Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bevacizumab (Avastin, Genentech, Inc, San Francisco, CA), a humanized monoclonal antibody against vascular endothelial growth factor, was recently approved for the treatment of metastatic breast cancer.A PubMed and OVID search was performed using keywords: bevacizumab, Avastin, wound healing, VEGF, angiogenesis, and colorectal cancer. Our objective was to review the current literature in regard to bevacizumab and its adverse effects on surgical wound healing.Bevacizumab has been associated with multiple complications in regard to wound healing, such as dehiscence, ecchymosis, surgical site bleeding, and wound infection. Current literature suggests patients should wait at least 6 to 8 weeks (>40 days) after cessation to have surgery (half-life = 20 days). In addition, postoperative reinitiation of bevacizumab must wait > or =28 days to prevent an increased risk of wound healing complications, and the surgical incision should be fully healed.The adverse effects of bevacizumab in regard to wound healing must be considered in all surgical patients.
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PMID:A review on bevacizumab and surgical wound healing: an important warning to all surgeons. 1946 Dec 91

Identification of molecular alterations in key proteins involved in breast cancer cell proliferation and survival resulted in the development of a new treatment strategy with target-based agents. The anti-ErbB-2 monoclonal antibody (mAb) trastuzumab and the dual epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor lapatinib are effective in patients with breast cancer that overexpresses ErbB-2. The anti-vascular endothelial growth factor-A mAb bevacizumab is approved in combination with taxanes for treatment of unselected patients with metastatic breast cancer. In addition, preclinical data suggest that signaling inhibitors can prevent or overcome resistance to endocrine therapy in estrogen receptor positive (ER+) breast cancer. However, the majority of signaling inhibitors explored in breast cancer patients has shown little activity, at least when used as monotherapy; and the results of clinical trials in ER+ breast cancer of combinations of signaling inhibitors and endocrine therapies are rather disappointing. Negative findings are likely due to mechanisms of intrinsic or acquired resistance to target-based agents. Breast carcinoma is a complex and heterogeneous disease and several different molecular alterations are involved in its pathogenesis and progression. The redundancy of oncogenic pathways activated in cancer cells, the heterogeneity of the mechanisms of resistance, and the plasticity of tumor cells that are capable to adapt to different growth conditions, significantly hamper the efficacy of each signaling inhibitor in breast cancer. Therefore, a comprehensive approach that takes into account the complexity of the disease is definitely required to improve the efficacy of target-based therapy in breast cancer.
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PMID:Target-based therapies in breast cancer: current status and future perspectives. 1952 14

Recent data reported an association between VEGF-A genotype of tumors and median overall survival as well as grade 3 or 4 hypertension when using bevacizumab in metastatic breast cancer. In the present case we report a discordant VEGF-A genotype between tumor and normal tissue in a patient with a responsive hepatic lesion of chemoresistant breast cancer treated with bevacizumab and paclitaxel. Moreover, we show that, despite the very low VEGF-A protein expression, the neoplastic lesion was well vascularized and responded to bevacizumab therapy. The discordance of VEGF-A polymorphisms in tumor and germline DNA may suggest the importance of obtaining both information in order to predict a superior overall survival or a lower risk of hypertension in patients treated with taxanes and bevacizumab.
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PMID:Discordant somatic and germline VEGF-A genotype in a cancer patient resistant to paclitaxel/bevacizumab with chemosensitive hepatic metastasis. 1966 67

The heterogeneity of metastatic breast cancer mandates the need to select therapies taking into account tumor and patient characteristics. Chemotherapy is indicated in the palliative setting especially when the disease is unresponsive to hormonal therapy or is hormone-receptor negative. The main chemotherapeutic agents are anthracyclines, taxanes, and capecitabine. The knowledge of the effects of currently approved agents and of the biology of breast cancer have paved the way for the evaluation of new treatment options, among which are anti-angiogenic agents. Angiogenesis inhibition has resulted in clinically significant improvements in the outcome of a variety of malignancies, including breast cancer. Bevacizumab, a monoclonal antibody anti-vascular endothelial growth factor (VEGF), is the most extensively studied anti-angiogenic compound. According to the results of a phase III trial in patients with untreated metastatic breast cancer, bevacizumab increases both objective response rate and median progression-free survival when combined with standard chemotherapy vs chemotherapy alone. The combination of anti-angiogenic drugs and other biologic agents is also being explored in an attempt to improve efficacy.
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PMID:First line targeted therapies in breast cancer: focus on bevacizumab. 1970 43

