Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0007124 (ductal carcinoma in situ)
 3,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HER-2/neu oncogene encodes a transmembrane tyrosine kinase receptor with extensive homology to the epidermal growth factor receptor. HER-2/neu has been widely studied in breast cancer. In this review, the association of HER-2/neu gene and protein abnormalities studied by Southern and slot blotting, immunohistochemistry, enzyme immunoassays, and fluorescence in situ hybridization with prognosis in breast cancer is studied in depth by review of a series of 47 published studies encompassing more than 15,000 patients. The relative advantages of gene amplification assays and frozen/fresh tissue immunohistochemistry over paraffin section immunohistochemistry are discussed. The significance of HER-2/neu overexpression in ductal carcinoma in situ and the HER-2/neu status in uncommon female breast conditions and male breast cancer are also considered. The potential value of HER-2/neu status for the prediction of response to therapy in breast cancer is presented in the light of a series of recently published studies showing a range of impact on the outcome of patients treated with hormonal, cytotoxic, and radiation therapies. The evidence that HER-2/neu gene and protein abnormalities in breast cancer predict resistance to tamoxifen therapy and relative sensitivity to chemotherapy regimens including adriamycin is presented. The review will also evaluate the status of serum-based testing for circulating the HER-2/neu receptor protein and its ability to predict disease outcome and therapy response. In the final section, the review will briefly present preliminary data concerning the use of antibody-based therapies directed against the HER-2/neu protein and their potential to become a new modality for breast cancer treatment. The recently presented phase III clinical trial evidence that systemic administration of anti-HER2 antibodies (Herceptin), alone and in combination with cytotoxic chemotherapy in patients with HER-2/neu overexpressing primary tumors, can increase the time to recurrence and overall response rates in metastatic breast cancer is reviewed.
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PMID:The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. 983 67

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

The HER-2/neu oncogene encodes a transmembrane tyrosine kinase receptor with extensive homology to the epidermal growth factor receptor. In this article, the association of HER-2/neu gene and protein abnormalities with prognosis and response to therapy with Herceptin and other therapies in breast cancer is presented. By considering a series of 80 published studies encompassing more than 25,000 patients, the relative advantages and disadvantages of Southern blotting, polymerase chain reaction amplification, and fluorescence in situ hybridization assays designed to detect HER-2/neu gene amplification are compared with HER-2/neu protein overexpression assays performed by immunohistochemical techniques applied to frozen and paraffin-embedded tissues and enzyme immunoassays performed on tumor cytosols. The significance of HER-2/neu overexpression in ductal carcinoma in situ and the HER-2/neu status in uncommon female breast conditions and male breast cancer also are considered. The role of HER-2/neu testing for the prediction of response to Herceptin therapy in breast cancer is presented as well as its potential impact on responses to standard and newer hormonal therapies, cytotoxic chemotherapy, and radiation. The review also will evaluate the status of serum-based testing for circulating HER-2/neu receptor protein and its ability to predict disease outcome and therapy response.
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PMID:Targeted therapy for cancer: the HER-2/neu and Herceptin story. 1469 77

Since the identification of the novel transforming gene neu in rat neuroblastomas in 1981, and the subsequent cloning of the human equivalent HER-2, there have been considerable developments concerning the role and value of HER-2 in human breast cancer. Early studies found gene amplification in 20-30% of breast carcinomas, with most studies linking this to poorer survival. Numerous antibodies have been generated against the oncoprotein and in many instances overexpression, as defined by membrane staining of breast cancer cells, correlated with gene amplification. Many studies, but not all, have found an association between HER-2 reactivity and poor prognosis. HER-2 can also be detected in high-grade ductal carcinoma in situ. HER-2 status can also aid prediction of response to hormonal and chemotherapy, but the present interest lies in the humanized monoclonal antibody against HER-2 (Herceptin) that has been developed. This is only of value if there is over-expression of HER-2 by a breast cancer, and so a reliable, accurate method of determination of HER-2 status is required. Immunohistochemistry is widely used and is relatively simple, with no major equipment requirements. However, there are variations in results with different antibodies and standardized methods, with controls for evaluating extent of reactivity required. Fluorescent in situ hybridization, which detects gene amplification, is an alternative approach that can be used with fixed embedded tissue but the technique is less widely available. HER-2 is the first oncoprotein involved in breast cancer in which there has been direct translation from the laboratory to the patient.
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PMID:The significance of histological determination of HER-2 status in breast cancer. 1473 35

