Cell Free EGFR mRNA Expression and Implications for Survival and Metastasis in Non-Small Cell Lung Cancer Cases

Background: NSCLC is a disease involving uncontrolled cell growth, which could result in metastases intonearby tissues beyond the lungs. Materials and Methods: The aim of the present study was to analyze the influenceof epidermal growth factor receptor (EGFR) gene expression on metastasis and survival in NSCLC patients.The present case-control study included 100 cases of NSCLC patients and 100 age and sex matched controls.EGFR gene expression was analyzed by quantitative real time PCR using serum RNA. Association with NSCLCpatient survival was analyzed by the Kaplan-Meier method. Results: We analyzed EGFR gene expression andobserved mean increased gene expression of 13.5 fold in NSCLC patients. Values reflected overall survival ofpatients with a median of 15.8 months in the cases of <13 fold increased gene expression vs 6.7 months with >13fold increased EGFR gene expression (p=0.005). Distant metastatic patients with <13 fold increased EGFR geneexpression had 7.9 months of median survival time while>13 fold increased EGFR gene expression had only 5months of median survival time (p=0.03). Non metastatic patients with <13 fold increased EGFR gene expressionhad 18 months of median survival time as compared to only 7.1 months with >13 fold increased expression.Conclusions: Higher cell free EGFR mRNA expression may play an important role in causing distant metastasesand reducing overall survival of NSCLC patients in the Indian population.     

Prevalence of EGFR Mutations and Clinico-Pathological Characteristics of Chilean Lung Cancer Patients

Background: Lung cancer (LC) is the second leading cause of cancer death in Chile, causing >3,000 deaths everyyear. Epidemiological LC data in Chile is scarce and scattered. Here, we aimed to quantify the prevalence of EpidermalGrowth Factor Receptor (EGFR) gene mutations in a Chilean cancer center. These data may identify individuals thatcould benefit from targeted therapies such as Tyrosine Kinase Inhibitors (TKIs). Methods: A total of 1,405 Biopsiesfrom 1,381 LC patients were retrospectively analyzed retrieving clinical data from EGFR mutants including age,gender, histological type, smoking habits and type of EGFR mutation. We also analyzed overall survival (OS) rates.Results: From all patients 21.7% had clinically relevant EGFR mutations, and a median age at diagnosis of 65 years.Most were female (64%), classified as adenocarcinomas (94.5%), and non-smokers/light smokers (93.1%). The mostprevalent mutation was exon-19 deletions (50.6%) followed by Leucine-to Arginine 858; OS was 15 months. Clinicalfollow-up information was available for 83 patients. The use of TKIs in these patients significantly improved OS.Conclusion: The prevalence of EGFR mutations in the studied population was 21.7%, comparable to other countriesin Latin America. The most frequent EGFR mutation was exon-19 deletion, OS in this group was 15 months, and TKIssignificantly improved OS.     

Overexpression of EGFR Protein in Bruneian Lung Cancer Patients

Background: Lung cancer is the leading cause of cancer death in Brunei Darussalam, accounting for almost20% of the total. The epidermal growth factor receptor (EGFR) is a member of the erbB family of tyrosine kinasereceptor proteins, which includes c-erbb2(HER2/neu), erb-B3, and erb-B4. EGFR overexpression is found in athird of all epithelial cancers, often associated with a poor prognosis. Materials and Methods: Protein expressionof EGFR in 27 cases of lung cancer tissue samples and 9 cases of normal lung tissue samples was evaluated usingan immunohistochemical approach. Results: The results demonstrated significant increase and overexpressionof EGFR in Bruneian lung cancer tissue samples in comparison to normal lung tissue. However, there was nosignificant relationship between clinicopathologic variables (age and sex) of patients and EGFR protein expression.Conclusions: EGFR is overexpressed in Bruneian lung cancer patient tissue samples in comparison to normallung tissue samples. This may indicate that EGFR protein over expression plays an important role in the genesisof this type of cancer in Brunei Darussalam.     

Staging with PET-CT in Patients with Locally Advanced Non Small Cell Lung Cancer is Superior to Conventional Staging Methods in Terms of Survival

Background: Of patients with non small cell lung cancer (NSCLC), around one third are locally advancedat the time of diagnosis. Because only a proprotion of stage III patients can be cured by surgery, in order toimprove the outcomes , sequential or concurrent chemoradiation, or concurrent chemoradiation with induction orconsolidation is offered to the patients with locally advanced NSCLC. Today, PET combined with computerizedtomography (PET-CT) is accepted as the most sensitive technique for detecting mediastinal lymph node andextracranial metastases from NSCLC. We aimed to compare PET-CT and conventional staging proceduresfor decisions regarding curative treatment of locally advanced NSCLC. Materials and Methods: A total of 168consecutive patients were included from Acibadem Kayseri Hospital, Acibadem Adana Hospital and KayseriResearch and Training Hospital in this study. Results: While the median PFS was 13.0±1.9 months in the PET-CTgroup, it was only 6.0±0.9 in the others (p<0.001). The median OS values were 20.5±15.6 and 11.5±1.5 months,respectively (p<0.001). Discussion: As a result, we found that staging with PET CT has better results in termsof survival staging. This superiority leads to survival advantage in patients with locally advanced NSCLC.     

