Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fas and Fas ligand (FasL) mediate T-lymphocyte cytotoxicity and may also induce physiologic apoptosis in breast epithelium associated with menstruation and cessation of lactation. Altered expression may thus be associated with breast carcinoma progression, chemotherapy response, or outcome. We performed a clinicopathologic analysis of immunohistochemical staining for Fas and FasL, as well as bax, bcl-2, glutathione-s-transferase, HER-2 (c-erbB-2), Ki67, P-glycoprotein, p53, and hormone receptors in pretreatment breast biopsies from 34 patients with locally advanced or limited stage IV breast carcinoma who received preoperative (neoadjuvant, primary) chemotherapy followed by lumpectomy or mastectomy. Neoplastic cells expressed Fas in 44% and FasL in 85% of pretreatment biopsies. Fas immunostaining was more frequent in tumors with larger size (p = 0.02) and pretreatment metastases (p = 0.03). Combined Fas and p53 staining correlated with pathologic complete response (4 of 5 CR versus 6 of 29 other, p = 0.02), as did combined p53 and lack of FasL staining (2 of 5 CR versus 0 of 29 other, p = 0.02), but individually Fas, p53, and lack of FasL immunostaining demonstrated only trends to correlation with CR (p = 0.13-0.15). No other biomarkers correlated with chemotherapeutic response. Neither FasL nor Fas expression was associated with the degree of peritumoral lymphocytic infiltration, or with expression of the other biomarkers. Recurrence was more frequent in Fas-expressing tumors (recurrent cases 7 of 10 Fas positive versus nonrecurrent 8 of 24 Fas positive, p = 0.07). In this patient group, Fas expression is associated with aggressive tumor behavior. Biomarker immunostaining correlates weakly with pathologic response to preoperative chemotherapy, in keeping with complex or heterogeneous tumor-drug interactions.
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PMID:Clinicopathologic Analysis of Fas, Fas Ligand, and Other Biomarkers in Locally Advanced Breast Carcinoma. 1134 71

Axillary lymph node status continues to be the single most important prognostic variable for breast cancer survival despite significant progress in the molecular and genetic characterization of breast malignancies. All patients with invasive breast cancer who underwent axillary lymph node dissection as part of their treatment were evaluated by 11 clinical and pathologic factors, including the primary lesion's T category (TNM staging system), whether the lesion was clinically palpable, the presence of lymphatic or vascular invasion, nuclear grade, estrogen and progesterone receptors, S-phase, age, HER2/neu overexpression, histology (infiltrating lobular or ductal), and ploidy. A total of 2282 axillary dissections were performed: 391 in patients with ductal carcinoma in situ (DCIS) [3 of which (0.8%) contained metastases] and 1891 in patients with invasive breast cancer [680 of which (36%) contained metastases]. Multivariate analysis of patients with invasive cancer identified four factors as independent predictors of axillary lymph node metastases: lymph/vascular invasion, tumor size, nuclear grade, tumor palpability. Among a group of 189 patients with nonpalpable, non-high-grade invasive lesions 15 mm or smaller without lymph/vascular invasion, only 6 (3%) had metastases to lymph nodes. If any three of the favorable factors were present, lymph node positivity was 6% or less. Clinical and pathologic feature of the primary lesions can be used to estimate the risk of axillary lymph node metastases. Such risk assessment can be used for the treatment decision-making process.
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PMID:Predicting axillary nodal positivity in 2282 patients with breast carcinoma. 1137 14

The HER2 oncogene and its relative oncoprotein, gp185HER2, a transmembrane glycoprotein belonging to the epidermal growth factor receptor family, are overexpressed in a wide range of solid tumors including breast and ovarian cancer. In patients with breast cancer, both humoral and cell-mediated HER2 immune responses have been found as well as in some patients with gp185HER2 nonoverexpressing tumors. To establish whether peptide sequences identified as HLA-A2-restricted T-cell epitopes are expressed in breast tumor cell lines and tissues, we produced and characterized by different methodologic approaches polyclonal antibodies raised against four gp185HER2 peptides. Two of the antibodies recognized peptides eluted from the HLA-A2 groove of the mDAmB231 breast cancer cell line expressing a basal level of gp185HER2. Paraffin-embedded primary and metastatic breast tumors were specifically immunostained by all four reagents, thereby showing an overlapping reactivity. When this immunoreactivity was compared with that obtained using two different monoclonal antibodies, in 105 breast primary tumors and 36 corresponding lymph node metastases, we identified a subset of tumors that were negative with anti-gp185HER2 monoclonal antibodies and positive with the four antipeptide antibodies. Our novel observations provide in vivo evidence of the complexity involved in evaluating HER2 expression, and open a new path for understanding the biologic significance of HER2 status in breast tumors.
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PMID:Polyclonal antibodies against gp185HER2 peptides: their putative role in the identification of a particular HER2 status in patients with breast cancer. 1139 99

