptor，EGFR）基因外显子13R497K和内含子1CA双核苷酸简单重复序列（CA）n的多态性与鼻咽癌放射敏感性的相关性。方法：对53例经病理确诊为鼻咽癌患者治疗前的外周血用PCR和PCR-RFLP方法进行EGFR多态性的分析；所有病例采用调强适行放射治疗方式行根治性放疗；临床放射敏感性评价应用肿瘤体积消退率Rv表示。统计分析采用SPSS13．0软件包，用KruskalWallis Test和X2检验分别分析基因型与肿瘤消退率和临床病理特征的关系。结果：R497KGTV-T型比Lyx／Arg和Arg／Arg型的GTV-T、GTV-N以及GTV-T＋GTV-N体积消退率大，放射敏感性高（PGTV-T=0．000；PGTV-N=0．000；PGTV-T＋GTV．N=0．001）；Lys／Arg与Arg／Arg型GTV-T、GTV-N以及GTV-T＋GTV—N体积消退率无统计学差异（PGTV-T=0．209；PGTV-N=0．143；PGTV-T＋GTV-N=0．459）。CA总数≥38时GTV-T、GTV-N、GTV—T＋GTV—N体积消退率比CA〈38时大，敏感性高（PGTV-T=0．001；PGTV，N=0．001和PGTV-T＋GTV-N=0．000）。结论：11497K Lys／Lys型比Lys／Arg和Arg／Arg型病人对放射治疗更敏感；（CA）n重复序列总数≥38的比CA〈38的病人对放射治疗更敏感。因此，测定EGFR的多态性将有利于预测鼻咽癌病人放疗前的临床放射敏感性，对选择合适的病人进行分类治疗优化个体治疗方案，具有较强的临床应用潜力。     

新疆维吾尔族与汉族NSCLC患者血清EGFR基因突变及临床特征分析

目的 表皮生长因子受体(epidermal growth factor receptor,EGFR)抑制剂对非小细胞肺癌(non-small cell lung cancer,NSCLC)EGFR基因突变患者有很好的疗效,因此EGFR基因突变状态对治疗方案的选择意义重大.新疆作为多民族聚集地,维吾尔族和汉族在基因、遗传方面存在差异,本研究主要探讨新疆地区汉族及维吾尔族初诊NSCLC患者血清EGFR突变差异及其与临床特征的关系.方法 选取2015-05-01-2016-08-30石河子大学医学院第一附属医院(65例)和喀什地区第一人民医院(51例)初次诊治的非小细胞肺癌患者116例,其中汉族70例,维吾尔族46例.采用二代测序法对患者进行血清EGFR突变检测,统计两组突变差异并分析其临床特征.结果 汉族NSCLC血清EGFR突变率27.1%(19/70),维吾尔族NSCLC血清EGFR突变率8.7%(4/46),差异有统计学意义,χ2=5.942,P=0.015.汉族腺癌突变率36.5%(19/52)高于维吾尔族腺癌突变率13.3%(4/30),差异有统计学意义,χ2=5.076,P=0.024.两者突变均以19、21外显子突变为主,差异无统计学意义,P=0.406.临床特征比较,汉族中女性、腺癌、不吸烟患者突变率较高,差异有统计学意义,P<0.05.维吾尔族中腺癌突变率较高,其它如年龄、临床分期、淋巴结转移情况等在汉族或维吾尔族中差异无统计学意义,P>0.05.Logistic多因素分析显示,种族是EGFR基因突变的独立影响因素,P<0.05,95%CI为0.145~1.599.而性别、年龄、是否吸烟和临床分析对EGFR突变影响不显著.结论 新疆维吾尔族和汉族血清EGFR突变与种族有关,与外显子类型、临床特征无明显关联.     

The use of first-generation tyrosine kinase inhibitors in patients with NSCLC and somatic EGFR mutations

Initial studies with the first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib in patients with non-small cell lung cancer (NSCLC) showed that, although most did not have an objective radiographic response, a minority of patients had dramatic and durable clinical and radiographic responses. The discovery of EGFR mutations in tumours from patients with NSCLC and the association of these mutations with clinical response to gefitinib and erlotinib provided an opportunity to tailor treatment to the mutation profile of the tumour. A number of retrospective reviews and prospective trials have established that gefitinib or erlotinib therapy leads to radiographic responses in approximately 75-80% of patients with NSCLC with EGFR mutations. Although a variety of mutations in EGFR have been identified, the two most common somatic activating EGFR mutations are the LREA deletions in exon 19 and the L858R substitution in exon 21. Together, these mutations make up 85-90% of EGFR mutations. At least two retrospective reviews have indicated a difference in the outcome of patients with different EGFR mutations: after treatment with gefitinib or erlotinib, patients with exon 19 deletions have an increased survival compared with those patients whose tumours have an L858R substitution. These findings remain to be confirmed in prospective studies. Improved understanding of the association of EGFR mutations with clinical outcome may improve the ability of physicians to match treatment to mutation status for patients with NSCLC.     

