乳腺癌患者血液HER-2浓度与组织HER-2表达水平的一致性研究

目的探讨复发转移乳腺癌患者血清HER-2浓度与组织HER-2表达水平的一致性。方法应用ELISA法测定血清HER-2浓度;应用免疫组化(IHC)法检测乳腺癌组织HER-2表达水平;对检测结果进行统计分析。结果组织HER-2阳性的复发转移乳腺癌患者中有62例血清HER-2阳性,阳性符合率为74.7%,组织HER-2阴性的患者有96例血清HER-2为阴性,阴性符合率为82.1%。血清HER-2水平与组织HER-2表达状态呈正相关(kappa=0.653,P<0.01)。结论复发转移乳腺癌患者血清HER-2浓度与组织HER-2表达水平无显著差别,两种检测方法具有较好的一致性,血清HER-2浓度可作为临床个体化治疗的参考依据。     

ELISA方法检测乳腺癌患者血清HER2的临床价值

目的：HER2基因扩增和HER2蛋白过表达是乳腺癌患者预后不良的分子标志,是临床指导靶向HER2治疗的标准。肿瘤细胞中HER2蛋白胞外域经蛋白酶裂解脱落入血,血清中HER2水平改变可以用于监测乳腺癌的进展和治疗疗效。本研究旨在分析血清HER2水平与乳腺癌组织HER2表达状态的相关性,并探讨血清HER2水平与临床病理因素的关系,以评价其潜在的临床应用价值。方法：分别采用ELISA和免疫组化方法检测70例乳腺癌患者血清HER2水平和肿瘤组织HER2表达状态,Spearmen秩相关分析二者的相关性,χ2检验分析血清HER2与临床病理因素的关系。结果：乳腺癌患者血清HER2水平和组织HER2表达呈正相关（r=0．686,P〈0．001）;肿瘤直径大于2cm患者血清HER2水平高于小于等于2cm患者（χ2=9．071,P=0．030）;临床II-III期患者血清HER2水平高于I期患者（χ2=9．001,P=0．030）;ER阴性患者血清HER2水平高于ER阳性患者（χ2=16．307,P〈0．0.001）：PR阴性患者血清HER2水平高于PR阳性患者（χ2=16．164,P〈0．001）,而血清HER2水平在不同患者年龄、组织学分级和淋巴结状态等临床病理因素各组间无统计学差异。结论：乳腺癌患者血清HER2水平可以反应肿瘤组织HER2表达状态,其水平升高提示乳腺癌恶性程度高、预后差,是潜在的乳腺癌预后预测和疗效监测的血清学标志,     

丝氨酸/苏氨酸激酶15在早期乳腺癌组织中的表达及与人类表皮生长因子受体2、雌激素受体的关系

目的:探讨丝氨酸/苏氨酸激酶15(STK15)在早期乳腺癌组织中的表达及其与人类表皮生长因子受体2(HER2)、雌激素受体(ER)的关系.方法:用免疫组化二步法检测76例有完整随访资料的早期乳腺癌患者乳腺癌组织中STK15、HER2、ER的表达,并进行统计学分析.结果:STK15、HER2、ER在早期乳腺癌组织中的阳性率分别为53.9%、55.3%、43.4%.STK15表达与HER2表达呈正相关(r=0.496,P<0.01).与ER表达呈负相关(r=-0.256,P<0.05).Kaplan-Meire分析并经Log-Rank检验,显示STK15阴性患者中位生存时间显著高于STK15阳性患者,差异有统计学意义(P<0.05).单因素分析示STK15、HER2、ER均与预后相关,多因素分析显示只有STK15与预后相关.结论:早期乳腺癌STK15表达与HER2、ER表达有关,STK15阳性表达的早期乳腺癌患者预后差,是早期乳腺癌独立的预后因素,可作为评价早期乳腺癌预后的生物学指标.     

荧光原位杂交与免疫组织化学技术检测乳腺癌人表皮生长因子受体2基因扩增及蛋白表达研究

目的 探讨荧光原位杂交(fluorescence in situ hybridization,FISH)和免疫组织化学(immunohistochemistry,IHC)检测乳腺癌人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)基因表达及扩增状态的临床意义.方法 采用FISH和IHC技术分别检测35例乳腺癌患者手术切除标本的HER2基因和蛋白表达情况及17号染色体倍体性,分析HER2基因扩增和蛋白表达状态的差异与17号染色体倍体性的相关性.结果 IHC与FISH检测的总符合率为82.8％;FISH检测HER2基因扩增情况与IHC检查HER2蛋白表达为(卅)、(++)和(-/+)者的符合率分别为93.3％,60.0％和90.0％; HER2基因绝对拷贝数阳性和阴性的患者中分别存在26.7％和10.0％的17号染色体多体扩增.结论 IHC是初步筛查HER2基因状态的首选方法;IHC检测HER2蛋白阳性的乳腺癌标本存在假阳性,FISH可准确、稳定地检测乳腺癌组织中HER2的基因状态及17号染色体倍体性.     

