Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The measurement of health-related quality of life (HRQL) was an important component of clinical trials of trastuzumab (Herceptin; Genentech, San Francisco, CA) in women with progressive HER2-overexpressing metastatic breast cancer who may or may not have had prior chemotherapy. Health-related quality of life was measured at baseline and specified intervals during therapy using the European Organization for Research and Treatment of Cancer core Quality of Life Questionnaire (QLQ-C30, version 1.0). Five domains were chosen a priori for analysis: global quality of life, physical, role and social functioning, and fatigue. In the phase II study, in which trastuzumab was given alone, there was no change in on-treatment QLQ-C30 scores compared with baseline. These results suggest that trastuzumab does not adversely affect HRQL during therapy. In the phase III study, the effects of trastuzumab plus chemotherapy were compared with those of chemotherapy alone. A comparison of QLQ-C30 scores during treatment did not show statistically significant differences between the two groups at the preset level of P = .01. However, comparison of on-treatment scores with baseline in patients receiving chemotherapy alone indicated mild worsening of physical and role functioning and of fatigue throughout the duration of treatment, whereas a similar comparison of those receiving chemotherapy with trastuzumab revealed mild worsening of role functioning at weeks 8 and 20 and of fatigue only at week 8. These results suggest that trastuzumab may be associated with an amelioration of the deleterious effects of chemotherapy alone. In summary, in the doses and schedules used in these studies, trastuzumab is not associated with worsening of HRQL.
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PMID:Health-related quality of life in women with metastatic breast cancer treated with trastuzumab (Herceptin). 1048 98

Human epidermal growth factor receptor-2 (HER2) is a member of the epidermal growth factor receptor family, which produces factors that are considered to be important mediators of cell growth. Overexpression of HER2, which occurs in approximately 25% to 30% of human breast cancers, has fostered considerable interest in innovative therapeutic modalities designed to target tumor cells demonstrating such overexpression. Trastuzumab (Herceptin; Genentech, San Francisco, CA), a humanized monoclonal antibody developed to target the HER2 receptor, is the most widely studied example of such a modality. In early clinical studies with trastuzumab, cardiomyopathy was observed with a clinical expression similar to that seen with the anthracyclines (ie, a potentially progressive decrease in cardiac systolic function). A number of possible explanations for this cardiotoxicity are explored in this report. The first is that trastuzumab has inherent toxicity. This consideration has some theoretical interest, since fetal myocardial cells exhibit HER2 receptors and the adult myocardium expresses HER3 receptors. A second possibility is that sequential stresses following doxorubicin administration contribute to cardiac dysfunction. A third explanation is that observational artifacts lead to an overestimation of trastuzumab cardiotoxicity. Approaches for additional study of the extent and severity of trastuzumab cardiotoxicity are briefly addressed.
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PMID:Cardiotoxicity in patients receiving transtuzumab (Herceptin): primary toxicity, synergistic or sequential stress, or surveillance artifact? 1048

Several recent publications have re-opened the question of whether HER2 status should be determined for all patients with newly diagnosed breast cancer. The barrier in the past to the use of HER2 has been the nonstandardization of HER2 status determination, which is the major caveat to its use today. Two test kits have been recently approved by the Food and Drug Administration for HER2 testing, one for determining HER2 amplification by fluorescence in situ hybridization and the other for measuring HER2 overexpression by immunohistochemistry. Neither of these tests, nor any of the other myriad tests used for HER2 determinations, has been validated in all the potential arenas for the use of HER2: refinement of estimates of prognosis of untreated low-risk patients, selection among treatment options for adjuvant therapy, and selection of patients for treatment with trastuzumab (Herceptin; Genentech, San Francisco, CA). The nonstandardization of testing has led to conflicting results and controversy as to the value of HER2 in evaluating breast cancer patient prognosis and the selection among therapeutic options. Thus, testing for HER2 is not yet routine for patients with newly diagnosed breast cancer, although it is of value for patients who develop metastatic disease and who need to know if they are candidates for trastuzumab.
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PMID:Should HER2 status be routinely measured for all breast cancer patients? 1048 3

This study compares the performance of 2 combined contraceptive vaginal rings (CVRs) releasing 1 mg norethindrone acetate (NET-Ac) and either 20 or 15 mcg ethinyl estradiol (EE) over 24 hours. 61 women selected at 3 clinic sites in Los Angeles, San Francisco and Sydney were included. The performance of the 2 CVRs was determined by luteal activity, menstrual bleeding patterns, sum levels of EE and NET-Ac, and effects on serum lipoproteins. Results showed that both CVRs worked effectively: no pregnancies occurred, and there was only 1 cycle of luteal activity suggestive of ovulation (serum progesterone 32 nmol/l) with each ring (0.9% of cycles with the 1/15 ring and 1.2% of cycles with the 1/20 ring). Although there was more luteal activity in 1/15 CVR users, only 3 cycles with a significant level of luteal activity (progesterone 10 nmol/l) occurred among compliant users. Consistent elevation in serum levels of NET and EE was observed during use of both rings. A significant difference in EE levels was observed between women in Los Angeles and Sydney using the same dose of rings. There were no significant changes in the total cholesterol, HDL and LDL cholesterol values during treatment. The increase in triglycerides remained within the normal range while mean body weight showed no change. Side effects were infrequent and were similar to those associated with other steroidal contraceptives. Overall, both CVRs performed well, showing only minor and mainly nonsignificant differences in effect on serum EE, NET, E2, on progesterone levels and lipids, and on vaginal bleeding patterns.
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PMID:A comparative study of two contraceptive vaginal rings releasing norethindrone acetate and differing doses of ethinyl estradiol. 1049 84

