UMLS:C0278488 - FACTA Search

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Query: UMLS:C0278488 (metastatic breast cancer)
7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the effects of a replication-defective adenovirus encoding p53 (RPR/INGN 201 [Ad5CMV-p53]; Adp53), alone or in combination with the breast cancer therapeutic doxorubicin (Adriamycin), to suppress growth and induce apoptosis in breast cancer cells in vitro. We have also examined the in vivo effect of intratumoral administration of Adp53, alone or in combination with doxorubicin, to suppress the growth of established subcutaneous MDA-MB-435 breast cancer tumors. Finally, using the MDA-MB-435 orthotopic model of metastatic breast cancer, we have examined the effect of systemic administration of Adp53, alone or in combination with doxorubicin, to reduce the incidence of metastases. We find that whereas in vitro treatment of cells with Adp53 reduces [(3)H]thymidine incorporation by about 90% at 48 hr, cell viability at 6 days is reduced by only some 50% relative to controls. Although apoptosis is detectable in Adp53-treated cultures, these results suggest that a large fraction of Adp53-treated cells merely undergo reversible cell cycle arrest. Combined treatment with Adp53 and doxorubicin results in a greater than additive loss of viability in vitro and increased apoptosis. In vivo, locally administered Adp53 suppresses growth of established subcutaneous tumors in nude mice and suppression is enhanced by doxorubicin. In the metastatic breast cancer model, systemic administration of Adp53 plus doxorubicin leads to a significant reduction in the incidence of metastases relative to Adp53 or doxorubicin alone. Taken together, these data indicate an additive to synergistic effect of Adp53 and doxorubicin for the treatment of primary and metastatic breast cancer.
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PMID:Tumor suppression and therapy sensitization of localized and metastatic breast cancer by adenovirus p53. 1133 93

We report on the prognostic significance of tumorbiologic parameters and CD34(+) cell dose in 120 patients with metastatic breast cancer (MBC) who received high-dose chemotherapy (HDCT) with autologous blood stem cell transplantation as first-line treatment. Her2/neu, p53, Ki67, and bcl-2 protein expression were studied using immunohistochemical staining on formalin-fixed, paraffin-embedded primary tumor sections. DNA content of tumor cells (DNA-index) and tumor cell proliferation (S-phase fraction) were measured by DNA flow cytometry. The relationship between these parameters and the CD34(+) cell dose and progression free (PFS) and overall survival (OS) was analyzed. With a median follow-up period of 40 months (range, 7-89 months), no more than two metastatic sites (relative risk [RR] = 3.84 [95% confidence interval (CI) 1.49-10]; p =.005) and hyperploidy (RR = 2.58 [95% CI 1.26-5.26]; p =.009) were independent predictors of longer PFS according to multivariate analysis. Independent prognostic factors of longer OS included one or two metastatic sites (RR = 4.16 [95% CI 1.96-4.16]; p <.001), a positive combined hormone receptor status (RR = 2.45 [95% CI 1.45-4.14]; p =.001) and a high number of infused stem cells (>7.8 x 10(6) CD34(+) cells per kg body weight) (RR = 2.0 [95% CI 1.17-3.42]; p =.01). In conclusion, positive hormone receptors, < or =2 metastatic sites, high DNA-index and high CD34(+) cell dose (>7.8 x 10(6) CD34(+) cells per kg) are predictors for a favorable outcome after autotransplantation for MBC. Our observation might indicate a favorable effect of HDCT in MBC patients with overexpression of Her2/neu who might have a worse prognosis when treated with conventional chemotherapy.
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PMID:Stem cell dose and tumorbiologic parameters as prognostic markers for patients with metastatic breast cancer undergoing high-dose chemotherapy with autologous blood stem cell support. 1179 20

This study assesses the potential value of the tumor markers p53, HER2, and Bcl-2 in predicting the clinical response to doxorubicin and paclitaxel as single agents in the treatment of metastatic breast cancer. The primary tumors of 114 patients in the European Organization for Research and Treatment of Cancer 10923 trial were assessed by immunohistochemistry using monoclonal antibodies; the results were correlated with clinical response to therapy. HER2 was positive in 24% of patients, p53 was positive in 25% of patients, and Bcl-2 was positive in 49% of patients. There was no correlation between the expression of any of the markers and the clinical response to either agent. Although methodologically limited, this study does not support the use of p53, HER2, or Bcl-2 to assist the selection of anthracycline versus taxane in metastatic breast cancer.
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PMID:A study of the value of p53, HER2, and Bcl-2 in the prediction of response to doxorubicin and paclitaxel as single agents in metastatic breast cancer: a companion study to EORTC 10923. 1189 48

