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

The human epidermal growth factor receptor-2 (HER2) gene (also known as c-erbB-2 or neu) is amplified in 20-30% of breast cancers. HER2 gene amplification and HER2 overexpression occur early in the development of breast cancers and are found in a high proportion of ductal carcinomas in situ (DCIS), non-invasive cancers that generally do not give rise to metastases. In DCIS, HER2 overexpression is found specifically in poorly histologically differentiated disease and not in well differentiated cancers. Various methods have been used to analyse the HER2 status of a tumour. These either measure the degree of HER2 gene amplification, receptor overexpression or the amount of circulating HER2 protein. In practice, immunohistochemistry is the most frequently used method, being available as a standard technique in all pathology laboratories. It is of critical importance to standardise the methods used for staining and to apply common interpretation criteria to enable direct comparison of results between laboratories.
 ...
PMID:Assessment of the need and appropriate method for testing for the human epidermal growth factor receptor-2 (HER2). 1134 95

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.
 ...
PMID:Predicting axillary nodal positivity in 2282 patients with breast carcinoma. 1137 14

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.
 ...
PMID:Dose intensity for breast cancer. 1143 Feb 5

Regional metastasis is an important factor in the prognosis and treatment of head and neck squamous cell carcinoma (HNSCC). The results of earlier studies suggested the possibility of predicting nodal metastasis in HNSCC using biological markers. To identify which factors may be relevant in the metastatic behaviour of these tumours, the expression of several markers involved in tumour progression was studied in both nodal metastases and their corresponding primary tumours. Expression of p53, Rb, cyclin D1, myc, bcl-2, EGFR, neu, E-cadherin, epithelial cell adhesion molecule (Ep-CAM), and nm23 was studied in 54 primary tumours and their corresponding metastases in patients with HNSCC. The expression of most genes involved in tumourigenesis (p53, Rb, cyclin D1, myc, bcl-2, EGFR, neu, and E-cadherin) was similar in primary tumours and metastases. The expression of nm23 and Ep-CAM was found to be more frequently lower than higher in metastases, compared with their primary tumours. Whereas most genetic alterations of primary tumours remain unchanged in metastases, expression of the cell adhesion molecule Ep-CAM and of nm23 is more frequently reduced than increased in metastases, compared with their primary tumours, suggesting relevance to the process of metastasis. This also implies differences in the regulation of markers involved in tumourigenesis and the process of metastasis.
 ...
PMID:Expression of genetic markers in lymph node metastases compared with their primary tumours in head and neck cancer. 1143 61

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.
 ...
PMID:Treatment of meningeal breast cancer xenografts in the rat using an anti-p185/HER2 antibody. 1144 23

Amplification of the HER-2/neu oncogene and amplification of the topoisomerase IIalpha gene are important determinators of the response to chemotherapy in advanced breast cancer. Assays of these genes are usually carried out using primary tumor samples, because biopsies from metastatic lesions are not usually taken. We studied the concordance of Her-2/neu and topoisomerase IIalpha amplification in primary breast tumors and their metastases by immunostaining and DNA in situ hybridization. HER-2/neu amplification, present in 28% of the primary tumors (n = 46), was always associated with amplification in its metastasis. Conversely, no metastases with HER-2/neu amplification were seen without amplification in the primary tumor. Topoisomerase IIalpha gene copy status (amplification/deletion/unaltered) remained generally unchanged in HER-2/neu-positive tumors, but in three cases, the predominant cell population in metastatic tissue was present only as a subpopulation in the primary tumor. We conclude that amplification of HER-2/neu measured in primary tumor reflects the status of metastases. Minor discrepancies between primary and metastatic tumors in topoisomerase IIalpha gene copy status may reflect evolvement of the amplicon structure in successive cell divisions.
 ...
PMID:Amplification of HER-2/neu and topoisomerase IIalpha in primary and metastatic breast cancer. 1145 72

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.
 ...
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.
 ...
PMID:HER2--a discussion of testing approaches in the USA. 1152 14

