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)

Human epidermal growth factor receptor 2 (HER2/neu) is an important target for the treatment of the breast cancers in which it is overexpressed. However, no approved anti-HER2/neu therapy is available for the majority of breast cancer patients, who express HER2/neu at low levels (with scores of 1+ or 2+/fluorescence in situ hybridization-negative). The trifunctional antibody ertumaxomab targets HER2/neu, CD3, and activating Fcgamma receptors. In presence of ertumaxomab, tri-cell complexes consisting of tumor cells, T cells, and accessory cells form to cause tumor cell lysis. In a phase I trial with metastatic breast cancer patients, ertumaxomab could be applied safely and resulted in radiographically confirmed clinical responses. In this study, we compare ertumaxomab- and trastuzumab-mediated killing of cancer cell lines that express HER2/neu at low and high levels. Under optimal conditions for trastuzumab-mediated destruction of HER2/neu-overexpressing cells, only ertumaxomab was able to mediate the elimination of tumor cell lines that express HER2/neu at low levels (1+). Ertumaxomab-mediated activity was accompanied by a Th1-based cytokine release, a unique mode of action of trifunctional antibodies. Competitive binding studies with trastuzumab and 520C9 mapped the binding site of ertumaxomab to the extracellular regions II and III of the HER2/neu ectodomain. This site is distinct from the binding site of trastuzumab, so that HER2/neu-expressing tumor cells can be eliminated by ertumaxomab in the presence of high amounts of trastuzumab. The ability of ertumaxomab to induce cytotoxicity against various tumor cell lines, including those with low HER2/neu antigen density, may provide a novel therapeutic option for breast cancer patients who are not eligible for trastuzumab treatment.
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PMID:The trifunctional antibody ertumaxomab destroys tumor cells that express low levels of human epidermal growth factor receptor 2. 1943 24

Sister Mary Joseph's nodule (SMJN) involving the umbilicus can often be a clinical sign of metastatic cancer, but rarely cancer originating from the breast. We report a rare case of umbilical metastases from breast cancer and reviewed the literature. A 54-year-old woman was referred to a pre-surgery clinic for an examination of an umbilical nodule. The patient had a history of ductal breast carcinoma. Cytological smear from fine needle aspiration showed epithelial neoplastic cells resembling those of breast carcinoma. Neoplastic cells from tissue were positive for cytokeratin 8-18, estrogen and progesterone receptor and negative for E-cadherin and had a low proliferative index. Her-2/neu immunodetection showed a 2+ equivocal positive rate, but Her-2/neu gene amplification was found on the cytological smear by fluorescence in situ hybridization analysis. Similar results were obtained within a tissue section. Concordant findings have been obtained when comparing the recent American Society of Clinical Oncology/College of American Pathologists scoring system. Fine needle aspiration from the SMJN is a useful tool for the diagnosis of metastatic breast cancer. Furthermore, the predictive biomarkers for tumors of the breast, hormonal receptors and Her-2/neu not only assist with the identification of the source of the metastatic disease but also provide clinical information for patient management.
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PMID:Her-2/neu evaluation in Sister Mary Joseph's nodule from breast carcinoma: a case report and review of the literature. 1951 52

The epidermal growth factor (EGF) receptors play an important role in epithelial cell function. Upon stimulation of these receptors, an extensive network of signal transduction pathways is activated, including the PI3K/AKT and Ras/Erk pathways. This activation leads to cellular proliferation and survival. In breast cancer, the EGF receptor, ErbB2 (HER2/neu), can be amplified and over-expressed and this is associated with poor prognosis and drug resistance. Trastuzumab is a monoclonal antibody against ErbB2 and has demonstrated activity in the therapy of breast cancer patients with over-expression of ErbB2, both in the metastatic and adjuvant setting. Recently, a tyrosine kinase inhibitor, lapatinib, that targets both ErbB1 and ErbB2, has also shown activity in metastatic breast cancer. In this review, we will discuss the ErbB receptors and their signaling networks in breast cancer, as well as the clinical activities of trastuzumab and lapatinib in this disease.
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PMID:Clinical activities of the epidermal growth factor receptor family inhibitors in breast cancer. 1970 33

