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)

The success of mammographic screening for breast cancer is that it involves increasingly more patients with small primary tumors formerly thought to have an overall excellent prognosis. Yet, only approximately two thirds of these patients actually have this favorable prognosis, while the remaining third develops metastatic disease. Thus, there is emerging evidence that epithelial tumor cells can disseminate into secondary organs at an earlier stage of primary tumor development than appreciated by current risk classifications. Bone marrow is one of the most prominent secondary organs screened for the presence of disseminated tumor cells. The current data suggest that bone marrow micrometastases represent a selected population of dormant and heterogeneous cancer cells. The analysis of micrometastatic cells opens a new avenue by which to assess the molecular determinants of both early tumor cell dissemination and subsequent outgrowth into overt metastases. Moreover, identifying therapeutic target structures (e.g., HER2/neu), monitoring the elimination of bone marrow micrometastases, and assessing treatment-resistant tumor cell clones might help to understand the current limitations of adjuvant systemic therapy. This review summarizes the current knowledge of the biological characteristics of micrometastatic cancer cells in bone marrow of breast cancer patients.
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PMID:Molecular determinants of occult metastatic tumor cells in bone marrow. 1189 16

Although only less than 10% of women with primary breast cancer have clinicopathologic signs of overt metastases, metastatic relapse occurs in about half of the cases with apparently localized tumors within five years after surgery. In 23% of the patients, bone marrow metastases are detectable at first relapse and this rate even increases in patients with metastatic breast cancer. However, hematogeneous or lymphatic spread of occult tumor cells can arise before diagnosis at an early stage of primary tumor growth and is regularly underestimated by currently available clinical and pathologic staging procedures. We studied cytokeratin-positive (CK+) cells in the bone marrow (BM) and tumor markers in the blood of 128 patients with primary breast cancer in order to obtain an early diagnosis of residual disease. In a second study, we monitored cytokeratin (CK)/17-1A positive cells in the BM and peripheral blood stem cells (PBSC) to evaluate whether dose intensive or high-dose (HD)-chemotherapy can eliminate micrometastases in high-risk breast cancer patients. The overall CK+ rate was 34% (44/128 patients), 29% (15/51) for patients with T1 tumors, 33% (28/84) for N0 patients and 31% (26/82) for patients with G1-2 breast carcinoma. Interestingly, 67% of CK+ patients were only positive in one of the two BM aspirates studied. At least one tumor marker including carcinoembryonic antigen, carbohydrate antigen 15-3 and tissue polypeptide antigen, was increased in 58/128 (45%) patients [21/58 (36%) were CK+ in the BM]. Surprisingly, levels for the extracellular domain of Her-2/neu in serum samples were within the normal range in every patient studied. After a 2-year follow-up, 7/128 patients relapsed (3/7 CK+/TM-; 2/7 CK-/TM+; 2/7 CK-/TM-). We concluded that studying two BM aspirates for CK+ cells by immunocytochemistry in combination with tumor marker determination is useful for identifying patients with a higher risk for relapse. A tumor cell enrichment technique, applied in 70 patients prior to immunocytochemistry using dynabeads directly coupled to an antibody (BerEp4) targeting the 17-1A antigen, did not enhance the detection rate of disseminated tumor cells in this patient group. We monitored CK+/17-1A+ cells in the BM and PBSC and studied Her-2/neu serum levels of patients with locally advanced (n=13, group 1) and metastatic breast cancer (n=30, group 2). CK+ cells were found in the BM of 3/13 (23%) group 1 patients before but not after chemotherapy resulting in an overall survival (OS) of 92% after a median follow-up of 33 months. Contamination of PBSC in 2/9 (22%) patients was not associated with decreased survival. In group 2 patients, the CK+ rate was 60% (18/30 patients) before and 40% (4/10 patients) after therapy with an OS rate of 43% after 29 months. PBSC samples were positive in 7/24 (29%) patients. CK+ BM and PBSC led to a rapid progress and short OS whereas tumor cell free BM and PBSC resulted in a mean OS of 30 months. The antigen 17-1A was detected on most CK+ cells in both patient groups before therapy, on all CK+ PBSC and on CK+ cells in group 2 patients after therapy. Increased Her-2/neu levels were found in group 2 patients before chemotherapy. In conclusion, micrometastatic cells are present in blood and PBSC grafts of high-risk breast cancer patients and can survive even HD-chemotherapy. Immunotherapeutic target antigens on the cell surface of these cells support the idea that a combined chemoimmunotherapy might be successful in eliminating minimal residual disease.
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PMID:A summary of two clinical studies on tumor cell dissemination in primary and metastatic breast cancer: methods, prognostic significance and implication for alternative treatment protocols (Review). 1195