Efficacy of EGFR tyrosine kinase inhibitors for non-adenocarcinoma NSCLC patients with EGFR mutation

Purpose

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) gefitinib and erlotinib have shown dramatic response rate (RR) and significant prolongation of progression-free survival (PFS) in non-small-cell lung cancer (NSCLC) patients with EGFR mutation. Since only a few patients with non-adenocarcinoma histology have been enrolled in clinical trials, the efficacy of EGFR TKIs in non-adenocarcinoma NSCLC patients with EGFR mutation has not yet been fully determined.

Methods

We retrospectively analyzed clinical outcomes, including RR, PFS, and OS, in patients who were treated with the EGFR TKIs gefitinib or erlotinib and compared the results with those of adenocarcinoma patients with EGFR mutation and non-adenocarcinoma patients with wild-type EGFR.

Results

Among 250 patients with non-adenocarcinoma of the lung who underwent EGFR mutation genotyping, 21 were found to have an EGFR mutation (8.4?%). Twelve of the 21 patients were treated with the EGFR TKIs gefitinib (n?=?6) or erlotinib (n?=?6). The most common mutation was exon 19 deletion (n?=?7). The RR and disease control rate for 12 patients receiving EGFR TKIs were 50 and 75?%, respectively. The median PFS was 3.67?months (95?% CI: 1.34?C5.99), which was significantly lower than that of 269 adenocarcinoma patients with EGFR mutation (13.53?months) but better than that of 32 non-adenocarcinoma patients with wild-type EGFR (1.83?months) who were treated with EGFR TKIs.

Conclusions

The results of this study show that the EGFR mutation rate in Korean patients with non-adenocarcinoma of the lung is relatively high and that the clinical outcomes of EGFR TKIs are modest.     

EGFR tyrosine kinase domain mutations are detected in histologically normal respiratory epithelium in lung cancer patients

To determine whether EGFR tyrosine kinase domain mutations are early events in the pathogenesis of lung adenocarcinomas, we tested for the presence of EGFR mutations in histologically normal bronchial and bronchiolar epithelia from lung adenocarcinomas bearing the common EGFR mutations. DNA was extracted from microdissected tissue obtained from 21 tumors with known EGFR mutations, 16 tumors without mutation, and 90 sites of normal bronchial and bronchiolar epithelium from the same surgical specimens. With the use of PCR and direct DNA sequencing, EGFR mutations identical to the tumors were detected in the normal respiratory epithelium in 9 of 21 (43%) patients with EGFR mutant adenocarcinomas but none in patients without mutation in the tumors. The finding of mutations being more frequent in normal epithelium within tumor (43%) than in adjacent sites (24%) suggests a localized field effect phenomenon. Our findings indicate that mutation of the tyrosine kinase domain of EGFR is an early event in the pathogenesis of lung adenocarcinomas, and suggest EGFR mutations as an early detection marker and chemoprevention target.     

Non-small-cell lung cancer harbouring mutations in the EGFR kinase domain

Key “driver” mutations have been discovered in specific subgroups of non-small-cell lung cancer (NSCLC) patients. Activating mutations in the form of deletions in exon 19 (del 19) or the missense mutation L858R in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) predict outcome to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib. Pooled data from several phase II studies show that gefitinib and erlotinib induce responses in over 70% of NSCLC patients harbouring EGFR mutations, with progression-free survival (PFS) ranging from 9 to 13 months and median survival of around 23 months. Two studies in Caucasian and Asian patients have confirmed that these subgroups of patients attain response rates of 70% with erlotinib and gefitinib, including complete responses, PFS up to 14 months and median survival up to 27 months. These landmark outcomes have been accompanied by new challenges: the additional role of chemotherapy and the management of tumours with the secondary T790M mutation that confers resistance to EGFR TKIs. Mechanisms of resistance to reversible EGFR TKIs should be further clarified and could be related to modifications in DNA repair. The presence of double mutations (T790M plus either L858R or del 19) at the time of diagnosis could be much more frequent than originally thought. The sensitivity to EGFR TKIs could be greatly influenced by the expression of genes involved in the repair of DNA double-strand breaks by homologous recombination and non-homologous end joining.     