We evaluated the efficacy and safety of weekly paclitaxel plus trastuzumab as first-line chemotherapy in women with HER2-overexpressing metastatic breast cancer (MBC), and we investigated the prognostic factors including magnitude of HER2/neu amplification in this population. We analyzed 54 patients with HER2-overexpressing MBC that were treated with weekly paclitaxel plus trastuzumab as first-line chemotherapy from February 2004 to December 2006. At a median follow-up of 28 months, median time to progression (TTP) was 16.6 months (95% CI, 9.4 to 23.7 months) and median overall survival was 25.6 months (95% CI, 21.8 to 27.3 months). Therapy was generally well tolerated, although three patients (5.5%) experienced reversible, symptomatic heart failure. Of the 27 patients evaluable for the HER2 FISH, patients with a HER2/CEP17 ratio of < or =4.0 had significantly shorter TTP than those with a HER2/CEP17 ratio of >4.0 (10.8 vs. 23.2 months, P=0.034). A HER2/CEP17 ratio of >4.0 was identified as significant predictive factor of TTP by multivariate analysis (P=0.032). The combination of weekly paclitaxel plus trastuzumab as first-line chemotherapy is an effective regimen in patients with HER2-FISH-positive MBC. Furthermore, the magnitude of HER2 amplification is an independent predictive factor of TTP.
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PMID:Weekly paclitaxel and trastuzumab as a first-line therapy in patients with HER2-overexpressing metastatic breast cancer: magnitude of HER2/neu amplification as a predictive factor for efficacy. 1979 92

PURPOSE The purpose of this study was to determine whether trastuzumab improves prognosis of women with metastatic human epidermal growth factor receptor 2 (HER2)/neu -positive breast cancer beyond that of women with HER2/neu-negative disease. PATIENTS AND METHODS Two thousand ninety-one women with metastatic breast cancer diagnosed from 1991 to 2007, with known HER2/neu status and who had not received trastuzumab in the adjuvant setting, were identified. Disease was classified into the following three groups: HER2/neu negative, HER2/neu positive without first-line trastuzumab treatment, and HER2/neu positive with first-line trastuzumab treatment. Overall survival (OS) was estimated using the Kaplan-Meier product-limit method and compared between groups with the log-rank test. Cox proportional hazards models were used to determine associations between OS and HER2/neu status after controlling for patient characteristics. Results One hundred eighteen patients (5.6%) had HER2/neu-positive disease without trastuzumab treatment, 191 (9.1%) had HER2/neu-positive disease and received trastuzumab treatment, and 1,782 (85.3%) had HER2/neu-negative disease. Median-follow-up was 16.9 months. One-year survival rates among patients with HER2/neu-negative disease, HER2/neu-positive disease and trastuzumab treatment, and HER2/neu-positive disease and no trastuzumab treatment were 75.1% (95% CI, 72.9% to 77.2%), 86.6% (95% CI, 80.8% to 90.8%), and 70.2% (95% CI, 60.3% to 78.1%), respectively. In a multivariable model, women with HER2/neu-positive disease who received trastuzumab had a 44% reduction in the risk of death compared with women with HER2/neu-negative disease (hazard ratio [HR] = 0.56; 95% CI, 0.45 to 0.69; P < .0001). This HR varied with time and was significant for the first 24 months and not significant after 24 months. CONCLUSION Our results show that women with HER2/neu-positive disease who received trastuzumab had improved prognosis compared with women with HER2/neu-negative disease.
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PMID:Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. 2047 95

