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。     

Human epidermal growth factor receptor 2 overexpression in breast cancer of patients with anti-Yo--associated paraneoplastic cerebellar degeneration

Isolated case reports suggest that breast tumors from patients with paraneoplastic cerebellar degeneration (PCD) and Yo antibodies overexpress human epidermal growth factor receptor 2 (HER2). HER2 overexpression is present in 15%-25% of breast cancers and is associated with poor prognosis. We retrospectively analyzed the status of HER2 in breast tumors of 27 patients with anti-Yo-associated PCD to evaluate whether HER2 overexpression in this group of patients is higher than expected. In addition, we analyzed HER2 status of 19 breast tumors from patients with paraneoplastic neurological syndromes and Ri antibodies to see whether HER2 was specifically related to anti-Yo-associated PCD. We also assessed cdr2 expression (the onconeural antigen recognized by Yo antibodies) in 21 HER2-positive breast tumors from patients without paraneoplastic neurological syndromes. HER2 was overexpressed in 26 patients (96.3%) with anti-Yo-associated PCD but only in 2 patients (10.5%) with paraneoplastic neurological syndromes associated with Ri antibodies (P< .0001). Only 5 (23.8%) of the 21 HER2-positive breast tumors showed cdr2 immunoreactivity. This study shows a very high frequency of HER2 overexpression in breast cancers in patients with anti-Yo-associated PCD but not in those from patients with Ri antibodies. Although the expression of cdr2 onconeural antigen is not high in HER2-positive breast cancers, HER2 overexpression seems to be an important requirement to develop an anti-Yo-associated PCD.     

Prognostic value of epidermal growth factor receptor in node-positive breast cancer

Summary The prognostic significance of EGFR (epidermal growth factor receptor) was studied in a cohort of 68 node-positive patients with breast cancer, who entered a controlled protocol of adjuvant therapy between February 1980 and June 1984. EGFR radioligand binding assay was carried out on frozen stored samples. Twenty five (37%) of 68 primary sites and 9 (41%) of 19 lymph node metastases assayed were EGFR-positive with a cut off value of 5 fmol/mg membrane protein; there is no statistical difference between the two distributions. EGFR was significantly correlated to ER and histological grade. EGFR-positive tumors and high levels of EGFR were mainly found in the ER-negative group of tumors (p = 0.008) and in histological grade III (p = 0.007). Fifty five patients could be followed for 40 to 92 months. EGFR was an independent prognostic factor for survival after 40 months (p = 0.05). EGFR⁺/ER^– patients had the lowest survival probability, but statistical significance was not reached (p = 0.06). The EGFR phenotype appeared as a prognostic parameter in node-positive patients, individualizing subgroups of patients with different early outcome, with potential therapeutic implication especially in the group of ER-negative patients. These results emphasize the need for a standardized assay methodology and for further clinical studies, particularly in protocols where adjuvant hormonal therapy is prescribed on the basis of steroid hormone receptor status, in order to assess the respective prognostic worth of EGFR and ER (or PR).     

229例人表皮生长因子受体2阳性Ⅳ期乳腺癌患者曲妥珠单抗的治疗分析

目的 探讨曲妥珠单抗对人表皮生长因子受体2(HER2)阳性Ⅳ期乳腺癌的治疗效果及患者预后的影响因素.方法 收集229例应用曲妥珠单抗治疗的HER2阳性Ⅳ期乳腺癌患者的临床资料,采用Cox比例风险回归模型分析HER2阳性Ⅳ期乳腺癌患者无进展生存时间(PFS)和总生存时间(OS)的影响因素.结果 229例HER2阳性Ⅳ期乳...     

Anthelminthic niclosamide inhibits tumor growth and invasion in cisplatin-resistant human epidermal growth factor receptor 2-positive breast cancer

