Surgical resection after gefitinib treatment in patients with lung adenocarcinoma harboring epidermal growth factor receptor gene mutation

Gefitinib is the first approved epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for the treatment of patients with advanced non-small cell lung cancer (NSCLC) who failed to respond to conventional chemotherapy. Gefitinib has fairly effective anti-tumour activity in patients with tumours harboring EGFR gene mutations. However, there has been no data about the preoperative gefitinib treatment in NSCLC patients. We reported here two cases of surgical resection of residual disease after dramatic response to gefitinib in patients with lung adenocarcinoma harboring EGFR gene mutation. Because both of our patients initially had advanced local tumour burden (bulky N2 disease), complete resection would not have been technically feasible. However, preoperative gefitinib treatment made it possible to achieve complete resection in both patients. We believe that clinical trials are required to evaluate the role of preoperative treatment of EGFR-TKIs in patients with locally advanced NSCLC harboring EGFR gene mutation.     

中国非小细胞肺癌患者表皮生长因子受体突变的研究

背景与目的:最近的研究结果表明,表皮生长因子受体(epidermalgrowthfactorreceptor,EGFR)基因酪氨酸激酶域的体细胞突变与非小细胞肺癌(non鄄smallcelllungcancer,NSCLC)患者对酪氨酸激酶抑制剂吉非替尼的敏感性密切相关。这些突变均发生在酪氨酸激酶域的ATP结合域附近,突变为19号外显子上的缺失突变,或18和21号外显子上的替代突变。研究发现,日本患者的突变率高于美国患者的突变率。本研究中我们分析中国NSCLC患者肺癌组织中EGFR突变情况。方法:收集2004年7月到10月间中山大学肿瘤防治中心52例可手术的NSCLC患者的新鲜组织标本,包括肿瘤组织标本和来自同一患者相应的正常肺组织标本。所有患者均未接受过吉非替尼治疗。采用PCR技术扩增EGFR基因的19和21号外显子,从正反两个方向对扩增片段进行DNA测序和分析。结果:52例1NNNSCLC患者中10例(19.2%)患者EGFR基因酪氨酸激酶域存在体细胞突变。10例突变中包括7例(70%)发生于19号外显子上的缺失突变,另外3例(30%)发生于21号外显子上的替代突变。腺癌(6/23,26.1%)、腺鳞癌(2/5,40.0%)和支气管肺泡癌(2/4,50.0%)的突变率高于鳞癌(0/20,0.0%)的突变率(P=0.025);非吸烟者的突变率(7/17,41.8%)高于吸烟者的突变率(3/35,8.6%)(P=0.009);而女性患者突变率(3/13,23.1%)与男性患者突变率(7/39,18.0%)无显著性差异(P=0.697)。结论:中国NSCLC患者EGFR的突变率较高,与日本患者的突变情况相似,明显高于高加索人种。     

High frequency of mutation of epidermal growth factor receptor in lung adenocarcinoma in Thailand

Recent reports have suggested influences of racial difference on the frequency of mutation of EGFR in lung cancer. We therefore sought to characterize the frequency and pattern of mutation of EGFR in lung adenocarcinoma in Thai patients. Overall, EGFR catalytic domain mutations were detected in 35/61 (57.4%). We found 29/60 (48.3%) of exon 19 deletions, 5/54 (9.3%) of exon 21 point mutations, and 1/54 (1.9%) of double-mutation of both exons. The presence of these mutations was significantly associated with non-smoking habit. In summary, we report a strikingly high prevalence of mutation of EGFR in Thai lung adenocarcinoma, which may explain the high response rate to the treatment with TKI among Asian populations.     