In breast cancer the membrane expression of HER2 receptor protein encoded by the HER2 proto-oncogene seems to have an ever growing clinical significance. In tissue cultures and animal experiments it was shown that the HER2 gene amplification induces malignant transformation and intensifies the aggressiveness of the tumour cells. Correlating with the so called pheno-and genotypic prognostic markers, the overexpression of HER2 in breast cancer predicts also poor prognosis and indicates enhanced potential for metastatisation. In some of the so called precancerous proliferations and "in situ" carcinomas we demonstrated the enhanced membrane staining of the HER2 receptor protein. In these cases we frequently observed DNA aneuploidy,the presence of p53 mutational protein and CD44v6 glycoprotein. The immunohistochemical studies of HER2 protein in invasive carcinomas have revealed, an interrelationship between the grade of differentiation, histological type, aggressiveness and biological behaviour of the "in situ" and invasive carcinomas. In clinical studies trastuzumab, a humanized monoclonal antibody recognizing extracellular domain of HER2 receptor protein, has proved to be effective in HER2 overexpressing metastatic breast cancer either as monotherapy or in combination with chemotherapeutical agents. The DAKO "HercepTest" is a semiquantitative, standardised method for the determination of HER2 overexpression.
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PMID:[Expression of HER2 in breast cancer] 1205 Jul 66

Two groups of patients were chosen from among 4,025 subjects examined in a breast screening program, one consisting of patients with stage I and the other of patients with stage IV breast cancer, characterized by neoplastic recurrence. In this comparison p53, HER and grading are of no direct help. We investigated receptor status at the time of the first operation and after complete surgical excision of the recurrence. The following variables were determined: oestrogen and progesterone receptor measures (ER, PR) in f.mol/ml, the 4 receptor phenotypes, the oestrogen-progesterone ratio and histological tumour grading in relation to oestrogen receptor positivity or negativity. Surgery consisted in quadrantectomy or total mastectomy, with axillary dissection or complete surgical excision of the recurrence. Adjuvant therapy was administered. The results show a different receptor percentage in recurrence compared to early breast cancer, which though not significant, indicates a reduced presence of ER+ PR+, ER- PR-, and an increase in the ER+PR- phenotype. Recurrence occurs more frequently when the lesion at the first operation is more advanced and if radiotherapy has not been included in the treatment. Histological grading shows a greater number of undifferentiated cells and a reduction in ER+ in recurrence, thus indicating a reduced target for the most widely used hormone treatments. The oestrogen-progesterone ratio is significantly increased (P < 0.01) in recurrence compared to stage I cancers. The cause of recurrence is a neoplastic embolism, often documented histologically. Recurrence does not necessarily mean a poor prognosis, because there is a survival rate after two years of 77% of the cases treated. These results obtained with widely used methods show the aggressiveness of some breast tumours, which can evolve and have a very poor prognosis even with the most complete therapy.
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PMID:The oestrogen-progesterone receptor ratio: an indicator of breast cancer evolution. 1223 50

Thirty HLA-A2 women with metastatic breast cancer received up to 14 vaccinations with MDA-MB-231-CD80, an HLA-A2 allogeneic breast cancer cell line, which had been lipofected with the cDNA for the CD80 costimulatory molecule. Tumor cells were administered with BCG or GM-CSF as an adjuvant. Sera obtained before and after vaccination were analyzed for antibodies to tumor cell lysate, MUC1, HER2/neu and p53. Since the cell line was grown in fetal bovine serum (FBS), sera were also analyzed for antibodies to FBS. Eighteen of 24 patients for whom sera were available exhibited anti-FBS activity at baseline. Eleven of these 18 patients and all six patients without baseline anti-FBS activity showed an increased titer after vaccination. The anti-FBS activity required that serum samples be absorbed in excess FBS to detect specific antibodies to tumor cell lysate. A two-fold increase in the titer of IgG specific to tumor cell lysate was observed in 6 patients. Eight of 24 patients made an antibody response to HER-2/neu, four of 24 to MUC1 and one of 24 to p53. Although antibody production to a variety of tumor cell-associated antigens was detected our results suggest that a whole cell vaccine comprising a CD80-transfected allogeneic breast cancer cell line with adjuvant BCG or GM-CSF was not a reliable method to induce significant antibody responses in women with advanced breast cancer.
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PMID:Identification of tumor-specific antibodies in patients with breast cancer vaccinated with gene-modified allogeneic tumor cells. 1261 8