Chemotherapy-resistant breast cancer displays aggressive clinical behavior, is poorly differentiated and is associated with the occurrence of epithelial-mesenchymal transition and the presence of cancer stem cells. The anthelmintic drug niclosamide has been shown to have numerous clinical applications in the treatment of malignant tumors, in addition to its traditional use in tapeworm disease. Our previous study demonstrated that niclosamide had an antiproliferative effect and could inhibit the stem-like phenotype of the breast cancer cells, suggesting that it might have the potential to be used in the treatment of triple-negative breast cancer. However, the specific function and underlying mechanism of action of niclosamide in chemoresistant human epidermal growth factor receptor 2 (HER2)-positive breast cancer remain unknown. The present study aimed to determine whether niclosamide can inhibit cell proliferation, invasion and epithelial-to-mesenchymal transition, as well as the stem-like phenotype in cisplatin-resistant HER2-positive breast cancer. Alamar Blue and Annexin V/7-AAD staining, mammosphere formation and Transwell assays were performed to assess the viability, apoptosis, stem-like phenotype and invasion ability of breast cancer cell lines, respectively. Signaling molecule expression was detected via western blotting and a xenograft model was used to verify the inhibitory effect of niclosamide in vivo. The results from the present study demonstrated that niclosamide inhibited the resistance of HER2-positive breast cancer to cisplatin both in vitro and in vivo. Furthermore, niclosamide combined with cisplatin could inhibit breast cancer cell invasion, epithelial-mesenchymal transition and cell stemness. The inhibitory effect of niclosamide was mediated by apoptosis induction and Bcl-2 downregulation. Taken together, the results of the present study suggested that niclosamide combined with cisplatin may be considered as a novel treatment for chemoresistant HER2-positive breast cancer.     

Role of epidermal growth factor receptor expression in primary breast cancer: results of a biochemical study and an immunocytochemical study

Summary We have conducted two series of studies, a biochemical study and an immunocytochemical study, to investigate the role of epidermal growth factor receptor (EGFR) expression in primary breast cancer patients. In the biochemical study, a consecutive 115 patients were included and EGFR was measured by a competitive binding assay with multipoint Scatchard analysis. In the immunocytochemical study comprising 126 patients, EGFR status was determined by immunostaining with anti-EGFR antibody EGFR1. Several agreements were found from these two studies. EGFR status was inversely correlated with estrogen receptor (ER) status. No significant correlation was found between EGFR status and tumor size, nodal metastases, or the expression of c-erbB-2 protein. Ki-67 immunoreactivity, a cellular proliferation marker, was enhanced in EGFR positive tumors over EGFR negative tumors, suggesting a linkage of EGFR expression to cellular proliferative activity. Post-operative follow up showed that relapse-free survival for EGFR positive patients was significantly worse than that for EGFR negative patients, particularly in node-positive patients. Multivariate analysis demonstrated a significance of EGFR status as an independent prognostic indicator in primary breast cancer. The group expressing EGFR and c-erbB-2 protein indicated a particularly high risk for relapse.     

Immunohistochemical detection of estrogen receptor,progesterone receptor,and human epidermal growth factor receptor 2 expression in breast carcinomas

BACKGROUND:

Fine‐needle aspiration (FNA) is a rapid and accurate procedure for the detection of breast carcinomas. The evaluation of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression by immunohistochemistry (IHC) is performed routinely on formalin‐fixed, paraffin‐embedded needle‐core (NC) or excision tissue block (TB) preparations, according to the American Society of Clinical Oncology/College of American Pathologist guidelines. In this retrospective study, the authors compared expression levels of ER, PR, and HER2 in ethanol‐fixed BC FNA cell block (CB) samples with expression levels in formalin‐fixed NC and TB samples.

METHODS:

Forty‐one breast carcinoma CB samples with concurrent or subsequent NC and TB samples were identified. Patients who had received neoadjuvant or adjuvant chemotherapy were excluded. CB samples initially were fixed in 50% ethanol (4‐12 hours), and this was followed by formalin fixation (minimum, 6 hours). NC samples were placed promptly in formalin for a minimum of 6 hours. Within 4 to 8 hours, TB samples were fixed in formalin for 6 to 48 hours. Fluorescence in situ hybridization (FISH) results were also compared.

RESULTS:

IHC for ER on alcohol‐fixed CB samples had good correlation with NC and TB samples. PR results on TB samples had excellent agreement with NC samples. A higher discordance rate wais observed when PR results were compared between CB samples and NC samples. HER2 detection on ethanol‐fixed CB samples resulted in a higher rate of positive and equivocal staining than NC or TB samples. HER2 IHC on TB samples demonstrated better correlation with FISH results than CB or NC samples.

CONCLUSIONS:

Alcohol fixation did not affect ER results in breast carcinoma, but it may alter tumor cell PR antigenicity. The authors concluded that CB samples could be used to triage patients for tamoxifen therapy, but they are not reliable for the assessment of HER2 status; therefore, CB results should be correlated with results from NC or TB samples. Cancer (Cancer Cytopathol) 2009. © 2009 American Cancer Society.     

