cNCCN指南对Her-2过表达型乳腺癌治疗的指导意义

摘 要：［目的］ 总结在cNCCN指导下的Her-2过表达型乳腺癌的临床特征、诊疗现状及相应预后;判定cNCCN指南对于Her-2过表达型乳腺癌临床治疗的指导价值。［方法］ 回顾性分析具有明确病理学诊断的530例Her-2过表达型乳腺癌患者资料,并进行预后因素分析。［结果］ 根据2007～2011各年cNCCN乳腺癌临床实践指南,紫杉类药物规范治疗组较非规范治疗组的OS延长(49.379个月 vs 2.087个月,P=0.024);而蒽环类规范治疗组与非规范治疗组的PFS及OS无统计学差异。对于AJCC分期Ⅲ期Her-2过表达型乳腺癌患者,紫杉规范治疗组较蒽环规范治疗组PFS明显延长(49.875个月 vs 31.594个月,P=0.036),而两组之间的OS无统计学差异(P=0.369);AJCCⅠ期,Ⅱ期,Ⅳ期及淋巴结阴性的紫杉规范治疗组与蒽环规范治疗组的PFS及OS无统计学差异(P<0.05)。规范放疗组较非规范放疗组延长了OS(54.360个月vs 45.927个月,P=0.044);赫塞汀规范治疗组较非规范治疗组的延长了PFS(66.758个月vs 52.863个月,P=0.027),但OS无统计学意义(P=0.059)。［结论］ 对于Her-2过表达型乳腺癌,规范的紫杉醇类化疗方案、规范放疗可延长患者的总生存,而赫塞汀规范应用可改善其无病生存期。     

雄激素受体在Her-2过表达型乳腺癌中的意义

摘 要：［目的］ 探讨雄激素受体（androgen receptor,AR）在人表皮生长因子受体-2（human epidermal growth factor receptor-2,Her-2）过表达型乳腺癌中的临床意义。［方法］ 用免疫组化方法检测有完整临床及随访资料的102例Her-2过表达型乳腺癌中AR表达,并分析其与临床病理特征及5年无疾病进展时间（disease-free survinal,DFS)的相关性。［结果］ AR在Her-2过表达型乳腺癌阳性率为75.5%（77/102）;淋巴结阴性组AR表达率为84.91%（45/53）,明显高于淋巴结阳性组的65.31%（32/49）(χ2=5.286,P=0.021);Ki-67阴性组AR表达率（89.47%,34/38）明显高于Ki-67阳性组的67.19%（43/64）(χ2=6.400,P=0.011）。生存分析显示,AR阳性组5年无瘤生存率为71.7%,明显低于AR阴性组的89.8%(χ2=5.736,P=0.017）。Cox回归分析显示,AR是影响Her-2过表达型乳腺癌5年DFS的独立预后因素（RR=3.961,95%CI：1.008~15.574）。［结论］ AR在Her-2过表达型乳腺癌中的表达率高,AR阳性患者预后较差,AR可能成为Her-2过表达型乳腺癌新的治疗靶点。     

应用2013年ASCO/CAP指南对Her-2IHC2+乳腺癌患者进行Her-2FISH分类

摘 要：［目的］探讨2013年ASCO/CAP指南对IHC2+乳腺癌患者Her-2FISH分类的影响。［方法］ 采用荧光原位杂交法检测173例Her-2免疫组化2+的乳腺癌患者的Her-2基因的状态并应用2013年ASCO/CAP指南的标准对检测结果进行分析。［结果］ 与2007年检测指南相比,使用2013年检测指南使36例患者发生了变化,取得了较高的阳性率（28.3% vs. 23.1%）和不确定率（16.2% vs. 4.0%）,阴性比例下降（55.5% vs. 72.8%）。［结论］ 2013年指南的使用提高了阳性率和不确定患者的比例,从而提高了Her-2靶向治疗的病例数。FISH对于IHC2+的患者能够起到最后分类的作用,而17号染色体多体在FISH不确定的患者中占很大的比例。     