血清肿瘤标记物与HER2阳性乳腺癌骨转移的相关性研究

目的观察人类表皮生长因子受体2(HER2)阳性乳腺癌的肿瘤标记物水平与骨转移的相关性。方法收集确诊为HER2阳性浸润性乳腺癌的100例患者,根据有无骨转移分为2组:骨转移组(n=40),未骨转移组(n=60)。采用ELISA法监测患者入院时、随访发生骨转移时血清糖类抗原(CA153)和癌胚抗原(CEA)水平,观察2组患者年龄、病理分型、血清肿瘤标记物和赫赛汀的应用情况等,比较2组患者上述指标的差异。采用受试者工作特征(ROC)曲线预测血清CA153、CEA对HER2阳性乳腺癌骨转移的价值。结果 HER2阳性乳腺癌患者中,骨转移组和未骨转移组入院时血清CEA、CA153水平差异无统计学意义(P0.05),ROC曲线发现血清CEA水平(AUC 0.72,95%CI0.63~0.81,P=0.01)和CA153水平(AUC 0.67,95%CI 0.60~0.77,P=0.03)为预测预测骨转移的因素。其中CA15317.2U/mL预测HER2阳性乳腺癌患者骨转移的敏感度为78.8%,特异度为45.0%;CEA2.64μg/L预测骨转移的敏感度为75.8%,特异度为43.3%。结论血清CA153和CEA水平对HER2阳性乳腺癌的骨转移有一定的预测价值。     

胃癌患者血清溶菌酶水平与癌组织溶菌酶表达的相关性研究

目的探讨胃癌组织中溶菌酶(LZM)表达与血清溶菌酶(LZM)水平的相关性以及两者与胃癌临床病理生理特征的关系。方法检测组织中LZM表达采用SP法;血清LZM水平检测采用MTS/PMS比色法。结果 (1)胃癌患者血清LZM水平为219.7±42.5 KU/L。癌组织中LZM表达阳性率为69.4%;胃癌患者血清LZM水平明显高于健康对照组和良性消化道疾病组,差异有统计学意义(P0.05)。(2)胃癌患者血清LZM水平与癌组织LZM阳性表达呈正相关(r=0.98,P0.001)。(3)胃癌组织中LZM阳性表达者血清LZM水平明显高于阴性表达者,差异有统计学意义(P0.05)。结论胃癌患者血清中LZM水平与癌组织中LZM的阳性表达率一样,能反映胃癌的发生、发展及评估预后。     

胃癌患者血清溶菌酶水平与癌组织溶菌酶表达的相关性研究

目的 探讨胃癌组织中溶菌酶(LZM)表达与血清溶菌酶(LZM)水平的相关性以及两者与胃癌临床病理生理特征的关系.方法 检测组织中LZM表达采用SP法;血清LZM水平检测采用MTS/PMS比色法.结果 (1)胃癌患者血清LZM水平为219.7±42.5 KU/L.癌组织中LZM表达阳性率为69.4 %;胃癌患者血清LZM水平明显高于健康对照组和良性消化道疾病组,差异有统计学意义(P<0.05).(2)胃癌患者血清LZM水平与癌组织LZM阳性表达呈正相关(r=0.98,P<0.001).(3)胃癌组织中LZM阳性表达者血清LZM水平明显高于阴性表达者,差异有统计学意义(P<0.05).结论 胃癌患者血清中LZM水平与癌组织中LZM的阳性表达率一样,能反映胃癌的发生、发展及评估预后.     

胃癌患者血清溶菌酶水平与癌组织溶菌酶表达的相关性研究

目的 探讨胃癌组织中溶菌酶(LZM)表达与血清溶菌酶(LZM)水平的相关性以及两者与胃癌临床病理生理特征的关系.方法 检测组织中LZM表达采用SP法;血清LZM水平检测采用MTS/PMS比色法.结果 (1)胃癌患者血清LZM水平为219.7±42.5 KU/L.癌组织中LZM表达阳性率为69.4 %;胃癌患者血清LZM水平明显高于健康对照组和良性消化道疾病组,差异有统计学意义(P<0.05).(2)胃癌患者血清LZM水平与癌组织LZM阳性表达呈正相关(r=0.98,P<0.001).(3)胃癌组织中LZM阳性表达者血清LZM水平明显高于阴性表达者,差异有统计学意义(P<0.05).结论 胃癌患者血清中LZM水平与癌组织中LZM的阳性表达率一样,能反映胃癌的发生、发展及评估预后.     