SUMMARY: The HER2 oncogene and its relative oncoprotein, gp185HER2, a transmembrane glycoprotein belonging to the epidermal growth factor receptor family, are overexpressed in a wide range of solid tumors including breast and ovarian cancer. In patients with breast cancer, both humoral and cell-mediated HER2 immune responses have been found as well as in some patients with gp185HER2 nonoverexpressing tumors. To establish whether peptide sequences identified as HLA-A2-restricted T-cell epitopes are expressed in breast tumor cell lines and tissues, we produced and characterized by different methodologic approaches polyclonal antibodies raised against four gp185HER2 peptides. Two of the antibodies recognized peptides eluted from the HLA-A2 groove of the mDAmB231 breast cancer cell line expressing a basal level of gp185HER2. Paraffin-embedded primary and metastatic breast tumors were specifically immunostained by all four reagents, thereby showing an overlapping reactivity. When this immunoreactivity was compared with that obtained using two different monoclonal antibodies, in 105 breast primary tumors and 36 corresponding lymph node metastases, we identified a subset of tumors that were negative with anti-gp185HER2 monoclonal antibodies and positive with the four antipeptide antibodies. Our novel observations provide in vivo evidence of the complexity involved in evaluating HER2 expression, and open a new path for understanding the biologic significance of HER2 status in breast tumors.
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PMID:Polyclonal Antibodies Against gp185HER2 Peptides: Their Putative Role in the Identification of a Particular HER2 Status in Patients With Breast Cancer. 1139 37

Despite nearly 20 years of study, the importance of chemotherapy dose intensity in breast cancer remains unclear. Substantial preclinical data suggest a dose-response relationship, and consistent data document that recipients of substandard dosing have inferior outcomes. The use of increased dose-intensive therapies is costly, may require the use of hematopoietic growth factor support, and can result in significant increases in both short- and long-term toxicities. In patients with metastatic disease, increased dose intensity frequently results in increased response rates. However, these increased responses have not translated into consistent improvements in time to progression or overall survival benefit. In the adjuvant setting, increases in the dose intensities of alkylating agents and anthracyclines have failed to support the concept of dose escalation beyond standard doses. Certain subgroups of patients, such as those whose tumors overexpress HER2/neu, may derive a benefit from more dose-intensive therapies. Early results of randomized trials of high-dose chemotherapy in the treatment of metastatic breast cancer and adjuvant therapy for high-risk, early-stage breast cancer, are provocative. However, the often conflicting data do not support the routine use of this modality outside of the study setting.
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PMID:Dose intensity for breast cancer. 1143 Feb 5

The metastatic spread of breast cancer to the leptomeninges (LM) is a painful, debilitating, and usually lethal condition. Current therapies are generally ineffective or extremely toxic. The current study evaluated monoclonal antibody therapy in an animal model of LM human breast cancer. Monoclonal antibody 4D5, which recognizes the extracellular domain of the HER2/neu receptor, was administered into the cerebrospinal fluid of athymic rats implanted with human breast cancer cell lines. Continuous intraventricular administration of 4D5 inhibited growth of SKBR3 cells that overexpress HER2/neu but not of MCF7 cells, which do not. Inhibition was dose-dependent, with higher doses of 4D5 producing an improved response. i.p. administration of cisplatin in addition to 4D5 did not improve results. Continuous administration of 4D5 into the lumbar, as opposed to the ventricular intrathecal space, was not therapeutically effective. Treatment with 4D5 did not result in outgrowth of cells lacking expression of the HER2/neu receptor. These results suggest that 4D5, administered regionally, may palliate LM metastases from HER2/neu-overexpressing breast carcinoma.
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PMID:Treatment of meningeal breast cancer xenografts in the rat using an anti-p185/HER2 antibody. 1144 23

The expression levels of a circulating extracellular domain of HER-2 can be detected in the plasma and serum of patients with metastatic breast cancer using an enzyme immunoassay (ELISA) method. In this study, we evaluated the clinical significance of high and low levels of HER-2 in the plasma of 46 patients with metastatic breast cancer enrolled in a clinical trial of high-dose chemotherapy (HDCT) using cyclophosphamide, mitoxantrone, and paclitaxel with autologous stem cell transplantation (ASCT). Using 2500 U/ml as the cut-point, 20 patients (46%) had elevated HER-2 levels (HER-2 positive). Our results suggest that patients with metastatic breast cancer and high soluble plasma HER-2 have a significantly poorer overall (OS) and progression-free survival (PFS) following high-dose chemotherapy with paclitaxel and ASCT. The median OS of patients with low levels of HER-2 was significantly longer (P < 0.01) than the median OS of patients with high levels of HER-2 (29.8 months vs 15.9 months). PFS was also significantly longer (P < 0.01) for patients who were HER-2-negative, than for patients who were HER-2-positive (13.0 vs 8.6 months). Univariate analysis showed that patients with liver or lung metastases had significantly reduced OS and PFS. Patients with metastases to two or more sites also had a significantly reduced time to disease progression, but not OS. In multivariable analysis, lung metastases contributed along with HER-2-positive status to determine a group of patients with significantly poorer OS. However, HER-2-positive status remained the only independent predictor of PFS.
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PMID:HER-2 expression is a prognostic factor in patients with metastatic breast cancer treated with a combination of high-dose cyclophosphamide, mitoxantrone, paclitaxel and autologous blood stem cell support. 1147 43

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

HER-2 gene amplification and protein overexpression has been associated with increased risk of advanced-stage breast cancer and poor prognosis. Recently, a single missense point mutation (Ile(655)Val) in the transmembrane domain of the HER-2 gene was associated with a 40% increase in breast cancer risk among women 45 years of age and younger. In this analysis, we measured the association between the Ile(655)Val variant and postmenopausal breast cancer among women participating in the Hawaii and Los Angeles Multiethnic Cohort. Risk of localized breast cancer was significantly elevated among women with the HER-2 variant, but not among women with regional or metastatic disease. Women with at least one copy of the Valine variant were approximately one-half as likely to have high-stage as low-stage breast cancer (P =.02), and this effect was present across racial/ethnic groups.
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PMID:Germ-line HER-2 variant and breast cancer risk by stage of disease. 1173 15


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