乳腺癌Her-2基因扩增及其蛋白表达与ER、PR的关系及临床意义

目的:探讨乳腺癌中Her-2基因及其蛋白表达状况,并研究其与ER、PR的关系及临床意义。方法:采用荧光标记原位杂交(FISH)和免疫组化法(IHC)检测45例乳腺癌组织中Her-2基因及其蛋白表达并检测ER、PR表达。实验数据采用SPSS统计软件处理。结果:在45例乳腺癌中有17例出现Her-2基因扩增,阳性率为37.7%。Her-2蛋白总阳性率为66.7%。Her-2基因阳性率在ER阳性组为32.3%,在ER阴性组为50.0%,Her-2基因阳性率在PR阳性组为27.5%,在PR阴性组为56.2%。FISH法检测Her-2基因扩增与Her-2蛋白过表达之间相关(P<0.05),而与淋巴结转移、组织学分级及ER、PR的表达无关(P>0.05)。结论:FISH检测Her-2基因扩增和免疫组化检测Her-2蛋白一致性较好,ER、PR和Her-2三者在乳腺癌的发生发展中起重要作用。     

人乳腺癌裸鼠移植瘤组织Duffy抗原趋化因子受体与Her-2蛋白表达相关性的探讨

目的:探讨人乳腺癌裸鼠移植瘤组织Duffy抗原趋化因子受体(DARC)与Her-2蛋白表达的相关性.方法:建立人乳腺癌裸鼠原位移植瘤模型,按细胞类型分为DARC低表达的MDA-MB-231裸鼠移植瘤、转染空质粒的MDA-MB-231(MDA-MB-231-vect)裸鼠移植瘤及转染DARC cDNA的MDA-MB-231(MDA-MB-231-DARC)裸鼠移植瘤.隔天观察裸小鼠的健康状况和肿瘤细胞的成瘤性,成瘤后每周测量1次各移植瘤的体积,至第2周及第4周时,分别处死各组实验动物8只,获取移植瘤,免疫组化检测原位移植瘤组织中DARC及Her-2蛋白表达;选取中国福利会国际和平妇幼保健院乳腺癌临床组织标本80例,通过免疫组化技术检测DARC和Her-2蛋白表达,并对其相关性进行分析.结果:虽然各组动物的成瘤率均为100%,但DARC转染后的 MDA-MB-231移植瘤(MDA-MB-231-DARC移植瘤)生长明显减慢(P=0.007),且裸鼠移植瘤组织中Her-2蛋白呈低表达,转染与未转染DARC的裸鼠移植瘤组织中Her-2蛋白表达差异有统计学意义,χ2=69.83,P=0.045;对人乳腺癌临床组织标本免疫组化检测结果显示,Her-2蛋白表达与DARC蛋白呈负相关,r=-0.464,P=0.026.结论:人乳腺癌裸鼠移植瘤组织中DARC的过表达抑制Her-2蛋白表达.     

Her-2/neu与术后复发晚期胃癌临床病理及预后的相关性研究

摘 要：［目的］ 探讨术后复发晚期胃癌患者Her-2/neu表达及与临床病理特征和预后的相关性。［方法］ 分别采用免疫组织化学法（IHC）及荧光原位杂交法（FISH）对108例术后复发晚期胃癌患者进行Her-2/neu表达的检测,分析其与患者的年龄、性别、Lauren分型、组织学分级及与预后的相关性。［结果］ 108例患者中,IHC法检测Her-2/neu阳性表达13例,FISH法检测Her-2/neu阳性表达14例,两种方法均为阳性表达者10例,一致率为61.5 %。15例正常胃黏膜中未见阳性表达。Her-2/neu表达与患者的年龄、性别、肿瘤部位、组织学分级、TNM分期、浸润深度、有无脉管浸润无关（P＞0.05）,而与患者的Lauren分型、淋巴结转移有关（P＜0.05）。Her-2/neu阳性患者的中位疾病进展时间（TTP）为22.4个月（95%CI：23.44~26.55）,阴性患者的中位TTP为25.0个月（95%CI：17.02~27.77）,两者差异无统计学意义(P=0.215)。［结论］ Her-2/neu可能是胃癌预后不良的标志之一。     

