Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human epidermal growth factor receptor HER2 or C-erbB-2/neu is a tyrosine kinase membrane receptor, which when activated, induces a phosphorylation cascade in cytoplasmic kinases leading to increased protein transcription and cellular growth. HER2 plays an important role in the biology of breast cancer, an observation that has led to the selection of HER2 as a potential target for breast cancer treatment. Trastuzumab (Herceptin) is the first anti-HER2 monoclonal antibody that has shown a survival benefit in metastatic breast cancer patients with HER2-positive tumours (Norton et al., Proc ASCO 2000 18, 127a (abstract 483)). Tumour HER2 status should no longer be ignored because of its direct implications for the optimal management of breast cancer patients. A high priority for future research is to refine and standardise HER2 testing in order to minimise false-negative results. Furthermore, this procedure would overcome current issues relating to test reproducibility between pathology laboratories and definitions of HER2 positivity. In the meantime, a HER2-positive status on testing using any approved technique has implications for clinical practice (Fig. 1). The treatment algorithm given in Fig. 1 considers the lack of level 1, evidence-based studies that demonstrate convincingly the value of HER2 as a predictive marker for resistance or sensitivity to classic forms of breast cancer therapy (Piccart et al., Eur J Cancer 2000, 36, 1755-1761). In addition, the algorithm incorporates the available data from 1999-2000, which were generated from prospective trials exploring the value of trastuzumab both as a single agent and in combination with chemotherapy.
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PMID:Closing remarks and treatment guidelines. 1116 89

The product of the HER-2/neu proto-oncogene, HER2, is the second member of the human epidermal growth factor receptor (HER) family of tyrosine kinase receptors and has been suggested to be a ligand orphan receptor. Ligand-dependent heterodimerization between HER2 and another HER family member, HER1, HER3 or HER4, activates the HER2 signaling pathway. The intracellular signaling pathway of HER2 is thought to involve ras-MAPK, MAPK-independent S6 kinase and phospholipase C-gamma signaling pathways. However, the biological consequences of the activation of these pathways are not yet completely known. Amplification of the HER2 gene and overexpression of the HER2 protein induces cell transformation and has been demonstrated in 10% to 40% of human breast cancer. HER2 overexpression has been suggested to associate with tumor aggressiveness, prognosis and responsiveness to hormonal and cytotoxic agents in breast cancer patients. These findings indicate that HER2 is an appropriate target for tumor-specific therapies. A number of approaches have been investigated: (1) a humanized monoclonal antibody against HER2, rhuMAbHER2 (trastuzumab), which is already approved for clinical use in the treatment of patients with metastatic breast cancer; (2) tyrosine kinase inhibitors, such as emodin, which block HER2 phosphorylation and its intracellullar signaling; (3) active immunotherapy, such as vaccination; and (4) heat shock protein (Hsp) 90-associated signal inhibitors, such as radicicol derivatives, which induce degradation of tyrosine kinase receptors, such as HER2.
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PMID:Biological and clinical significance of HER2 overexpression in breast cancer. 1118 Jul 65

HER-2 (c-erbB-2, neu) is an important prognostic and predictive factor in breast cancer. Clinical trials utilizing a humanized version of the anti-HER-2 murine monoclonal antibody 4DS, trastuzumab (Herceptin; Genentech Inc, South San Francisco, CA), have shown antitumor activity in patients with HER-2-positive metastatic breast cancer. Improved response and survival rates have been shown when trastuzumab was added to first-line combination chemotherapy with anthracycline/cyclophosphamide or paclitaxel, compared to the same chemotherapy alone. The Breast Cancer Intergroup has recently completed several trials evaluating new chemotherapy treatment approaches for patients with node-positive breast cancer, which form the basis for several ongoing and planned clinical trials incorporating trastuzumab. These clinical trials and the evolving role of trastuzumab-containing adjuvant systemic therapy for breast cancer will be reviewed.
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PMID:Ongoing and planned adjuvant trials with trastuzumab. 1123 24

Studies with human breast cancer cell lines have shown a causal association between overexpression of the HER-2/neu proto-oncogene receptor and the acquisition of resistance to tamoxifen. Some clinical studies also indicate that patients with tumors showing high HER-2 levels or high levels of the circulating ectodomain of HER-2 may have a lower response to tamoxifen compared with tumors with low HER-2 levels or low circulating ectodomain. Treatment with anti-HER-2 antibodies seems to restore tamoxifen activity in some experimental systems. However, whether anti-HER-2 therapies will increase tamoxifen action and/or reverse this putative oncogene-mediated resistance in patients with estrogen receptor-positive, hormone-dependent tumors, is unclear. We are conducting a phase II trial of a humanized anti-HER-2 monoclonal antibody, trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) in combination with tamoxifen in patients with estrogen receptor-positive metastatic breast cancer. Other prospective randomized clinical trials are needed to directly evaluate the contribution of HER-2 signaling to antiestrogen resistance in vivo.
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PMID:Ongoing and planned trials of hormonal therapy and trastuzumab. 1123 26