The efficacy of trastuzumab for metastases coupled with the relatively poor prognosis of patients with node-positive, HER2-positive breast cancer has led to the evaluation of trastuzumab as an adjuvant therapy. A prospective, randomized, three-arm, phase III trial is being conducted by the Breast Intergroup (N9831) for women with primary, operable, histologically confirmed, node-positive breast carcinoma that strongly overexpresses (3+) HER2 protein and/or displays HER2/neu gene amplification, as determined by local laboratory testing. The protocol requires confirmatory central testing of HER2 status using the HercepTest immunohistochemistry and the Vysis PathVysion fluorescence in situ hybridization (FISH) assays. Tumor specimens from the first 119 patients enrolled in N9831 were centrally tested; 74% were found to be HercepTest 3+ and 66% were found to have HER2 gene amplification. Only six of nine (67%) of the specimens submitted by local laboratories as FISH positive could be confirmed by central assays. The concordance for central HercepTest and central FISH assays was 92%. The poor concordance (74%) between local and central testing for HER2 status has led to modifications in the eligibility criteria for N9831.
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PMID:Concordance between local and central laboratory HER2 testing in the breast intergroup trial N9831. 1269 58

TGF-betas play diverse and complex roles in many biological processes. In tumorigenesis, they can function either as tumor suppressors or as pro-oncogenic factors, depending on the stage of the disease. We have developed transgenic mice expressing a TGF-beta antagonist of the soluble type II TGF-beta receptor:Fc fusion protein class, under the regulation of the mammary-selective MMTV-LTR promoter/enhancer. Biologically significant levels of antagonist were detectable in the serum and most tissues of this mouse line. The mice were resistant to the development of metastases at multiple organ sites when compared with wild-type controls, both in a tail vein metastasis assay using isogenic melanoma cells and in crosses with the MMTV-neu transgenic mouse model of metastatic breast cancer. Importantly, metastasis from endogenous mammary tumors was suppressed without any enhancement of primary tumorigenesis. Furthermore, aged transgenic mice did not exhibit the severe pathology characteristic of TGF-beta null mice, despite lifetime exposure to the antagonist. The data suggest that in vivo the antagonist may selectively neutralize the undesirable TGF-beta associated with metastasis, while sparing the regulatory roles of TGF-betas in normal tissues. Thus this soluble TGF-beta antagonist has potential for long-term clinical use in the prevention of metastasis.
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PMID:Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects. 1207 Feb 99

We prepared a plasmid encoding 147 amino acid residues from the N terminus of c-erbB-2/HER2/neu (HER2), which included both a cytotoxic T lymphocyte (CTL) epitope (HER2p63) and a helper epitope (HER2p1), using the mammalian expression vector pCAGGS-New (pCAGGS147HER2). In a parallel analysis with a Tetramer assay and CTL assay, good specificity and sensitivity of a quantitative enzyme-linked immunospot (ELISPOT) assay to detect functional HER2p63-specific CD8(+) T cells were demonstrated after intramuscular immunization of pCAGGS147HER2. In an ELISPOT assay for HER2p63, spots of IFN gamma-producing cells were first detected 10 days after the first immunization, and additional immunizations increased the number of spots. HER2p63-specific CD8(+) T cells were detected over a period of more than 10 months after the last immunization. In hosts receiving more than three immunizations, surprisingly high numbers of specific CD8(+) T cells were persistently detectable. HER2 protein-specific antibodies of IgG class with dominance of IgG2a remain detectable 6 months after single or multiple immunizations. The antibodies however, were not reactive with cell surface HER2 antigens. Total suppression of tumor growth was observed when syngeneic HER2(+) tumor cells (2 x 10(6)) were injected subcutaneously 14 days after a single immunization with pCAGGS147HER2. Furthermore, the number of pulmonary metastases decreased significantly when DNA vaccination was initiated on the day of, or 3 days after, intravenous injection (1 x 10(6) cells).
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PMID:HER2 peptide-specific CD8(+) T cells are proportionally detectable long after multiple DNA vaccinations. 1208 Mar 82

