HER-2/neu Status: A Neglected Marker of Prognostication and Management of Breast Cancer Patients in India

Background: Categorizing breast tumors based on the ER, PR and HER/Neu 2 receptor status is necessary in order to predict outcome and assist in management of breast cancer. Herfe we assessed this question in South Indian patients. Materials and Methods: A total of 619 formalin fixed paraffin embedded breast tumor tissues were collected from pathology archives after receipt of ethical clearance. With the help of primary and secondary conjugated antibodies, expression status of ER, PR and HER2/neu was determined. All the experimental data were assessed for correlations with histopathological features of tumors and clinical presentation of the subjects. Results: In the present study, the ages ranged from 20-87 years with a mean of 50.0±12.q years, and majority of the tumors (84%) were of infiltrating duct cell carcinoma type. Assessment of ER, PR and Her-2/neu expression showed that 46% were triple negative. Interestingly, an inverse relation between ER, PR and HER-2/neu was apparent in 41.2% (p<0.0001) of the tumors, of which 24.5% (p<0.0001) were ER and PR co-negative but HER-2 positive. Conclusions: ER and PR positive tumors are less common (i.e<30%) compared to HER-2/neu positive tumors (i.e>50%) in Indian breast cancer patients, underlining the need for effective diagnostic screening and specific therapeutic managements in order to improve the survival rate of patients in low resource countries such as India.     

色素原位杂交在检测乳腺癌患者组织中HER2基因的应用

[目的]探讨色素原位杂交（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）检测组织HER2状态的差异性。[方法]采用SPOT—Light HER2 CISH^TM试剂盒，以CISH方法对40例IHC EnVision法染色分别为（＋＋＋）、（＋＋）、（＋）和阴性（-）的乳腺癌石蜡切片标本进行HER2基因状态的检测。[结果]HER2表达IHC（＋＋＋）的8例标本中，7例为HER2基因扩增CISH检测，1例无扩增；（＋＋）的13例标本中，5例为HER2基因扩增．8例无扩增；（＋）的10例标本中，2例为HER2基因扩增，7例无扩增；（-）的9例标本均无扩增。两种方法对乳腺癌组织HER-2／neu状态的检测有一定的差异性（kappa=0．458，P=0．003）。[结论]IHC是HER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一定的差异性，建议IHCC（＋＋＋～＋）患者进一步作CISH检测确诊。     

三阴乳腺癌与激素受体阴性、HER-2阳性乳腺癌的临床病理特征及预后对比分析

目的:在未接受针对HER-2靶点的分子靶向治疗的情况下,对比分析三阴乳腺癌与激素受体阴性、HER-2阳性乳腺癌的I临床病理特征和影响预后的因素.方法:收集2000年1月至2004年12月江西省肿瘤医院收治的222例激素受体阴性的乳腺癌,根据免疫组化法检测的HER-2状态,将其分为3组:三阴组(IHC0～+)、三阴待定组(IHC++)、HER-2阳性组(IHC+++).回顾性的分析3组患者的临床病理特征和生存情况.结果:统计显示,3组患者的临床病理特征无显著差异.5年DSF三阴组76.3%、三阴待定组74.7%、HER.2阳性组58.2%(P=0.019);5年0S分别为77.6%、75.9%和59.7%(P=0.011).结论:三阴乳腺癌与激素受体阴性、HER-2阳性乳腺癌的临床病理特征无显著差异.在未使用针对HER-2靶点的分子靶向治疗的情况下,激素受体阴性、HER-2阳性乳腺癌比三阴乳腺癌预后更差.     

