Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
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Human epidermal growth factor receptors (HER/erbB) constitute a family of four cell surface receptors involved in transmission of signals controlling normal cell growth and differentiation. A range of growth factors serve as ligands, but none is specific for the HER2 receptor. HER receptors exist as both monomers and dimers, either homo- or heterodimers. Ligand binding to HERI, HER3 or HER4 induces rapid receptor dimerization, with a marked preference for HER2 as a dimer partner. Moreover, HER2-containing heterodimers generate intracellular signals that are significantly stronger than signals emanating from other HER combinations. In normal cells, few HER2 molecules exist at the cell surface, so few heterodimers are formed and growth signals are relatively weak and controllable. When HER2 is overexpressed multiple HER2 heterodimers are formed and cell signaling is stronger, resulting in enhanced responsiveness to growth factors and malignant growth. This explains why HER2 overexpression is an indicator of poor prognosis in breast tumors and may be predictive of response to treatment. HER2 is a highly specific and promising target for new breast cancer treatments. The recombinant human anti-HER2 monoclonal antibody (rhuMAb-HER2, trastuzumab, Herceptin) induces rapid removal of HER2 from the cell surface, thereby reducing its availability to heterodimers and reducing oncogenicity.
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PMID:The basic biology of HER2. 1152 19

This report summarizes the efficacy of trastuzumab (Herceptin) based on its completed clinical trial program in patients with HER2-positive metastatic breast cancer for phase I and II studies which have been completed to date and were integral in the submission that led to approval of trastuzumab for clinical use in the USA. There were three small-scale, phase I clinical trials conducted, which were primarily designed to determine the safety and pharmacokinetics of trastuzumab (10-500 mg) administered i.v. as single or weekly doses. This was followed by two phase II clinical trials of fixed-dose trastuzumab either as a single-agent or in combination with cisplatin in 46 and 39 patients, which produced overall response rates of 11.6%, and 24.3%, respectively. In a pivotal phase II clinical trial, trastuzumab was administered on a bodyweight-adjusted basis as a single agent to 222 patients with HER2-positive metastatic breast cancer who had relapsed after one or two prior chemotherapy regimens. The overall response rate was 21% when assessed in evaluable patients by the investigators and 15% when analyzed on an intent-to-treat basis by an independent Response Evaluation Committee. The pharmacokinetics of trastuzumab were evaluated in these studies and the results are summarized.
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PMID:Phase I and II clinical trials of trastuzumab. 1152 22

A pivotal, randomized, multicenter, phase III trial was conducted to compare chemotherapy in combination with trastuzumab (Herceptin) vs. chemotherapy (anthracycline plus cyclophosphamide [AC] or paclitaxel) alone as first-line treatment for HER2-positive metastatic breast cancer. Results from a total of 469 patients, randomized to receive either chemotherapy alone or chemotherapy plus trastuzumab, revealed that the addition of trastuzumab improved time to disease progression significantly (7.6 vs. 4.6 months. P = 0.0001) compared with chemotherapy alone. The increase was higher in the trastuzumab plus paclitaxel subgroup (6.9 vs. 3.0 months, P = 0.0001) than in the trastuzumab plus AC subgroup (8.1 vs. 6.1 months. P = 0.0003). Patients receiving combination therapy also had a greater overall response rate (49% vs. 32%, P = 0.0002) and a longer median response duration (9.3 vs. 5.9 months, P = 0.0001) than those who received chemotherapy alone. Most importantly, median follow-up of 29 months revealed a significantly increased median survival in patients receiving trastuzumab plus chemotherapy (25.4 vs. 20.3 months, P < 0.025) compared with those receiving chemotherapy alone. Trastuzumab plus chemotherapy was well tolerated; adverse events were typically mild-to-moderate chills and fever and occurred in approximately 40% of patients, primarily following the first administration only.
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PMID:Trastuzumab combined with chemotherapy for the treatment of HER2-positive metastatic breast cancer: pivotal trial data. 1152 23