The human epidermal growth factor receptor HER2 or C-erbB-2/neu is a tyrosine kinase membrane receptor, which when activated, induces a phosphorylation cascade in cytoplasmic kinases leading to increased protein transcription and cellular growth. HER2 plays an important role in the biology of breast cancer, an observation that has led to the selection of HER2 as a potential target for breast cancer treatment. Trastuzumab (Herceptin(R)) is the first anti-HER2 monoclonal antibody that has shown a survival benefit in metastatic breast cancer patients with HER2-positive tumours (Norton et al., Proc ASCO 2000 18, 127a (abstract 483)). Tumour HER2 status should no longer be ignored because of its direct implications for the optimal management of breast cancer patients. A high priority for future research is to refine and standardise HER2 testing in order to minimise false-negative results. Furthermore, this procedure would overcome current issues relating to test reproducibility between pathology laboratories and definitions of HER2 positivity. In the meantime, a HER2-positive status on testing using any approved technique has implications for clinical practice (Fig. 1). The treatment algorithm given in Fig. 1 considers the lack of level 1, evidence-based studies that demonstrate convincingly the value of HER2 as a predictive marker for resistance or sensitivity to classic forms of breast cancer therapy (Piccart et al., Eur J Cancer 2000, 36, 1755-1761). In addition, the algorithm incorporates the available data from 1999-2000, which were generated from prospective trials exploring the value of trastuzumab both as a single agent and in combination with chemotherapy.
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PMID:Closing remarks and treatment guidelines. 1134 98

HER2 (neu, erbB-2), a receptor related to the human epidermal growth factor receptor, has now become more important as a predictive marker of treatment response. While the value and direction of the treatment/HER2 interaction may vary, depending on the agents, dose, or schedule of drug administration, there is little disagreement that HER2 testing is an important part of breast cancer evaluation. In 1998, trastuzumab (Herceptin) was approved for the treatment of HER2-positive metastatic breast cancer patients by the Food and Drug Administration of the USA. Patients with abnormal HER2 in their breast cancer cells (generally 2 or 3+ with the HercepTest, overexpression by other immunohistochemical assays or amplification by fluorescence in situ hybridization [FISH] assay) have demonstrated the greatest response to trastuzumab treatment. It is unclear which test (method, reagent, cut-off points, etc.) is best to use to evaluate HER2 for this purpose because parallel testing of the same cancers from patients who received trastuzumab has only recently been initiated and the data are limited. It is widely believed that breast cancers without HER2 alterations will not be responsive to trastuzumab, although a clinical trial to test this specific hypothesis has not been initiated. There are also concerns that clonal heterogeneity for HER2 within a tumor, or between primary and metastatic cancer foci, may affect treatment response; yet we do not currently evaluate these parameters. Consensus regarding the best methods, reagents, or cut-off points to define HER2 status for determining trastuzumab responsivity has not yet been reached. HER2 testing for other prognostic or predictive purposes, e.g. to determine whether patients are likely to respond to other agents, such as dose-intensive doxorubicin, may be less. Data from the Cancer and Leukemia Group B trial 8541 (companion 8869) suggest that, with proper controls in high-volume laboratories, many of the available methods produce comparable results.
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PMID:HER2--a discussion of testing approaches in the USA. 1152 14

The search for a simple, sensitive test to reliably determine prognosis and predict response to therapy in patients with cancer is an important area of translational research. In this issue of Clinical Cancer Research, Hayes et al. (Clin. Cancer Res., 7: 601-604, 2001) report the results of an ancillary Cancer and Leukemia Group B protocol designed to determine whether the circulating extracellular domain of HER-2/neu (ECD-HER-2) was indicative of prognosis or predictive of response to therapy in women with metastatic breast cancer. Results were drawn from a sample of 242 patients of whom 89 had elevated values of the protein. These women had been enrolled in a variety of Cancer and Leukemia Group B protocols evaluating either the efficacy of dose in the use of megestrol acetate as second-line hormonal treatment or in patients enrolled into several chemotherapeutic protocols, many containing doxorubicin. They report that patients with pretreatment elevation of ECD-HER-2 had a worse prognosis than those who did not, but that there was no convincing correlation of elevated ECD-HER-2 with response to either endocrine or chemotherapy. Although the small number of patients and the retrospective study design allows one to draw only tentative conclusions, this report raises several important issues for the conduct of translational research and points to several new hypotheses for future testing.
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PMID:The prognostic and predictive values of ECD-HER-2. 1155 82