HER-2 Positive Breast Cancer - a Mini-Review

Breast cancer is one of among all cancers with increased incidence, high mortality rate, and high economic and social costs. The the most common type of cancer among females worldwide, breast cancer is actually the uncontrolled proliferation of cells which attain malignancy. Recently it has shown that breast cancer contributes 11% among all types of cancer diagnosed globally on an annual basis and it is one of the leading causes of death among women. The human epidermal growth factor receptor 2 (HER-2) is a receptor tyrosine-protein kinase erbB-2 normally involved in the proliferation and division of breast cells. In some abnormal cases the HER2 gene does not work correctly and makes too many copies of itself. HER2-positive (HER2) breast cancers constitute an aggressive type of breast cancer and tend to grow faster and are more likely to spread. However, therapies that specifically target HER2, such as Herceptin (traztuzumab), are very effective. HER2 targeted therapies, has significantly improved the therapeutic outcome for patients with HER2 positive breast cancer.     

早期乳腺癌患者手术、化疗后血清HER-2/neu ECD水平变化

目的：探讨乳腺癌患者手术或化疗后血清HER-2／neu ECD水平变化的临床意义。方法：双抗体夹心ELISA法检测早期乳腺癌患者及其配对手术、化疗前后血清HER-2／neu ECD水平，进行统计分析。结果：82例乳腺癌患者手术后，血清HER-2／neu ECD水平90．24％（74／82）下降，3．66％（3／82，C．V≤5％）未变化，6．10％（5／82）升高；46例乳腺癌患者化疗后HER-2／neu ECD水平升高组（15／46）对化疗的反应率73．33％（11／15）与HER-2／neu ECD水平非升高组（HER-2／neu ECD水平下降或不变，C．V≤5％，31／46）对化疗的反应率77．42％（24／31）无差别（P〉0．05）。结论：检测乳腺癌患者血清HER-2／neu ECD水平变化对预后可能具有一定的临床提示意义。     

HER-2/neu在新辅助化疗乳腺癌中的表达及其意义分析

目的：检测并分析HER－2／neu在新辅助职乳腺癌组织中的表达，探讨新辅助化疗患者中HER－2/neu的临床意义。方法：采用免疫组织化学法分别检测HER－2／neu在165例新辅助化疗及73例未化学乳腺癌组织中的表达状况，统计分析HER－2/neu表达与化疗、病理类型及腋淋巴结转移情况的关系。结果：新辅助化疗组HER－2／neu表达低于未化疗组（29．7％比43．8％，P＜0．05）；浸润性非特殊型乳腺部HER-2/neu阳性表达明显高于浸润性特殊型（粘液腺癌0／4），但浸润性非特殊型乳腺癌之间HER－2／neu表达差异无显著性意义；腋淋巴结转移组HER-2/neu表达明显高于腋淋巴结阴性组（40．1％比25．0％，P＜0．05）。结论：HER-2/neu可能成为在新辅助化疗乳腺癌患者优于淋巴结状况的一个评价肿瘤生物学行为、预测治疗效果指导综合治疗方案制定以及判断预后的重要标志。     

Influence of Neoadjuvant Chemotherapy on HER2/neu Status in Invasive Breast Cancer

IntroductionReliably estimating HER2/neu expression in breast cancer is important for predicting patient prognosis and optimizing adjuvant therapeutic strategies. In this retrospective cohort study, effects of NAC on HER2/neu status in invasive breast cancer were evaluated, and the related factors were analyzed.Patients and MethodsOne hundred thirty-one patients with primary breast cancer were treated with anthracycline- and/or taxane-based NAC. HER2/neu status was evaluated by IHC on core needle biopsies of primary tumors before NAC and surgical resection specimens of post-NAC residual breast cancers or tumor-positive axillary lymph nodes. Thirty-two pairs of specimens with discordant HER2/neu IHC scores were analyzed by fluorescence in situ hybridization (FISH).ResultsA significant difference in HER2/neu status by IHC between core needle biopsies and surgical resection specimens in patients receiving NAC was observed. After NAC, 23.4% (29 of 124) of tumors showed downregulated HER2/neu expression by IHC. Alterations of HER2/neu IHC scores did not significantly correlate with tumor subtype, pathologic response to NAC, adjuvant regimen, or time interval from the last chemotherapy to surgery. HER2/neu protein overexpression level was associated with favorable pathologic response to anthracycline and taxane-based chemotherapy. However, tumors with altered HER2/neu IHC scores after NAC revealed stable HER2/neu gene amplification/nonamplification by FISH analysis.ConclusionNeoadjuvant chemotherapy for breast carcinoma resulted in the HER2/neu status alteration by IHC, but they have stable gene amplification status by FISH. HER2/neu protein overexpression indicated greater sensitivity to neoadjuvant anthracycline- and taxane-based chemotherapy. Thus, retesting HER2/neu IHC status in residual tumors after NAC should be considered in order to optimize adjuvant systemic therapy.     