非小细胞肺癌EGFR突变的分子影像学在体检测

靶向药物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)改变了非小细胞肺癌的治疗格局,研究表明只有EGFR敏感突变人群能从中获益.EGFR突变检测的主流方法是针对EGFR的DNA序列进行分析,标本可以是手术或穿刺获取的肺癌组织、胸水肿瘤细胞、循环肿瘤细胞、外周血游离DNA,其最大的缺点是无法分析EGFR突变的异质性.针对EGFR在蛋白质水平进行突变检测分析的技术尚不成熟,但随着分子影像学的发展,基于正电子发射型计算机断层显像(positron emission computed tomography,PET)-计算机断层扫描(computed tomography,CT)的靶向EGFR分子探针的研发,使得在体检测肺癌组织的EGFR突变状态成为了可能,而且可以检测EGFR突变的异质性.本文综述了目前靶向EGFR突变的分子探针的研究结果及进展.     

非小细胞肺癌靶向治疗研究进展

目前肺癌的生物靶向药物抗表皮生长因子受体(Epidermal Growth Factor Receptor,EGFR)已成功地应用于肺癌临床治疗.但肺癌分子生物学机制十分复杂,新的生物靶点药物在临床中的重要作用日益受到关注.本文对上述分子生物学标志物在肺癌治疗中的作用及其相关临床研究进展进行综述.     

TUBB3/STMN1基因表达与非小细胞肺癌EGFR通路的相关性

背景与目的已有研究表明分子标志物在指导肺癌个体化治疗中起着重要作用。本研究旨在探讨非小细胞肺癌（non-small cell lung cancer, NSCLC）抗微管类药物靶点TUBB3（tubulin, beta 3 class III)/STMN1（stathmin 1）基因表达水平与EGFR（epidermal growth factor receptor）、KRAS（Kirsten rat sarcoma viral oncogene homolog）、BARF（v-raf murine sarcoma viral oncogene homolog B）、PI3K（phosphatidylinositol-4,5-bisphosphate 3-kinase）基因突变的相关性,为NSCLC预后及药物疗效判断提供参考依据。方法回顾性分析我院经病理确诊的46例NSCLC患者手术切除的肿瘤标本,通过分支DNA-液相芯片法检测TUBB3、STMN1基因mRNA表达水平,通过xTAG液相芯片法检测EGFR、KRAS、BRAF、PI3K基因突变,对检测结果应用SPSS 19.0软件采用Spearman相关进行分析基因表达与基因突变的关系。结果抗微管靶点TUBB3和STMN1存在很强的共表达性,TUBB3基因高表达时,STMN1趋向于高表达（P=0.006）。EGFR E21突变与TUBB3存在负相关关系：EGFR E21无突变时TUBB3趋向于高表达（P=0.004,6）。KRAS E2突变与STMN1存在正相关关系：KRAS E2突变时STMN1趋向于高表达（P=0.038,6）。结论抗微管耐药相关因子TUBB3和STMN1与EGFR通路的关键因子突变相关,提示了EGFR突变和KARS突变是调控TUBB3/STMN1表达的重要因素,为研究化疗药物耐药性提供了重要的参考因素。     

Significance of Serum Neuron-specific Enolase as a Predictor of Relapse of Small Cell Lung Cancer

We conducted a prospective study to evaluate the significanceof serum neuron-specific enolase (NSE) as a predictor of relapseof small cell lung cancer (SCLC). Patients entered into thestudy were drawn from those who had shown a complete or partialresponse to first-line chemotherapy with a concurrent declinein the NSE level to less than 10 ng/ml. When the serum NSE levelincreased to more than 15 ng/ml, the patient was restaged onthe basis of clinical, radiological, and bronchoscopic examinations.During the period from August 1988 to December 1990, 57 patientswith SCLC were enrolled and followed up until May 1992; Of thesepatients, 45 had clinical relapses, and 14 (31%) of them showeda clear elevation of the serum NSE level prior to the clinicalrecognition of relapse. Although one false-positive case wasnoted, this involved only a transient elevation of the NSE level.In patients who showed increased NSE levels, the relapses occurredin more difficult to detect silent sites such as the adrenalgland, liver, and deep lymph nodes. In addition, the percentageof patients demonstrating high NSE levels who were able to benefitfrom salvage chemotherapy was higher than for those who didnot (P<0.05). Our results indicate that serial NSE measurementsare useful for the early prediction of SCLC relapse and shouldhelp to facilitate early administration of salvage chemotherapyfor affected patients.(P<0.05)     

