Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HER-2/neu proto-oncogene amplification or oncoprotein overexpression is an important prognostic factor and a predictive factor for resistance to endocrine therapy and adjuvant chemotherapy in breast cancers. Moreover, it is an entry criterion in the assessment of patients for whom Herceptin (Trastuzumab) treatment is considered. The overexpression rate of HER-2/neu oncoprotein has been identified in 10% to 40% of human breast cancers. In Taiwan, a higher grade of pathobiologic characteristics of familial breast cancer was also noted than that found in the non-familial group. It is worthwhile to evaluate whether the overexpression is more frequent in familial breast cancers. Fifty-six familial and 111 non-familial breast cancers were studied between 1990 and 1999 to assess both the overexpression of HER-2/neu oncoprotein immunohistochemically and the correlation with the histological type, grade and stage of breast carcinoma. The overexpression rate is higher in the familial breast cancer group (50.0%) when compared with non-familial breast cancer group (36.9%), which did not prove to be statistically significant (P = 0.1068). However, when the infiltrating ductal carcinomas of both groups are compared, it is statistically significant (52.3% vs. 33.7%, P = 0.0429). Overexpression correlated with node status and histological grade of infiltrating ductal carcinomas in non-familial and overall breast cancers. It also correlated with nuclear pleomorphism and mitotic counts, but not tubule formation or tumor size. All 3 cases of Paget's disease revealed overexpression, whereas all 12 cases of mucinous and one case of metaplastic carcinoma and one case of medullary carcinoma were negative. The overexpression rate was higher both in familial and non-familial intraductal carcinomas (57.1% vs. 73.3%, P = 0.4716). No statistical difference was identified between the 2 subsets. A case of infiltrating ductal carcinoma combined with intraductal carcinoma revealed heterogeneous staining in the component of ductal carcinoma in situ, while the invasive component did not. This suggests that overexpression decreases within individual tumors as they evolve from in situ to invasive lesioins. The HER-2/neu may imply a different role in intraductal carcinoma, Paget's disease and invasive duct carcinoma. Although the overexpression rate of HER-2/neu oncoprotein of familial breast cancer was not significantly higher than that of the non-familial group, it is appropriate to evaluate the rate of HER-2/neu overexpression according to the histological type of breast cancers from familial breast cancer and non-familial breast cancer. The prognoses will be needed for future evaluation.
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PMID:Expression of HER-2/NEU oncoprotein in familial and non-familial breast cancer. 1141 60

In breast cancer amplification of the HER-2/neu oncogene and over-expression of the protein product is associated with poor prognosis, predicts response to some chemotherapeutic regimens and is the target for Herceptin treatment. To date there are several methods to assess the amplification/over-expression of HER-2/neu with each having advantages and disadvantages. We have studied amplification and over-expression of HER-2/neu in 250 consecutive cases of breast cancer (220 invasive and 30 in situ carcinomas) presenting to the Department of Pathology at Women's College Campus of Sunnybrook and Women's College Health Sciences Center. Thirty percent of the invasive carcinomas were node positive. HER-2/neu protein over-expression was assessed by immunohistochemistry (IH) using antibody CB11 and amplification of the gene by differential PCR. The percentage of tumor cells showing CB11 staining was determined and the most significant cut off point for positivity was > or =10% moderate or strong complete membranous staining. The gene was considered amplified if the density score of the product was > or =2. There was 94% concordance between the two methods (P value.0001). Both methods were positive in 16% of cases and negative in 78% of cases. Discrepant cases were examined by FISH which confirmed the IH results in 9/11 invasive carcinomas. These results show that there is excellent concordance between IH and PCR. However, immunohistochemistry is easier to perform and cheaper than PCR and could be used in routine assessment of HER-2/neu in breast cancer patients.
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PMID:Defining a test for HER-2/neu evaluation in breast cancer in the diagnostic setting. 1145

The HER-2/neu oncogene is localized to chromosome 17q and shares significant homology with the epidermal growth factor receptor. As a result of its potential role in the selection of therapy, HER-2/neu testing has reached near-standard-of-practice status in breast cancer. There is considerable interest in HER-2/neu as a prognostic factor and target of therapy in tumors of the gastrointestinal tract. In this review of HER-2/neu expression in esophageal squamous cell carcinoma and adenocarcinomas of the esophagus, stomach, and colon, a wide range of expression of HER-2/neu from 0 to 83% likely reflects both differences in methods and reagents, as well as study bias associated with patient selection (i.e., early versus advanced disease). For esophageal squamous cell carcinoma, little information exists as to the prognostic significance of HER-2/neu expression. In adenocarcinoma associated with Barrett's esophagus there is contradictory data. However, most of the information available indicates that this marker has significant prognostic value. In gastric adenocarcinoma, the wide expression range may truly reflect patient selection because HER-2/neu positivity appears linked to advanced rather than early disease with limited invasion. The majority of studies favor a significant prognostic value of HER-2/neu status for this tumor. Finally, in colorectal cancer HER-2/neu overexpression also appears to be a significant adverse outcome indicator as judged by the current published literature. In conclusion, given that either HER-2/neu protein overexpression or gene amplification is associated with approximately one-fourth of all gastrointestinal tract malignancies, strategies designed to employ the marker in therapy selection appear warranted. During the next several years it will not be surprising to see these tumors treated with antiHER-2/neu modalities such as Herceptin, likely in combination with other agents initially for patients with advanced disease, and possibly for individuals with high-risk lesions in an adjuvant setting.
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PMID:The HER-2/neu oncogene in tumors of the gastrointestinal tract. 1145 21

