人表皮生长因子受体2低表达乳腺癌病理检测及其异质性研究进展

人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)是乳腺癌的生物标志物之一。近年研究表明以曲妥珠单抗德鲁特康(T-DXd)、曲妥珠单抗多卡木嗪(SYD985）为代表的新型抗体药物偶联物可能使HER2低表达乳腺癌患者受益。按照目前的评分系统,HER2低表达乳腺癌患者占所有乳腺癌总数一半以上,从靶向治疗中获益的患者或可达到60%～70%。然而,HER2低表达乳腺癌是否具有独特生物学特异性的临床亚型尚有争议。     

人表皮生长因子受体-2及雌激素受体与乳腺癌的关系

乳腺癌与人表皮生长因子受体-2及雌激素受体关系密切,这两种受体也是乳腺癌的分类标准和治疗靶点。在大多数乳腺癌患者中,人表皮生长因子受体-2信号途径和雌激素受体信号途径参与了细胞的增生存活过程。而且在乳腺癌病例中,人表皮生长因子受体-2和雌激素受体呈现出一定程度的负相关。这说明这两种受体活化后有一些联系。本文简要综述了人表皮生长因子受体-2和雌激素受体的联系以及这种联系在乳腺癌治疗中的意义。     

人表皮生长因子受体-2与细胞增殖抗原Ki67在乳腺癌组织中的表达及其临床意义

目的：探讨人表皮生长因子受体-2（HER-2）与细胞增殖抗原Ki67在乳腺癌组织中的表达情况及其与临床特征的关系。方法选取103例乳腺癌患者,获得组织标本,采用免疫组化方法检测HER-2与Ki67的表达水平,并分析其与临床特征之间的关系。结果103例乳腺癌患者中HER-2、Ki67染色阳性者分别有68例和78例,阳性率分别为66.02%和75.73%。TNM分期、淋巴结转移情况以及雌激素受体（ER）表达均影响HER-2表达（P﹤0.05）。Ki67阳性表达率在不同TNM分期和淋巴结转移情况的患者中比较,差异有统计学意义（P﹤0.05）。结论 HER-2和Ki67在乳腺癌组织中与患者的TNM分期和淋巴结转移情况相关,可作为重要的临床检测指标。     

乳腺癌钼靶X线表现与雌激素受体、孕激素受体及人表皮生长因子受体-2的关系

目的:探讨乳腺痛的钼靶X线表现与雌激素受体(ER)、孕激素受体(PR)以及人表皮生长因子受体-2(C-erbB-2)表达之间的关系.方法:将111例经手术病理证实的乳腺癌患者钼靶X线征象中的肿块、钙化、结构扭曲、毛刺与ER、PR、C-erbB-2表达情况进行比较.结果:111例中,有肿块67例(60.36%),有毛刺22例(19.82%),有钙化者41例(36.94%),有结构扭曲者21例(18.92%).ER阳性59例(53.15%),PR阳性46例(41.44%),C-erbB-2阳性56例(50.45%).肿块、钙化和结构扭曲与ER的表达无显著统计学意义;有毛刺组的ER阳性表达高于无毛刺组,有显著统计学意义.肿块、钙化、结构扭曲和毛刺均与PR的表达无显著统计学意义.有肿块组中C-erbB-2阳性表达低于无肿块组;有钙化组的C-erbB-2阳性表达高于无钙化组,都有显著统计学意义.结构扭曲和毛刺与C-erbB-2的表达没有显著统计学意义.结论:乳腺癌患者的钼靶X线表现可在某种程度上反映ER、PR、C-erbB-2的表达状况.     