This trial was conducted to assess the efficacy and safety of sorafenib in patients with metastatic breast cancer. In this multinational, open-label phase II study, patients with metastatic breast cancer that had progressed after at least one prior chemotherapy regimen were continuously treated with oral sorafenib, 400 mg twice daily. The primary endpoint was overall best response; a secondary endpoint was percentage of patients with stable disease for greater than or equal to 16 weeks. Biomarker analysis were also performed. Of the 56 patients enrolled into the study, 54 were treated with at least one dose of sorafenib. Partial response was observed in one patient (2%) and stable disease in 20 patients (37%); no complete responses were observed. Disease stabilization for greater than or equal to 16 weeks was seen in 12 patients (22%); stabilization for greater than or equal to 6 months in seven patients (13%). The most common drug-related grade 3 adverse events were rash/desquamation (6%), hand-foot skin reaction (4%), and fatigue (4%). Baseline vascular endothelial growth factor levels, levels of soluble epidermal growth factor receptor during treatment and both baseline and changes in soluble human epidermal growth factor receptor 2 levels correlated significantly with clinical outcomes. Although the primary endpoint of overall response rate showed minimal improvement on sorafenib 400 mg twice-daily treatment, the rate of disease stabilization was encouraging in patients treated with one or more lines of chemotherapy. The treatment had a clinically manageable toxicity profile. Further investigation of single-agent sorafenib in this patient population is not recommended; however, studies investigating combinations of sorafenib with chemotherapeutic agents are warranted and ongoing.
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PMID:Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer. 1973 18

Sunitinib malate (SUTENT) is an oral, multitargeted tyrosine kinase inhibitor that blocks several pathways central to angiogenesis and tumor cell proliferation and migration, including vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs). Sunitinib has demonstrated clinical activity as a single agent in patients with metastatic breast cancer and it is hypothesized that enhanced clinical benefit may be derived by combining sunitinib with chemotherapy or other targeted agents. The current report describes four patients with advanced/metastatic breast cancer who experienced clinically meaningful responses following treatment with sunitinib in combination with docetaxel.
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PMID:Early experience with sunitinib, combined with docetaxel, in patients with metastatic breast cancer. 1974 25

A growing body of evidence indicates that interactions between neoplastic cells and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) are crucial in promoting tumor cell invasion and progression. Macrophages have an ambiguous role in these processes as this M1 phenotype correlates with tumoricidal capacity, whereas TAMs of M2 phenotype exert tumor-promoting effects. In this study, we provide evidence that interactions between mouse breast tumor cells and TAMs remodel the TME, leading to the upregulation of Fra-1, a member of the FOS family of transcription factor. In turn, this proto-oncogene initiates activation of the IL-6/JAK/Stat3 signaling pathway. This creates a malignant switch in breast tumor cells, leading to increased release of proangiogenic factors MMP-9, vascular endothelial growth factor and transforming growth factor-beta from tumor cells and intensified invasion and progression of breast cancer. Proof of the concept for the crucial role played by transcription factor Fra-1 in regulating these processes was established by specific knockdown of Fra-1 with small interfering RNA, which resulted in a marked suppression of tumor cell invasion, angiogenesis and metastasis in a mouse breast cancer model. Such a strategy could eventually lead to future efficacious treatments of metastatic breast cancer.
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PMID:The role of proto-oncogene Fra-1 in remodeling the tumor microenvironment in support of breast tumor cell invasion and progression. 1996 54