Following the pivotal clinical trials of trastuzumab (Herceptin), further phase II and III studies have been initiated. Preliminary results from a phase II, dose-response study of single-agent trastuzumab in 113 HER2-positive metastatic breast cancer patients without prior chemotherapy for stage IV disease have shown that the overall response rate was 23% (six complete responses and 20 partial responses), with similar results using both standard- and high-dose regimens of trastuzumab. Another phase II study of trastuzumab plus paclitaxel, both given weekly, in 63 HER2-positive and -negative patients with metastatic breast cancer produced an overall response rate of 62% in HER2-positive and 44% in HER2-negative patients. A further phase II study is underway to investigate the combination of trastuzumab plus docetaxel in 30 HER2-positive patients with metastatic breast cancer. Finally, a number of European studies are at an advanced stage of planning or are about to start patient recruitment. These include docetaxel +/- trastuzumab, aromatase inhibitor +/- trastuzumab, CMF (cyclophosphamide, methotrexate, 5-fluorouracil) +/- trastuzumab, vinorelbine + trastuzumab, all in HER2-positive patients, and epirubicin-cyclophosphamide (EC) + trastuzumab in HER2-positive patients vs. EC alone in HER2-negative patients. The results from these trials should be available over the next one to two years.
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PMID:Ongoing trials with trastuzumab in metastatic breast cancer. 1152 25

Current evidence shows that adjuvant cytotoxic or hormonal therapy increases the disease-free and overall survival of patients. The analysis by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) showed that anthracycline/cyclophosphamide (AC)-containing regimens are more effective than those without AC, providing an 11% greater reduction in the risk of death compared with non-AC-containing regimens. In addition, paclitaxel and docetaxel have significant anti-tumor activity in previously treated patients and sequential treatment with paclitaxel may further reduce the risk of recurrence and improve survival. Tamoxifen is effective in reducing the risk of recurrence and death in patients with estrogen receptor (ER)-positive tumors. The addition of tamoxifen to combination chemotherapy in patients with ER-positive tumors further reduces the risk of recurrence and improves survival. Debate on the effectiveness of tamoxifen in HER2-positive patients is currently underway. A number of trials are in progress or planned to investigate the use of the anti-HER2 monoclonal antibody trastuzumab (Herceptin) in the adjuvant setting. These include a National Surgical Adjuvant Breast and Bowel Project (NSABP) adjuvant trial (AC --> paclitaxel vs. AC --> paclitaxel + trastuzumab) and an Intergroup study (AC --> paclitaxel vs. AC --> paclitaxel + trastuzumab vs. AC --> paclitaxel --> trastuzumab). Results from these trials will determine whether this novel therapy has a survival benefit in early breast cancer.
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PMID:Future directions in the adjuvant treatment of breast cancer: the role of trastuzumab. 1152 26

The HER family of receptors has an important role in the network of cell signals controlling cell growth and differentiation. Although the activity of the HER receptor is strictly controlled in normal cells, HER2 receptor overexpression plays a pivotal role in transformation and tumorigenesis. HER2 gene amplification and/or overexpression of the receptor has been detected in subsets of a wide range of human cancers including breast cancer, and is an indicator of poor prognosis. It is proposed that overexpressed HER2 in combination with HER3 causes high activity of cell-signaling networks, thereby resulting in tumor cell proliferation. Thus, the HER2 receptor is an attractive target for new anti-cancer treatments. Monoclonal antibodies directed against the receptor are the most promising of these, and the humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin) has shown significant clinical efficacy in clinical trials. The anti-tumor mechanisms of anti-HER2 monoclonal antibodies are not completely understood. However, some tumor types are not sensitive to trastuzumab, suggesting that the response of a tumor to trastuzumab may not only be dependent on overexpressed HER2, but may also be influenced by other members of the HER receptor family expressed in the tumor cell.
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PMID:The role of overexpressed HER2 in transformation. 1152 29