EGFR 19和21外显子突变肺癌患者的临床特征比较和预后分析

背景与目的近年来,通过对表皮生长因子受体（epidermal growth factor receptor, EGFR）等相关信号通路的研究及对EGFR酪氨酸激酶抑制剂（EGFR-tyrosine kinase inhibitors, EGFR-TKIs）疗效及安全性的探索,证实了靶向治疗已成为肺癌的重要治疗手段之一。然而,在各中心试验中EGFR-TKIs应用于不同EGFR突变亚型患者的效果不尽相同,其原因尚有争议。因此,本研究通过对比EGFR 19和21外显子突变肺癌患者的临床特点和预后分析,以明确不同EGFR突变亚型肺癌患者的临床病理生理特征的差异,并为TKIs应用于EGFR不同突变亚型疗效差异的研究提供理论依据。方法研究对象为EGFR外显子19或21突变阳性肺癌患者共113例。其中47例患者采用Real-time PCR或测序分析EGFR突变状况,余66例患者则是采用x-TAG液相芯片技术进行分析。收集临床资料,同时定期随访,以死亡作为患者终点事件,并应用SPSS 19.0软件进行统计学分析。结果在本研究中,EGFR外显子突变阳性患者共113例。其中,19外显子突变患者56例,平均年龄为（57.02±11.31）岁;21外显子突变患者57例,平均年龄为（62.25±7.76）岁,两组患者在年龄分布上存在明显差异（P<0.05）;EGFR外显子突变阳性患者以女性（61.9%）、非吸烟（72.6%）、腺癌（84.1%）多见,但两组患者在性别、吸烟状况、组织类型、分化程度及TNM分期等临床特征方面均无明显差异（P>0.05）。进一步分析发现,19外显子突变患者相对21外显子突变患者多好发于右侧（P<0.05）。对所有具有完整随访资料的91例（80.53%,91/113）患者预后分析发现,两组患者总生存期无统计学差异（中位生存期19外显子组和21外显子组分别为1,051 vs 1,076天,P=0.566）。进一步分析发现,在年龄>61岁、男性、吸烟、IV期肺癌患者中,19外显子突变组患者均表现出相对较好的预后,但均无统计学差异。结论 EGFR 19外显子突变肺癌患者相对21外显子突变肺癌患者年龄较小,且右侧原发较为多见。两者在性别、吸烟状况、组织类型、分期及分化程度上无明显差别。两者总生存时间无差异,但仍然需要进一步研究论证。     

Cyclooxygenase-2 Expression is not a Marker of Poor Survival in Lung Cancer

Objective: Cyclooxygenase-2 (COX-2) has been claimed to play role in carcinogenesis and be related to a badprognosis in tumours. The aim of this study was to investigate the relationship between COX-2 expression andclinical and pathological parameters in early and advanced stage lung cancer patients. Materials and Methods: Atotal of 73 patients with lung cancer (27 adenocarcinomas, 33 squamous cell carcinomas, 4 large cell carcinomasand 9 small cell cancer) were analysed retrospectively. COX-2 expression was evaluated by immunohistochemistryin resection materials or lung biopsies. Tumor cells demonstrating more intense staining than smooth muscle andendothelial cells were recorded as COX-2 positive. We investigated the correlation between increased COX-2expression and histological type of the tumor, the stage of the disease and survival. Results: COX-2 expressionwas observed in 55% of the adenocarcinomas, 45% of the squamous cell carcinomas and 22% of the small cellcarcinomas. No correlation was apparent between COX-2 expression and disease stage, histological type and thesurvival. Conclusion: The results of this study do not support COX-2 expression as an independent prognosticfactor in lung cancer. However, since results of the literature are different, further studies made in larger seriesare needed.     

Survival Analysis in Advanced Non Small Cell Lung Cancer Treated with Platinum Based Chemotherapy in Combination with Paclitaxel,Gemcitabine and Etoposide

Background: The wide spectrum of clinical features in advanced stages of non-small cell lung cancer(NSCLC) probably contributes to disparities in outcomes because of different prognostic variables significantfor stage IIIB/IV patients. Hence the aim of this study was to check for favorable response of patients to variouschemotherapeutic combinations with respect to patient survival in stage IIIB and stage IV NSCLC disease. Weselected those patients for our study who were receiving treatment with paclitaxel, gemcitabine or etoposide incombination with platinum based drugs. Materials and Methods: Seventy-two patients who visited the hospitalfrom June 2009 to November 2012 with confirmed diagnosis of lung cancer were included, and data were collectedfor follow up and classified according to treatment received with respect to patients’ regimen and response, andoverall survival. This study analyzed tumor variables that were associated with clinical outcome in advancedNSCLC patients who were undergoing first-line chemotherapy for stage IIIB/IV NSCLC. Results: Comparativedata on various parameters like age, gender, stage, histology, site of disease, metastatic site and chemo-regimenswas analyzed; these parameters predicted variable significant improvement for overall survival (p≥0.05). Oneand two year survival rates were 20.8% and 15.3% . Conclusions: In this study we found slight improvementin survival rates in NSCLC and clinical outcomes with one combination (carboplatin+paclitaxel). Overall therewere only marginal differences in survival rates for other chemo-regimens evaluated in this study.     