Female transgenic FVB mice transfected with the mammary erbB-2/neu oncogene were injected 0.1 ml 0.9% solution of sodium chloride (control), 1 meg Vilon peptide (Lys-Glu) or Epitalon peptide (Ala-Glu-Asp-Glu), s.c., 5 days in succession once a month, beginning from the age of 2 months. The characteristics of mammary tumor induction in the control and experimental groups did not differ until the age of 9 months. Later on, Epitalon-treated mice revealed distinct inhibition of carcinogenesis. One tumor per animal was detected in 7% (control), 4% (Vilon) and 16% (Epitalon) (p < 0.05). Two or more tumors per animal were in 75%, 95% and 56%, respectively (p < 0.05). Largest diameter of mammary adenocarcinoma in the Epitalon group was smaller than in controls by 33% (p < 0.05). Although the number of mice with metastases to the lung in all three groups was practically identical, their incidence in the Vilon group was 2.6 times higher than in Epitalon-treated animals (p < 0.05). Largest diameter of metastasis in the Epitalon group was the smallest, too. Our data point to inhibition of mammary carcinogenesis by Epitalon in transgenic erbB-2/neu mice.
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PMID:[Effect of Epitalon and Vilon treatment on mammary carcinogenesis in transgenic erbB-2/NEU mice]. 1210 68

Endocrine therapy remains an important approach to the treatment of metastatic breast cancer because of its effectiveness and excellent tolerability. In the last 10 years, a number of new endocrine therapies have been introduced. These include the luteinizing hormone-releasing hormone agonists, which produce menopausal changes in premenopausal women; the aromatase inhibitors, which prevent production of estrogen in postmenopausal women; and the estrogen receptor down-regulator fulvestrant (Faslodex), which is effective in postmenopausal women whose tumors have progressed following response to other selective estrogen receptor modulators. The endocrine cascade for the treatment of premenopausal women with metastatic disease now involves the concurrent or sequential combination of a luteinizing hormone-releasing hormone analogue and tamoxifen, whereas the cascade for the treatment of postmenopausal women can begin with tamoxifen followed by an aromatase inhibitor or with an aromatase inhibitor followed by tamoxifen. The optimal cascade following the use of an aromatase inhibitor and tamoxifen in postmenopausal women remains unclear, but fulvestrant and megestrol acetate or the use of an aromatase inactivator (exemestane) following an aromatase inhibitor are all available options with some activity. Over the next few years, clinical trials will clarify the optimal sequence of endocrine therapy for postmenopausal women. The use of estrogen and progesterone receptor status to select for endocrine therapy is undeniably crucial. HER2/neu overexpression may also predict response to endocrine therapy, but this remains controversial.
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PMID:Endocrine therapy of advanced disease: analysis and implications of the existing data. 1253 1

