Epidermal growth factor receptor mutations in small cell lung cancer

PURPOSE: The vast majority of epidermal growth factor receptor (EGFR) mutations occur in lung adenocarcinoma, and even rare cases of other subtypes with this mutation, such as adenosquamous cell carcinoma, are associated with adenocarcinoma histology. According to this adenocarcinoma-specific nature of EGFR mutation, analysis of EGFR mutations with small cell lung cancers (SCLC) may provide a clue to its histogenesis. EXPERIMENTAL DESIGN: The mutational status of the EGFR gene was accessed in a cohort of 122 patients with SCLC; all patients were from a single institute. When the EGFR mutated, its gene copy number was also examined. RESULTS: EGFR mutations were detected in five SCLCs (4%). The patients were mainly in the light smoker and histologic combined subtype. All but one of the tumors harbored gene amplifications. Notably, in three tumors of the combined SCLC subtype, both components of adenocarcinoma and SCLC harbored an EGFR mutation, whereas gene amplification was detected only in the adenocarcinoma component. A partial response was achieved in a patient (with an EGFR mutation) who was treated with gefitinib. CONCLUSIONS: Although EGFR mutations are rare in SCLC, a combined subtype of SCLC with adenocarcinoma in light smokers may have a chance of harboring EGFR mutations. For patients with an EGFR mutation, EGFR tyrosine kinase inhibitor can be a treatment option. In terms of molecular pathogenesis, it is suggested that some SCLCs may have developed from pre-existing adenocarcinomas with EGFR mutations, but the development may not be simply linear, taking into consideration the discordant distribution of EGFR amplification.     

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。     

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 gene mutation defines distinct subsets among small adenocarcinomas of the lung

Epidermal growth factor receptor (EGFR) gene mutations are frequently detected in lung cancer, especially in adenocarcinoma, in females, and non-smoking patients. EGFR mutations are closely associated with clinical response to EGFR tyrosine kinase inhibitor. Bronchioloalveolar carcinoma (BAC) appearance is a good predictor of response to this agent. Noguchi et al. subdivided small peripheral adenocarcinoma of the lung into two groups. One group was characterized with tumor cell growth replacing the normal alveolar cells with varying degree of fibrosis (types A-C), and the other shows non-replacing and destructive growth (types D-F). Using probes for the 13 mutations which have been previously described, we have genotyped the EGFR gene status in surgically resected atypical adenomatous hyperplasias (AAH) and small peripheral adenocarcinomas up to 2 cm in diameter using TaqMan PCR assay. In 95 small-sized adenocarcinomas, the EGFR mutations were detected in 37 patients (38.9%), and no mutations were found in five AAHs. In small peripheral adenocarcinomas, EGFR mutations were found 47.1% of types A, B, or C adenocarcinomas; it was less frequent (16%) in Noguchi's types D, E or F adenocarcinomas. These results suggest that type D, F adenocarcinomas are not derived from the less malignant types A-C adenocarcinomas; rather, they have arisen de novo by distinct mechanisms. Although types A and B adenocarcinomas are almost 100% cured by surgery, some type C adenocarcinoma show lymph node metastasis and relapse. EGFR mutation analysis may help identify patients who will respond to treatment with tyrosine kinase inhibitors, e.g., gefitinib.     

中国肺腺癌患者上皮生长因子受体基因突变的研究

目的:分析我国肺腺癌患者上皮生长因子受体(EGFR)基因突变的发生率和突变类型。方法:在上海、杭州和昆明等地收集61例肺腺癌及其正常肺组织,采用PCR扩增和基因测序方法对组织DNA中EGFR外显子19~21基因突变进行分析。结果:正常肺组织中EGFR基因均为野生型,肺腺癌组织中EGFR基因突变检测率为47.5%(29/61),其中外显子19和21突变分别占突变总数的55.2%(16/29)和44.8%(13/29),外显子20未检测到突变。外显子19突变发生在第746~752位密码子,均为碱基缺失突变,有6种不同类型。外显子21突变全部是第858位密码子碱基替换突变。EGFR基因突变与患者性别和年龄无显著相关性。但昆明和上海等地患者的基因突变存在明显差异。结论:EGFR基因突变是一种肿瘤特异性的体细胞遗传改变,突变发生率约占肺腺癌总数的一半,其中以外显子19和21突变为主。我国EGFR基因突变存在地域差异。     