Prognostic and predictive value of c-erbB-2 (HER-2/neu) gene amplification in human Breast Cancer

Amplification of the c-erbB-2 (HER-2/neu) proto-oncogene is detected in 10-30% of human breast cancers and has been shown to be accompanied by the overexpression of its protein in the cancer cell membrane. c-erbB-2 gene amplification is one of the first genetic alterations to be used clinically as a prognostic indicator, a predictive factor of response to doxorubicin (adriamycin) chemotherapy, and a test of patient eligibility for therapy with trastuzumab, a humanized anti-c-erbB-2 antibody. There are two types of tests to detect c-erbB-2 amplification/overexpression: immunohistochemistry and fluorescence in situ hybridization (FISH). Accurate identification of cases with c-erbB-2 amplification/overexpression requires an optimized combination of immunohistochemical and FISH tests.     

HER-2/neu is a tumor rejection target in tolerized HER-2/neu transgenic mice

HER-2/neu (neu-N) transgenic mice, which express the nontransforming rat proto-oncogene, develop spontaneous focal mammary adenocarcinomas beginning at 5-6 months of age. The development and histology of these tumors bears a striking resemblance to what is seen in patients with breast cancer. We have characterized the immunological responses to HER-2/neu (neu) in this animal model. neu-positive tumor lines, which were derived from spontaneous tumors that formed in neu-N animals, are highly immunogenic in parental, FVB/N mice. In contrast, a 100-fold lower tumor challenge is sufficient for growth in 100% of transgenic animals. Despite significant tolerance to the transgene, neu-specific immune responses similar to those observed in breast cancer patients can be demonstrated in neu-N mice prior to vaccination. Both cellular and humoral neu-specific responses in transgenic mice can be boosted with neu-specific vaccination, although to a significantly lesser degree than what is observed in FVB/N mice, indicating that the T cells involved are less responsive than in the nontoleragenic parental strain. Using irradiated whole-cell and recombinant vaccinia virus vaccinations we are able to protect neu-N mice from a neu-expressing tumor challenge. T-cell depletion experiments demonstrated that the observed protection is T cell dependent. The vaccine-dependent neu-specific immune response is also sufficient to delay the onset of spontaneous tumor formation in these mice. These data suggest that, despite tolerance to neu in this transgenic model, it is possible to immunize neu-specific T cells to achieve neu-specific tumor rejection in vivo. These transgenic mice provide a spontaneous tumor model for identifying vaccine approaches potent enough to overcome mechanisms of immune tolerance that are likely to exist in patients with cancer.     

曲妥珠单抗联合新辅助化疗对HER-2阳性乳腺癌患者近远期疗效的影响

目的 探讨曲妥珠单抗联合新辅助化疗对表皮生长因子受体-2(HER-2)阳性乳腺癌患者的疗效.方法 选取HER-2阳性乳腺癌患者58例,随机分为观察组和对照组,各29例.对照组给予表柔比星联合多西他赛的方案进行新辅助化疗,观察组在对照组的基础上给予曲妥珠单抗治疗.比较两组患者的近期、远期疗效.结果 观察组有效率(RR)及病理完全缓解(pCR)率明显优于对照组,5年总生存率(OS)及5年无病生存率(DFS)明显高于对照组.结论 曲妥珠单抗联合新辅助化疗治疗HER-2阳性乳腺癌近期疗效显著,并可有效改善患者预后,值得临床推广应用.     

