Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over-expression of the HER2/neu (HER2) proto-oncogene in breast carcinoma imparts an enhanced metastatic potential. Metastasis requires escape of the tumor cell from the vasculature into subjacent tissue, a transmigration event across an endothelial cell (EC) monolayer. EC retraction has been reported to precede transmigration in several tumor metastatic models. Using intact human iliac vein EC monolayers, we tested the abilities of MCF-7 breast cancer cells and HER cells, a transfected MCF-7 line over-expressing HER2, to induce EC retraction. We further analyzed whether HER2 signaling influenced cancer cell-induced EC retraction. MCF-7 or HER cells were co-cultured onto mature EC monolayers. More HER than MCF-7 cells induced EC retraction (76 +/- 19% vs. 17 +/- 12%, p < 0.001) with resultant exposure of subendothelial matrix (6.80 +/- 2.86% vs. 0.85 +/- 0.39%, p < 0.001). Blockade of HER2 signaling using Herceptin nearly eliminated EC retraction (p < 0.01), while stimulation of HER2 using heregulin-beta1-augmented EC retraction (p < 0.05). Further, there was no difference between cell lines in either the number of cells adhered or the strength of adherence to EC under shear stress. These data suggest that HER2 signaling enhances metastasis in breast cancer cells by inducing EC retraction, a process that appears to precede endothelial transmigration.
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PMID:HER2/neu over-expression induces endothelial cell retraction. 1116 50

In recent years, the clinical application of paclitaxel (Taxol), docetaxel (Taxotere), vinorelbine (Navelbine), and trastuzumab (Herceptin) has improved the management of advanced breast cancer. With the introduction of gemcitabine, a new drug with significant activity in breast cancer has become available. As a single agent, gemcitabine (Gemzar) provides response rates in the range of 25% to 46% in breast cancer, depending on starting dose and status of prior chemotherapy for metastatic disease. Higher response rates are observed when gemcitabine is combined with other classes of cytotoxic drugs. Studies conducted in our laboratory detected high degrees of synergy between gemcitabine and cisplatin (Platinol) in a variety of human tumors in primary culture. These analyses identified breast cancer as a target for this combination. The combination of cisplatin plus gemcitabine is active in relapsed breast cancer patients. The activity observed in drug-resistant patients suggests relative non-cross resistance with other drug combinations.
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PMID:Gemcitabine plus cisplatin in breast cancer. 1125 86

Determining the HER2 status of breast carcinomas is a prerequisite for the use of the monoclonal antibody trastuzumab (Herceptin), which has recently been licensed for the treatment of metastatic disease. This necessitates a test based on archival material. The preferred analyses are immunohistochemistry with fluorescent in situ hybridisation (FISH) as a follow up test for ambiguous results. Guidelines have been developed for standardised, well controlled procedures for the provision of reliable results. A group of three reference laboratories has been established to provide advice, quality assurance, and materials, where needed.
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PMID:Recommendations for HER2 testing in the UK. 1126 71

This report summarises the clinical efficacy and safety findings from clinical trials of the new anti-HER2 monoclonal antibody Herceptin(R) (trastuzumab). Data from pivotal trials indicate that trastuzumab is active when added to chemotherapy in patients with advanced metastatic breast cancer. In particular, the combination significantly prolonged the median time to disease progression, increased the overall response rate, increased the duration of response, and improved median survival time by approximately 25% compared with chemotherapy alone. Furthermore, trastuzumab is active as a single agent in women with HER2-positive metastatic breast cancer, inducing durable objective tumour responses. In total, 15% of patients who had received extensive prior treatment for metastatic disease had an objective response. The median duration of response was 9.1 months following administration of single-agent trastuzumab. Notably, 2% of patients were free of disease progression at 6 months. The safety profile of trastuzumab either given alone or in combination was favourable.
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PMID:Clinical trials of Herceptin(R) (trastuzumab). 1134 96

Following confirmation of the appropriate dosage, safety and potential efficacy of Herceptin(R) (trastuzumab) in small-scale phase I and II trials involving patients with refractory disease, a large trial was conducted in 222 patients with breast cancer who had relapsed after one or two chemotherapy regimens for their metastatic disease. The results showed a positive and durable overall response rate (15% according to a response evaluation committee (REC) assessment) using trastuzumab monotherapy (initial dose 4 mg/kg intravenously (i.v.) followed by 2 mg/kg i.v. weekly). In another recently completed phase II trial, 113 patients were randomised to two dose levels (initial dose of 4 mg/kg i.v. dose followed by 2 mg/kg i.v. weekly, or initial dose of 8 mg/kg followed by 4 mg/kg i.v. weekly) of single-agent trastuzumab as first-line therapy for metastatic disease. The preliminary overall response rate was 23% based on investigator assessment, and tolerability was excellent as in previous trials; efficacy was similar in both dose groups, but the side-effects tended to be more frequent in the higher dose group. The preferred dosage is therefore the same as that currently recommended, i.e. an initial dose of 4 mg/kg i.v. followed by 2 mg/kg weekly i.v. until disease progression.
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PMID:First-line, single-agent Herceptin(R) (trastuzumab) in metastatic breast cancer. a preliminary report. 1134 97

