Clinicopathologic Features and Molecular Biomarkers as Predictors of Epidermal Growth Factor Receptor Gene Mutation in Non-Small Cell Lung Cancer Patients

Lung cancer ranks first in the incidence and mortality of cancer in the world, of which more than 80% are non-small cell lung cancer (NSCLC). The majority of NSCLC patients are in stage IIIB~IV when they are admitted to hospital and have no opportunity for surgery. Compared with traditional chemotherapy, specific targeted therapy has a higher selectivity and fewer adverse reactions, providing a new treatment direction for advanced NSCLC patients. Tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR-TKIs) are the widely used targeted therapy for NSCLC patients. Their efficacy and prognosis are closely related to the mutation status of the EGFR gene. Clinically, detecting EGFR gene mutation is often limited by difficulty obtaining tissue specimens, limited detecting technology, and economic conditions, so it is of great clinical significance to find indicators to predict EGFR gene mutation status. Clinicopathological characteristics, tumor markers, liquid biopsy, and other predictors are less invasive, economical, and easier to obtain. They can be monitored in real-time, which is supposed to predict EGFR mutation status and provide guidance for the accurate, individualized diagnosis and therapy of NSCLC patients. This article reviewed the correlation between the clinical indicators and EGFR gene mutation status in NSCLC patients.     

Epidermal Growth Factor Receptor Mutations in Lung Adenocarcinomas: A Single Center Study from Iran

Introduction: Lung cancer is the fifth leading tumor in Iran, and while its incidence remains relatively low, it has been increasing steadily. Targeted therapies have brought new hope to patients with non small cell lung cancer (NSCLC). The epidermal growth factor receptor (EGFR) gene is the prototype member of the type I receptor tyrosine kinase (TK) family and plays a pivotal role in cell proliferation and differentiation. Studies from Asian countries have revealed a higher frequency of EGFR mutations than in the West. The aim of this study was to measure the frequency and type of EGFR mutations in a group of Iranian patients with lung adenocarcinomas. Methods: Formalin fixed paraffin embedded (FFPE) lung adenocarcinoma tissues from 103 Iranian patients were sequentially tested for EGFR mutations by the polymerase chain reaction (PCR) followed by direct nucleotide sequencing of exons 18, 19, 20, and 21. Patient’s demographics and other clinical details were obtained from the medical records of hospitals affiliated to Iran University of Medical Sciences, Tehran, Iran. Statistical analyses were performed with SPSS v.20. Results: EGFR mutations were detected in 25/103 (24.3%) patients. The most frequent was an exon 21 point mutation (L858R) (15 patients; 60%), followed by one in exon 19 (10 patients; 40%). The frequency of EGFR mutations in never-smoker patients was significantly higher than in smokers (68% versus 32%; p < 0. 01). Conclusion: EGFR mutation frequency is higher than in the West but lower than in East Asian and almost equal to reported rates for Indian and North African populations. Smoking is negatively associated with EGFR mutations in Iranian lung adenocarcinomas.     

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.     

表皮生长因子受体突变:gefitinib和erlotinib治疗非小细胞肺癌的靶点研究进展

Gefitinib和erlotinib是表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)类药物,是目前治疗非小细胞肺癌(NSCLC)的热点,已在多个临床试验中证实,东亚人群、女性、无吸烟史和腺癌患者有效,进一步的研究揭示癌症病人EGFR酪氨酸激酶区突变与对EGFR-TKI的敏感性密切相关。这些突变包括框架缺失、点突变等多种类型。本文综述了EGFR突变的研究现状和进展。     

Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancers in a Multiethnic Malaysian Patient Population