Clinical predictors versus epidermal growth factor receptor mutation in gefitinib-treated non-small-cell lung cancer patients

BACKGROUND: Clinical predictors including Asian, female, adenocarcinoma and never-smoker and epidermal growth factor mutation are associated with gefitinib responsiveness in non-small-cell lung cancer. Direct comparison between clinical predictors and EGFR mutation for their predictive power has not been reported. PATIENTS AND METHODS: For 120 Korean NSCLC patients treated with gefitinib, we have analyzed EGFR mutational status in exons 18, 19 and 21. Patients were grouped according to the number of clinical predictors (female, adenocarcinoma and never-smoker). Response rate (RR), time-to-progression (TTP) and overall survival (OS) were analyzed. Multivariate analysis was performed to investigate which approach yielded better prediction. RESULTS: RRs according to number of clinical predictors were 0: 3.4%, 1: 17.1%, 2: 29.4% and 3: 33.3% (p=0.002). Patients with gefitinib-sensitive EGFR mutation showed 61.9% RR compared with 12.1% in the remaining patients (p<0.001). RRs were higher in patients with the EGFR mutations regardless of the number of clinical predictors. In multivariate analysis, gefitinib-sensitive EGFR mutation showed higher odds ratio of response (9.6, 95% confidence interval [CI] 3.2-28.7) compared with number of clinical predictors (1.7, 95% CI 1.1-2.7). Hazard ratio (HR) of TTP was also better in gefitinib-sensitive EGFR mutation (0.24, 95% CI 0.12-0.47) than number of clinical predictors (0.83, 95% CI 0.69-0.99). Only gefitinib-sensitive EGFR mutation was associated with improved OS (HR 0.25, 95% CI 0.12-0.52). CONCLUSION: EGFR mutation should be analyzed whenever possible for effective prediction of objective benefit from gefitinib in NSCLC patients with one or more clinical predictors.     

Relationship between epidermal growth factor receptor gene mutation and copy number in Chinese patients with non-small cell lung cancer

Epidermal growth factor receptor(EGFR) gene mutation and copy number are useful predictive markers that guide the selection of non-small cell lung cancer(NSCLC) patients for EGFR-targeting therapy.This study aimed to investigate the correlation between EGFR gene mutation and copy number and clinicopathologic characteristics of Chinese patients with NSCLC.NSCLC specimens collected from 205 patients between November 2009 and January 2011 were selected to detect EGFR gene mutations with real-time polymerase chain reaction(RT-PCR) and to detect EGFR gene copy number with fluorescence in situ hybridization(FISH).EGFR mutations primarily occurred in females,non-smokers,and patients with adenocarinomas(all P < 0.001).Tissues from 128(62%) patients were FISH-positive for EGFR,including 37(18%) with gene amplification and 91(44%) with high polysomy.EGFR gene mutation was correlated with FISH-positive status(R = 0.340,P < 0.001).Multivariate analysis showed that not smoking(OR = 5.910,95% CI = 2.363-14.779,P < 0.001) and having adenocarcinoma(OR = 0.122,95% CI = 0.026-0.581,P = 0.008) were favorable factors for EGFR gene mutation.These results show a high frequency of EGFR FISH positivity in NSCLC tissues from Chinese patients and a significant relevance between EGFR gene mutations and FISH-positive status.Among the FISH-positive samples,EGFR gene mutation occurred more frequently in samples with gene amplification compared to those with high polysomy,suggesting that EGFR mutation and gene amplification should be used as clinical decision parameters to predict response to EGFR-targeting therapy.     

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。     

中国人非小细胞肺癌表皮生长因子受体EGFR基因突变与血浆纤维蛋白原水平之间的相关性(英文)

Objective:The plasma fibrinogen levels had not only been used as an independent prognostic parameter for the patients with non-small cell lung cancer (NSCLC), but also as a promising biomarker for evaluating the efficacy of chemotherapy. This study aimed to investigate the correlation between the plasma fibrinogen levels and epidermal growth factor receptor (EGFR) gene mutation and clinical-pathological characteristics of Chinese patients with NSCLC. Methods:In this retrospective study, NSCLC specimens collected from 352 patients between November 2009 and November 2011 were selected to detect EGFR gene mutation with real-time polymerase chain reaction (RT-PCR). In these specimens, 308 ones were also detected EGFR gene copy number with fluorescence in situ hybridization (FISH). Coagulation makers were examined prior to the operations. The association between the plasma fibrinogen levels and EGFR gene mutation and clinical-pathological characteristics were analyzed using SPSS 16.0 software. Results:The median pre-operation plasma fibrinogen level was 3.55 g/L (109/352) patients with higher plasma fibrinogen level (> 4.0 g/L). The lower plasma fibrinogen levels correlated significantly with EGFR gene mutations (P < 0.001), the similar result was seen in platelet counts (P = 0.026). A linear correlation was found between the plasma fibrinogen levels and the platelet counts in NSCLC patients (R 2 = 0.209, P < 0.001). Pre-operation plasma fibrinogen levels correlated with gender (P < 0.001), smoking status (P < 0.001), and histology (P < 0.001). There were significant link between the above clinical-pathological characteristics and EGFR gene mutations. In addition, EGFR gene mutation was correlated with FISH-positive status (P < 0.001). Moreover, both plasma fibrinogen level (P = 0.024) and the EGFR gene copy number (P = 0.040) had significant relationships with the pathological TNM stage. Conclusion:This study showed that a significant relevance between plasma fibrinogen levels and EGFR gene mutations. The plasma fibrinogen level might be as a clinical decision parameter for evaluating the efficacy of anti-EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. The patients of NSCLC had higher indicate have poor benefits from anti-EFGR TKIs. In addition, pre-operation plasma fibrinogen level could be used as an indepedent prognostic biomarker for the patients with NSCLC.     