In the treatment of breast cancer, combination chemotherapy is used to overcome drug resistance. Combining doxorubicin and vinorelbine in the treatment of patients with metastatic breast cancer has shown high response rates; even single-agent vinorelbine in patients previously exposed to anthracyclines results in significant remission. Alterations in protein kinase-mediated signal transduction and p53 mutations may play a role in drug resistance with cross-talk between signal transduction and p53 pathways. The aim of this study was to establish the effects of doxorubicin and vinorelbine, as single agents, in combination, and as sequential treatments, on signal transduction and p53 in the breast cancer cell lines MCF-7 and MDA-MB-468. In both cell lines, increased p38 activity was demonstrated following vinorelbine but not doxorubicin treatment, whether vinorelbine was given prior to or simultaneously with doxorubicin. Mitogen-activated protein kinase (MAPK) activity and p53 expression remained unchanged following vinorelbine treatment. Doxorubicin treatment resulted in increased p53 expression, without changes in MAPK or p38 activity. These findings suggest that the effect of doxorubicin and vinorelbine used in combination may be achieved at least in part through distinct mechanisms. This additivism, where doxorubicin acts via p53 expression and vinorelbine through p38 activation, may contribute to the high clinical response rate when the two drugs are used together in the treatment of breast cancer.
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PMID:Doxorubicin and vinorelbine act independently via p53 expression and p38 activation respectively in breast cancer cell lines. 1269 97

Racial disparity in the presentation of breast cancer and the outcome of its treatment is well established. However, the causes remain unexplained. The scarcity of reports about the prognostic significance of p53, bcl-2, and HER-2/neu in Arab females with breast cancer has been the impetus to this study. We evaluated the prognostic significance of altered expression of p53, bcl-2, HER-2/neu in Omani Arab females with non-metastatic breast cancer with correlation to other established prognostic factors. We have retrospectively analyzed the immunohistochemical expression of p53, HER-2/neu and bcl-2 in paraffin embedded blocks of 72 females diagnosed with invasive breast cancer between 1992 and 2002. The expression of the above proteins was correlated with other prognostic factors and univariate and multivariate analysis was carried out for all prognostic factors. Overexpression of p53 significantly correlated with younger age (<40), pre-menopausal status, poor differentiation with inverse correlation with bcl-2 expression. Expression of bcl-2 immunopostivity significantly correlated to low histological grade and positive estrogen and progesterone receptor status. On univariate and multivariate p53 overexpression and lack of bcl-2 immunostaining resulted in worse survival outcome, but not Her-2/neu overexpression. Expression patterns of p53 and bcl-2 are independent predictors of survival in Omani Arab population which may help to stratify these patients into different risk groups.
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PMID:Significance of p53, Bcl-2, and HER-2/neu protein expression in Omani Arab females with breast cancer. 1468 28

The angiogenic inducer CYR61 is differentially overexpressed in breast cancer cells exhibiting high levels of Heregulin (HRG), a growth factor closely associated with a metastatic breast cancer phenotype. Here, we examined whether CYR61, independently of HRG, actively regulates breast cancer cell survival and chemosensitivity, and the pathways involved. Forced expression of CYR61 in HRG-negative MCF-7 cells notably upregulated the expression of its own integrin receptor alphavbeta3 (>200 times). Small peptidomimetic alphavbeta3 integrin antagonists dramatically decreased cell viability of CYR61-overexpressing MCF-7 cells, whereas control MCF-7/V remained insensitive. Mechanistically, functional blockade of alphavbeta3 specifically abolished CYR6-induced hyperactivation of ERK1/ERK2 MAPK, whereas the activation status of AKT did not decrease. Moreover, CYR61 overexpression rendered MCF-7 cells significantly resistant (>10-fold) to Taxol-induced cytotoxicity. Remarkably, alphavbeta3 inhibition converted the CYR61-induced Taxol-resistant phenotype into a hypersensitive one. Thus, the augmentation of Taxol-induced apoptotic cell death in the presence of alphavbeta3 antagonists demonstrated a strong synergism as verified by the terminal transferase-mediated dUTP nick-end labeling (TUNEL) assay and by flow cytometric analysis for DNA content. Indeed, functional blockade of alphavbeta3, similarly to the pharmacological MAPK inhibitor U0126, synergistically increased both the proportion of CYR61-overexpressing breast cancer cells in the G2 phase of the cell cycle and the appearance of sub-G1 hypodiploid (apoptotic) cells caused by Taxol. Strikingly, CYR61 overexpression impaired the accumulation of wild-type p53 following Taxol exposure, while inhibition of alphavbeta3 or ERK1/ERK2 MAPK signalings completely restored Taxol-induced upregulation of p53. Moreover, antisense downregulation of CYR61 expression abolished the anchorage-independent growth of breast cancer cells engineered to overexpress HRG, and significantly increased their sensitivity to Taxol. Our data provide evidence that CYR61 is sufficient to promote breast cancer cell proliferation, cell survival, and Taxol resistance through a alphavbeta3-activated ERK1/ERK2 MAPK signaling. The identification of a 'CYR61-alphavbeta3 autocrine loop' in the epithelial compartment of breast carcinoma strongly suggests that targeting alphavbeta3 may simultaneously prevent breast cancer angiogenesis, growth, and chemoresistance.
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PMID:A novel CYR61-triggered 'CYR61-alphavbeta3 integrin loop' regulates breast cancer cell survival and chemosensitivity through activation of ERK1/ERK2 MAPK signaling pathway. 1559 21