乳腺癌钼靶X线表现与雌激素受体、孕激素受体及人表皮生长因子受体-2的关系

目的：探讨乳腺癌的钼靶x线表现与雌激素受体（ER）、孕激素受体（PR）以及人表皮生长因子受体-2（C—erbB-2）表达之间的关系。方法：将111例经手术病理证实的乳腺癌患者钼靶X线征象中的肿块、钙化、结构扭曲、毛刺与ER、PR、C—erbB-2表达情况进行比较。结果：111例中,有肿块67例（60．36％）,有毛刺22例（19．82％）,有钙化者41例（36．94％）,有结构扭曲者21例（18．92％）。ER阳性59例（53．15％）,PR阳性46例（41．44％）,C—erbB-2阳性56例（50．45％）。肿块、钙化和结构扭曲与ER的表达无显著统计学意义;有毛刺组的ER阳性表达高于无毛刺组,有显著统计学意义。肿块、钙化、结构扭曲和毛刺均与PR的表达无显著统计学意义。有肿块组中C—erbB-2阳性表达低于无肿块组;有钙化组的C—erbB-2阳性表达高于无钙化组,都有显著统计学意义。结构扭曲和毛刺与C—erbB-2的表达没有显著统计学意义。结论：乳腺癌患者的钼靶X线表现可在某种程度上反映ER、PR、C—erbB-2的表达状况。     

人表皮生长因子受体2阳性转移性乳腺癌靶向治疗进展

人表皮生长因子受体2 (HER-2)阳性乳腺癌约占全部乳腺癌的15%～20%,是最具侵袭性的乳腺癌亚型之一。靶向治疗具有高效、低毒、精确杀伤的特点。近20年来,单克隆抗体、酪氨酸激酶抑制剂、抗体偶联药物等靶向药物,不断改变着HER-2阳性转移性乳腺癌的治疗格局,显著改善了患者的预后。文章将讨论不同类型抗HER-2靶向药物在HER-2阳性转移性乳腺癌治疗中的最新进展。     

人类表皮生长因子受体2在胃癌根治术后复发患者中的表达及其意义

目的探讨胃癌根治术后复发患者中人类表皮生长因子受体2(HER2)表达与临床病理特征及预后的关系。方法回顾性分析2011年12月至2019年3月福建省肿瘤医院收治的116例胃癌根治术后复发患者的临床资料,分析切除肿瘤组织中HER2表达与患者临床病理特征及预后的关系。结果116例胃癌患者根治术后标本中HER2阳性率为19.8%(23/116)。高中分化胃癌患者HER2阳性率高于低分化胃癌患者[33.3%(11/33)比14.5%(12/83)],差异有统计学意义(χ^2=5.292,P<0.05]。肺转移患者HER2阳性率高于不伴有肺转移的患者[42.1%(8/19)比15.5%(15/97)],差异有统计学意义(χ^2=5.517,P<0.05)。不同性别、年龄、肿瘤部位、复发部位、TNM分期、转移部位数及是否有神经脉管侵犯、肝转移、局部复发的患者间HER2阳性率比较,差异均无统计学意义(均P>0.05)。HER2表达与无病生存期无关(P>0.05)。结论HER2表达与胃癌的分化程度及远处转移部位有关,但其尚不能作为预测胃癌复发的指标。     

表皮生长因子受体表达与乳腺癌激素受体水平和预后的关系

应用免疫组化ＡＢＣ方法研究７５例乳腺癌冰冻组织表皮生长因子受体（ＥＧＦＲ）的表达，结合临床资料和ＥＲ、ＰＲ测定结果进行分析，探讨ＥＧＦＲ表达与乳腺癌预后的关系。结果表明，ＥＧＦＲ阳性３０例（４０％），ＥＧＦＲ表达与肿瘤大小、腋淋巴结状况，临床分期和年龄无关，与ＥＲ、ＰＲ存在着显著的负相关（Ｐ＜０．００５）。全组中位随诊时间为６０个月，ＥＧＦＲ阳性组术后总生存率明显低于阴性组（Ｐ＜０．００１）。在无腋淋巴结转移的病例中，ＥＧＦＲ阳性组和阴性组术后生存情况也有显著差异（Ｐ＜０．０１），提示ＥＧＦＲ表达与乳腺癌不良的预后有关。调整分析乳腺癌有关的预后因素，各组病例中均以ＥＧＦＲ表达阳性组的预后为差，说明ＥＧＦＲ对乳腺癌预后具有独立的作用，不受其他因素的影响。经Ｃｏｘ模型多因素分析显示，ＥＧＦＲ和腋淋巴结受累与否是对乳腺癌术后生存情况有显著性影响的两个因素。     