7例肺腺癌转化小细胞癌患者的临床病理特征分析

目的:分析总结肺腺癌转化为小细胞癌的临床病理特征。方法:回顾性分析2014年1月至2018年12月7例于河北医科大学第四医院确诊为肺腺癌转化为小细胞肺癌(small cell lung cancer,SCLC)患者的临床、病理及随访资料。结果:随访截至2020年6月1日。肺腺癌发生小细胞癌转化的中位时间为31个月,转化前应用酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKI)的中位时间为14个月。3例患者的转化部位与原发部位相同。7例患者转化前神经元特异性烯醇化酶(neuron-specific enolase,NSE)水平均升高,病情进展部位多为多个部位,肺、骨、脑、胸膜及淋巴结常见。7例患者转化后的免疫组织化学指标显示TTF1均为阳性,而Napsin A均为阴性,Syn、CD56、AE1/AE3均为阳性,Ki67均为高表达,PD-L1均不表达转化后基因检测显示,6例患者仍保持原有EGFR基因突变类型。转化后治疗主要为以化疗为主的综合治疗,中位无进展生存期为6个月,5例患者死亡,中位生存时间为10个月。结论:肺腺癌一旦发生小细胞癌转化,疾病进展迅速,生存期...     

Epidermal growth factor receptor status and S-phase fractions in gastric carcinoma

The correlation with epidermal growth factor (EGF) receptor expression and clinicopathologic findings were studied in 242 gastric carcinomas. They were stained for EGF receptor by means of an immunohistochemical technique using a monoclonal antibody against the receptor. S-Phase fractions were measured by in vivo bromodeoxyuridine (BrdU) labeling and indirect immunohistochemical staining using anti-BrdU monoclonal antibody. In normal gastric epithelium, EGF receptor immunoreactivity could not be found. EGF receptor was found in 76 (31.4%) of 242 gastric carcinomas. Diffusely infiltrating types of carcinomas were more likely than localized tumors to be EGF receptor-positive. In addition, EGF receptor-positive tumors had significantly higher values of BrdU labeling indices than EGF receptor-negative tumors. The patients with EGF receptor-positive carcinomas also had a poorer prognosis than did negative cases. These results suggested that EGF receptor-positive tumors may have higher proliferative activity and local extension may progress more rapidly, and also seem to show that EGF receptor status may possibly be a useful prognostic marker for gastric carcinomas.     

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.     

CT影像组学特征预测晚期肺腺癌EGFR基因突变的价值研究

目的:探究影像组学特征对于晚期肺腺癌EGFR基因突变状态的预测价值.方法:回顾性分析2013年04月至2019年09月期间青岛大学附属医院收治的339例晚期肺腺癌患者,其中237例作为训练组,102例作为验证组,从患者胸部CT动脉期及静脉期图像中各提取396个影像组学特征.依次应用mRMR和LASSO在训练组进行特征筛...     

Epidermal growth factor receptor mutations in patients with non-small cell lung cancer

A year has passed since mutations of the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) were discovered in patients with non-small cell lung cancer (NSCLC) who had dramatic clinical responses to treatment with gefitinib. Additional laboratory and clinical studies have provided further insight into the biological impact of EGFR mutations in cell culture experiments and in patients with NSCLC. In vitro characterizations of NSCLC cell lines and host cell lines transfected with these mutant and wild-type EGFR show that most cell lines with mutated EGFR are growth-inhibited by 10- to 100-fold lower concentrations of gefitinib and erlotinib compared with wild-type EGFR. NSCLC lines with mutations of the EGFR treated with concentrations of gefitinib and erlotinib that are achievable in the plasma undergo apoptosis rather than growth arrest. Retrospective studies of patients with NSCLC-treated gefitinib have reported a close association between EGFR mutations, increased chance of clinical response and longer survival. This review will provide information on the impact of EGFR mutations on gefitinib and erlotinib treatment by in vitro experiments, the outcome of NSCLC patients with these mutations when treated with gefitinib and erlotinib, and the subsets of patients with NSCLC in whom these mutations arise.     