The study was performed for answering the question whether metastatic breast cancer has the same overexpression of HER2/neu as primary breast tumor. We assumed that study on this subject could give a valuable information for proper interpretation of HER2/neu overexpression in breast cancer patients designated for therapy with Herceptin. Our study was performed on 71 breast cancer patients qualified for clinical trial with Herceptin therapy. All patients selected for this trial have had surgery and two episodes of unsuccessful adjuvant therapy. Tissue samples were routinely fixed in 4% formalin and embedded in paraffin. Immunohistochemical assays were performed on 5 microns slides using DAKO HercepTest and semi-quantitative methods to determine HER2 protein overexpression were used. All study cases were subdivided into two groups. First group--49 cases in which expression of HER2 was examined in tissue from primary breast tumors, and second group--22 cases in which expression of HER2 was examined in tissue from metastatic lesions. In the whole study group (71 cases) overexpression was confirmed in 29 (40.8%) cases. In the group of primary breast tumors overexpression of HER2 was present in 20 (40.8%) of cases. In the group of metastatic breast tumors overexpression of HER2 was present in 9 (40.9%) of cases. The result suggests that overexpression which appears in primary breast carcinoma is also preserved in metastases. Direct prove of such a conclusion, would be a study on HER2/neu expression estimated in primary and metastases in the same patients. It requires a proper quantity and quality of material. Our results indicate that there is no difference between the estimation of HER2/neu overexpression in primary and metastatic breast cancer in patients with disseminated disease after double failure of chemotherapy. Evaluation of overexpression of HER2/neu in cases of planned Herceptin therapy can be done both in material from primary and from metastatic tumor.
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PMID:Expression of HER2/neu in primary and metastatic breast cancer. 1150 77

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

Herceptin is the first therapy for breast cancer which targets an oncogene product. This humanized antibody to HER-2 has been shown to have activity as a single agent in a phase II trial of heavily pre-treated patients with advanced breast cancer and, in phase III studies, its use with chemotherapy is associated with higher response rates, longer time to progression and improved survival when compared with chemotherapy alone. Retrospective analysis of data from these pivotal trials suggests that attributable benefit of herceptin is greater in those patients who express HER-2 at the highest levels, that is 3+ expression by immunohistochemistry. Further analysis also implies that cases which are positive for HER-2 by fluorescent in situ hybridization may also benefit from treatment regardless of whether they express HER-2 at the 2+ or 3+ level. Use of herceptin as first-line therapy for metastatic disease in early studies suggest that response rates and clinical benefit rate similar to chemotherapy may be achievable and that survival using this sequential approach may not be compromized. Other combinations of herceptin and chemotherapy have been investigated with phase II data suggesting considerable activity with weekly taxol and when combined with navelbine. The non-linear pharmacokinetics of herceptin suggest that, as doses increased, half-life increases and may be feasible on a 3-weekly schedule. The role of herceptin in the adjuvant setting in the management of breast cancer will be tested in randomized studies of patients who express HER-2 at the highest levels; two of these studies have already begun.
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PMID:Update on HER-2 as a target for cancer therapy: herceptin in the clinical setting. 1173 89

The aggressiveness of human epidermal growth factor receptor-2 (HER2)-positive breast cancer and the poor prognosis of women with this disease demand the availability of accurate and reliable tests for HER2 status and the optimization of HER2-targeted therapy. The distinctive clinical pattern of HER2-positive breast cancer underlines the importance of testing for HER2 status and efforts are ongoing to validate the two major methods in use-immunohistochemistry (IHC), which measures cell membrane HER2 expression, and fluorescence in situ hybridization (FISH), which measures gene copy number. Clinical trial results demonstrate that there is an association between strong HER2 overexpression (IHC 3+) and optimal response to therapy with the novel recombinant HER2 antibody Herceptin. High levels of concordance between IHC 3+ and FISH-positive status have been observed, and response to treatment with Herceptin is similar for patients whose breast cancers are IHC 3+ and those who are FISH-positive. Observations to date have led to the formulation of an algorithm for HER2 status determination and Herceptin use which recommends that: (i) the HER2 status of all women with breast cancer be determined at presentation, (ii) all IHC 3+ and FISH-positive patients with metastatic disease should receive Herceptin, (iii) Herceptin should be used early in the course of metastatic breast cancer and preferably first line, and (iv) Herceptin therapy should be continued until disease progression.
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PMID:Maximizing the response to Herceptin therapy through optimal use and patient selection. 1198 22

Amplification of the human epidermal growth factor receptor-2 (HER2) gene and overexpression of the encoded protein are seen in 20-30% of breast cancers, and are associated with aggressive disease and relatively poor prognosis. Thus, HER2 represents an appropriate target for anticancer treatment and the humanized anti-HER2 monoclonal antibody Herceptin has been developed for this purpose. The efficacy of Herceptin has been confirmed in two pivotal trials-a monotherapy study in 222 women with HER2-positive metastatic breast cancer who had already received one or two chemotherapy regimens for metastatic disease and a study comparing Herceptin plus chemotherapy with chemotherapy alone in 469 patients previously untreated for metastatic disease. Herceptin monotherapy was associated with longer median response duration and survival than previous chemotherapy. Addition of Herceptin to chemotherapy increased response rates, time to disease progression and survival duration. Benefit was greatest in patients with high-level HER2 overexpression. Herceptin was well tolerated, with mild to moderate infusion-related reactions, usually seen with the first infusion only, being the most common event. Most patients respond to conventional supportive treatment. Cardiotoxicity, the most serious adverse event observed, occurred mainly in patients exposed to anthracyclines and was generally manageable. Thus, Herceptin represents a significant development in the management of HER2-positive breast cancer.
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PMID:Efficacy and safety of Herceptin in women with metastatic breast cancer: results from pivotal clinical studies. 1198 25


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