PURPOSE Preclinical studies indicate that metronomic chemotherapy is antiangiogenic and synergistic with other antiangiogenic agents. We designed a phase I/II study to evaluate the safety and activity of adding dalteparin and prednisone to metronomic cyclophosphamide and methotrexate in women with measurable metastatic breast cancer (MBC). PATIENTS AND METHODS Patients received daily dalteparin and oral cyclophosphamide, twice-weekly methotrexate, and daily prednisone (dalCMP). The primary study end point was clinical benefit rate (CBR), a combination of complete response (CR), partial response (PR), and prolonged stable disease for > or = 24 weeks (pSD). Secondary end points included time to progression (TTP), duration of response, and overall survival (OS). Biomarker response to treatment was assessed by using plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptors (sVEGFRs) -1 and -2. Results Forty-one eligible patients were accrued. Sixteen (39%) had no prior chemotherapy for MBC; 15 (37%) had two or more chemotherapy regimens for MBC. Toxicities were minimal except for transient grade 3 elevation of liver transaminases in 11 patients (27%) and grade 3 vomiting in one patient (2%). One patient (2%) had CR, six (15%) had PR, and three (7%) had pSD, for a CBR of 10 (24%) of 41 patients. Median TTP was 10 weeks (95% CI, 8 to 17 weeks), and median OS was 48 weeks (95% CI, 32 to 79 weeks). VEGF levels decreased but not significantly, whereas sVEGFR-1 and -2 levels increased significantly after 2 weeks of therapy. There was no correlation between response and VEGF, sVEGFR-1, or sVEGFR-2 levels. CONCLUSION Metronomic dalCMP is safe, well tolerated, and clinically active in MBC.
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PMID:Phase I/II trial of metronomic chemotherapy with daily dalteparin and cyclophosphamide, twice-weekly methotrexate, and daily prednisone as therapy for metastatic breast cancer using vascular endothelial growth factor and soluble vascular endothelial growth factor receptor levels as markers of response. 2002 1

Metastasis is one of the most important factors related to breast cancer therapeutic efficacy. Ursolic acid, a naturally occurring triterpenoid, has various anticancer activities. In this study, we first observed that ursolic acid exerted a dose- and time-dependent inhibitory effect on the migration and invasion of highly metastatic breast MDAMB231 cells at non-cytotoxic concentrations. This effect was associated with reduced activities of metalloproteinase-2 (MMP-2) and u-PA, which correlated with enhanced expression of tissue inhibitor of MMP-2 and plasminogen activator inhibitor-1, respectively. Ursolic acid suppressed the phosphorylation of Jun N-terminal kinase, Akt and mammalian target of rapamycin, but had no effect on the phosphorylation of ERK and p38. Ursolic acid also strongly reduced the levels of NFkappaB p65, c-Jun and c-Fos proteins in the nucleus of MDAMB231 cells. A time-dependent inhibition of the protein levels of Rho-like GTPases, growth factor receptor-bound protein 2, Ras and vascular endothelial growth factor in cytosol by ursolic acid treatment was also observed. In conclusion, we demonstrated that the anti-invasive effects of ursolic acid on MDAMB231 cells might be through the inhibition of Jun N-terminal kinase, Akt and mammalian target of rapamycin phosphorylation and a reduction of the level of NFkappaB protein in the nucleus, ultimately leading to downregulation of MMP-2 and u-PA expression. These results suggest that ursolic acid has potential as a chemopreventive agent for metastatic breast cancer.
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PMID:Ursolic acid, a naturally occurring triterpenoid, suppresses migration and invasion of human breast cancer cells by modulating c-Jun N-terminal kinase, Akt and mammalian target of rapamycin signaling. 2035 21

Significant advances have been made in the treatment of patients with breast cancer in recent years. As increasing numbers of patients become long-term survivors, there must be a greater focus on treatment-induced chronic toxicities, such as left ventricular dysfunction, congestive heart failure (CHF), and/or secondary treatment malignancies. More recently, the HER2-targeted monoclonal antibody (MoAb) trastuzumab has been found to increase the risk for CHF, particularly when used in combination with an anthracycline or in anthracycline-pretreated patients. In early-stage breast cancer, CHF has been reported in up to 4% of trastuzumab-treated, anthracycline-pretreated patients. Given this background, the clinical development of bevacizumab, a MoAb to vascular endothelial growth factor, is proceeding--with careful consideration given to cardiac safety--in this setting. Cardiac toxicity has been reported in association with bevacizumab-based therapy in patients with advanced or metastatic breast cancer, many of whom were previously exposed to anthracyclines. Although there is currently little evidence to suggest that bevacizumab increases the risk or worsens the severity of cardiac events in these patients, it is anticipated that ongoing, well-designed prospective trials will fully evaluate the cardiac safety of bevacizumab in patients with early-stage breast cancer. This review analyzes the cardiac safety profile of bevacizumab in breast cancer, with a focus on early-stage disease, and the ongoing clinical development of this important new drug.
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PMID:Integrating bevacizumab into the treatment of patients with early-stage breast cancer: focus on cardiac safety. 2035 33


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