Epidermal growth factor receptor protein expression and gene amplification in small cell carcinoma of the urinary bladder.

PURPOSE: Small cell carcinoma of the urinary bladder is a highly aggressive malignancy with an average life expectancy of only a few months. Epidermal growth factor receptor (EGFR) has been implicated in the pathogenesis and progression of many malignancies. This study was done to investigate EGFR protein expression and gene amplification in a large series of small cell carcinomas of the urinary bladder. EXPERIMENTAL DESIGN: Fifty-two cases of urinary bladder small cell carcinoma were included in this study. Immunostaining for EGFR was done on paraffin-embedded tissue sections, and gene amplification for EGFR was done by fluorescence in situ hybridization. EGFR expression was correlated with clinicopathologic characteristics and clinical outcome. RESULTS: All 52 patients, except 1, had advanced disease (T2 or above) at presentation. Immunohistochemically, positive EGFR expression was observed in 14 of 52 (27%) cases. No EGFR gene amplification was observed in any of 52 cases by fluorescence in situ hybridization. Forty cases had polysomy and the remaining 12 cases displayed disomy. No correlation between EGFR protein expression and gene amplification was shown. There was no correlation between EGFR expression and clinicopathologic characteristics. CONCLUSIONS: EGFR is expressed in a subset of urinary bladder small cell carcinomas; however, expression of EGFR does not correlate with clinicopathologic variables. At the molecular level, EGFR overexpression in small cell carcinoma of the urinary bladder does not seem to be caused by gene amplification. The expression of EGFR raises the possibility that EGFR may be a potential therapeutic target in the treatment of this malignancy.     

Epidermal growth factor receptor expression in human lung cancer cell lines

Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cell lines were studied for epidermal growth factor (EGF) receptor expression. All NSCLC cell lines tested (eight of eight) had specific EGF binding sites, whereas only five of 11 SCLC cell lines bound EGF. NSCLC and SCLC cell lines expressed the same type of high affinity EGF binding sites with a Kd of 0.5 to 4.5 nM; however, NSCLC cells bound significantly more EGF than SCLC cell lines. The amount of binding sites in NSCLC cells ranged between 71 and 1,000 fmol/mg of protein and in SCLC cells, between 26 and 143 fmol/mg of protein. The two SCLC cell lines with EGF binding values within the range of NSCLC belonged to the variant subtype of SCLC. By means of an anti-erbB serum and indirect radioimmunoprecipitation, a strong Mr approximately 170,000 protein band could be detected in the NSCLC cell lines. This protein corresponds to the EGF receptor molecule. Its identity was proven by competition with excess erbB antigen for the antibody during the radioimmunoprecipitation. Furthermore, this Mr 170,000 protein exhibited protein kinase activity as evidenced by in vitro autophosphorylation. The radioactivity incorporated into the Mr 170,000 band in radioimmunoprecipitation and protein kinase assays was 10 to 100 times lower in these SCLC cell lines which were positive in the EGF binding assay compared to the NSCLC cell lines. We conclude that NSCLC in contrast to SCLC expresses high levels of EGF receptors which may be used to facilitate the differential diagnosis in some cases of lung cancer. These data suggest that EGF may play a role in growth and differentiation of NSCLC.     