表皮生长因子受体及DNA含量在乳腺癌预测因素中的地位

用免疫组化法检测４６例乳腺癌组织中ＥＧＦＲ及ＥＲ，流式细胞技术检测ＤＮＡ倍体状况，结合病理因素及临床随访结果进行分析，结果发现：１）ＥＧＦＲ与ＥＲ呈显著负相关（Ｐ＜０．０５），与肿瘤组织学分级呈显著正相关（Ｐ＜０．０１），不同月经状况、肿瘤大小、淋巴结受累情况及ＴＮＭ分期中ＥＧＦＲ阳性率无显著差异，ＥＧＦＲ阳性患者生存期显著低于ＥＧＦＲ阴性患者的生存期；２）ＤＮＡ含量与ＥＲ呈负相关，与组织学分级，肿瘤大小及ＥＧＦＲ呈显著正相关，ＤＮＡ异倍体患者生存期明显低于二倍体肿瘤患者的生存期（Ｐ＜０．０１）。提示：ＥＧＦＲ、ＤＮＡ可作为乳腺癌预测预后的有效生物学信息。     

新辅助化疗对乳腺癌雌激素受体、孕激素受体、人表皮生长因子受体-2的影响

乳腺癌是目前全世界女性发病率最高的恶性肿瘤,发病率呈逐年上升的趋势,对于晚期的乳腺癌患者,乳腺癌术前新辅助化疗能有效地消灭病灶癌细胞,临床降期,增加保乳手术率,是世界上公认的标准治疗方法。同时,乳腺癌也是一种激素依赖型恶性肿瘤,通过检测乳腺癌组织中雌激素受体(ER)、孕激素受体(PR)、人表皮生长因子受体-2(Her-2)对于指导术后内分泌治疗及曲妥珠单抗治疗有重要意义。乳腺癌的治疗步入"精准化"时代,由于术后的全身内分泌治疗及曲妥珠单抗治疗主要基于上述标志物的状态,所以在新辅助化疗作用残余癌组织中,这些肿瘤标志物是否会发生改变还存在争议,这些标志物的变化对于全身治疗方案的影响仍无定论。作者通过复习文献,总结归纳了新辅助化疗前后,乳腺癌组织中ER、PR及Her-2的变化情况。     

Expressional Correlation of Human Epidermal Growth Factor Receptor 2, Estrogen/Progesterone Receptor and Protein 53 in Breast Cancer

Background: This study aimed to show the localization of estrogen / progesterone receptors, human epidermalgrowth factor receptor 2 (Her-2) and protein 53 (p53) by immunohistochemistry in a series of consecutive breastcancer patients. Materials and Methods: The study covered invasive breast cancers from 299 patients presentingat the Oncogenetic Clinic and Pathology Centers of Ahwaz Jondishapour University of Medical Sciences Hospitalin Iran during the time period from 2009 to 2011. The Scarff-Bloom Richardson scoring method was used. Results:Of the 299, 27% (80/299) were <40, 33% (100/299) were 41-50, and the remaining 40% (119/299) were>50 yearsold. The highest incidence of breast cancer in this study population was in the group of more than 50 year age,and the most common histological type of breast cancer was the invasive ductal carcinoma, which accountedfor 68% (203/299) of the cases. Out of possible total of 207, 6% (13/207), 41% (85/207), and 53% (109/207) werescored as grade І, ІІ, ІІІ, respectively. Conclusion: Our findings demonstrated a lack of association betweenlabeling for the markers studied and tumor size and age of the patients. We confirmed an association betweenER labeling and nuclear grade of breast cancer. The conflicting results obtained compared with the literature bebecause of differences in the immunohistochemical techniques applied in the various studies and to the scoringsystems used.     

