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)

The HER2 gene (also known as neu and as c-erb-B2) encodes a 185-kd transmembrane glycoprotein receptor with intrinsic tyrosine kinase activity. HER2 is overexpressed in 25% to 30% of human breast cancers, plays a role in the pathogenesis of breast cancer, and predicts for a worse prognosis in patients with metastatic disease. Trastuzumab (Herceptin; Genentech, Inc, So. San Francisco, CA), a humanized monoclonal antibody that targets the HER2 oncogene receptor, was shown to be active in preclinical models. In initial phase I clinical trials, trastuzumab was found to be safe and to exhibit dose-dependent pharmacokinetics. Three phase II studies of single-agent trastuzumab, which was administered weekly in the outpatient setting, have now been conducted in patients with HER2-overexpressing metastatic breast cancer. In the initial phase II study, the response rate was 11% in a heavily pretreated patient population. In a pivotal follow-up study of single-agent trastuzumab, more than 200 patients who had received at least one prior chemotherapeutic regimen for metastatic disease were entered. Despite a number of unfavorable baseline characteristics, the response rate reported by an independent response evaluation committee was 15%. A more recent study in previously untreated patients has shown a 23% response rate. The median duration of response in these trials has ranged from 6.6 to 9.1 months. In these three phase II studies, trastuzumab has been shown to be safe. The most clinically significant adverse event has been cardiac dysfunction syndrome, which occurred in less than 5% of patients. Trastuzumab is not associated with the other commonly observed side effects of chemotherapy, such as alopecia, mucositis, and neutropenia. The results from these studies demonstrate that trastuzumab is active and safe in patients with metastatic HER2-overexpressing breast cancer.
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PMID:Clinical trials of single-agent trastuzumab (Herceptin). 1104 53

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

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

Metastatic breast cancer is a partially chemotherapy-sensitive neoplasm. Most chemotherapy groups have activity in this disease, and the most active single drugs are the taxanes, especially docetaxel (Taxotere; Aventis Pharmaceuticals, Inc, Parsippany, NJ), and the anthracyclines. The alkylating agents, antimetabolites, and vinca alkaloids are also widely used. The platinum coordination complexes, which are widely used in oncology, are also active in metastatic breast cancer, but the availability of other drugs that are less toxic and easier to administer has resulted in their having a strictly limited use in this setting. Cisplatin appears to be somewhat more active than carboplatin, but direct comparative studies are lacking. The identification of the prominent activity of the taxanes has led to the investigation of wholly novel non-anthracycline-containing combination regimens, and platinum/taxane doublets appear to be particularly active. More recently, reports that trastuzumab (Herceptin, Genentech, South San Francisco, CA), a novel monoclonal antibody directed against the protein product of the HER2/(neu) oncogene, has a powerful synergistic interaction with docetaxel and with platinum agents have prompted evaluation of the triplet docetaxel/platinum/trastuzumab in the therapy of metastatic breast cancer.
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PMID:The platinum agents: a role in breast cancer treatment? 1130 72

The rationale for the combined use of docetaxel (Taxotere; Aventis Pharmaceuticals, Inc, Parsippany, NJ) and trastuzumab (Herceptin; Genentech, South San Francisco, CA) in HER2/neu-overexpressing breast cancer patients are several-fold. Docetaxel is a highly active chemotherapeutic agent in metastatic breast cancer. Response rates, time to progression, and survival are improved when trastuzumab is combined with chemotherapy. Finally, preclinical findings demonstrate synergistic cytotoxic activity when docetaxel and trastuzumab are combined. In addition, their different mechanisms of action and a nonoverlapping toxicity profile suggest the potential for a highly useful combination while minimizing potential cardiotoxicity. An ongoing pilot phase II evaluation is being conducted with every-3-week docetaxel plus weekly trastuzumab. Preliminary findings suggest an active and well-tolerated regimen. Efficacy data indicate an encouraging overall major response rate of 45% in first- and second-line metastatic breast cancer patients. Preliminary results from a second phase II trial of weekly docetaxel and trastuzumab have been reported. In 14 patients treated to date, grade (3/4) toxicities are infrequent. An overall response rate of 54% is reported thus far with 26 cycles (156 weeks) of therapy delivered. The preliminary data for the docetaxel and trastuzumab combinations look favorable from both a safety and an efficacy perspective. The lack of cardiac function changes despite frequent cardiac monitoring is promising. For the adjuvant therapy of HER2/neu-overexpressing breast cancer, the high level of efficacy of docetaxel and the need to identify nonanthracycline agents for combined use with trastuzumab place a high emphasis on the potential utility of docetaxel and trastuzumab-based regimens.
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PMID:Docetaxel (Taxotere) plus trastuzumab (Herceptin) in breast cancer. 1130 73

Chemotherapy plays an important role in the management of metastatic breast cancer. The anthracyclines (doxorubicin, epirubicin) and the taxanes (paclitaxel, docetaxel) are considered the most active agents for patients with advanced breast cancer. Traditionally, the anthracyclines have been used in combination with cyclophosphamide and 5-fluorouracil (FAC, FEC). The taxanes have single-agent activity similar to older combination chemotherapy treatments. There is great interest in developing anthracycline/taxane combinations. Capecitabine is indicated for patients who progress after anthracycline and taxane therapy. Vinorelbine and gemcitabine have activity in patients with metastatic breast cancer and are commonly used as third- and fourth-line palliative therapy. The role of high-dose chemotherapy is not well-defined and remains experimental. Novel cytotoxic therapy strategies include the development of anthracycline, taxane, and oral fluoropyrimidine analogues; antifolates; topoisomerase I inhibitors, and multidrug resistance inhibitors. A better understanding of the biology of breast cancer is providing novel treatment approaches. Oncogenes and tumor-supressor genes are emerging as important targets for therapy. Trastuzumab, a monoclonal antibody directed against the Her-2/neu protein, has been shown to prolong survival in patients with metastatic breast cancer. Other novel biologic therapies interfere with signal transduction pathways and angiogenesis. The challenge for the next decade will be to integrate these promising agents in the management of metastatic and primary breast cancer.
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PMID:Chemotherapy of metastatic breast cancer: what to expect in 2001 and beyond. 1130 25

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

Despite nearly 20 years of study, the importance of chemotherapy dose intensity in breast cancer remains unclear. Substantial preclinical data suggest a dose-response relationship, and consistent data document that recipients of substandard dosing have inferior outcomes. The use of increased dose-intensive therapies is costly, may require the use of hematopoietic growth factor support, and can result in significant increases in both short- and long-term toxicities. In patients with metastatic disease, increased dose intensity frequently results in increased response rates. However, these increased responses have not translated into consistent improvements in time to progression or overall survival benefit. In the adjuvant setting, increases in the dose intensities of alkylating agents and anthracyclines have failed to support the concept of dose escalation beyond standard doses. Certain subgroups of patients, such as those whose tumors overexpress HER2/neu, may derive a benefit from more dose-intensive therapies. Early results of randomized trials of high-dose chemotherapy in the treatment of metastatic breast cancer and adjuvant therapy for high-risk, early-stage breast cancer, are provocative. However, the often conflicting data do not support the routine use of this modality outside of the study setting.
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PMID:Dose intensity for breast cancer. 1143 Feb 5

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


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