非小细胞肺癌EGFR不同突变状态的脑转移发生特点及治疗

目的 有研究显示,表皮生长因子受体(epidermal growth factor receptor,EGFR)的突变状态,与非小细胞肺癌(non-small cell lung cancer,NSCLC)脑转移存在相关性.本研究进一步探讨EGFR不同突变状态的NSCLC患者,脑转移发生的特点以及相应的治疗.方法 选取2009-04-01-2014-12-01中国人民解放军火箭军总医院肿瘤科病理确诊断的231例NSCLC患者的临床资料,进行回顾性研究.并应用实时定量PCR方法,检测上述患者的EGFR突变状态.利用x2检验比较EGFR不同突变状态的患者,脑转移特点的差异.Kaplan-Meier法进行生存分析.结果 EGFR检测结果示野生型119例,18、19、20、21号外显子及19/21双突变的分别有3例、58例、5例、42例和4例.19号外显子突变患者的脑转移发生率(55.2％)显著高于野生型患者(41.2％),P=0.04.伴21号外显子突变＞3个脑转移病灶患者(47.6％)的比例显著高于野生型患者(28.6％),P＜0.01.此外,伴21号外显子突变患者的中位脑转移年龄(63岁)也显著高于野生型患者(52岁),P=0.02.对于伴有EGFR突变的脑转移患者,脑转移后接受过酪氨酸激酶抑制剂(tyro-sine kinase inhibitors,TKIs)的患者,其中位脑转移后生存期显著长于接受常规化疗的患者(未达到vs 9个月),P=0.01.结论 伴EGFR特定位点突变的患者有更高的脑转移发生率、脑转移数目及脑转移时年龄.TKIs可改善伴EG-FR突变脑转移患者的预后.     

Outcomes of Malaysian patients with advanced lung adenocarcinoma and unknown epidermal growth factor receptor mutation status treated with gefitinib

Aims: To evaluate the response and progression‐free survival (PFS) of Malaysian patients with advanced lung adenocarcinoma and unknown epidermal growth factor receptor (EGFR) mutation status treated with gefitinib. Methods: A retrospective analysis of consecutive patients with EGFR mutation unknown stage III or IV lung adenocarcinoma with EGFR mutation unknown treated with gefitinib until disease progression. Results: Of 71 patients, none had complete response while 26 (36.6%) had partial response and 26 (36.6%) had stable disease. Multivariate analysis showed the independent predictor of response to gefitinib was Eastern Cooperative Oncology Group (ECOG) performance status 1 (odds ratio [OR] 5.39, 95% confidence interval [CI 1.64–17.74]P = 0.006). The median PFS was 6.5 months and was significantly longer in female than male patients (39.0 vs 21.2 weeks; P < 0.001), never smokers vs smokers (32.3 vs 8.3 weeks, P = 0.001), and stage III versus stage IV disease (44 vs 24 weeks, P = 0.021). In a multivariate Cox proportional hazards model with age group, gender, ethnicity, smoking history, disease stage, ECOG performance status and prior cytotoxic chemotherapy as covariates, the independent predictors of longer median PFS were female gender (HR 95% CI 0.38 [0.22–0.66]; P < 0.001) and stage III disease (HR 95% CI 0.54 [0.30–0.98], P = 0.042). Conclusion: In our patients with EGFR mutation unknown advanced lung adenocarcinoma treated with gefitinib, the response rate was 36.6% and the median PFS was significantly longer in female patients, never smokers and patients with stage III disease.     