非小细胞肺癌外周血游离DNA及肿瘤细胞EGFR基因突变检测方法的研究进展

非小细胞肺癌(non-small cell lung cancer,NSCLC)是肺癌中最常见的类型.表皮生长因子受体(epidermal growth factor receptor,EGFR)酪氨酸激酶受体抑制剂(tyrosine kinases inhibitors,TKIs)是目前最重要的靶向治疗药物,对于有EGFR敏感突变的NSCLC,采用EGFR-TKIs治疗能取得明显的临床疗效;T790M突变是最常见的EGFR-TKIs耐药机制,通过对外周血进行EGFR基因突变检测,可以筛选出EGFR-TKIs治疗有效或治疗过程中对其产生耐药的患者.其定量分析不仅在肿瘤的早期诊断中具有重要意义,而且是疗效评价及随访的重要生物学指标.目前,用于检测外周血EGFR突变的方法有很多,其中以在数字PCR基础上建立起来的ddPCR灵敏度最高,实现了对样本的高通量检测,定量程度较其他方法更为精确,在临床基因诊断中具有广阔的应用前景.     

长春瑞滨联合奥沙利铂治疗晚期非小细胞肺癌的临床研究

目的：观察长春瑞滨（NVB）联合奥沙利铂（LOHP）治疗晚期非小细胞肺癌的临床疗效及不良反应。方法：将经病理组织学或细胞学确诊为非小细胞肺癌的患者作为研究对象，60剜患者随机分为治疗组和对照组，各30例。治疗组给予NVB加LOHP治疗，21天为一周期，用2周期；对照组给予NVB加DDP（顺铂）治疗，21天为一周期，用2周期。结果：总有效率治疗组为43．3％，对照组为40．0％（P〉0．05）。不良反应以白细胞减少、恶心、呕吐以及周围神经炎为主，Ⅲ～Ⅳ度的恶心、呕吐、肾功能损害及心功能不全主要发生在对照组，周围神经炎主要发生在治疗组（P〈0．05）。结论：长春瑞滨联合奥沙利铂治疗晚期非小细胞肺癌的近期疗效与长春瑞宾联合顺铂治疗的疗效相似，均有较好的疗效。但长春瑞滨联合奥沙利铂组的不良反应比长春瑞滨联合顺铂组轻，病人更容易耐受，可以作为晚期非小细胞肺癌的一线治疗方案，更适宜老年患者及心肺功能不全的患者。     

非小细胞肺癌的DNA表达谱(英文)

作为新一代基因诊断技术,DNA芯片已广泛应用于肺癌分子分类、基因表达和分子通路的病理变异分析、预后及转移监测、个体化治疗和药物开发等.基于技术差异、不同患者人群和生物多样性等因素,目前DNA芯片发展的主要障碍为缺乏机械性、可靠性和可重复性.冀望借着更好的标准化和分析手段,利用高维数据分析方法来减少噪音,未来DNA芯片技术或能实际应用于肺癌的个体化诊疗.     

The Role of EGFR Inhibition in the Treatment of Non‐Small Cell Lung Cancer

The identification of certain molecular mechanisms underlying lung carcinogenesis and progression has led to the development of targeted agents against different families of growth factors and receptors. The epidermal growth factor receptor (EGFR) is one such target for therapeutic exploitation. Inhibition of EGFR downstream signaling can be accomplished through two primary mechanisms: (a) the direct blocking of intracellular kinase activity with small‐molecule tyrosine kinase inhibitors (TKIs) (e.g., gefitinib, erlotinib) and (b) the blocking of EGFR ligand binding using antibodies directed against the extracellular domain of the receptor (e.g., cetuximab). Resistance to available EGFR‐targeted treatments has emerged as a substantial clinical issue in non‐small cell lung cancer (NSCLC). Several novel agents with the potential to overcome such resistance are currently in clinical development, including irreversible EGFR TKIs, monoclonal antibodies, and TKIs directed against multiple signaling pathways. Here we discuss the clinical application of the currently available EGFR‐targeted agents in NSCLC, the underlying mechanisms of resistance, and the novel agents in clinical development that may overcome resistance.