Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We established an RT-PCR method to measure the amount of a 2.3-kb alternatively spliced mRNA of the human c-erbB-2/HER-2 proto-oncogene relative to the 4.6-kb full-length transcript. For the first time, we demonstrated production of c-erbB-2 extracellular domains via alternative splicing in breast cancer tissues, lymph node and bone marrow micrometastases. In 15 c-erbB-2-positive primary breast tumor samples, we found two significantly distinct subgroups: 6/15 had a low level of the extracellular fragment, and 9/15 showed an average 4.4-fold higher amount of the alternatively spliced mRNA. Additionally, six lymph nodes and six bone marrow aspirates from metastatic breast cancer patients were analyzed: 5/6 lymph nodes and 6/6 bone marrow aspirates were found to produce elevated relative amounts of the truncated fragment. The results demonstrate that our method is suitable for sensitive detection of c-erbB-2-positive micrometastasis and strongly suggest that the alternatively spliced c-erbB-2 variant is involved in the development of micrometastasis in breast cancer.
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PMID:Differential expression of alternatively spliced c-erbB-2 mRNA in primary tumors, lymph node metastases, and bone marrow micrometastases from breast cancer patients. 964 24

The HER2/neu proto-oncogene is overexpressed in 25% to 30% of patients with breast cancer. Trastuzumab (Herceptin; Genentech, San Francisco, CA), a recombinant humanized monoclonal antibody with high affinity for the HER2 protein, inhibits the growth of breast cancer cells overexpressing HER2. In this phase II study the efficacy and toxicity of weekly administration of trastuzumab was evaluated in 46 patients with metastatic breast cancer whose tumors overexpressed HER2. A loading dose of 250 mg trastuzumab was administered intravenously, which was followed by 10 weekly doses of 100 mg each. Upon completion of this treatment period, patients with no disease progression could receive a weekly maintenance dose of 100 mg. Patients in this trial had extensive metastatic disease, and most had received prior anticancer therapy. Ninety percent of patients achieved adequate serum levels of trastuzumab. Toxicity was minimal, and no antibodies against trastuzumab could be detected. Objective responses were observed in 5 of the 43 evaluable patients, which included 1 complete remission and 4 partial remissions, for an overall response rate of 11.6%. Responses were seen in mediastinum, lymph nodes, liver, and chest wall lesions. Minor responses (seen in 2 patients) and stable disease (14 patients) lasted for a median of 5.1 months. These results demonstrate that trastuzumab is well tolerated and clinically active in patients with HER2-overexpressing metastatic breast cancers who have received extensive prior therapy. The regression of human cancer through the targeting of putative growth factor receptors such as HER2 warrants further evaluation of trastuzumab in the treatment of breast cancer.
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PMID:Phase II study of weekly intravenous trastuzumab (Herceptin) in patients with HER2/neu-overexpressing metastatic breast cancer. 1048 97

We conducted a phase I pharmacokinetic dose escalation study of a recombinant humanized anti-p185HER2 monoclonal antibody (MKC-454) in 18 patients with metastatic breast cancer refractory to chemotherapy. Three or six patients at each dose level received 1, 2, 4 and 8 mg kg(-1) of MKC-454 as 90-min intravenous infusions. The first dose was followed in 3 weeks by nine weekly doses. Target trough serum concentration has been set at 10 microg ml(-1) based on in vitro observations. The mean value of minimum trough serum concentrations at each dose level were 3.58 +/- 0.63, 6.53 +/- 5.26, 40.2 +/- 7.12 and 87.9 +/- 23.5 microg ml(-1) respectively. At 2 mg kg(-1), although minimum trough serum concentrations were lower than the target trough concentration with a wide range of variation, trough concentrations increased and exceeded the target concentration, as administrations were repeated weekly. Finally 2 mg kg(-1) was considered to be sufficient to achieve the target trough concentration by the weekly dosing regimen. One patient receiving 1 mg kg(-1) had grade 3 fever, one at the 1 mg kg(-1) level had severe fatigue defined as grade 3, and one at 8 mg kg(-1) had severe bone pain of grade 3. No antibodies against MKC-454 were detected in any patients. Objective tumour responses were observed in two patients; one receiving 4 mg kg(-1) had a partial response in lung metastases and the other receiving 8 mg kg(-1) had a complete response in soft tissue metastases. These results indicate that MKC-454 is well tolerated and effective in patients with refractory metastatic breast cancers overexpressing the HER2 proto-oncogene. Further evaluation of this agent with 2-4 mg kg(-1) weekly intravenous infusion is warranted.
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PMID:Dose escalation and pharmacokinetic study of a humanized anti-HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. 1060 42

The HER-2/neu proto-oncogene is a useful prognostic and predictive biomarker in breast cancer. In addition, use of a humanized monoclonal antibody against HER-2/neu has recently been shown to have efficacy in the treatment of metastatic breast cancer. In order to examine the potential of HER-2/neu as a biomarker and as a target for HER-2/neu monoclonal antibody treatment in melanoma, we examined the HER-2/neu status in 40 advanced stage melanomas. Using fluorescence in situ hybridization for determining the gene amplification status and immunohistochemistry for detecting protein overexpression, we found that only one out of 40 cases of melanoma had an altered HER-2/neu status. These results demonstrated that HER-2/neu amplification and overexpression are not common in advanced stage melanoma and thus, HER-2/neu would have limited value as a biomarker or as a target for immunotherapy in melanoma.
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PMID:Amplification and overexpression of HER-2/neu are uncommon in advanced stage melanoma. 1092 35