Background: Mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) in nonsmallcell lung cancer (NSCLC) are predictive of response to EGFR-targeted therapy in advanced stages of disease.This study aimed to determine the frequency of EGFR mutations in NSCLCs and to correlate their presencewith clinical characteristics in multiethnic Malaysian patients. Materials and Methods: In this prospective study,EGFR mutations in exons 18, 19, 20 and 21 in formalin-fixed paraffin-embedded biopsy specimens of consecutiveNSCLC patients were asessed by real-time polymerase chain reaction. Results: EGFR mutations were detected inNSCLCs from 55 (36.4%) of a total of 151 patients, being significantly more common in females (62.5%) than inmales (17.2%) [odds ratio (OR), 8.00; 95% confidence interval (CI), 3.77-16.98; p<0.001] and in never smokers(62.5%) than in ever smokers (12.7%) (OR, 11.50; 95%CI, 5.08-26.03; p<0.001). Mutations were more commonin adenocarcinoma (39.4%) compared to non-adenocarcinoma NSCLCs (15.8%) (p=0.072). The mutation ratesin patients of different ethnicities were not significantly different (p=0.08). Never smoking status was the onlyclinical feature that independently predicted the presence of EGFR mutations (adjusted OR, 5.94; 95%CI, 1.94-18.17; p=0.002). Conclusions: In Malaysian patients with NSCLC, the EGFR mutation rate was similar to thatin other Asian populations. EGFR mutations were significantly more common in female patients and in neversmokers. Never smoking status was the only independent predictor for the presence of EGFR mutations.     

EGFR突变与非小细胞肺癌临床病理和TKI治疗疗效预测相关性分析

目的 肺癌是目前发病率第1位的肿瘤,是癌症相关死亡最重要的原因.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)可延长患者的生存期.本研究探讨非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的EGFR突变状态与临床病理特征的关系,以及TKI治疗不同基因突变NSCLC患者的预后分析.方法 回顾性分析2013-09-03-2014-09-13在郑州大学第一附属医院进行EGFR检测的758例NSCLC住院患者临床资料,分析临床病理特征与突变状态的关系,并比较常见突变TKI治疗的疗效.结果 758例NSCLC患者中,EGFR突变377例(49.7％),其中男性突变率为37.9％ (150/396),女性为62.7％ (227/362),x2=46.634,P＜0.001.＜60岁突变率为52.7％(186/353),≥60岁为47.2％(191/405),x2=2.308,P=0.074.吸烟患者突变率为55.1％(298/541),不吸烟患者为36.4％(79/217),x2 =21.612,P＜0.001.腺癌突变率为54.4％(360/662),非腺癌为17.7％(17/96),x2=45.103,P＜0.001.在非腺癌中,鳞癌突变率为15.3％(9/59),腺鳞癌为54.5％(6/11),黏液表皮样癌为10.0％(1/10),其他为6.3％(1/16).多因素Logistic回归分析显示,女性、腺癌为EGFR突变的独立危险因素,P＜0.001;而吸烟史为非独立相关因素,P=0.681.常见突变为19缺失突变(25.9％,196/758)和21点突变(20.6％,156/758).TKI治疗19突变的中位无进展生存期(progression-free survival,PFS)为7.0个月,95％ CI为6.344～7.656;21突变的中位PFS为7.7个月,95％CI为5.986～9.414;19突变的中位PFS略短于21突变,但二者之间的差异无统计学意义,x2=1.194,P=0.274.结论EGFR突变在女性、无吸烟史及腺癌患者中较高,且女性及腺癌为独立危险因素;但也应重视对鳞癌及有吸烟史患者的EGFR突变检测.TKI治疗19和21突变NSCLC患者的PFS差异无统计学意义.     

非小细胞肺癌患者表皮生长因子受体突变对靶向治疗的疗效影响及生存分析

目的 探讨表皮生长因子受体(EGFR)基因突变对非小细胞肺癌(NSCLC)患者靶向治疗疗效及生存的影响.方法 83例经一线化疗失败的中晚期NSCLC患者,通过基因测序按照是否存在EGFR基因第19或21号外显子突变分为突变型组和野生型组,两组均给予吉非替尼口服治疗,250 mg/次,期间进行其他常规检查和定期随访.分析EG-FR突变与患者疗效及生存的关系.结果 女性、腺癌、不吸烟的NSCLC患者的突变率高于相应的男性、鳞癌、吸烟的NSCLC患者,差异均有统计学意义(P<0.05),而年龄、TNM分期与EGFR突变无明显相关(P>0.05).78例患者获得随访,其中突变型组32例,患者治疗的客观有效率(ORR)和疾病控制率(DCR)分别为64.7%和94.1%;明显高于46例野生型组的38.8%和71.4%,差异均有统计学意义(P<0.05).突变型组患者的无进展生存期(PFS)和中位生存时间分别为7.3个月和16.1个月,均较野生型组患者的3.5个月和8.3个月显著延长(P<0.01).结论 存在EGFR基因第19或21号外显子突变的NSCLC患者对应用吉非替尼治疗较敏感,效果较好,生存时间较长.EGFR基因突变可作为评估NSCLC患者分子靶向治疗疗效及生存的预测因子.     