Combined Estrogen Receptor and Progesterone Receptor Level Can Predict Survival Outcome in Human Epidermal Growth Factor Receptor 2-positive Early Breast Cancer

BackgroundIn human epidermal growth factor receptor 2 (HER2)-positive breast cancer, emerging evidence imply that clinical behaviors differ according to hormone receptor (HR) status. However, there is no conclusion about the relevance between estrogen receptor (ER) or progesterone receptor (PR) expression and clinical outcome of HER2+ breast cancer. Our study aimed to determine the influence of different ER/PR levels on survival outcome of HER2+ early breast cancer.Patients and MethodsNine hundred and nineteen early HER2+ breast cancer patients treated between 2009 and 2016 were retrospectively reviewed and HR+/HER2+ patients were further divided based on ER level (Low/L: 1%-9%; Median/M: 10%-79%; High/H: 80%-100%) and PR level (Low/L: 0%-19%; High/H: 20%-100%) according to restricted cubic spline (RCS) smoothing curve. Disease-free survival (DFS) and overall survival (OS) were estimated by Kaplan–Meier method and log rank test.ResultsFour hundred and forty two HR+/HER2+ and 477 HR-/HER2+ breast cancer patients were included in our study and 73.2% received target therapy (HR+ 69.7%, HR- 76.5%). While HR+/HER2+ breast cancer showed better survival than HR-/HER2+ subtype in 5-year disease free survival (DFS, 93.0% vs. 86.8%, P < .001), no significant difference was observed between DFS in ER+/PR+ and ER+/PR- subgroup (94.4% vs. 90.4%, P = .22). However, a potential correlation was found between ER/PR levels and DFS in HR+/HER2+ (P = .074) tumors. In HR+/HER2+ breast cancer, all subgroups showed DFS improvement trend versus M-ER/L-PR. In all HER2+ patients, hazard ratio of H-ER/H-PR compared with HR- subtype was 0.10 (95%CI 0.01-0.74, P = .024) in all patients and 0.14 (95%CI, 0.02-1.02, P = .053) in patients receiving anti-HER2 therapy.ConclusionER/PR expression may become a predictor of survival benefit in HER2+ early breast cancer and a higher ER/PR level might be associated with better DFS.     

Reproductive Factors and Subtypes of Breast Cancer Defined by Estrogen Receptor,Progesterone Receptor,and Human Epidermal Growth Factor Receptor 2: A Register-Based Study From Korea

BackgroundThe relationship between reproductive breast risk factors and breast cancer survival in patients with different breast cancer subtypes is not well known.MethodsWe examined a large-sized, retrospective study of 23,882 subjects from the Korean Breast Cancer Registry. The breast cancer subtype was determined by immunohistochemical staining for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). Information regarding reproductive factors, including breastfeeding, age at first birth (AFB), and parity, was gathered. Multivariate Cox regression analysis was used to estimate the association among breast cancer subtypes, such as luminal A, luminal B, Her-2/neu overexpressing, and triple negative breast cancer (TNBC), and breast cancer survival as dependent variables and adjusting for age and stage.ResultsHigh parity (≥ 5) increased the recurrence risk of luminal A and B breast cancer (hazard ratio [HR], 1.95; 95% confidence interval [CI], 0.96-3.97; P = .0055 and HR, 1.12; 95% CI, 0.42-3.02, respectively; P = .0073) in breast cancer–specific survival (BCSS), but 1 to 3 child births decreased the recurrence risk of luminal A breast cancer (HR, 0.56; 95% CI, 0.34-0.91; P = .0055) and luminal B breast cancer (HR, 0.32; 95% CI, 0.17-0.61; P = .0073) in BCSS. Early AFB (< 20 years) increased the recurrence risk of luminal A breast cancers (HR, 1.61; 95% CI, 0.62-4.26; P = .039) in BCSS and of TNBC (HR, 1.31; 95% CI, 0.78-2.21; P = .0006) in overall survival. Her-2/neu overexpressing breast cancer had no correlation with parity and AFB in breast cancer survival.ConclusionsHigh parity (≥ 5) and early AFB (< 20 years) were correlated with worse clinical outcomes in patients with luminal breast cancer, but not with other subtyped breast cancers.     