显色原位杂交(CISH)技术在检测乳腺癌HER-2/neu基因状态中的应用

目的 显色原位杂交(CISH)在检测乳腺癌患者组织中HER2基因状态的临床应用,比较CISH与免疫组化(IHC)检测HER2状态的差异性.方法 采用试剂盒,以cIsH方法对216例IHC EnVision法染色阳性和阴性的浸润非特异性乳腺癌石蜡切片标本进行HER2基因状态的检测.同时进行雌激素(ER)、孕激素(PR)表达的检测.结果 HER2表达IHC(+++)的111例标本中,IHC 3+者中CISH显示扩增者102例(扩增率91.1%),58例IHC 2+者中CISH显示扩增者33例(扩增率56.9%),17例I-HC 1+者中CIsH显示扩增者4例(扩增率23.5%),30例IHC 0者中CISH显示扩增者2例(扩增率6.6%),两种方法总符合率77.3%(167/216),两者明显相关(P<0.01).另外,216例标本中,CISH检测的HER2基因扩增例数142例,无扩增者74例;ER阳性者为88例,阴性者128例;PR阳性者为94例,阴性者122例.基因扩增表达与ER、PR蛋白表达呈负相关性性(0.01).结论 IHC是HER2表达初步筛查的首选方法,由于蛋白表达和基因扩增检测结果存在明显相关性,符合率高,CISH检测方法一定程度上可替代FISH检测法.建议IHC(+++～+1)患者可进一步作CISH法检测HER2基因扩增来确诊,同时进行ER、PR的检测,更有利于临床治疗方案的选择.     

乳腺癌组织中CC3/Tip30蛋白的表达及其临床意义

目的:探讨CC3/Tip30在乳腺癌组织中的表达及其临床意义。方法:应用免疫组化方法检测112例乳腺癌组织与36例正常乳腺组织CC3/Tip30蛋白的表达情况,分析其与乳腺癌临床病理特征及预后的关系。结果:CC3/Tip30在乳腺癌组织中的阳性表达率为44.64%,明显低于在正常乳腺组织中的表达,乳腺癌组织中CC3/Tip30蛋白表达与TNM分期(χ2=3.902,P=0.048,r=-0.187)、淋巴结转移(χ2=5.508,P=0.019,r=-0.222)和Her-2(χ2=4.908,P=0.027,r=0.209)相关,而与患者年龄、肿瘤大小以及ER、PR表达状态无关;CC3/Tip30表达阳性组和阴性组的5年特异生存率分别为68.00%和43.50%,差异有统计学意义(P=0.001)。结论:CC3/Tip30蛋白在乳腺癌组织中表达下调,其缺失与乳腺癌的发展有关,且预后不良,可能为乳腺癌综合治疗提供依据。     

Predicting tissue HER2 status using serum HER2 levels in patients with metastatic breast cancer

BACKGROUND: Immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) are reliable ways to identify overexpression or amplification of the HER-2/neu (HER2, symbol ERBB2) gene, but each technique requires a high-quality tissue sample, which may not be available. We investigated whether serum concentrations of the HER2 extracellular domain (ECD) can be used as an alternative to tissue HER2 status in metastatic breast cancer, and we defined an optimal decision-level concentration of serum HER2 for prediction of tissue HER2 status. METHODS: In 195 patients with metastatic breast cancer, we determined HER2 expression by IHC and performed FISH analysis on tumors for which IHC staining was graded as 2+. We measured serum HER2 by immunoassay and used ROC curve analysis to determine optimal serum HER2 ECD concentrations for differentiation between positive and negative HER2 status. RESULTS: IHC results were 0/1+ for 30 (15%) of the patients, 2+ for 89 (46%), and 3+ for 76 (39%). FISH revealed HER2 amplification in 19 (21%) of the IHC 2+ tumors. Mean (SE) serum HER2 ECD was 22.2 (5.1) microg/L in the tissue HER2-negative group, significantly lower than the concentration of 363 (96) microg/L in the tissue HER2-positive group (P<0.0001). ROC curve analysis showed 95% specificity and 62% sensitivity for tissue HER2 positivity at 37 microg/L of serum HER2. CONCLUSION: To use serum HER2 concentration as an alternative to direct determination of tissue HER2 status, we suggest 37 microg/L as a cutoff for predicting positive tissue HER2 with 95% specificity. Sensitivity, however, is low.     