EGFR mutation testing in NSCLC: Patterns of care and outcomes in Western Australia

Aims:   This study evaluated the EGFR mutation status, administration of gefitinib or erlotinib and outcomes of patients assessed for EGFR mutations since the commencement of testing in Western Australia.
Methods:   A retrospective study identified patients with NSCLC who undergone EGFR mutation testing in the Department of Anatomical Pathology, Royal Perth Hospital, Western Australia from March 2005 until May 2007. Patient characteristics, cancer history, treatment, outcomes and survival were collected from the medical records and pathology reports.
Results:   Tumor samples from 64 patients were sequenced for mutations in exons 18–21 EGFR and, of these, 53 patients with NSCLC were included in the analysis. The mean age at diagnosis was 61 years (range 19–80) and most of the tumor samples tested were from female patients (76%). Overall 36% of patients tested were mutation-positive with 95% of mutations occurring in exons 19 or 21. A total of 63% of mutation-positive and 18% of mutation-negative patients were treated with gefitinib or erlotinib. Of these, 83% of patients whose tumors had an EGFR mutation had a favorable response following treatment, compared to 17% of mutation-negative patients. The duration of treatment was longer in mutation-positive patients (mean 30 weeks vs 9 weeks).
Conclusion:   EGFR mutation testing is not routinely performed in NSCLC in Western Australia. Referral for testing is at the discretion of the treating physician, accounting for the high proportion of women and adenocarcinoma histology. Selection of mutation-positive tumors for treatment with gefitinib or erlotinib is associated with good responses to treatment. This study supports the use of gefitinib or erlotinib in routine clinical practice in patients with NSCLC carrying an EGFR mutation.     

非小细胞肺癌上皮-间质转化与EGFR突变以及临床病理特征之间的关系

目的探讨非小细胞肺癌(NSCLC)上皮-间质转化(EMT)与表皮生长因子受体(EGFR)突变和临床病理特征之间的关系。方法采用免疫组化法检测NSCLC患者癌组织中E-钙黏素和波蛋白的表达情况。采用卡方检验和Logistic回归分析,探讨临床病理特征和EGFR基因型NSCLC中EMT的影响。结果62例NSCLC标本中,上皮表型35.48%(22/62)。EGFR突变NSCLC中,上皮表型显著高于野生型(77.78%vs18.18%;P<0.0001);女性显著高于男性(54.55%vs25%;P=0.02);腺癌高于其他病理类型(39.47%vs29.17%;P=0.4087);不吸烟者稍高于吸烟者(42.42%vs27.59%;P=0.2231);年龄<60岁和年龄≥60岁组差异无统计学意义(43.33%vs28.12%;P=0.211),早期肺癌与晚期肺癌组差异无统计学意义(38.24%vs32.12%;P=0.6178)。结论EGFR突变型、女性、非吸烟者、腺癌倾向于上皮表型,与EGFR酪氨酸激酶抑制剂疗效分布人群的临床特征相一致。     