HER-2/neu in bladder carcinoma

A total of 66 bladder cancer patients were studied to verify possible relationships between HER-2/neu alterations and pathological characteristics, and to define a poor prognosis patient subgroup with respect to time to recurrence, time to progression and survival. Tumor and healthy tissue specimens were analyzed for HER-2/neu DNA amplification and protein overexpression by Southern and Western blot techniques and evaluated statistically. 13% of cases were amplified and 39% were overexpressed. HER-2/neu alterations were not significantly associated with pathological staging or tumor grading. Multifocal tumors had a higher percentage and overexpression with respect to monofocal tumors. Actuarial analyses did not show a significant statistical correlation between HER-2/neu amplification and overexpression and clinical outcome. Clinical evaluation of HER-2/neu status showed that this gene is not related to tumor relapse, progression or patient survival.     

HER-2过表达与乳腺癌治疗的研究进展

人类表皮生长因子受体-2（HER-2）是一种与乳腺癌发生、发展密切相关的癌基因。HER-2过表达可能预测对内分泌治疗和细胞毒性化疗药物敏感性。Herceptin是针对HER-2的分子靶向药物，其肿瘤治疗作用受到广泛关注。HER-2过表达乳腺癌病人在肿瘤发展的各个病期中表现为预后差。全文是根据使用曲妥珠单抗来治疗转移性乳腺癌或作为术后辅助治疗情况下获得的数据来说明HER-2阳性表达在乳腺癌治疗中的作用．或者作为独立的预后因子，或作为预测抗癌治疗反应的一项标志物.     

HER-2 therapy. HER-2/neu diagnostics in breast cancer

HER-2/neu status of the primary breast cancer (PBC) is determined by immunohistochemistry and fluorescent in situ hybridization. Because of a variety of technical factors, however, the PBC may not accurately reflect the metastatic tumor in terms of HER-2/neu status. Recently published guidelines recommend that tumors be defined as HER-2/neu positive if 30% or more of the cells are 3+. Circulating levels of the HER-2 extracellular domain can be measured in serum using a test cleared by the US Food and Drug Administration, and increased serum HER-2/neu levels to above 15 ng/ml can reflect tumor progression. Studies comparing tissue HER-2/neu status of the PBC and HER-2/neu levels above 15 ng/ml in metastatic breast cancer patients are also reviewed.     

Pneumocystis carinii Pneumonia during Treatment for Recurrent Breast Cancer: A Case Report

We describe a case of Pneumocystis carinii pneumonia (PCP) ina woman with recurrent breast cancer without human immunodeficiencyvirus (HIV) infection. The PCP was associated with severe lymphocytopeniadue to treatment with anticancer agents in combination withgranulocyte colony-stimulating factor (G-CSF). Despite the severelymphocytopenia, the total leucocyte count never fell below3000/mm³ during the treatment. It was difficult to determinewhether the patient's respiratory failure was caused by severeinfectious pneumonia, hypersensitivity pneumonia or pneumonitiscarcinomatosis. She was treated with steroid for suspected drug-inducedhypersensitivity pneumonia. However, as her condition did notimprove, PCP was suspected, and sulfamethoxazole-trimethoprimwas administered. At the same time, anticancer drugs were administeredto half the progression of the cancer, since lymphangitis carcinomatosawas also suspected. The severe respiratory failure did not improve,and the patient died on day 23 after admission. At autopsy,the cause of death was confirmed to be respiratory failure dueto PCP.     

TCH方案术前新辅助化疗对HER-2阳性乳腺癌的疗效观察

目的 观察TCH方案术前新辅助化疗对HER-2阳性乳腺癌的近期疗效及毒副反应.方法 37例女性HER-2阳性乳腺癌患者给予TCH方案术前新辅助化疗,治疗3～4周期后进行疗效和毒副反应评价.结果 37例患者中CR 5例,PR 28例,NC 4例,PD 0例,有效率为89.2％.主要毒副反应:中性粒细胞减少22例(59.5％),恶心呕吐15例(40.5％),肝功能异常8例(21.6％).结论 TCH方案用于HER-2阳性乳腺癌患者术前辅助化疗疗效较好,毒副反应可耐受.     