Her-2和Cox-2在乳腺癌组织中的表达及其相关性

目的 探讨癌基因Her-2和Cox-2在乳腺癌组织中的表达及其相关性.方法 应用免疫组化技术,检测40例人乳腺癌中Her-2和Cox-2蛋白的表达情况,分析其相互关系及与乳腺癌的临床病理特征间的联系.结果 40例乳腺癌组织中Her-2表达阳性率为35﹪(14/40),与肿瘤分期、淋巴结转移及阴性激素受体状态密切相关(P＜0.05);Cox-2表达阳性率为47.5﹪(19/40),与肿瘤分期、组织学分级、阴性激素受体状态密切相关(P＜0.05);二者表达与肿瘤大小无关,两者的表达存在显著的相关性(P＜0.01).结论 Cox-2在乳腺癌中高水平表达且与Her-2密切相关,提示乳腺癌中Her-2和Cox-2存在相互调控机制共同促进肿瘤的发生和发展.     

VES对Her-2、p53共表达乳腺癌细胞的抑制作用及机制

目的:研究VES对Her-2、p53共表达乳腺癌细胞株MDA-MB-453细胞的增殖、凋亡的影响、通过检测Her-2、p53探讨VES抑制乳腺癌细胞生长的机制。方法:应用MTT法检测VES对MDA-MB-453细胞增殖的影响;流式细胞仪检测细胞周期变化及细胞凋亡;RT-PCR和免疫细胞化学法分别检测Her-2基因mRNA和Her-2、p53蛋白表达水平。结果:VES能抑制乳腺癌MDA-MB-453细胞增殖,随VES剂量的增加,抑制作用增强。其中20μg/ml VES处理组在48h后受到明显抑制,抑制率达52.25%;经VES处理后细胞出现凋亡,5μg/ml处理48h后,凋亡率为39.52%;药物干预组使肿瘤细胞大量阻滞于G1期(P<0.01);RT-PCR和免疫细胞化学法结果表明,VES能抑制Her-2基因mRNA的转录水平,从而抑制其蛋白的表达,也能降低p53蛋白的表达。结论:VES可诱导Her-2、p53共表达乳腺癌MDA-MB-53细胞凋亡,抑制增殖。其机制可能是通过抑制Her-2基因mRNA及蛋白的表达和通过抑制突变型p53蛋白的表达使细胞停滞于G1有关。     

TF和Her-2在乳腺癌中的表达及临床意义

目的:探讨组织因子 (tissue factor,TF)和人表皮生长因子受体-2(human epidermal growth factor receptor 2, Her-2)在乳腺癌组织中的表达及其在临床诊断和评价预后中的意义.方法:应用免疫组织化学法检测了45对包括原发乳腺癌组织及其癌旁组织共90例以及30例乳腺良性病变组织中TF,Her-2的表达,分析其与临床病理指标的关系及其和5年无病生存率的关系.结果:45例乳腺癌组织中,TF表达阳性的为31例(68.9%),Her-2表达阳性的为26例(57.8%).30例乳腺良性病变组织中TF表达阳性的4例(13.3%),6例(20.0%)Her-2表达阳性的6例(20.0%).TF,Her-2的表达在癌组织与良性病变组织中均有显著差异(P<0.001).45对癌组织与癌旁组织中,TF与Her-2在癌组织中的表达均显著高于癌旁组织(P<0.001),2者差异有统计学意义.TF,Her-2表达阳性时,与乳腺癌病理分级、淋巴结是否转移呈正相关.结论:TF,Her-2可能参与乳腺癌组织的发生发展过程,2者结合可共同应用于临床共同预测乳腺癌患者的预后.     