Clinical value of enzyme immunoassay of epidermal growth factor receptor in human breast cancer

Summary Epidermal growth factor receptor (EGFr) levels were analyzed in 140 primary breast cancer specimens by immunohistochemical assay (ICA), competitive binding assay (BA), or enzyme immunoassay (EIA). Thirtynine of 118 specimens (33.1%) were scored as positive by ICA, 30 of 116 (25.9%: cut-off level 10 fmol/mg protein) by BA, and 31 of 80 (38.9%: cut-off level 5 fmol/mg protein) by EIA. Agreement on EGFr status was 72.3% (68/94) between ICA and BA, 77.0% (57/74) between BA and EIA, and 73.8% (59/80) between EIA and ICA. These discrepancies are based on assay differences and the heterogeneous distribution of cancer cells within specimens. Regardless of the assay method used, EGFr status had a significantly negative correlation with estrogen receptor status. Although EGFr-ICA and BA status had no relationship with prognosis, patients with medium and high EGFr-EIA level tumors (over 5 fmol/mg protein) had shorter relapse-free periods than those with low level tumors. However, the prognostic value of positive EGFr-EIA status was weaker than that ofc-erbB-2 overexpression.     

Expression of epidermal growth factor receptor mRNA and protein in primary breast carcinomas

The expression of epidermal growth factor receptor (EGFR) mRNA and protein has been determined in a group of breast carcinomas and compared to oestrogen and progesterone receptor (ER, PgR) status, as well as pathological features. In situ hybridization using a digoxigenin-labelled oligonucleotide probe was applied to formalin-fixed paraffin-embedded sections, and immunohistochemistry was used to determine EGFR protein.EGFR mRNA was detected in 66% of carcinomas with a third having labelling similar to normal breast tissue, 22% heterogeneous weak to strong labelling, and 11% strong labelling. EGFR protein was detected in 36% and these tumours had a strong correlation to lack of ER and high histological grade. The presence of EGFR protein was strongly correlated with more intense labelling for EGFR mRNA (p < 0.0001). This contrasted with normal breast in which both EGFR protein and mRNA were present with varying degrees in both tumours and a normal breast control. The ER-/PgR- carcinomas showed the full range of EGFR mRNA labelling. It is postulated that oestrogen or oestrogen regulated proteins are involved in regulation of EGFR mRNA and protein. In a proportion of tumours lacking steroid receptors regulation is lost, leading to EGFR overexpression.     

表皮生长因子、雄激素受体和表皮生长因子受体在肝癌组织中的表达及影响因素分析

目的探讨肝癌患者肝癌组织中的表皮生长因子(EGF)、雄激素受体(AR)、表皮生长因子受体(EGFR)的表达情况及临床意义。方法采用免疫组织化学染色法检测EGF、AR、EGFR在90例肝癌患者的肝癌组织和90例非肝癌患者的非肝癌组织中的表达情况,比较不同临床特征肝癌患者肝癌组织中EGF、AR、EGFR的表达情况,分析肝癌患者肝癌组织中EGF、AR、EGFR表达的影响因素。结果肝癌组织中的EGF、AR、EGFR的阳性表达率均明显高于非肝癌组织,差异均有统计学意义(P﹤0.01)。有肝炎史、Ⅲ+Ⅳ期、中低分化、有淋巴结转移的肝癌患者肝癌组织中EGF、AR、EGFR的阳性表达率均高于无肝炎史、Ⅰ+Ⅱ期、高分化、无淋巴结转移的肝癌患者,差异均有统计学意义(P﹤0.05);不同年龄、性别、肿瘤直径的肝癌患者肝癌组织中EGF、AR、EGFR的阳性表达率比较,差异均无统计学意义(P﹥0.05)。Logistic回归分析结果显示,有淋巴结转移、TNM分期为Ⅲ+Ⅳ期是肝癌患者肝癌组织中EGF、AR、EGFR表达的独立危险因素。结论EGF、AR、EGFR在肝癌患者的肝癌组织中呈高表达,且其表达与肝癌患者的淋巴结转移情况和TNM分期密切相关。     

Systemic therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative early stage and metastatic breast cancer

Hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is defined by the presence of the estrogen receptor and/or the progesterone receptor and the absence of HER2 gene amplification. HR-positive/HER2-negative breast cancer accounts for 65%–70% of all breast cancers, and incidence increases with increasing age. Treatment varies by stage, and endocrine therapy is the mainstay of treatment in both early stage and late-stage disease. Combinations with cyclin-dependent kinase 4/6 inhibitors have reduced distant recurrence in the early stage setting and improved overall survival in the metastatic setting. Chemotherapy is used based on stage and tumor biology in the early stage setting and after endocrine resistance for advanced disease. New therapies, including novel endocrine agents and antibody-drug conjugates, are now changing the treatment landscape. With the availability of new treatment options, it is important to define the optimal sequence of treatment to maximize clinical benefit while minimizing toxicity. In this review, the authors first discuss the pathologic and molecular features of HR-positive/HER2-negative breast cancer and mechanisms of endocrine resistance. Then, they discuss current and emerging therapies for both early stage and metastatic HR-positive/HER2-negative breast cancer, including treatment algorithms based on current data.     