吉非替尼一线、二线治疗老年晚期非小细胞肺癌比较研究

目的观察吉非替尼治疗老年晚期非小细胞肺癌的临床疗效及毒副作用,并对一线及二线应用吉非替尼的疗效及毒副作用进行对比研究。方法收集大连医科大学附属第二医院肿瘤科2003年4月～2008年3月16例一线及61例二线应用吉非替尼治疗的老年晚期非小细胞肺癌患者的临床资料,评价其疗效及毒副作用,对比一线及二线治疗的疗效及毒副作用。结果16例一线治疗的患者,CR 0%（0/16）,PR 37.5%（6/ 16）,SD 50%（8/16）,PD 12.5%（2/16）,临床缓解率37.5%,疾病控制率87.5% （14/16）;毒副作用：皮疹37.5%（6/16）,腹泻31.25（5/16）,肝功受损12.5%（2/ 16）。61例二线治疗的患者,CR 3.3%（2/61）,PR 32.8%（20/61）,SD 41%（25/ 61）,PD 21.3%（13/61）,临床缓解率36.1%,疾病控制率78.7%（48/61）;毒副作用：皮疹49.2%（30/61）,腹泻23%（14/61）,肝功受损9.8%（6/61）,其他毒副作用占10%[包括肺间质改变占1.6%（1/61）,脱发1.6%（1/61）,嗜睡1.6%（1/ 61）,乏力3.2%（2/61）,食欲下降3.2%（2/61）]。77例患者临床症状缓解时间在4～12天,其中50例患者PS评分下降1～2分,一线及二线治疗PS评分改善无差异。结论吉非替尼治疗老年晚期非小细胞肺癌疗效较好,可以改善生存质量,毒副作用轻微,一线与二线疗效及毒副作用无差异,可以作为PS评分≥2的老年患者的首选药物。     

Evaluation of Novel Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

The epidermal growth factor system is a well characterized growth factor receptor pathway, the deregulation of which has been be associated with neoplastic growth. Overexpression or amplification of the epidermal growth factor receptor (EGFR) or one of its ligands has been linked with the malignant transformation of cells and is correlated with poor prognosis in patients. PD 153035, a quinazoline, has been shown to inhibit the tyrosine kinase activity of EGFR by blocking ATP binding (Fry et al., Science 265: 1093-1095, 1994). We set out to determine whether the growth inhibition caused by this agent and five related compounds is a direct result of the blocking of EGFR signaling. The effects on cell proliferation produced by these agents were tested on several tumor cell lines and EC50 values obtained. The EGF responsive cell lines A-431 and MDA-MB-468 exhibit EC50 values of 3 and 6.7 micro M, respectively, for PD 153035 which was found to be the most potent. The agents were then tested for their ability to block the paradoxical high dose EGF induced inhibition of A-431 and MDA-MB-468 cell growth as well as EGF induced phosphorylation in A-431 cells. These compounds are able to completely block the effects of exogenously added EGF at 0.5 microM or less. However, higher doses (EC50's >or= 2 microM) were needed to block the growth of human tumor cell lines potentially implicating a second site of action for these compounds.     

大肠癌细胞FoxQ1与EGFR基因表达的相关性

目的 探讨大肠癌细胞中FoxQ1与EGFR基因间的相关性,为研究大肠癌中FoxQ1基因在EGFR通路中的作用机制奠定基础。 方法 应用荧光定量PCR以293-T细胞中FoxQ1及EGFR基因相对表达量为1作为参照,检测大肠癌细胞系DLD1、HT29、LOVO、HCT116中FoxQ1及EGFR基因mRNA相对表达量;荧光定量检测经shRNA-FoxQ1慢病毒干扰后的DLD1细胞（命名为DLD1-shRNAFoxQ1）中EGFR的相对表达量改变;DLD1-shRNA-FoxQ1经EGFR酪氨酸激酶抑制剂Erlotinib HCl和siRNA-EGFR处理后,荧光定量PCR分别检测FoxQ1和EGFR基因mRNA相对表达量。结果 （1）FoxQ1在DLD1、HT29、LOVO、HCT116细胞系中的相对表达量分别为83.09、59.58、0.06、0.03,EGFR的相对表达量分别为4.95、3.67、2.08、1.36;（2）经shRNA-FoxQ1干扰的DLD1 细胞EGFR表达量随FoxQ1表达量的降低而增高;（3）细胞DLD1-shRNA-FoxQ1、DLD1-shRNA-Control分别经 siRNA-EGFR处理抑制EGFR的表达后,FoxQ1表达量随EGFR表达量的降低而增高,经Erlotinib HCl阻断EGFR酪氨酸激酶后,FoxQ1表达量增高。结论 大肠癌细胞系中FoxQ1与EGFR基因的表达趋势基本一致;同时两者间可能相互存在负反馈调节机制,从而维持大肠癌细胞中FoxQ1与EGFR高表达的状态。     

Association of Human Epidermal Growth Factor Receptor-2 Expression and Clinicopathological Findings in Patients with Colorectal Cancer