Shed HER2 surrogacy evaluation in primary breast cancer patients: a study assessing tumor tissue HER2 expression at both extracellular and intracellular levels

The aim of the present study was to investigate serum HER2 extracellular domain (ECD) as a putative surrogate marker of the shedding phenomenon of HER2 receptor from the tumor tissue of primary breast cancer (BC) patients. A pilot retrospective study was conducted on 100 matched serum and tissue samples from patients with node-positive primary BC, stage II/III. Analysis of association and concordance between serum HER2 ECD levels (measured by chemiluminescence immunoassay) and the expression in matched tumor tissue of HER2 ECD and intracellular receptor domain (ICD) (determined by immunohistochemistry) were performed. The median serum HER2 ECD level was 9.4?ng/ml and cutoff values were set at 15.2?ng/ml or 13.0?ng/ml. HER2 ICD and ECD were overexpressed in tumor tissue of 19.8% and 6.9% of patients, respectively. Statistically significant associations were found between serum HER2 ECD levels and tissue expression of both HER2 ICD and ECD (p?<?.001; Fisher analysis). Moreover, strong concordances were found between serum HER2 ECD levels and tissue expression of HER2 ICD or ECD (cutoff 15.2?ng/ml: 80 and 92.5%, respectively). Our findings support a role for serum HER2 ECD as a surrogate marker of tissue HER2 status in primary BC, both for HER2 ICD or ECD expression.     

Correlation between the in vitro ATP-based chemosensitivity assay and HER2/neu expression in women with breast cancer

Several in vitro chemosensitivity tests have been developed to predict the chemotherapeutic response of tumours prior to initiation of individualized treatment for breast cancer. This study investigated whether the in vitro chemosensitivity response of cell lines derived from breast cancer patients was affected by HER2/neu expression. We cultured breast cancer cell lines from 50 patients and the adenosine triphosphatebased chemotherapy response assay (ATPCRA) was performed with 5-fluorouracil, gemcitabine, docetaxel, doxorubicin, methotrexate, vinorelbine and paclitaxel. 5-fluorouracil combined a high median cell death rate (32.4%) with the narrowest range of cytotoxic effects (7.3-65.7%). In addition, gemcitabine showed significantly greater activity in HER2/neupositive patients. In contrast, docetaxel was significantly less effective in HER2/neu-positive patients. No significant correlation was found between the other agents and HER2/neu expression. The use of the ATP-CRA test for metastatic tissue from patients with recurrent disease might be a useful approach to determine the most effective chemotherapy regimen.     

Serum HER2/ECD value in stage I and II early breast cancer �C need of a lower cut-off?

BACKGROUND: HER2 overexpression is well-established risk factor of worse prognosis in metastatic and early breast cancer. HER2 positivity can be determined from tumor tissue by immunohistochemical staining or by fluorescent in situ hybridization, or from serum by measuring concentration of HER2 receptor extracellular domain (HER2/ECD). HER2/ECD correlates well with worse prognosis in metastatic and locally advanced (stage III) disease if serum concentration is >15 ng/ml, but there are no consistent data for patients with early breast cancer. METHODS AND RESULTS: 41 patients with stage I and II breast cancer and 52 healthy controls were included into the study. HER2/ECD was determined before surgery and correlated with HER2/neu overexpression, Ki67, hormone receptor status and disease stage, and compared with value in healthy controls. Mean serum HER2/ECD concentration in patients was 8.62 ng/ml and 5.78 ng/ml in controls, and the difference was statistically significant (p = 0.000061). The best diagnostic cut-off value was 7.7 ng/ml, with 76.92% sensitivity and 72.92% specificity. Positive predictive value of the test was 69.77% and negative predictive value was 79.55%, with 74.71% of patients correctly classified. Serum HER2/ECD correlated with hormone receptors status, and no correlation with histological overexpression has been observed. CONCLUSION. Serum HER2/ECD concentration of ≥7.7 ng/ml has possible diagnostic value in stage I and II breast cancer. It should not be used as a determinant of HER2 positivity. Prognostic significance of HER2/ECD in early breast cancer, its correlation with hormone receptor status, and interconnection between hormone receptors and HER2 receptor signaling should be further analyzed, since it may have therapeutic implications.     