HIF-1α表达与乳腺癌预后的关系

摘 要：［目的］ 探讨缺氧诱导因子-1α蛋白(HIF-1α)在乳腺癌中的表达情况及其与乳腺癌临床特征和预后的关系。［方法］ 选择56例女性原发性乳腺癌患者的癌组织标本。采用免疫组化法检测癌组织中HIF-1α蛋白的表达状况,分析HIF-1α蛋白表达与各临床特征以及乳腺癌预后的相关性。［结果］ HIF-1α蛋白在乳腺癌组织中的阳性表达率（73.2%）及高表达率（41.1%）均明显高于乳腺良性肿瘤组织（P＜0.05）。HIF-1α蛋白表达与乳腺癌淋巴结转移、病理学分期及组织学分级有关（P＜0.05）。乳腺癌组织中HIF-1α高表达病例5年存活率为29.2%,明显低于HIF-1α低表达病例（81.2%）（P=0.000）。HIF-1α蛋白与Her-2蛋白同时阳性组的患者预后最差（P<0.0001）。 ［结论］ 乳腺癌组织中HIF-1α的高表达与预后差、生存期短有关,HIF-1α的高表达是乳腺癌的危险因素,有助于判断肿瘤的侵袭性和转移能力。HIF-1α蛋白与Her-2蛋白均为乳腺癌的影响因素,在乳腺癌的进展中可能具有协同作用。     

Assessment of Her-2/neu gene amplification status in breast carcinoma with equivocal 2+ Her-2/neu immunostaining

Background and purposeAmplification of Her-2/neu gene occurs in 25–30% of breast carcinomas. FDA approved trastuzumab (Herceptin) is effective only in tumors having the gene amplification. Immunohistochemistry (IHC) for Her-2/neu protein is widely used but false positive and false negative results exist. Fluorescence in-situ hybridization (FISH) has both excellent sensitivity and specificity in detecting Her-2/neu amplification. Comparative studies have shown discordant results in proportion of cases with equivocal 2+ immunostain. This study is thus conducted to ascertain the frequency of Her-2/neu gene amplification by FISH in breast carcinoma specified as score 2+ by IHC and to correlate these findings with parameters of prognosis in breast cancer.MethodsFrom October 2008 till May 2010 all paraffin blocks from cases with invasive breast carcinoma which were scored as 2+ by IHC were eligible for the study, there were 50 cases. Immunohistochemical evaluation of Her-2/neu was performed using the HercepTest. All cases were immunohistochemically evaluated for ER and PR. FISH was performed using FDA approved Path-Vysion Her-2/neu/CEP 17 dual color probe.ResultsNine cases (18%) out of 50 cases scored as Her-2/neu 2+ by IHC showed true gene amplification with a median value of scoring ratio 4.28 ranging from 2.37 to 13.26. Another two cases showed low level of amplification but when corrected for Her-2/neu/CEP ratio they did not show true amplification as they were associated with polysomy 17. With the exception of tumor size, neither patient’s age, histologic grade nor lymph node status were correlated with Her-2/neu gene amplification. Significant inverse correlation existed between Her-2/neu gene amplification and ER (P = 0.01), PR status (P < 0.001).ConclusionEven though FISH is a more complex and expensive procedure, it should be considered the method of choice for assessment of Her-2/neu gene status especially for equivocal cases by IHC that are not accompanied by true gene amplification in the majority of breast carcinoma cases.     

Her-2/neu基因与放射敏感性

Her-2受体己成为一些恶性肿瘤的重要生物靶标,在恶性肿瘤的生物行为中发挥重要作用.其过度表达可能与肿瘤的放射抗拒密切相关,因此抗Her-2受体抗体可能具有放射增敏作用.抗Her-2受体抗体结合放射治疗可能为肿瘤治疗开辟新的道路.     

Her-2基因与乳腺癌靶向治疗

近年来随着肿瘤分子生物学技术的发展,分子靶向药物治疗已成为众多学者关注的热点领域,对乳腺癌的治疗策略产生了重大影响.其中,人表皮生长因子受体-2(Her-2)已证实为一个有效的分子靶向治疗的靶标,针对乳腺癌Her-2的分子靶向治疗成为近来继化疗和内分泌治疗后又一重要的治疗手段.     