EGFR不同突变亚型与肺腺癌脑转移预后的相关性分析

目的 探讨肺腺癌脑转移患者EGFR不同突变亚型与预后的相关性。方法 回顾分析2010—2015年本院收治的经EGFR基因突变检测的肺腺癌脑转移患者256例临床资料,筛选脑转移的预后影响因素。Kaplan-Meier法计算生存率Logrank法检验和单因素预后分析,Cox模型多因素预后分析。结果 全组患者中位生存期为10.13个月。单因素分析显示性别、EGFR突变状态、19外显子缺失突变、脑转移时KPS评分、靶向治疗与预后有关(P=0.006、0.001、0.010、0.000、0.003),多因素分析显示脑转移时KPS评分、19外显子缺失突变为脑转移患者预后影响因素(P=0.000、0.045)。将全组病例纳入RPA预后分级指数,检验显示差异有统计学意义(P=0.000)。结论 19外显子缺失突变是肺腺癌脑转移患者的预后影响因素,可以考虑将其纳入肺腺癌脑转移瘤预后评分系统。EGFR-TKI使EGFR基因突变肺腺癌脑转移患者生存获益,尤其是19外显子缺失突变患者。     

E-cadherin expression and epidermal growth factor receptor mutation status predict outcome in non-small cell lung cancer patients treated with gefitinib

It is known that an epidermal growth factor receptor (EGFR) gene mutation(s) is present in a percentage of non-small cell lung cancers (NSCLCs). Gefitinib, an inhibitor of the tyrosine kinase activity of EGFR, is effective on most of them. The EGFR mutation status alone cannot fully predict the response to gefitinib and the prognosis for the patients. We hypothesized that information on the expression levels of phosphorylated-EGFR and -Akt, and E-cadherin, alone or in combination with information on the EGFR mutation, may refine our ability of prediction. We investigated 24 NSCLCs that had recurred after surgery and were treated with gefitinib. Specimens resected by surgery were subjected to the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp reaction to determine the EGFR mutation status, and to immunohistochemical staining of phosphorylated-EGFR and -Akt, and E-cadherin to determine their expression levels. The EGFR mutation status was predictive of responsive disease (complete response: CR + partial response: PR) and controlled disease (CR + PR + stable disease: SD). Positive E-cadherin staining was predictive of longer time to progression (12.4 vs. 5.9 months, p<0.05) and overall survival (OS) (18.4 vs. 13.0 months, p<0.05). Together the patients with an EGFR mutation and the patients with positive E-cadherin staining defined a patient group with a median OS of 18.4 months and excluded the patient group with the median OS of 3.7 months. Neither p-Akt nor p-EGFR staining was associated with the response and survival. In patients with surgically resected NSCLC tumors, the EGFR mutation status and E-cadherin staining can select patients who will benefit from gefitinib therapy.     

表皮生长因子受体少见突变型非小细胞肺癌临床病理特征及治疗分析

  目的  分析非小细胞肺癌患者表皮生长因子受体（epidermal growth factor receptor,EGFR）少见突变型的临床病理参数及EGFR-TKIs治疗的初步疗效。  方法  收集2012年1月至2016年4月新疆医科大学附属肿瘤医院经病理证实的29例非小细胞肺癌携带少见EGFR突变患者临床病理资料,分析少见突变型的临床病理特征及与EGFR-TKIs疗效之间的关系。  结果  在29例少见突变患者中,最常见的远处转移器官依次为同侧/对侧肺组织、骨、脑、肝、肾上腺,最常见的淋巴结转移依次为肺门淋巴结、锁骨上/下淋巴结、颈根部淋巴结及纵隔淋巴结。少见突变中单突变16例,L861Q 5例,G719X 5例,20ins 4例,S768I 2例。双突变型11例,S768I及20ins突变4例,L858R及S768I双突变1例,19Del及T790M双突变1例,L861Q及G719X双突变2例,19Del及S768I突变1例,20ins及G719X突变1例,T790M及G719X突变1例。三突变2例,L858R、L861Q及G719X突变1例,S768I、20ins及G719X突变1例。一线EGFR-TKIs治疗客观缓解率（objective response rate,ORR）43.75%,疾病控制率（disease control rate,DCR）50.00%,中位无疾病进展生存期（median progression-free survival,mPFS）5.50个月。二线EGFR-TKIs治疗ORR为28.57%,DCR为42.85%,mPFS为4.00个月。三线EGFR-TKIs治疗ORR为33.33%,DCR为50.00%,mPFS为2.67个月。  结论  EGFR少见突变对EGFRTKIs治疗的有效率及生存时间存在较大个体差异,EGFR少见突变患者的ORR及PFS均较经典突变患者低,部分高于野生型。对少见突变患者,EGFR-TKIs治疗一线疗效略优于二、三线,但无显著性差异。      