A significant number of women with advanced breast cancer fail to respond to standard-dose chemotherapy. From the beginning of 1999, 17 women with HER2 positive advanced breast cancer received Herceptin as monotherapy or in combination with paclitaxel or other non-anthracyclines. Eight (47%) women previously received high-dose chemotherapy followed by haematopoiesis stem cell rescue. Three women received Herceptin alone, eleven Herceptin plus paclitaxel and three Herceptin and some of the other non-anthracyclines (CCNU, cisplatin and gemcitabine). In the group of patients who received Herceptin monotherapy, one has partial response (PR), one stable disease (SD) and in the third patient the disease progressed. Out of three patients who received Herceptin in combination with other non-anthracyclines, two have SD and one progressed. In the group of 11 women who received Herceptin + Taxol, 7 (64%) patients achieved PR, 2 (18%) SD, and 2 (18%) had disease progression. Grade 3-4 neutropenia has been observed in four (23%) women. Febrile neutropenia was observed in two cases and resolved completely when antibiotics were introduced. Other grade 3 toxicity that has been noted is peripheral neuropathy in three (18%) patients, diarrhoea in four (23%) and onycholysis in one (6%). Serial heart ultrasound showed no significant decline in left ventricular ejection fraction. According to our preliminary experience, Herceptin therapy showed promising results in women with metastatic breast cancer.
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PMID:Trastuzumab in the treatment of advanced breast cancer: single-center experience. 1152 30

Reliable detection of HER2 overexpression is important for the success of trastuzumab (Herceptin) therapy. Several methods are available for measuring HER2 expression at the DNA, RNA or protein level. The method most frequently employed is immunohistochemical (IHC) detection of the HER2 receptor in paraffin sections. Advantages include the precise localization of the HER2 protein, the availability of paraffin material and the ease of the procedure. However, IHC can be influenced by the sensitivity/specificity of the antibody, tissue treatment and, in particular, subjective assessment. These disadvantages do not exist in the detection of gene amplification by fluorescence in situ hybridization (FISH) or polymerase chain reaction. However, FISH requires expensive equipment that is not widely available in pathology laboratories. Another approach quantitates shed HER2 antigen in the serum by an enzyme-linked immunosorbent assay. The key advantage of this method is the ease of sampling blood, however, serum HER2 concentrations do not accurately reflect the tumor status. Furthermore, this method does not register single-cell expression, which is important for therapeutic decision making. For routine diagnostics, the combination of IHC and FISH is useful. In addition to improving the accuracy and comparability of HER2 assays, these optimized protocols may further enhance the efficacy of trastuzumab therapy by selecting those patients most likely to respond.
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PMID:Current use of HER2 tests. 1152 31

Presently, metastatic breast cancer cannot be cured and therefore good palliation of symptoms and longer overall survival make the most important targets, always considering quality of life. In addition to the established hormonal therapies or chemotherapy regimens, several recent advances have accelerated progress in metastatic breast cancer treatment. As demonstrated in recent studies, the third-generation aromatase inhibitors are playing a significant role in the improvement of the therapeutic approach. The development of new drugs with novel mechanisms of action, such as taxanes, used alone in innovative schedules or in association with other drugs (mainly the anthracyclines), vinorelbine and gemcitabine, or capecitabine, which is administered orally, has broadened the scope of metastatic breast cancer chemotherapy. A new investigation field is represented by high-dose chemotherapy with stem cell support, which has provided controversial preliminary results but is also acknowledged to deserve larger and randomized trials. Finally, the emergence of biological therapies such as the anti-HER2 monoclonal antibody Trastuzumab opens new and exciting prospects for the treatment of this disease. Moreover, the present trend is to try to rationalize the therapeutic approach on the basis of biological parameters which are prognostic and predictive of treatment response.
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PMID:Strategies of medical treatment for metastatic breast cancer (Review). 1156 48

Salivary duct carcinoma (SDC) is a highly malignant salivary gland tumor with aggressive clinical behavior, and is characterized by its histological resemblance to invasive ductal carcinoma of the breast. Overexpression and/or amplification of proto-oncogene Her2/neu has been shown to influence both prognosis and treatment of breast cancer. Since salivary duct carcinoma and ductal breast carcinoma share many common characteristics, HER2/neu overexpression might also be important in SDC. However, data on the expression of c-erbB2/HER2/neu in salivary gland tumors are still scarce. Therefore, we have evaluated 15 cases of salivary duct carcinomas (SDC) for HER2/neu overexpression using immunohistochemistry with the HercepTest. Overexpression, identified as strong or moderate membrane immunostaining, was observed in all but one case of SDC in most neoplastic cells. Thus, our study suggests that anti-HER2/neu therapy with Herceptin is beneficial for patients with aggressive salivary duct carcinoma.
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PMID:Salivary duct carcinoma--a highly aggressive salivary gland tumor with HER-2/neu oncoprotein overexpression. 1156 26


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