Her-2与胃癌的分子靶向治疗

人表皮生长因子受体-2 (Her-2)是一种具有酪氨酸激酶活性的185 000的跨膜糖蛋白,在细胞分裂增殖信号跨膜转导中发挥重要功能,最终从多个途径影响肿瘤细胞的生物活动,如肿瘤细胞增殖、黏附、转移和分化等相关基因的调控.研究表明Her-2在胃癌患者中过表达率约12％～ 35％,是胃癌的预后不良因素,而Her-2单克隆...     

Her-2的研究进展与乳腺癌

原癌基因Her-2在许多肿瘤细胞中呈高表达，与乳腺癌的发生和发展有重要关系。其中Her-2在Her受体的信号网络系统和细胞周期的调节中发挥重要作用。对Her-2信号网络系统的研究也有助于找到以Her-2为靶分子的抗肿瘤治疗的有效方法。针对Her-2的单克隆抗体的抑制剂有广阔的应用前景。     

Her-2表达在食管胃结合部腺癌中的作用研究进展

近几十年来,食管胃结合部腺癌的发病率正在逐年上升。Her-2表达与食管胃结合部腺癌预后的研究结果呈现争议,研究认为这是因为Her-2检测的局限性和组织标本的异质性而导致不同的结果。对于Her-2过表达的食管胃结合部腺癌,综合治疗包括新辅助放化疗、辅助放化疗、手术治疗及靶向治疗在临床疗效中的地位越来越突出,中医药治疗也在辅助治疗中起到重要作用。     

Her-2 targeted therapy: Beyond breast cancer and trastuzumab

Her-2 is a validated therapeutic target in breast cancer. The two critical questions that remain regarding Her-2 targeting concern 1) the relevance of Her-2 inhibition in other malignancies and 2) the ability of novel agents to achieve greater Her-2 inhibition than trastuzumab. The contribution of cell signaling effects and immunologic mechanisms to the effect of trastuzumab in vivo remains poorly understood. Thus, the preclinical data that support the greater efficacy of novel Her-2 antibodies or small molecule tyrosine kinase inhibitors remain to be validated in clinical trials. In this review, we discuss the evidence from recent trastuzumab clinical trials as a point of departure for consideration of novel Her-2 targeted therapies. Preliminary results from early clinical trials suggest that Her-2 tyrosine kinase inhibitors may extend the population for which this strategy offers therapeutic effect.     

p53 and Her-2/neu in juvenile angiofibromas

The pathogenesis of juvenile angiofibroma (JA) remains unsolved. Further, it is unknown whether this fibrovascular tumour arises from the endothelial or stromal cells. Comparative genomic hybridisation analysis of these tumours revealed deletions of chromosome 17, including regions for the tumour suppressor gene p53 as well as the Her-2/neu oncogene, which are altered in many human tumours. In order to analyse if they are also important for progression of JA, the p53 gene and Her-2/neu gene were evaluated in 7 tumours by two-colour in situ hybridisation analysis using probes for the centromer of chromosome 17 either with a specific probe against p53 or Her-2/neu. In 5 out of 7 JAs, gene losses were detected for both genes ranging from 10.5 to 31.5%, respectively. Gene amplifications were not observed. Semi-quantitative RT-PCR analysis from laser microdissected single endothelial cells and fibroblasts showed up-regulated p53 mRNA levels in 4 out of the 7 JAs analysed in both investigated cell types and in one case in only endothelial cells. Her-2/neu mRNA was noted to be up-regulated in 2 JAs and down-regulated in 1 JA for both cell types. Western blot analysis as well as immunohistochemistry detected no p53 protein in the 5 investigated JAs, indicating absence of mutated p53. Our findings indicate that chromosomal losses on chromosome 17 imply p53 gene and Her-2/neu gene losses in JAs. However, comparison of p53 and Her-2/neu mRNA levels in laser microdissected endothelial and stromal cells were not conclusive to answer the question of the tumour cell of origin in JA.