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

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

In breast cancer the membrane expression of HER2 receptor protein encoded by the HER2 proto-oncogene seems to have an ever growing clinical significance. In tissue cultures and animal experiments it was shown that the HER2 gene amplification induces malignant transformation and intensifies the aggressiveness of the tumour cells. Correlating with the so called pheno-and genotypic prognostic markers, the overexpression of HER2 in breast cancer predicts also poor prognosis and indicates enhanced potential for metastatisation. In some of the so called precancerous proliferations and "in situ" carcinomas we demonstrated the enhanced membrane staining of the HER2 receptor protein. In these cases we frequently observed DNA aneuploidy,the presence of p53 mutational protein and CD44v6 glycoprotein. The immunohistochemical studies of HER2 protein in invasive carcinomas have revealed, an interrelationship between the grade of differentiation, histological type, aggressiveness and biological behaviour of the "in situ" and invasive carcinomas. In clinical studies trastuzumab, a humanized monoclonal antibody recognizing extracellular domain of HER2 receptor protein, has proved to be effective in HER2 overexpressing metastatic breast cancer either as monotherapy or in combination with chemotherapeutical agents. The DAKO "HercepTest" is a semiquantitative, standardised method for the determination of HER2 overexpression.
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PMID:[Expression of HER2 in breast cancer] 1205 Jul 66

The ERBB2 proto-oncogene, commonly referred to as the human epidermal growth factor receptor-2 (HER2) gene, encodes a 185 kd receptor tyrosine kinase. Overexpression of the protein leads to constitutive activity of the HER2 receptor and breast tumor development through enhanced cell proliferation, survival, motility and adhesion. Overabundance of the HER2 receptor, typically caused by amplification of the HER2 gene, is present in approximately 10-30% of invasive breast cancers, and is associated with an aggressive disease course and decreased disease-free and overall survival in node-positive patients. Tratuzumab, a humanized murine monoclonal antibody, offers a targeted treatment modality for tumors that over express the HER2 protein. Tratuzumab, shown to be effective and initially approved for treatment of metastatic breast cancer, has recently been shown to be very effective in the adjuvant setting. Thus, to offer prognostic information and to direct appropriate treatment it is important to provide accurate laboratory assessment of the status of HER2. This article provides an overview of the methods currently used to assess HER2.
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PMID:HER2 testing: a review of detection methodologies and their clinical performance. 1718 84

A growing body of evidence indicates that interactions between neoplastic cells and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) are crucial in promoting tumor cell invasion and progression. Macrophages have an ambiguous role in these processes as this M1 phenotype correlates with tumoricidal capacity, whereas TAMs of M2 phenotype exert tumor-promoting effects. In this study, we provide evidence that interactions between mouse breast tumor cells and TAMs remodel the TME, leading to the upregulation of Fra-1, a member of the FOS family of transcription factor. In turn, this proto-oncogene initiates activation of the IL-6/JAK/Stat3 signaling pathway. This creates a malignant switch in breast tumor cells, leading to increased release of proangiogenic factors MMP-9, vascular endothelial growth factor and transforming growth factor-beta from tumor cells and intensified invasion and progression of breast cancer. Proof of the concept for the crucial role played by transcription factor Fra-1 in regulating these processes was established by specific knockdown of Fra-1 with small interfering RNA, which resulted in a marked suppression of tumor cell invasion, angiogenesis and metastasis in a mouse breast cancer model. Such a strategy could eventually lead to future efficacious treatments of metastatic breast cancer.
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PMID:The role of proto-oncogene Fra-1 in remodeling the tumor microenvironment in support of breast tumor cell invasion and progression. 1996 54

The study of proto-oncogene Her-2/neu using the fluorescence in situ hybridization (FISH) technique in routinely paraffin-embedded formalin-fixed tissue has become commonplace over the past decade and mandatory among invasive breast cancer expressing a score 2+ by immunohistochemical analysis of c-erbB2 protein. The patient's eligibility for treatment with the biological drug trastuzumab/herceptin is based on the evidence of a Her-2/neu proto-oncogene amplification (ratio Her-2/neu/CEP-17>2.2). However, although the exclusion is declared in the absence of Her-2/neu gene amplification (ratio Her-2/neu/CEP-17 <1.8) according to the American Society of Clinical Oncology/College of American Pathologists recommendations, there are borderline cases (1.8<ratio Her-2/neu/CEP-17>2.2) that need to be investigated (eg, ductal carcinoma in situ with microinvasion, metastatic breast cancer). In such cases with Her-2/neu genetic heterogeneity it is difficult to count the nuclear signals in the areas of invasive tumor using fluorescence. The availability of a Fluorescence Immunophenotyping and Interphase Cytogenetics as a Tool for Investigation of Neoplasms technique, based on the simultaneous evaluation of immunostaining with anticytokeratins (CKAE1/AE3 and CK19), together with FISH for Her-2/neu gene status [it is therefore useful and of current applicability in breast cancer blocks (formalin-fixed and paraffin-embedded)], permits a more easy identification of even single neoplastic cells by immunofluorescence and then a better evaluation of Her-2/neu status gene by the FISH technique, as shown in our study.
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PMID:Simultaneous fluorescence immunophenotyping and Her-2/neu genotyping (FICTION) in breast carcinoma candidates to target therapy. 2241 57


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