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)

Human epidermal growth factor receptor-2 (HER2/erbB-2) belongs to a family of four transmembrane receptors involved in signal transduction pathways that regulate cell growth and differentiation. Overexpression/amplification of HER2 is associated with malignancy and a poor prognosis in breast cancer. HER2 acts as a networking receptor that mediates signaling to cancer cells, causing them to proliferate. HER receptors exist as monomers but dimerize on ligand binding. HER ligands are bivalent growth factor molecules whose low-affinity site binds to HER2. No HER2-specific ligand has been identified but HER2 is the preferred heterodimerization partner for other HER receptors. HER2-containing heterodimers are relatively long-lived and potent. HER3 has no inherent activity and is the major and most potent dimerization partner of HER2. HER2 overexpression biases the formation of HER2-containing heterodimers, leading to enhanced responsiveness to stromal growth factors and oncogenic transformation. Removal of HER2 from the cell surface or inhibition of its intrinsic enzymatic activity may reduce oncogenicity. Our research suggests that the antitumor efficacy of HER2-specific antibodies such as Herceptin relates to their ability to direct HER2 to a Cbl- dependent endocytosis and degradation pathway. The reported clinical therapeutic efficacy of anti-HER2 monoclonal antibodies in breast cancer highlights the importance of understanding the biology of HER2.
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PMID:Biology of HER2 and its importance in breast cancer. 1169 82

Large pivotal phase II and III clinical trials investigated the therapeutic efficacy and safety of the humanized anti-HER2 monoclonal antibody, Herceptin, alone and in combination with standard chemotherapy, respectively, in HER2-positive metastatic breast cancer. Eligible patients were HER2 2+ and 3+ overexpressors, as determined by immunohistochemistry (IHC). Herceptin was well tolerated in both trials. Single-agent second/third-line Herceptin produced durable tumor responses. First-line Herceptin in combination with chemotherapy, in particular paclitaxel, significantly improved time to disease progression, duration of response and time to treatment failure. Combination therapy also provided a significant 25% improvement in overall survival. These clinical benefits have led to the approval of Herceptin for clinical use in the USA and elsewhere. Greater efficacy was noted in IHC 3+ patients compared with the overall population in both trials. Retrospective fluorescent in situ hybridization (FISH) testing of patient-tumor HER2 status revealed similar clinical outcomes in IHC 3+ and FISH-positive patients, consistent with the reported high concordance between IHC and FISH. Responses in the single-agent Herceptin trial were seen exclusively in FISH-positive patients. Approximately a quarter of HER2 2+ patients test FISH positive and may therefore benefit from therapy. Numerous studies are underway or planned to evaluate other Herceptin combinations and regimens in the metastatic and adjuvant settings.
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PMID:Herceptin alone or in combination with chemotherapy in the treatment of HER2-positive metastatic breast cancer: pivotal trials. 1169 83

Incorporation of a new biological marker such as HER2 into routine clinical practice requires proof that it provides reproducible information independent of, and better than, conventional pathologic criteria, and that it influences treatment decisions. In breast cancer, HER2 amplification/overexpression predicts for a poor clinical outcome and an enhanced survival benefit from the HER2-targeted therapy, Herceptin, and may predict for resistance to some conventional therapies. Thus, HER2 is considered to be a clinically important molecule and testing for HER2 abnormalities is already part of routine patient assessment in many parts of the world. There is currently no gold standard for HER2 testing. The main challenge is to standardize and technically validate HER2 testing methodologies. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are the most common HER2 tests used, and show a high level of concordance. HER2 testing approaches based on the polymerase chain reaction (PCR) are under extensive investigation and appear promising. A Canadian HER2 testing algorithm designed to increase the validity and reproducibility of HER2 testing has been compiled. HER2-positive cases are defined as those with >10% of tumor cells with moderate/strong, complete membrane staining in the invasive component, by IHC. Confirmatory HER2 testing using either FISH or quantitative PCR is recommended for indeterminate cases. Additional studies are required to calibrate HER2 testing results to clinical outcome.
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PMID:Testing for HER2 status. 1169 84