HER-2/neu在乳腺癌血清中的表达及意义

目的 分析乳腺癌HER-2／neu表达水平并探讨其临床意义。方法 用ELISA方法分析127例乳腺癌患者，30例良性疾病及40名健康体检者血清可溶性HER-2／neu水平并用免疫组化（mc）方法分析乳腺癌组织切片中癌细胞的HER-2／neu染色。结果乳腺癌患者血清中可溶性HER-2／neu水平与正常对照和良性乳腺疾病相比，有显著性差异（P〈0．05）。随TNM分期进展，乳腺癌患者可溶性HER-2／neu阳性率逐步升高。结论 乳腺癌患者血清中可溶性HER-2／neu水平呈过度表达，而且与免疫组化结果呈正相关。     

人表皮生长因子受体3在乳腺癌组织中的表达及临床意义

目的探讨人表皮生长因子受体(HER)3基因在乳腺癌组织中的表达及其与临床病理学特征和预后的相关性。方法采用免疫组织化学法检测126例乳腺癌组织中HER3的表达,分析其表达与患者年龄、月经情况、TNM分期、肿瘤大小、淋巴结转移、雌激素受体(ER)、孕激素受体(PR)、HER2及预后的关系。结果 (1)乳腺癌组织中HER3的阳性表达率为30.2%。HER3阳性表达在乳腺癌绝经患者中占43.3%,高于未绝经者的18.2%(P0.05);淋巴结转移阳性的乳腺癌患者HER3阳性表达率为40.0%,高于无淋巴结转移患者的21.2%,差异有统计学意义(P0.05);HER2阳性的乳腺癌患者HER3阳性表达率为42.5%,高于HER2阴性者的24.4%,差异有统计学意义(P0.05)。(2)HER3阳性患者的五年无病生存率更低(P0.05)。(3)HER3与HER2均阳性的乳腺癌患者淋巴结转移率较高(P0.05)。结论 HER3的表达可能在乳腺癌的发生和发展过程中起重要作用,并影响其预后,HER3可能成为判断乳腺癌预后的指标及临床治疗的靶点。     

Polyclonal antibodies against gp185HER2 peptides: their putative role in the identification of a particular HER2 status in patients with breast cancer

The HER2 oncogene and its relative oncoprotein, gp185HER2, a transmembrane glycoprotein belonging to the epidermal growth factor receptor family, are overexpressed in a wide range of solid tumors including breast and ovarian cancer. In patients with breast cancer, both humoral and cell-mediated HER2 immune responses have been found as well as in some patients with gp185HER2 nonoverexpressing tumors. To establish whether peptide sequences identified as HLA-A2-restricted T-cell epitopes are expressed in breast tumor cell lines and tissues, we produced and characterized by different methodologic approaches polyclonal antibodies raised against four gp185HER2 peptides. Two of the antibodies recognized peptides eluted from the HLA-A2 groove of the mDAmB231 breast cancer cell line expressing a basal level of gp185HER2. Paraffin-embedded primary and metastatic breast tumors were specifically immunostained by all four reagents, thereby showing an overlapping reactivity. When this immunoreactivity was compared with that obtained using two different monoclonal antibodies, in 105 breast primary tumors and 36 corresponding lymph node metastases, we identified a subset of tumors that were negative with anti-gp185HER2 monoclonal antibodies and positive with the four antipeptide antibodies. Our novel observations provide in vivo evidence of the complexity involved in evaluating HER2 expression, and open a new path for understanding the biologic significance of HER2 status in breast tumors.     

乳腺癌患者血清HER-2／neu浓度及临床意义的分析

目的分析乳腺癌患者血清人表皮生长因子受体．2（HER-2／neu）的水平与组织HER-2表达水平的差异,分析血清HER-2／neul的影响因素以及与化疗疗效的相关性。方法采用酶联免疫吸附（ELISA）方法检测37例可手术的早期乳腺癌患者及74例晚期转移性乳腺癌患者血清HER-2／neu的水平,分析血清HER-2／neu与组织中HER-2的表达、临床参数的相关性。结果晚期乳腺癌患者血清HER-2／neu的水平与组织HER-2的状态一致性较好（P〈0．05）,早期乳腺癌患者中两者则无明显关系。乳腺癌血清HER-2的水平与血清CA153、CEA均无明显相关性。晚期乳腺癌血清HER-2的水平与肿瘤大小、远处转移数目、脉管瘤栓具有明显关系,而与月经状况、ER、PR均无明显关系（P〉0．05）。血清HER-2水平的变化与化疔疗效有关（P〈0．05）。结论晚期乳腺癌患者血清HER-2／neu水平与肿瘤组织中HER-2表达是一致的且与肿瘤负荷密切相关,可作为组织学检测的重要补充方法。