Background: To determine the frequency of HER-2 overexpression in colorectal cancer (CRC) patients,and to explore the relationship between clinicopathological prognostic factors and their effects on survival,based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) analysis. Materials andMethods: The study included 80 patients with a histologically proven diagnosis of CRC that received adjuvantFOLFOX-4 chemotherapy at our department between March 2006 and September 2010. Patient data wereanalyzed retrospectively. Results: The median follow-up period and age of the patients were 24 months and59 years, respectively. In immunohistochemical staining, 3+ staining was found in 2 patients (2.5%) while 2+was in 13 (16%) . FISH for HER-2 was performed for all of these 15 patients; samples which were 3+ showedpositivity but the ones with 2+ were negative. There was no significant correlation between HER-2 expressionand age, gender, tumor localization, histological subtype, grade, lymphovascular and perineural invasion, orpTN stage (P>0.05), even when the patients with HER-2 overexpression were analyzed separately. There wasalso no significant relationship between progression-free survival (PFS) and overall survival (OS), and HER-2expression, gender, tumor localization, obstruction-perforation, bleeding, histological type, grade, lymphovascularand perineural invasion, or pT staging (P>0.05); however, there was a significant relationship between lymphnode involvement, and PFS and OS (P<0.05). Conclusions: Evaluation of HER-2 overexpression in a morecomprehensive, multi-center, prospective trial with standardized methods will be an appropriate approach.     

EGFR-TKI治疗对NSCLC患者血清CEA的影响

目的 探讨表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)治疗对非小细胞肺癌(NSCLC)患者血清癌胚抗原(CEA)的影响.方法 选取NSCLC患者81例,均接受EGFR-TKI治疗,监测患者治疗前后的CEA水平.结果 完全缓解(CR)+部分缓解(PR)患者治疗后的CEA水平低于治疗前(P﹤0.05);进展(PD)患者治疗后的CEA水平高于治疗前(P﹤0.05);稳定(SD)患者治疗前后的CEA水平比较,差异无统计学意义(P﹥0.05);CR+PR患者治疗前的CEA水平高于SD和PD患者(P﹤0.05);不同年龄、性别、吸烟史、组织类型、临床分期和治疗药物的NSCLC患者的近期疗效比较,差异无统计学意义(P﹥0.05);基线CEA≥5 ng/ml患者的近期疗效优于基线CEA﹤5 ng/ml的患者(P﹤0.05);基线CEA≥5 ng/ml组患者的中位无疾病进展时间为16.61个月(95%CI:12.22~20.43个月),长于基线CEA﹤5 ng/ml组患者的9.82个月(95%CI:5.21~14.40个月)(P﹤0.05).结论 血清CEA监测有助于判断NSCLC患者EGFR-TKI治疗效果,CEA治疗前高水平可能预示靶向药物治疗效果好.     

吉非替尼治疗52例晚期非小细胞肺癌优势人群的临床观察

目的探讨吉非替尼单药治疗临床选择的晚期非小细胞肺癌患者的疗效与不良反应。方法2007年1月～2008年10月共52例、腺癌、不吸烟的晚期非小细胞肺癌患者接受吉非替尼250mg/d口服治疗,观察患者的疗效、TTP、MST和毒副反应。结果本组52例患者均可评价疗效,其中完全缓解3例,部分缓解21例,无变化22例,进展6例。有效率为46.2%,疾病控制率为88.5%,中位TTP为454.67天,1年无进展生存率为52%,MST为597.9天,1年生存率为60%。最常见不良反应主要为皮疹和腹泻。有效率与患者性别、年龄、一般状况、分期及既往治疗无关;与皮疹相关,没有皮疹的病人疗效差（ORR=0.143,95%CI：0.035～0.590）。TTP与患者性别、一般状况、分期及既往治疗无关;只有患者年龄与TTP相关,50岁以下病人的TTP明显缩短疾病进展风险增加（HR=4.196,P=0.0005）;腹泻与TTP相关,没有出现腹泻的病人疾病进展风险大（HR=2.637,P=0.0303）。结论吉非替尼治疗河南本地腺癌、不吸烟的晚期NSCLC的疗效显著,总体生存明显获益,不良反应轻微。