The pivotal phase II and III Herceptin trials proved the efficacy and safety of second- or third-line single-agent Herceptin and first-line Herceptin in combination with chemotherapy, respectively. In the current trial, 114 patients were randomized to one of two dose groups of first-line Herceptin monotherapy: standard dose of 4 mg/ kg initial dose followed by 2 mg/kg intravenous (i.v.) weekly; or high dose of 8 mg/kg initial dose followed by 4 mg/kg i.v. weekly. The regimen was generally well tolerated. A similar incidence of adverse events was demonstrated in the two dose groups with the possible exception of acute infusion-related events such as fever and chills as well as rash and dyspnea, which appear to be more prevalent in the higher dose group. The overall response rate was 26% and response rates were similar between the two dose groups (24% for the standard Herceptin dose group and 28% for the high Herceptin dose group). Subgroup analysis determined a higher response rate in IHC 3+ patients (35%) and FISH-positive patients (41%). When women with stable disease for > or =6 months were included with responders, the clinical benefit rate in IHC 3+ patients was 47%. Median survival was 24.4 months, which is comparable with the survival rate seen in the pivotal phase III combination trial (25 months). Therefore, single-agent Herceptin is an important new option for the first-line treatment of HER2-positive metastatic breast cancer patients.
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PMID:First-line Herceptin monotherapy in metastatic breast cancer. 1169 86

Preclinical data indicate that trastuzumab (Herceptin) has the potential for synergistic or additive effects in combination with therapies including chemotherapy and hormonal agents, providing the rationale for a number of clinical trials in women with HER2-positive metastatic breast cancer. A recently reported phase II trial has demonstrated that trastuzumab plus vinorelbine is both effective (overall response rate 75%) and well tolerated, with the major side effects being typical of single-agent vinorelbine. Other combinations of trastuzumab with a variety of other chemotherapeutic and hormonal agents are also being assessed. In an effort to overcome the cardiotoxicity observed with trastuzumab plus doxorubicin in the pivotal phase III trial, combination regimens involving potentially less toxic anthracyclines such as epirubicin and liposomal formulations of doxorubicin are ongoing. In addition, trials are investigating whether trastuzumab can reverse the resistance to hormonal therapy that develops in most women with metastatic breast cancer. These and other studies will identify the regimens that produce the best outcomes with the fewest possible side effects in women with HER2-positive breast cancer.
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PMID:New combinations with Herceptin in metastatic breast cancer. 1169 88

The taxanes and Herceptin have been shown to possess significant clinical activity in metastatic breast cancer. Preclinical testing of taxane/Herceptin combinations demonstrated additive and synergistic interactions with paclitaxel and docetaxel, respectively. In a pivotal clinical trial, combination of paclitaxel (3-weekly) and Herceptin was associated with an increased response rate compared with paclitaxel monotherapy (41% vs. 17%; p = 0.001). The combination therapy also significantly improved time to disease progression (6.9 vs. 2.7 months; p < 0.05). In a phase II study of weekly paclitaxel plus Herceptin in patients with normal or increased tumor HER2 levels, a response was observed in 60% of patients and the regimen was well tolerated. Responses were more frequent in patients with HER2-overexpressing tumors (83% vs. 45%). Preliminary results from a phase II study of Herceptin plus docetaxel in patients with HER2-overexpressing tumors indicate significant activity, with a response observed in 7 (44%) of 16 evaluable patients. The preliminary results of a trial of weekly docetaxel and Herceptin demonstrate a response rate of 54% in 13 evaluable patients. Additional European trials of Hercep- tin/taxane combinations as first- and second-line and adjuvant therapy are ongoing. The results of the studies to date indicate that regimens combining Herceptin with 3-weekly and weekly taxane are effective and well tolerated.
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PMID:Interaction between Herceptin and taxanes. 1169 87

Approximately 25,000 patients have been treated to date with the humanized anti-HER2 monoclonal antibody, Herceptin. This therapy has proved effective and well tolerated in patients with HER2-positive metastatic breast cancer; adverse events were generally infusion-related fever and chills of mild-to-moderate severity. Cardiotoxicity and infusion-related reactions emerged as the two main safety concerns with the use of Herceptin. Retrospective analysis revealed a higher incidence of heart failure when Herceptin was combined with anthracyclines than that expected with anthracyclines alone. Age, anthracycline exposure and cardiac risk factors were found to be predictors of cardiac adverse events. Patients experiencing cardiac dysfunction responded well to standard cardiac medication and the majority improved. Cardiac function should be monitored regularly and Herceptin should be discontinued if significant heart failure develops unless the benefits for an individual patient outweigh the risks. Of 25,000 patients, 74 (0.3%) were reported to have experienced a serious infusion-related reaction. The majority occurred during or shortly after the first infusion and were characterized by respiratory symptoms. Most patients were successfully treated; a total of 33 patients continued Herceptin therapy with no recurrence of infusion reactions. Although the benefit to risk ratio of Herceptin remains favorable, physicians must be vigilant and aggressive in managing cardiotoxicity and infusion-related reactions.
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PMID:Retrospective analysis of the safety of Herceptin immunotherapy in metastatic breast cancer. 1169 89