Monoclonal antibody to HER-2/neu receptor enhances radiosensitivity of esophageal cancer cell lines expressing HER-2/neu oncoprotein

PURPOSE: The role of HER-2/neu in the response of esophageal cancer to radiation is not well known. The purpose of this study was to evaluate the effect of an anti-HER-2/neu antibody trastuzumab on the proliferation, cell cycle distribution, and radiosensitivity of esophageal cancer cell lines. EXPERIMENTAL DESIGN: Expression of HER-2/neu protein by four esophageal squamous cancer cell lines (KE4, TE8, TE9, and TE10) and an esophageal adenocarcinoma cell line (SKGT4) was assessed using immunohistochemical (IHC) analysis and flow cytometry. We also evaluated HER-2/neu oncogene expression by fluorescence in situ hybridization. As a control for HER-2/neu protein expression and gene amplification, breast cancer cell lines (MCF7, MDA MB175VII, and SKBR3) were also examined. The cytotoxity of trastuzumab (0.1-200 microg/mL) was estimated by the MTT assay, and the cell cycle distribution was determined by flow cytometry. The effect of 10 microg/mL trastuzumab combined with radiation was assessed by a clonogenic assay. RESULTS: Flow cytometry and IHC revealed that two esophageal cancer cell lines (TE9 and SKGT4) showed HER-2/neu expression (IHC 1+ and mean fluorescence intensity of 11-20), while the other esophageal cancer cell lines were negative for HER-2/neu expression. Although trastuzumab alone had no effect on the esophageal cancer cell lines, the combination of 10 microg/mL trastuzumab with radiation showed a synergistic effect on the HER-2/neu expressing cell lines. CONCLUSIONS: This study suggested that trastuzumab plus irradiation may be effective for the treatment of esophageal cancers, including adenocarcinoma and squamous cell cancer with HER-2/neu expression.     

Pre-existent immunity to the HER-2/neu oncogenic protein in patients with HER-2/neu overexpressing breast and ovarian cancer

Immunomodulatory strategies, such as antibody therapy and cancer vaccines, are increasingly being considered as potential adjuvant therapies in patients with advanced stage breast cancer to either treat minimal residual disease or prevent relapse. However, little is known concerning the incidence and magnitude of the pre-existent breast cancer specific immune response in this patient population. Using the HER-2/neu oncogenic protein as a model, a well-defined tumor antigen in breast cancer, we questioned whether patients with advanced stage HER-2/neu overexpressing breast and ovarian cancers (III/IV) had evidence of pre-existent immunity to HER-2/neu. Forty-five patients with stage III or IV HER-2/neu overexpressing breast or ovarian cancer were evaluated for HER-2/neu specific T cell and antibody immunity. Patients enrolled had not received immunosuppressive chemotherapy for at least 30 days (median 5 months, range 1–75 months). All patients were documented to be immune competent prior to entry by DTH testing using a skin test anergy battery. Five of 45 patients (11%) were found to have a significant HER-2/neu specific T cell response as defined by a stimulation index 2.0 (range 2.0–7.9). None of eight patients who were HLA-A2 had a detectable IFN secreting T-cell precursor frequency to a well-defined HER-2/neu HLA-A2 T cell epitope, p369-377. Three of 45 patients (7%) had detectable HER-2/neu specific IgG antibodies, range 1.2–8.9g/ml. These findings suggest that patients with advanced stage HER-2/neu overexpressing breast and ovarian cancer can mount a T cell and/or antibody immune response to their tumor. However, in the case of the HER-2/neu antigen, the pre-existent tumor specific immune response is found only in a minority of patients.