Monoclonal antibody therapy is beginning to realize its promise. Efficacy has been seen in clinical trials using antibodies that target tumor cell surface antigens such as B-cell idiotypes, CD20 on malignant B cells, CD33 on leukemic blasts, and HER2/neu on breast cancer. Unconjugated immunoglobulins directed against CD20 induce partial and complete responses in up to 50% of patients with advanced, indolent non-Hodgkin's lymphoma. When such antibodies are conjugated to radionuclides, complete and overall response rates increase. Conjugates composed of anti-CD33 antibodies and the chemotherapy agent, calicheamicin, show promising activity in patients with relapsed or refractory acute myelogenous leukemia Treatment of patients with advanced breast cancer using the anti-HER2/neu antibody, trastuzumab (Herceptin; Genentech, San Francisco, CA) leads to objective responses in some patients with overexpression of the HER2/neu oncoprotein. These exciting results provide a basis for further refinement of the existing approaches to develop new antibody-based cancer therapy strategies.
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PMID:Monoclonal antibody therapy of cancer. 1056 Oct 17

Herceptin (trastuzamab, Genentech, San Francisco, CA, USA) prolongs survival in metastatic breast cancer patients whose tumours overexpress the HER2/neu protein. Compared with chemotherapy alone, patients receiving chemotherapy and Herceptin have a significantly longer time to progression, a higher response rate and a longer duration of response. These effects are most marked in first-line treatment of metastatic disease. The addition of Herceptin is associated with few additional side-effects, apart from cardiac toxicity in patients concurrently receiving anthracyclines. As such, it seems reasonable for Herceptin to become considered as one of the routine treatment options in metastatic breast cancer. It would therefore be appropriate for HER2 status testing to be incorporated into the assessment of all patients with metastatic disease. The use of this medication will be limited by its cost. Furthermore, data are lacking on appropriate treatments durations in responders.
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PMID:Herceptin (trastuzamab) in advanced breast cancer. 1091 83

Several recent advances have led to accelerated progress in breast cancer therapy. The development of new drugs with novel mechanisms of action, such as the taxanes, or oral bioavailability, such as capecitabine, has expanded the horizons of available chemotherapy. The use of tumor-related proteins or genes as markers of sensitivity or resistance to systemic therapy may allow for more predictable outcomes. Finally, the emergence of biological therapies such as the HER2/neu monoclonal antibody trastuzumab (Herceptin; Genentech, Inc, So. San Francisco, CA) represents an exciting new direction that opens doors to new concepts in antitumor therapy. This report will review the most exciting possibilities for expanding the field of breast cancer management.
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PMID:State-of-the-art chemotherapy for advanced breast cancer. 1104 51

The physical characteristics of tumor antigens that would make the most ideal targets for antibody therapeutics include cell surface expression; high, stable expression levels in tumor cells; low or absent expression in normal tissues; lack of a soluble form of the antigenic target; and lack of internalization of the antigen/antibody complex. HER2/neu is a 185-kd surface membrane protein that is overexpressed in approximately 25% of human breast cancers due to amplification of the HER2 gene. Overexpression of the gene results in ligand-independent activation of HER2 kinase, causing mitogenic signal transduction and increased cell proliferation. Consequently, patients with this alteration have a worse clinical prognosis. Trastuzumab (Herceptin; Genentech, Inc, So. San Francisco, CA), a humanized anti-HER2 monoclonal antibody, has significant clinical activity against metastatic breast cancers with HER2/neu overexpression, despite the fact that the p185HER2 protein product lacks some of the ideal characteristics of tumor antigens listed above. We propose that the efficacy of trastuzumab may be explained on the basis of its effects on signal transduction, which is independent from its immune mechanism(s) of action. Furthermore, trastuzumab is synergistic with some chemotherapeutic drugs, resulting in improved therapeutic efficacy. Thus, in the case of trastuzumab, a clear distinction may be drawn between the use of monoclonal antibodies as immuneactive agents and their use to achieve a desired cellular/biochemical activity.
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PMID:Biological rationale for HER2/neu (c-erbB2) as a target for monoclonal antibody therapy. 1104 52

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

Trastuzumab (Herceptin; Genentech, Inc, So. San Francisco, CA) is a high-affinity, humanized anti-HER2 antibody that has shown benefit in the therapy of patients with metastatic HER2-overexpressing breast cancer. Results from initial clinical trials of trastuzumab as a single agent or in combination with chemotherapy established important guidelines for the therapy of HER2-positive tumors, but represent an early phase of clinical development. Preclinical studies have shown additive and synergistic effects of trastuzumab when given in combination with several chemotherapeutic agents, and a series of clinical trials exploring these new combinations is under way or will be started shortly. Substantial effort will be directed toward promising schedules and combinations, such as weekly paclitaxel with trastuzumab or combinations of platinum, taxanes, and trastuzumab. Due to the unexpected cardiac toxicity observed with the combination of doxorubicin plus trastuzumab, new studies will be designed to prospectively assess cardiac function and will incorporate anthracyclines with less cardiotoxicity, such as liposomal doxorubicin. Combination studies are not limited to cytotoxic agents, as laboratory and clinical data have demonstrated that HER2 overexpression results in resistance to hormonal therapy. Therefore, a series of studies combining hormonal treatments with trastuzumab is being considered. Finally, the integration of trastuzumab into the adjuvant and neoadjuvant settings will be studied by United States and European cooperative groups.
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PMID:Current and planned clinical trials with trastuzumab (Herceptin). 1104 54


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