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。     

C－erbB－2，人表皮生长因子及其受体在大肠癌中表达的意义

用ＡＢＣ免疫组化法测定２００例大肠癌组织中Ｃ－ｅｒｂＢ－２，人表皮生长因子（ｈＥＧＦ）及其受体（ＥＧＦＲ）。结果发现：１）Ｃ－ｅｒｂＢ－２，ｈＥＧＦ，ＥＧＦＲ在２００例大肠癌中阳性表达分别为３６％、４４％、４７％，三者共同阳性为１６．５％。２）ｈＥＧＦ，ＥＧＦＲ在大肠癌ＤｕｋｅｓＣ、Ｄ期，肿瘤＞２ｃｍ、低分化腺癌，有深度浸润和淋巴结转移者阳性率显著高于其它各型（Ｐ＜０．０１）。３）Ｃ－ｅｒｂＢ－２，ｈＥＧＦ和ＥＧＦＲ阳性病例存活率明显低于这些阴性病例（Ｐ＜０．０１）。结果表明，Ｃ－ｅｒｂＢ－２，ｈＥＧＦ和ＥＧＦＲ在大肠癌的侵袭性生长中起重要作用，ｈＥＧＦ和ＥＧＦＲ可作为大肠癌患者高度恶性的生物学指标。     

乳腺癌组织中孕激素受体与雌激素受体DNA结合功能关系的研究

目的：观察３６例（Ｅ２＋）乳腺癌患者组织ＰＲ和ＥＲ ＤＮＡ结合功能的关系,进而探讨（Ｅ２＋／ＰＲ＋）表型内分泌治疗无反应的分子机制。方法：用激素结合法和迁移率改变法。结果：１）用含有ＥＲ的ＭＣＦ－７细胞株作为阳性对照,２２℃Ｍｇ＾２＋存在条件下,迁移率改变法中ＥＲ－ＥＲＥ复合物的形成是激素依赖性的,证实了ＥＲ－ＥＲＥ复合物的特性。（２）激素结合法和迁移率改变法检测结果显示,３６例（Ｅ２＋）乳腺癌中     

Paraneoplastic Encephalitis Associated with Locally Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer

Paraneoplastic neurologic diseases (PND) are rare but can occur in patients with common malignancies including breast cancer. In patients with hormone receptor (HR)-negative human epidermal growth factor receptor 2 (HER2)-positive breast cancer, PND have been reported in association with anti-Yo antibodies and with clinical presentation of paraneoplastic cerebellar degeneration. We describe the case of a woman with progressively altered mental status and seizures, ultimately requiring admission. Based on her clinical presentation, imaging findings, and evidence of neural-directed antibodies in her serum and cerebrospinal fluid, she was diagnosed with paraneoplastic limbic encephalitis (LE) due to an underlying HR-negative, HER2-positive breast cancer. She showed a transient response to immunosuppression but had more significant improvement after surgical resection and initiation of chemotherapy along with HER2-directed therapy. To the best of our knowledge, this is the first documented case of paraneoplastic LE in a patient with HR-negative, HER2-positive breast cancer likely caused by the production of an unclassified anti-neuronal antibody.     

Estrogen Receptor Mutations and Changes in Estrogen Receptor and Progesterone Receptor Protein Expression in Metastatic or Recurrent Breast Cancer

To investigate the frequency of estrogen receptor ( ER ) gene mutation in metastatic or recurrent breast cancer, metastatic lymph nodes or recurrent breast cancer tissue from 35 patients with ER-positive primary tumors were screened for mutations in the hormone-binding domain of the ER gene by sequence analysis. Four missense mutations, Val316Ile, Gly344Val, Ala430Val and Gly494Val, were identified in these lesions. Second, to clarify whether there is any disparity in hormone receptor status between primary and metastatic or recurrent tumors, we immunohistochemically studied 117 specimens including the above 35 specimens obtained from metastatic or recurrent breast cancer patients using monoclonal anti-ER and progesterone receptor (PgR) antibodies. Although hormone receptor status, especially ER, was highly maintained through disease progression, negative change in PgR expression at relapse (33%) was identified more frequently than in metastatic lymph nodes (6.7%). Therefore, it was suggested that development of PgR-negative phenotype might correlate with disease progression in some breast cancer patients. These results suggest that ER mutations in metastatic or recurrent breast cancer may be more frequent than in primary lesions, irrespective of high maintenance of ER protein expression through disease progression.