Frequency of epidermal growth factor receptor mutations in Bangladeshi patients with adenocarcinoma of the lung

Background

Worldwide studies on lung adenocarcinoma have demonstrated a genetic divergence of the epidermal growth factor receptor (EGFR) pathway according to ethnicity, such as higher frequency of activated EGFR mutations among East Asian patients. However, such information is still lacking in some developing countries.

Methods

We investigated the frequency of EGFR mutations among Bangladeshi patients with adenocarcinoma of the lung. Fine-needle aspiration tissue samples were collected from 61 Bangladeshi patients. Polymerase chain reaction–single-strand conformation polymorphism was performed on extracted DNA for mutational analysis of EGFR exons 19 and 21.

Results

EGFR mutations were found in 14 of 61 (23.0 %) Bangladeshi patients. There was no significant difference in EGFR mutation rate with regard to patient’s age, sex, smoking history, clinical stage of lung cancer, subtypes of adenocarcinoma, and tumor differentiation.

Conclusion

The present study revealed that the EGFR mutation rate in Bangladeshi patients with adenocarcinoma of the lung was higher than in African–American, Arabian, and white Caucasian patients, and was lower than in East Asia.     

Targeting the epidermal growth factor receptor in non-small cell lung cancer

The epidermal growth factor receptor (EGFR) has been implicated in a multiplicity of cancer-related signal transduction pathways like cellular proliferation, adhesion, migration, neoangiogenesis and apoptosis inhibition, all of them important features of cancerogenesis and tumour progression. The inhibition of this receptor has been discovered as a suitable pharmaceutical intervention aimed at interrupting tumour activity. In cancer, both monoclonal antibodies and small molecules with anti-tyrosine kinase activity have been assessed in several trials with significant efficacy in clinical applications. The current review focuses in particular on the clinical data of EGFR inhibition in non-small cell lung cancer with emphasis on tyrosine kinase inhibition.     

Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib.

PURPOSE: Non-small cell lung cancers carrying activating mutations in the gene for the epidermal growth factor receptor (EGFR) are highly sensitive to EGFR-specific tyrosine kinase inhibitors. However, most patients who initially respond subsequently experience disease progression while still on treatment. Part of this "acquired resistance" is attributable to a secondary mutation resulting in threonine to methionine at codon 790 (T790M) of EGFR. EXPERIMENTAL DESIGN: We sequenced exons 18 to 21 of the EGFR gene to look for secondary mutations in tumors with acquired resistance to gefitinib in 14 patients with adenocarcinomas. Subcloning or cycleave PCR was used in addition to normal sequencing to increase the sensitivity of the assay. We also looked for T790M in pretreatment samples from 52 patients who were treated with gefitinib. We also looked for secondary KRAS gene mutations because tumors with KRAS mutations are generally resistant to tyrosine kinase inhibitors. RESULTS: Seven of 14 tumors had a secondary T790M mutation. There were no other novel secondary mutations. We detected no T790M mutations in pretreatment specimens from available five tumors among these seven tumors. Patients with T790M tended to be women, never smokers, and carrying deletion mutations, but the T790M was not associated with the duration of gefitinib administration. None of the tumors had an acquired mutation in the KRAS gene. CONCLUSIONS: A secondary T790M mutation of EGFR accounted for half the tumors with acquired resistance to gefitinib in Japanese patients. Other drug-resistant secondary mutations are uncommon in the EGFR gene.