Involvement of epidermal growth factor receptor overexpression in the promotion of breast cancer brain metastasis

BACKGROUND:

Brain‐metastatic breast cancer (BMBC) is increasing and poses a severe clinical problem because of the lack of effective treatments and because the underlying molecular mechanisms are largely unknown. Recent work has demonstrated that deregulation of epidermal growth factor receptor (EGFR) may correlate with BMBC progression. However, the exact contribution that EGFR makes to BMBC remains unclear.

METHODS:

The role of EGFR in BMBC was explored by serial analyses in a brain‐trophic clone of human MDA‐MB‐231 breast carcinoma cells (231‐BR cells). EGFR expression was inhibited by stable short‐hairpin RNA transfection or by the kinase inhibitor erlotinib, and it was activated by heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF). Cell growth and invasion activities also were analyzed in vitro and in vivo.

RESULTS:

EGFR inhibition or activation strongly affected 231‐BR cell migration/invasion activities as assessed by an adhesion assay, a wound‐healing assay, a Boyden chamber invasion assay, and cytoskeleton staining. Also, EGFR inhibition significantly decreased brain metastases of 231‐BR cells in vivo. Surprisingly, changes to EGFR expression affected cell proliferation activities less significantly as determined by a 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay, an anchorage‐independent growth assay, and cell cycle analysis. Immunoblot analysis suggested that EGFR drives cells' invasiveness capability mainly through phosphoinositide 3‐kinase/protein kinase B and phospholipase C γ downstream pathways. In addition, EGFR was involved less in proliferation because of the insensitivity of the downstream mitogen‐activated protein kinase pathway.

CONCLUSIONS:

The current results indicated that EGFR plays more important roles in cell migration and invasion to the brain than in cell proliferation progression on 231‐BR cells, providing new evidence of the potential value of EGFR inhibition in treating BMBC. Cancer 2012. © 2012 American Cancer Society.     

Epidermal growth factor receptor expression in 780 breast cancer patients: A reappraisal of the prognostic value based on an eight-year median follow-up

Purpose:Because new therapeutic approaches target tumorsexpressing epidermal growth factor receptor (EGFR), the aim was toundertake a thorough analysis of the expression profile of EGFR inbreast cancer and to reassess its prognostic value. Patients and methods:Tumor EGFR levels were determined by aspecific ligand binding assay in 780 consecutive breast cancer patientsfollowed in our institute between 1980 and 1993. Mean age was 61 years(25–85 years). All patients had undergone tumor resection withaxillary lymph node dissection: 373 patients (47.8%) underwentmastectomy, 37 (5%) subcutaneous mastectomy and 370(47.2%) tumorectomy. Results:EGFR levels ranged between non-detectable up to 789fmol/mg protein. EGFR median value was 9 fmol/mg protein and only asmall proportion of patients exhibited a relatively marked EGFRexpression. There was no link between tumor size, grade, node status andEGFR tumoral levels. There was a constant and significant decrease inEGFR tumoral levels according to patient age. A significant inverserelationship was found between estradiol receptors (ER) and EGFR. Medianfollow-up was 97 months with a minimum at 4 months and a maximum at228 months. From univariate analysis it was found that histologicalgrade, tumor size, node status and ER status were all significantpredictors of survival, considering metastasis-free as well as overallsurvival. Using multivariable analysis, only histological grade, tumorsize and node status remained independent predictors of survival. Conclusion:EGFR determination is of limited value as aprognostic indicator in breast cancer.     

受体O型蛋白酪氨酸磷酸酶与表皮生长因子受体2在乳腺癌中表达的相关性

目的:分析受体0型蛋白酪氨酸磷酸酶(PTPRO)与表皮生长因子受体2(HER2)在乳腺癌中的表达及其临床意义.方法:采用免疫组织化学EnVision法检测50例原发乳腺癌组织中PTPRO与HER2的表达状态并结合临床病理资料进行统计分析.结果:乳腺癌组织中PTPRO阳性表达率40.0％(20/50),PTPRO表达缺失同淋巴结转移和孕激素受体表达相关(P ＜0.05);HER2阳性表达率68％ (34/50),同肿瘤大小、淋巴结转移和孕激素受体表达相关(P＜0.05).PTPRO与HER2表达呈负相关(P =0.026).结论:PTPRO与HER2表达同乳腺癌临床病理特征密切相关,联合检测二者具有潜在的临床诊断意义.