We have previously shown in mice that vaccination with three Her-2-peptides representing B-cell epitopes of the extracellular domain of Her-2/neu induces Her-2/neu-specific IgG antibodies with strong anti-tumor activity in vitro and in vivo. We have now finalized a phase I clinical trial with an anti-Her-2/neu vaccine-construct of immunopotentiating reconstituted influenza virosomes with the three peptides in patients with metastatic breast cancer (MBC). Ten MBC patients with low protein overexpression of Her-2/neu of MBC (+ or ++ upon immunohistochemistry, FISH negative) and positive hormone receptor status were enrolled in a single center phase I study. The virosomal formulated vaccine, consisting of 10 microg/peptide, was intramuscularly applied three times on days 1, 28, and 56. The primary endpoint of the study, which lasted 12 weeks, was safety, the secondary endpoint immunogenicity. Local erythema at the injection site was the only vaccine-related side effect occurring in four patients. In 8 of 10 patients an increase in peptide-specific antibody titer measured by ELISA was found. Importantly, the induced antibodies were also directed against the native Her-2/neu protein. Cellular immune responses, as measured by in vitro production of IL-2, IFN-c, and TNF-a of PBMCs showed a marked increase after vaccination in the majority of vaccinees. Notably, the number of CD4+CD25+Foxp3+T regulatory cells, which were significantly increased compared to healthy controls prior to vaccination, was markedly reduced following vaccination. In all, the immunological responses after vaccination indicated that the patients in stage IV of disease were immunocompetent and susceptible to vaccination. The Her-2/neu multipeptide vaccine was safe, well tolerated and effective in overcoming immunological tolerance to Her-2/neu. The induction of anti-Her-2-specific antibodies could result in clinical benefit comparable to passive anti-Her-2 antibody therapy.
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PMID:A virosomal formulated Her-2/neu multi-peptide vaccine induces Her-2/neu-specific immune responses in patients with metastatic breast cancer: a phase I study. 2009 22

In spite of the current explosion of interest in biomarker research, industry seems to be struggling to incorporate these advances into drug development and healthcare delivery. Biomarkers in Medicine explored the issues with Dr Walter Carney, a pioneer in linking diagnostics with medicines to target therapies to stratified patient groups. Dr Carney and his colleagues were the first to discover the circulating human epidermal growth factor receptor (HER)2/neu oncoprotein in women with metastatic breast cancer. He has been granted numerous patents pertaining to the HER2/neu and ras oncoproteins, as well as having published extensively in this area. Dr Carney joined the DuPont Medical Products Department in 1982 where he held a variety of management positions in the Diagnostics Division. He was Vice President and General Manager of the Diagnostics and Research Products Division and in 1997 was appointed President of Oncogene Science. Dr Carney also held the position of Vice President of Proprietary Drug Development Programs for OSI Pharmaceuticals until Oncogene Science joined Bayer Diagnostics in late 1999. As part of Bayer HealthCare, Dr Carney continued as Head of the Oncogene Science business, which is a Center of Excellence for Oncology and is focused on the use of novel biomarker tests in linking diagnostics with pharmaceuticals. Oncogene Science is now part of the Global Siemens Medical Solutions Diagnostics, which is the first integrated diagnostics company and driving medical innovation by combining circulating biomarkers with imaging biomarkers.
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PMID:On target? The challenge of integrating biomarker research in drug development. Interview with Walter Carney. 2047 57