An international meeting on 'New Drugs in Cancer Therapy' was held at the National Tumor Institute of Naples, on 17-18 June 2004. The first session of the meeting focused on analogs of conventional anti-cancer drugs, such as taxanes, platinum compounds, anthracyclines and topoisomerase I inhibitors. The data of a phase II trial of BMS-247550, an epothilone B analog, in patients with renal cell carcinoma were reported. Data were also presented on BBR-3464, a trinucleate platinum analog which was developed on the grounds of greater potency, a more rapid rate of DNA binding and the ability to induce apoptosis regardless of the p53 status of the cell. Pegylated-coated liposomal formulation doxorubicin (Caelyx) has shown efficacy in metastatic breast cancer and in advanced ovarian cancer; sabarubicin is a third-generation anthracycline with equal or superior potency to doxorubicin or idarubicin in a variety of human tumor cell lines of different histotypes. The main mechanisms of resistance to topoisomerase I inhibitors were discussed; data on diflomotecan were reported, showing a narrow therapeutic index of the drug. The second session of the meeting focused on the ErbB family as a target for anti-cancer therapy. Recent evidence of a correlation between epidermal growth factor receptor (EGFR) mutations at exons 18-21 and clinical response of advanced non-small cell lung cancer to gefitinib therapy was commented on. The issue of the association between ErbB2 expression and gefitinib activity was addressed, while clinical data of a phase II study of gefitinib in advanced breast cancer were presented. Monoclonal antibodies targeting EGFR represent another worthwhile way to interfere with EGFR-driven signal transduction. Cetuximab is reaching market registration in advanced colorectal cancer; in particular, due to the results of the BOND study. The recently presented results of the Bonner study strongly support the activity of this drug in head and neck cancer. A step forward in the research on anti-EGFR monoclonal antibodies may be represented by humanized monoclonal antibodies, such as EMD 72000 and ABX-EGF. Imatinib mesylate is probably the most outstanding example of an effective targeted therapy--its activity in gastrointestinal stromal tumors was so exciting that the drug reached the market without undergoing phase III evaluation. The third session of the meeting was on angiogenesis inhibitors. Drugs may interfere with the angiogenic process via different mechanisms and there is a sound rationale for combining anti-angiogenic agents with chemotherapy or multiple anti-angiogenic strategies. Clinical results obtained with direct anti-angiogenic agents have been negative up to now, but some exciting results have been seen with bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF). A few VEGF-tyrosine kinase inhibiting small molecules, such as ZD6474, AZD2171 and PTK/ZK, are undergoing clinical trials. The fourth session of the meeting was on interference with intracellular signal transduction. Farnesyl transferase inhibitors exert their action by interfering with either pro-Ras or RhoB farnesylation. Several clinical studies of different phases with compounds belonging to this class have been carried out, either alone or in combination with chemotherapy; unfortunately, all of them have turned out to be negative. Cell cycle inhibitors, such as CYC-202 and BMS-387032, represent a class of interesting compounds which are in the early phase of development and whose clinical results are eagerly awaited. Another strategy to achieve cell cycle inhibition is to target heat shock protein 90, a molecular chaperone required for protein folding. Clinical data on depsipeptide, a histone deacetylase (HDAC) inhibitor with activity in T cell lymphoma, were presented. Suberoylanilide hydroxamic acid is another small molecular weight inhibitor of HDAC activity. Phase I/II clinical trials have shown low toxicity and evidence of anti-tumor activity; on the other hand, this compound has potential for synergism with radiotherapy, chemotherapy and biologicals.
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PMID:New drugs in cancer therapy, National Tumor Institute, Naples, 17-18 June 2004. 1565 20

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