The recombinant humanized anti-HER-2 monoclonal antibody trastuzumab (Herceptin) is directed against the human epidermal growth factor receptor on the surface of breast cancer cells. Herceptin was approved in Germany in September 2000 after evaluation in clinical trials involving women with metastatic breast cancer who had tumors overexpressing HER-2/neu. A prerequisite for its use is the diagnosis of the HER-2/neu receptor status in individual patients because trastuzumab is only effective in patients with a high (score +3) overexpression of the HER-2/neu receptor. The only approved diagnostic method is the immunohistochemical DAKO-Hercep test. Clinical experience with this novel biological agent has been obtained in 2 Phase III trials involving 469 and 222 patients, where trastuzumab was used as first- or second-line therapy. The addition of trastuzumab to chemotherapy regimens was associated with longer time to progression, a higher rate and duration of response and longer survival. When used as a single agent in metastatic breast cancer that had progressed after chemotherapy, there was an overall response rate of 15%. The median duration of response was 9.1 months and median survival was 13 months. Unwanted effects included potentially severe cardiotoxicity and in 40% of patients infusion-associated fever and/or shivering that usually occurred only during the first infusion. In patients with moderate HER-2/neu expression, unwanted drug effects outweigh a relatively weak therapeutic effect. In cases of high overexpression, the cancer may go into regression and survival may be prolonged with a relatively small impairment in the life quality. The costs of trastuzumab-therapy are high amounting to an additional 48,000 DM per patient per year. Recommendations for diagnosis and therapy in Mecklenburg-Vorpommern have been formulated in discussions between oncologists, practitioners, scientists and regulatory authorities.
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PMID:Opinion on the use of the antitumor drug trastuzumab (Herceptin) in patients with metastatic breast cancer in the county Mecklenburg-Vorpommern. 1172 72

Overexpression of the HER-2/neu oncogene appears to have prognostic significance in breast cancer. Recently, some have reported a relationship between increased immunohistochemical expression in osteosarcoma and poor clinical outcome. Despite limited data, a pilot trial of Herceptin, which targets the oncogene product, has been initiated for the therapy of some metastatic osteosarcomas (CCG-P9852). Archival formalin-fixed, paraffin-embedded tissue obtained from 41 patients diagnosed with osteosarcoma was examined immunohistochemically by 2 antibodies against the HER-2/neu oncogene product: CB-11 (monoclonal, 1/100) and Oncor (polyclonal, 1/200). All but one tumor (case of recurrent dedifferentiated parosteal osteosarcoma) represented primary tumor samples; when applicable, only prechemotherapy biopsies were analyzed. The study sample included the full spectrum of histologic subtypes and grades of osteosarcoma (25 conventional high grade; 3 telangiectatic; 1 small cell; 6 parosteal; 1 periosteal; and 5 low-grade intramedullary). A case of metastatic breast cancer with known overexpression of the HER-2/neu oncogene served as the positive control. Complete membranous positivity, considered prognostically significant in breast cancer, was not seen in any of our osteosarcoma cases. At least focal cytoplasmic positivity was documented in 40 (98%) tumors using the CB11 antibody and in 34 (83%) using the Oncor antibody. The intensity of the cytoplasmic staining (0, 1-3+) did not correlate with histologic subtype/grade, response to chemotherapy (<90% versus > or = 90% necrosis), metastasis, or survival. Immunohistochemical overexpression of the HER-2/neu oncogene, defined as complete membranous positivity, is not present in our series of osteosarcomas. Cytoplasmic positivity is observed in most osteosarcomas, irrespective of histologic subtype/grade, and is not associated with response to preoperative chemotherapy or disease progression.
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PMID:Clinicopathologic analysis of HER-2/neu immunoexpression among various histologic subtypes and grades of osteosarcoma. 1174 51

The HER-2/neu protein is thought to be a unique and useful target for antibody therapy of cancers overexpressing the HER-2/neu gene. The recombinant humanized anti-HER-2 monoclonal antibody, trastuzumab (Herceptin) was approved for clinical use in the US in 1998. In Japan, it was approved and later became available in June, 2001. We have treated 41 patients with metastatic breast cancer with trastuzumab purchased from the US. In this paper, the details of the patients we experienced are reviewed.
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PMID:Compassionate use of humanized anti-HER2/neu protein, trastuzumab for metastatic breast cancer in Japan. 1179 Nov 23


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