The purpose of this study was to investigate whether Her-2/neu expression at diagnosis of osteosarcoma could provide biologic and prognostic information that predicts the risk of pulmonary metastases and outcome. Human epidermal growth factor (Her-2/neu) expression in 25 initial pretreatment osteosarcoma biopsies and 12 posttreatment pulmonary metastatic osteosarcoma resection specimens was assessed by standard immunohistochemical techniques on formalin-fixed paraffin-embedded tissue. As a screening analysis to determine if gene amplification may be a mechanism for increased Her-2/neu expression, FISH analysis was conducted on seven Her-2/neu immunostain-positive samples and five Her-2/neu immunostain-negative samples. Cytoplasmic Her-2/neu reactivity was identified in 11/25 (44%) of primary tumors and in 7/12 (58%) resection specimens from pulmonary metastases. Cytoplasmic Her-2/neu expression was associated with shorter overall metastasis-free survival. Her-2/neu gene amplification was identified by FISH analysis in six of the seven immunostain-positive samples but was also identified in two of the five immunostain-negative samples. Her-2/neu expression in patients with osteosarcoma is associated with an increased risk of metastasis and may define a subset of patients with a more aggressive tumor phenotype. Her-2/neu gene amplification may provide a mechanism for Her-2/neu overexpression in certain cases of osteosarcoma. Whether Her-2/neu expression influences outcome needs to be examined further in a prospective fashion. The hope is that Her-2/neu expression will identify patients who may benefit from the addition of directed biologic therapy.
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PMID:Her-2/neu expression in osteosarcoma increases risk of lung metastasis and can be associated with gene amplification. 1254 70

We compared the prognostic value of routine pathology, cytokeratin-positive (CK+) cells in the bone marrow (BM) and serum tumour markers (TM) in patients with non-small cell lung cancer (NSCLC) at the time of diagnosis with regard to overall survival (OS) and time to progression (TTP). Eighty patients with NSCLC, staged as T2-4, N0-3, M0 (n=52), M1 (n=27), (Mx = 1) were evaluated. Treatment included chemo-radiotherapy with cisplatin/etoposide and subsequent radical surgical resection. There were 23 complete responders, 50 non-responders and 7 patients who died of non-lung cancer causes. The median follow-up was 12 months (range 1-44 months). Besides routine pathology for tissue and BM, CK+ BM cells were detected by immunocytochemistry (IC) and 4 different tumour markers as well as the shedded domain of the oncoprotein Her-2/neu and urokinase plasminogen activator uPA were determined by radio- or enzyme-immunoassay. Patients classified as stage IV and patients with metastases had a significantly lower TTP and OS. No significant correlation was demonstrated for grading, tumour size or number of involved lymph nodes. The tumour marker tissue polypeptide antigen (TPA) and Cyfra 21-1 were the only marker which significantly correlated with OS. Interestingly, routine pathology could not detect minimal residual BM involvement as IC was able to (p=0.0004) and the presence of even a few CK+ cells significantly correlated with reduced OS. Thus, we conclude that the detection of CK+ cells should be added to routine pathology and for tumour marker determination, studies should focus on Cyfra 21-1 and TPA.
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PMID:Evaluation of different markers in non-small cell lung cancer: prognostic value of clinical staging, tumour cell detection and tumour marker analysis for tumour progression and overall survival. 1257 92

Neuroblastic tumors (NT) are the most frequently occurring extracranial solid tumors during childhood. The overall 5-year survival is approximately 20% for patients with metastatic disease. Novel treatments are therefore intensively sought and tumor-targeted immuno- and chemotherapy appear promising. The HER2/neu oncogene, which is highly homologous to the EGF receptor, was initially isolated from rat neuroblastoma cells. HER2/neu over-expression is frequently detected in breast tumors and constitutes an important unfavorable prognostic factor. HER2/neu is a suitable target for antibody-based immunotherapy, as demonstrated by the clinical efficacy of the Herceptin monoclonal antibody (mAb), which reacts with its extracellular domain. Expression of HER2/neu has also been reported to be a negative prognostic factor in a small survey of NT tumors. Here, we have investigated HER2/neu expression in 14 human and 2 murine neuroblastoma (NB) cell lines by flow cytometric analysis and in 93 NT by means of a certified immunohistochemical system. HER2/neu over-expression was found in 2 human cell lines and 11 tumors (14% for both types of samples). No significant association was found between HER2/neu expression and stage, age, sex, ploidy, histological type or subtype. Moreover, log rank test indicated that overall and event-free survival was not significantly different in HER2/neu positive and negative patients. These data suggest that HER2/neu should not be considered as a relevant prognostic factor in NT, and that HER2/neu-based immunotherapy may be feasible only in a minority of NT patients.
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PMID:Expression of HER2/neu is uncommon in human neuroblastic tumors and is unrelated to tumor progression. 1259 75


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