Measurement of molecular markers predictive of response to therapy should enable more selective and effective utilization of anticancer agents. The predictive value of HER2 remains a complex and inconclusive subject. In metastatic breast cancer, HER2-positive, ER-positive patients can show responses to endocrine treatment, but experience shorter time to progression and survival than HER2-negative patients. In the adjuvant setting, weak, retrospective evidence suggests that tamoxifen is potentially harmful in HER2-positive patients and that there is no benefit from prolonged tamoxifen therapy. It has not yet been demonstrated conclusively that HER2 positivity increases resistance to adjuvant cyclophosphamide, methotrexate, 5-FU (CMF), but there are indications that HER2-positive patients benefit more from adequately dosed anthracyclines than from CMF. The greatest value of HER2 as a predictive marker lies in the prediction of response to therapies that target HER2, such as Herceptin. Patients with strongly HER2-positive breast cancer derive significant clinical benefit from single-agent and combined Herceptin therapy. HER2 testing has become an integral part of the optimal management of the breast cancer patient. Best current practice in adjuvant breast cancer therapy based on the current knowledge of the potential predictive power of HER2 constitutes not denying tamoxifen to HER2-positive, ER-positive patients or CMF to HER2-positive patients. Outside of clinical trials, adequately dosed anthracycline-based chemotherapy is the current preferred adjuvant treatment option for HER2-positive patients.
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PMID:The predictive value of HER2 in breast cancer. 1169 91

The humanized anti-p185(HER2) monoclonal antibody trastuzumab has been shown to effectively inhibit the growth of HER2-overexpressing breast cancer cells in vivo and in vitro. The treatment of cancer cells with trastuzumab results in downregulation of the HER2 receptor. Further downstream cellular events include the accumulation of the cyclin-dependent kinase inhibitor p27 and cell cycle arrest. In vivo, trastuzumab induces antibody-dependent cellular cytotoxicity. Trastuzumab also inhibits constitutive HER2 cleavage/shedding mediated by metalloproteases. The ability of trastuzumab to inhibit HER2 cleavage may correlate with the clinical anticancer activity of the multifunctional HER2-targeting antibody.
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PMID:Mechanism of action of trastuzumab and scientific update. 1170 90

The development of Herceptin (Trazumatab) makes testing for HER2 status important for choosing optimal therapy in breast cancer. This study addresses the precision, accuracy, and reproducibility of HER2 assays. HER2 was assessed retrospectively by immunohistochemistry (IHC) with Dako 'Herceptest', by IHC with the monoclonal antibody CB11, and by fluorescence in situ hybridization (FISH, PathVysion), in a series of 216 formalin-fixed breast carcinomas including 191 for which quantitative HER2 data from radioimmunohistochemistry (Q-IHC) were available. All tests were scored independently by two observers. Positivity rates varied between Herceptest (12.6%), FISH (19.4%), and CB11 IHC (28.5%). Kappa values showed that IHC-based tests were more susceptible to inter-observer variation (kappa=0.67 and 0.74 for Herceptest and CB11, respectively) than FISH (kappa=0.973). Overall test accuracy (see the Materials and methods section) for CB11 IHC (83.8%) was lower than Herceptest (87.4%) or FISH (93.2%). FISH predicted p185 HER2 overexpression (determined by Q-IHC) better (concordance index C.Ind. 0.90) than CB11 IHC (C.Ind.=0.85) or Herceptest (C.Ind.=0.81). Of 42 cases with gene amplification by FISH, 67% were positive in the Herceptest (2+ or 3+) vs. 83% with CB11. Of 174 cases negative by FISH, 96% were negative in the Herceptest and 68% with CB11. In conclusion, FISH is the most accurate, reproducible, and precise predictor of HER2 overexpression in routine diagnostic laboratories.
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PMID:Evaluating HER2 amplification and overexpression in breast cancer. 1174 73


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