The HER-2/neu oncogene, a member of the epidermal growth factor receptor or erb gene family, encodes a transmembrane tyrosine kinase receptor that has been linked to prognosis and response to therapy with the anti-HER-2-humanized monoclonal antibody, trastuzumab (Herceptin, Genentech, South San Francisco, CA) in patients with advanced metastatic breast cancer. HER-2/neu status has also been tested for its ability to predict the response of breast cancer to other therapies including hormonal therapies, topoisomerase inhibitors, and anthracyclines. This review includes an analysis of 80 published studies encompassing more than 25,000 patients designed to consider the relative advantages and disadvantages of the various methods of measuring HER-2/neu in clinical breast cancer specimens. Southern blotting, PCR amplification detection, and fluorescence in situ hybridization assays designed to detect HER-2/neu gene amplification are compared with HER-2/neu protein overexpression assays performed by immunohistochemical techniques applied to frozen and paraffin-embedded tissues and enzyme immunoassays performed on tumor cytosols. The significance of HER-2/neu overexpression in ductal carcinoma in situ and the HER-2/neu status in uncommon female breast conditions and male breast cancer are also considered. The role of HER-2/neu testing for the prediction of response to trastuzumab therapy in breast cancer is reviewed along with the current studies designed to test whether HER-2/neu status can predict the response to standard and newer hormonal therapies, cytotoxic chemotherapy, and radiation. The review will also evaluate the status of serum-based testing for circulating HER-2/neu receptor protein and its ability to predict disease outcome and therapy response.
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PMID:Targeted therapy in breast cancer: the HER-2/neu gene and protein. 1476 15

Recently published clinical trial data have produced compelling evidence for increased survival when Herceptin is administered to patients whose tumors are HER2 amplified. Therefore, the accuracy of HER2 status is essential to determine which patients should or should not receive Herceptin. Although HER2 results obtained by FISH and IHC are often in agreement, there is a persistent group of cases in which results are discordant, particularly among tumors with intermediate results. A multivariable analysis was undertaken to determine relative significance of various clinical and pathologic findings for patients diagnosed with infiltrating ductal carcinoma, and a data model was produced that predicts which patients are most likely to have HER2 amplified tumors. Correlates of HER2 amplification were higher Scarff-Bloom-Richardson grade, younger age at diagnosis, and a comedo ductal carcinoma in situ component.
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PMID:A data model to predict HER2 status in breast cancer based on the clinical and pathologic profiles of a large patient population at a single institution. 1671 90

Glycoprotein nonmetastatic B (GPNMB) is a potential oncogene that is particularly expressed in melanoma and breast cancer (BC). To clarify its clinical significance in BC, we measured serum GPNMB in vivo and investigated its cross talk with human epidermal growth factor 2 (HER2). GPNMB was expressed in four of six breast cell lines (SK-BR-3, BT-474, MDA-MD-231, and MDA-MD-157), two of six colorectal cell lines, and two of four gastric cancer (GC) cell lines. We established a GPNMB quantification system using enzyme-linked immunosorbent assay (ELISA) for these cell lines. We measured serum GPNMB in vivo in 162 consecutive BC patients and in 88 controls (50 colorectal cancer [CC] and 38 GC patients). The GPNMB concentration in BC, CC and GC was 8.163, 5.751 and 6.55 ng/mL, respectively. The GPNMB level was significantly higher in BC patients than in CC patients (P = 0.021). The HER2-rich subtype of BC patients had significantly higher GPNMB levels than other subtypes (vs. Luminal; P = 0.038; vs. DCIS; P = 0.0195). These high GPNMB levels decreased after treatment (surgery/chemotherapy). Next, we examined the relationship between GPNMB and HER2 in vitro using SK-BR3 and BT-474 (HER2-positive/GPNMB-positive) cells. GPNMB depletion by small interfering RNA (siRNA) increased both HER2 expression and phosphorylation. Trastuzumab (Tra) in combination with docetaxel promoted cell growth inhibition, and treatment with Tra or an Extracellular signal-related kinase (ERK) inhibitor enhanced GPNMB expression. These results indicate that GPNMB might be a surrogate marker for BC and may cross talk with the HER2 signal pathway. GPNMB may therefore emerge as an important player in anti-HER2 therapy.
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PMID:Clinical significance of glycoprotein nonmetastatic B and its association with HER2 in breast cancer. 2607 87

The standard treatment for ductal carcinoma in situ (DCIS) of the breast is surgical resection, followed by radiation. Here, we tested localized therapy of DCIS in mice using the immunoconjugate 225Ac linked-trastuzumab delivered through the intraductal (i.duc) route. Trastuzumab targets HER-2/neu, while the alpha-emitter 225Ac (half-life, 10 days) delivers highly cytotoxic, focused doses of radiation to tumors. Systemic 225Ac, however, elicits hematologic toxicity and at high doses free 213Bi, generated by its decay, causes renal toxicity. I.duc delivery of the radioimmunoconjugate could bypass its systemic toxicity. Bioluminescent imaging showed that the therapeutic efficacy of intraductal 225Ac-trastuzumab (10-40 nCi per mammary gland; 30-120 nCi per mouse) in a DCIS model of human SUM225 cancer cells in NSG mice was significantly higher (p<0.0003) than intravenous (120 nCi per mouse) administration, with no kidney toxicity or loss of body weight. Our findings suggest that i.duc radioimmunotherapy using 225Ac-trastuzumab deserves greater attention for future clinical development as a treatment modality for early breast cancer.
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PMID:Effective treatment of ductal carcinoma in situ with a HER-2- targeted alpha-particle emitting radionuclide in a preclinical model of human breast cancer. 2711 27