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

The molecular mechanisms mediating the anti-proliferative effects of the murine anti-HER2 monoclonal antibody (4D5) were investigated in HER2-overexpressing human carcinoma cell lines. Treatment with 4D5 resulted in a dramatic accumulation of BT-474 breast carcinoma cells in G1; concomitant with reduced expression of proteins involved in sequestration of the cyclin E/Cdk2 inhibitor protein p27, increased association of p27 with Cdk2 complexes and Cdk2 inactivation. No equivalent effects were observed in BT-474 cells treated with a control, non-inhibitory HER2 monoclonal antibody (FRP5) or in a HER2-overexpressing cell line insensitive to 4D5 treatment (MKN7 gastric carcinoma cells), confirming the relationship between these molecular changes and 4D5-mediated inhibition of proliferation. Increased p27 expression was also observed in 4D5-treated BT-474 cells; however an antisense approach demonstrated that this increase was not required for Cdk2 inactivation or establishment of the G1 block. These data suggest that 4D5 interferes with HER2 receptor signaling, resulting in downregulation of proteins involved in p27 sequestration. This causes release of p27, allowing binding and inhibition of cyclin E/Cdk2 complexes and inhibition of G1/S progression. This model was confirmed using a second 4D5-sensitive. HER2-overexpressing breast tumor line (SKBR3), and suggests that the dependency of a given tumor cell on elevated HER2-receptor signaling for the maintenance of p27 sequestration proteins may determine the clinical response to treatment with the humanized anti-HER2 monoclonal antibody Herceptin (trastuzumab).
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PMID:Modulation of p27/Cdk2 complex formation through 4D5-mediated inhibition of HER2 receptor signaling. 1152 16

The search for new methods of treating cancer, combined with advances in our understanding of carcinogenesis, molecular biology and technology, has resulted in the development of novel biologic agents with proven clinical efficacy. One such agent is trastuzumab (Herceptin), a humanized monoclonal antibody that targets the human epidermal growth factor receptor-2 (HER2). HER2 is a member of a family of receptors that interact with each other and various ligands to stimulate various intracellular signal transduction pathways involved in cell growth control. HER2 is overexpressed in 20%-30% of women with breast cancer and is associated with aggressive tumor characteristics and poor prognosis. Trastuzumab is the first humanized monoclonal antibody to be approved for therapeutic use and the first oncogene-targeted treatment with proven survival benefit in women with HER2-positive metastatic breast cancer. However, its mechanism of action has not been fully characterized and appears to be complex. This paper reviews current knowledge of the mechanism of action of trastuzumab, including HER2 protein downregulation, prevention of HER2-containing heterodimer formation, initiation of G1 arrest and induction of p27, prevention of HER2 cleavage, inhibition of angiogenesis, and induction of immune mechanisms. The significance of these mechanisms for selection of concomitant chemotherapy is also considered.
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PMID:Mechanism of action of anti-HER2 monoclonal antibodies. 1152 20

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 human epidermal growth factor receptor-2 (HER2) is overexpressed/amplified in a range of tumor types including breast, ovarian, bladder, salivary gland, endometrial, pancreatic and non-small-cell lung cancer (NSCLC). HER2 is implicated in disease initiation and progression, associated with poor prognosis, and may also predict the response to chemotherapy and hormonal therapy. Anti-HER2 monoclonal antibodies (MAbs) have been designed to specifically antagonize the function of the HER2 receptor in HER2-positive tumors. Clinical phase II and III trials have demonstrated the efficacy of the humanized anti-HER2 MAb, trastuzumab (Herceptin), both as a single agent and in combination with chemotherapy in HER2-positive, metastatic breast cancer patients. However, the prevalence of HER2 overexpression/amplification in various tumor types raises the possibility of using anti-HER2 MAbs to antagonize the abnormal function of overexpressed HER2 receptors in HER2-positive tumors other than breast. Preliminary in vitro studies indicate that anti-HER2 MAbs suppress the proliferation of ovarian, gastric and NSCLC cell lines that overexpress the HER2 receptor. These results indicate that anti-HER2 MAbs may have important therapeutic significance in patients presenting with these or other human carcinomas. Clinical trials are either planned or underway to assess the therapeutic role of trastuzumab in NSCLC, bladder and ovarian cancer.
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PMID:Targeting HER2 in other tumor types. 1152 27

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


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