Based largely on studies of cell lines in vitro and of transgenic mouse models, disruptions of transforming growth factor (TGF) beta signaling are thought to contribute to the development and progression of human breast cancer. However, whether and how TGF-beta signaling becomes disrupted during human breast cancer development in vivo remains largely unknown. To address this question, we have compared the patterns of expression and activation of the postreceptor components of the TGF-beta signaling pathway, the so-called Smads, in human breast cancer cell lines with those in breast carcinoma specimens. None of the breast carcinoma cell lines were growth arrested by TGF-beta in vitro. Each of the tumor cell lines expressed normal levels of Smad2 and -3. Moreover, TGF-beta treatment induced phosphorylation of Smad2 (Smad2P) in each of these lines, except those that lacked TGF-beta type II receptors. Moreover, only one of the cell lines failed to express Smad4. Among 456 cases of human breast carcinoma assembled in tissue microarrays, the majority (92%) expressed Smad2, Smad2P, as well as Smad4, indicating their ability to proliferate within a microenvironment that contains bioactive TGF-beta. Thirty cases (6.6%) failed to express Smad2P, suggesting the loss of TGF-beta receptor signaling. Nine cases (2%) failed to express Smad4, and 3 of these also failed to express Smad2P. Thus, the phenotypes of breast tumors in vivo paralleled that of human breast cancer cell lines in terms of Smad2P and Smad4 expression. Loss of Smad signaling was not associated with any particular histological subtype, histological or nuclear grade, estrogen- or progesterone receptor expression, or HER2/neu expression. Loss of Smad4 was inversely correlated with the presence of axillary lymph node metastases. Most importantly, among patients with stage II breast cancer, lack of Smad2P expression in the tumor was strongly associated with shorter overall survival. Finally, analysis of a small cohort of hereditary breast cancers failed to reveal any association between BRCA1 or BRCA2 genotype and alterations in Smad signaling.
 ...
PMID:Alterations of Smad signaling in human breast carcinoma are associated with poor outcome: a tissue microarray study. 1180 1

Amplification of Her-2/neu in breast carcinoma is associated with poor prognosis, short disease-free interval, and short survival time in both node-negative and -positive patients. Little is known about the starting point of amplification of Her-2/neu and how it progresses from benign to malignant breast lesions. We attempted to address these questions by evaluating amplification of Her-2/neu in benign, premalignant, and malignant lesions using fluorescence in situ hybridization (FISH). Twenty-six patients with Her-2/neu-overexpressing invasive ductal carcinomas (as judged by strong immunoreactivity with Her-2/neu antibody) and coexisting lesions of ductal hyperplasia (DH), atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) in the vicinity of the invasive tumor (as judged by review of the hematoxylin and eosin-stained sections), as well as metastatic carcinoma in axillary lymph nodes (mets) were selected for this study. In the primary carcinomas, a close relationship was present between overexpression as detected by immunohistochemistry (IHC) and amplification as demonstrated by FISH (85% concordance). Among these patients, amplification of Her-2/neu in ADH was demonstrated in 7 of 13 cases with ADH, and in DCIS, in 21 of 22 cases with DCIS. There was no amplification in DH or normal ductal epithelium. Significantly, in all 12 patients with synchronous positive axillary lymph nodes, there was concordant amplification of Her-2/neu in the primary and metastatic carcinoma. Amplification was consistent in multifocal metastases, despite morphological heterogeneity in some patients. Amplification ratios increased from ADH to DCIS to invasive carcinoma (P <.01, ADH versus DCIS; P <.05, DCIS versus invasive cancer), but there was no difference in amplification ratios between primary cancers and synchronous axillary metastases (P >.05). We also evaluated Her-2/neu amplification in 21 patients without Her-2/neu overexpression in their primary carcinomas (as judged by absent immunoreactivity with Her-2/neu antibody). Three showed amplification in both primary and metastatic lesions, with a low amplification ratio (approximately 2). One patient had amplification in the primary tumor but not in an axillary metastasis. Two patients exhibited slight amplification in the metastatic carcinoma (ratios 1.6 and 2), but not in their primary cancers. This FISH study indicates that amplification of Her-2/neu can emerge de novo in any stage of the disease process, from ADH to metastatic lesions, but most often appears first in ADH or DCIS. The degree of Her-2/neu amplification increases with progression to invasive carcinoma, there being no further increase in synchronous metastasis. Our data suggest that amplification of Her-2/neu appears to be mainly involved in initiation of breast oncogenesis and that its role in progression of breast cancers is uncertain.
 ...
PMID:Amplification of Her-2/neu gene in Her-2/neu-overexpressing and -nonexpressing breast carcinomas and their synchronous benign, premalignant, and metastatic lesions detected by FISH in archival material. 1185 May 40


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>