Current treatment for late-stage metastatic breast cancer is largely palliative. alpha-Particles are highly potent, short-range radiation emissions capable of sterilizing individual cells with one to three traversals of the cell nucleus. The alpha-emitter, (213)Bi (T(1/2) = 45.6 min), was conjugated to a 100-nm diameter liposomal-CHX-A''-DTPA construct, upon which the rat HER2/neu reactive antibody, 7.16.4, was grafted. A conjugation time of 10 minutes was achieved giving a specific activity corresponding to 0.1 (213)Bi atom per liposome; stability in vitro and in vivo was confirmed. Efficacy in a rat/neu transgenic mouse model of metastatic mammary carcinoma was investigated. Three days after left cardiac ventricular injection of 10(5) rat HER-2/neu-expressing syngeneic tumor cells, macrophage-depleted Neu-N mice were treated by i.v. injection with (a) 19.2 MBq (520 muCi) of liposome-CHX-A''-DTPA-(213)Bi, (b) 19.2 MBq of liposome-CHX-A''-DTPA-(213)Bi-7.16.4, (c) 4.44 MBq (120 muCi) of (213)Bi-7.16.4, and (d) cold (nonradioactive) liposome-CHX-A''-DTPA-7.16.4 as control. Treatment with (a) increased median survival time to 34 days compared with 29 days for the untreated controls (P = 0.013) and 27 days for treated cold controls. Treatment with the radiolabeled antibody-conjugated liposome (b) increased median survival time to 38 days (P = 0.0002 relative to untreated controls). The radiolabeled antibody-treated group (c) gave a median survival of 39 days, which was similar to that for the radiolabeled antibody-conjugated liposome-treated group (P = 0.5). We have shown that the (213)Bi radiolabeled immunoliposomes are effective in treating early-stage micrometastases, giving median survival times similar to those obtained with antibody-mediated delivery of (213)Bi in this animal model.
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PMID:Immunoliposomal delivery of 213Bi for alpha-emitter targeting of metastatic breast cancer. 2065 Dec 54

Silver-enhanced in-situ hybridization (SISH) is an emerging tool for the determination of the Her-2/neu amplification status in breast cancer. SISH is technically comparable to fluorescence in-situ hybridization (FISH) but does not require a fluorescence microscope for its interpretation. Although recent studies on histologic evaluations of SISH are promising, we aimed to evaluate its performance on 71 cytologic breast cancer specimens with the new combined Her-2/Chr17 probe. Her-2/neu status as routinely determined by FISH was available for all patients. We found SISH signals in cytologic cell blocks and smear specimens easy to evaluate in most cases. Small numbers of tumor cells and difficulties in identifying tumor cells in lymphocyte-rich backgrounds were limiting factors. Her-2/neu status, as determined by Her-2/Chr17 SISH, was basically identical to the results of the corresponding FISH. The discrepancies were mainly owing to the heterogeneity of Her-2/neu amplification in the tumor tissue. Interobserver agreement for the SISH evaluation was high (kappa value: 0.972). We conclude that Her-2/Chr17 SISH is a useful and accurate method for the evaluation of the Her-2/neu gene amplification status in cytologic breast cancer specimens, particularly in metastatic breast cancer lesions. The advantages of signal permanency and bright-field microscopic result interpretation make this technique an attractive alternative to the current FISH-based gold standard.
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PMID:Determination of the Her-2/neu gene amplification status in cytologic breast cancer specimens using automated silver-enhanced in-situ hybridization (SISH). 2066 Oct 16

Every oncologist has a dream - doing more with less toxicity. Targeted therapies seem to be the key for an oncologist's dreams by defining subgroups of those patients who benefit more from a specific treatment and those who do not. For a few years now, targeted therapies have played a major role in the treatment of primary as well as metastatic breast cancer. In this article, we describe targeted therapies that already play an important role in clinical decisions in the treatment of metastatic as well as primary breast cancer. The humanised monoclonal antibody trastuzumab is a very effective agent in primary and metastatic breast cancer, but only for those patients whose tumours are overexpressing HER2/neu. Bevacizumab is an antibody directed against vascular epidermal growth factor ligand A which plays a role in angiogenesis. Up to now there is no predictive factor known for this treatment. Furthermore, we would like to give an impression of new agents and strategies under investigation like tyrosine kinase inhibitors and other small molecules.
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PMID:Targeted Therapy: Can It Substitute for Chemotherapy? 2107 6


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