非小细胞肺癌组织表皮生长因子受体基因突变的临床意义

目的探讨非小细胞肺癌(NSCLC)肿瘤组织表皮生长因子受体(EGFR)基因突变及其相关因素.方法抽取80例手术切除肿瘤组织DNA,采用巢式PCR方法对编码EGFR基因的第18、19和21外显子片段进行扩增和测序,用Chromas软件分析基因突变或缺失.结果21例肿瘤组织存在EGFR基因突变或缺失,发生率为26.25%,其中13例为EGFR第19外显子阅读框内多核苷酸的缺失,8例为第21外显子2 573位核苷酸点突变.这些突变均为杂合子型.肺腺癌突变率为42.10%(16/38),显著高于鳞癌的9.68%(3/31)和鳞腺混合癌的18.2%(2/11)(χ2=9.702,P ＜0.01);女性患者突变率为48.28%(14/29),显著高于男性患者的13.73%(7/51)(χ2=11.4,P＜0.01);不吸烟者突变率为40%(16/40),显著高于吸烟者的12.50%(5/40)(χ2=7.812,P＜0.01).EGFR基因突变与患者年龄、TNM分期等因素无关.Logistic回归分析提示患者性别和组织类型是影响EGFR突变的2个主要因素.结论NSCLC存在EGFR基因的突变或缺失,其中以女性、腺癌和不吸烟患者突变率较高.     

原发SCLC中EGFR突变异质性及其预后关系

目的 在大规模中国人群SCLC标本中检测EGFR基因突变频率,分析原发SCLC中EGFR基因突变的异质性和临床特征。方法 2009—2014年间共收集557例单纯SCLC患者组织样本。利用双脱氧测序法进行EGFR突变检测。χ²检验分析临床因素与EGFR突变的相关性,Kaplan-Meier法进行生存分析,Cox模型多因素预后分析。结果 在557例标本中检测到38例EGFR突变(6.8%),其中经典突变有E19 deletion的3例、 E21 L858R的3例、E20 T790M突变的1例,余均为非经典突变。EGFR突变与患者性别、年龄、临床分期无相关性。不吸烟者与吸烟患者之比在EGFR突变组(11/36)与EGFR野生组(86/398)差异无统计学意义(P=0.080)。对患者治疗史进行匹配发现EGFR突变者生存预后比EGFR野生型好,中位生存期分别为(24.43±9.46)个月∶(14.17±0.84)个月(P=0.020)。采用Cox回归分析提示局限期(HR=2.610,P=0.000)、<65岁(HR=1.476,P=0.010)和EGFR突变是预后影响因素(HR=0.576,P=0.039)。结论 在初诊SCLC患者中存在EGFR突变亚群,其突变类型异质性较高,EGFR突变与SCLC患者的生存呈正相关。     

EGFR酪氨酸激酶域基因变异及相关蛋白表达与gefitinib治疗晚期非小细胞肺癌疗效相关性的研究进展

Gefitinib是一种选择性EGFR酪氨酸激酶抑制剂,是目前非小细胞肺癌(NSCLC)靶向治疗的热点之一,临床研究发现,患者对gefitinib的疗效有明显的差异。本文对EGFR基因及其蛋白与gefitinib疗效的相关性进行了回顾,探讨预示gefitinib疗效的标志物,有助于gefitinib在NSCLC治疗中的最优化使用。     

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。     

Mutations of the epidermal growth factor receptor tyrosine kinase domain and associations with clinicopathological features in non-small cell lung cancer patients

Somatic tyrosine kinase (TK) domain mutations of the epidermal growth factor receptor (EGFR) gene are associated with sensitivity of non-small cell lung cancer (NSCLC) to tyrosine kinase inhibitors (TKI's), however their incidence in distinct populations is not clarified. We sequenced exons 18-21 of the EGFR TK domain from 60 Greek and Czech patients, enrolled in an adjuvant chemotherapy trial following total resection for stages I-IIIa disease. Somatic mutations were found in 9/60 patients (15.0%), several being novel. EGFR mutations were more common in Stage I tumors (p = 0.023), they were also more common in women and never smokers; however, no other significant association of clinicopathological features with mutations was found. Median TTP and OS of patients with and without mutations were 13.2 and 40 months compared to 22.9 and 43.2 months, respectively. These differences were not statistically significant. K-ras (5/60, 8%) and EGFR mutations were found to be mutually exclusive. We identified a wide spectrum of somatic EGFR TK mutations reporting a relatively high incidence (15%) in NSCLC patients of Greek and Czech origin. As ethnicity seems to be a factor for the origin of these mutations, further studies in distinct populations are warranted.