Clinical outcomes of EGFR kinase domain duplication to targeted therapies in NSCLC

Kinase domain duplications of the epidermal growth factor receptor (EGFR-KDD) have been identified and implicated to be oncogenic in nonsmall cell lung cancers (NSCLCs). However, its prevalence and clinical contributions in lung cancer are largely unknown. Here, we conducted a multicenter record review of 10,759 NSCLC patients who underwent genetic testing using next-generation sequencing (NGS) targeting EGFR exons and the introns involved in EGFR-KDD rearrangements. EGFR-KDDs were identified in a total of 13 patients, which is approximately 0.12% of the total population reviewed, and also consisted of 0.24% (13/5394) of EGFR mutation-positive patients. A total of 85% of patients (11/13) were identified with the canonical EGFR-KDD duplication of exons 18–25, while the remaining two cases harbored duplications of EGFR exons 14–26 and exons 17–25, which have not been previously described. Importantly, none of the 13 patients had other coexisting driver mutations, highlighting the potential oncogenic role of this type of alteration. Three out of five patients who had exon 18–25 duplications showed partial antitumor responses to targeted therapies, while the other two patients demonstrated no clinical improvement. Furthermore, our data suggested that the EGFR T790 M mutation and EGFR amplification may represent the major resistance mechanisms against targeted therapies in tumors bearing EGFR-KDD. In summary, our findings provide valuable insight into the prevalence of EGFR-KDDs in NSCLCs and their clinical outcomes to targeted therapies.     

The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies

To understand the role of human epidermal growth factor receptor (hEGFR) kinase domain mutations in lung tumorigenesis and response to EGFR-targeted therapies, we generated bitransgenic mice with inducible expression in type II pneumocytes of two common hEGFR mutants seen in human lung cancer. Both bitransgenic lines developed lung adenocarcinoma after sustained hEGFR mutant expression, confirming their oncogenic potential. Maintenance of these lung tumors was dependent on continued expression of the EGFR mutants. Treatment with small molecule inhibitors (erlotinib or HKI-272) as well as prolonged treatment with a humanized anti-hEGFR antibody (cetuximab) led to dramatic tumor regression. These data suggest that persistent EGFR signaling is required for tumor maintenance in human lung adenocarcinomas expressing EGFR mutants.     

Prediction of effectiveness of EGFR tyrosine kinase inhibitors for the patients with by EGFR mutations

EGFR-TKI has been synthesized as a potential target for cancer therapy because EGFR is overexpressed and associated with poor prognosis of lung cancer. It was reported that EGFR mutations were more sensitive to EGFRTKI than those without the mutations among lung cancer patients. A subgroup of patients of Asian origin, female sex, adenocarcinoma, and no history of smoking were significantly associated with a high rate of EGFR mutations. These patients with EGFR mutations were not only favorable responders but also had a longer survival than without. In this article, we discuss the EGFR-TKI predictive factors by EGFR mutations.     

Outcome of advanced NSCLC patients harboring sensitizing EGFR mutations randomized to EGFR tyrosine kinase inhibitors or chemotherapy as first-line treatment: a meta-analysis

BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are effective as first-line treatment of advanced non-small-cell lung cancer patients with EGFR mutations (EGFR-M+).Patients and methodsWe conducted a literature-based meta-analysis to quantify the magnitude of benefit with upfront EGFR TKI in EGFR-M+ patients. Meta-regression and sensitivity analyses were also carried out to identify additional predictors of outcome and to assess the influence of trial design.ResultsFive trials (805 patients) were identified (three trials prospectively enrolling EGFR-M+ patients and two retrospective analyses of EGFR-M+ patients). TKI significantly increased progression-free survival (PFS) [hazard ratio (HR) 0.45, 95% confidence interval (CI) 0.36–0.58, P < 0.0001] and overall response rate (ORR) (HR 2.08, 95% CI 1.75–2.46, P < 0.0001)] over chemotherapy, while significantly decreasing neutropenia. No significant difference was observed in overall survival. The rate of exon-19 mutations, female gender, and nonsmoking status were identified as additional predictors of outcome at meta-regression analysis. A significant interaction with trial design was found for both PFS (P = 0.028) and ORR (P = 0.008), suggesting a larger advantage for patients treated within prospective trials.ConclusionsIn EGFR-M+ patients, first-line TKI increase both PFS and ORR by ∼25%, while significantly decreasing toxicity. The role of additional predictive factors and the influence of trial design on the magnitude of the observed benefit warrant further investigation.