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

Metastatic breast cancer is still defined as an incurable disease, with the lungs being the most common metastatic sites in breast cancer patients. Epidermal growth factor receptor (EGFR), a member of receptor tyrosine kinase family, is known to be involved in survival, migration, angiogenesis and metastasis of cancer. The spontaneous pulmonary metastasis mouse model was applied to evaluate the effects of the EGFR tyrosine kinase inhibitor, erlotinib, on the prevention of pulmonary metastasis in curatively resected breast carcinoma. The expression of EGF and EGFR was significantly strong in pulmonary metastatic nodules compared to those in primary breast carcinoma tissue. A treatment of erlotinib (oral gavage, 50 mg/kg/day, every day for 6 weeks) given to mastectomized mice inhibited the incidence of pulmonary metastasis. The number of metastatic pulmonary nodules was significantly reduced in the erlotinib-treated group compared with the control. Therefore, erlotinib may play a role in preventing pulmonary metastasis, which shows the strong expression of EGF and EGFR after curative resection of primary breast cancer.
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PMID:Erlotinib prevents pulmonary metastasis in curatively resected breast carcinoma using a mouse model. 1678 33

Clinical studies indicate that Herceptin (trastuzumab), a recombinant humanized monoclonal antibody directed against the human epidermal growth factor receptor-2 (HER-2) tyrosine kinase growth factor receptor, provides a significant but transient survival advantage to a subset of patients with HER-2-overexpressing metastatic breast cancer when given as a first-line agent. Increased insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling has recently been identified as a potential factor adversely influencing the response to Herceptin. We examined the effect of recombinant human IGF binding protein 3 (rhIGFBP-3), an antagonist of IGF-IR signaling, in Herceptin-resistant breast cells in vitro and in tumors in vivo. Consistent with results obtained using HER-2- or IGF-IR-transfected cells (MCF-7/HER2-18 and SKBR3/IGF-IR, respectively), we found that rhIGFBP-3 significantly reduced IGF-I-induced IGF-IR phosphorylation and displayed a synergistic interaction with Herceptin against cultured HER-2-overexpressing breast cancer cells in vitro. We show, for the first time, the antitumor activity of rhIGFBP-3 against advanced-stage MCF-7/HER2-18-transfected human breast cancer xenografts and its potentiation of Herceptin activity. We also provide evidence that IGF-IR activation counters the early suppressive effect of Herceptin on HER-2 signaling via Akt and p44/p42 mitogen-activated protein kinase (MAPK), and that inhibition of HER-2-overexpressing human breast tumor growth by rhIGFBP-3 is associated with restored down-regulation of Akt and p44/p42 MAPK phosphorylation in vitro and in vivo. These results emphasize the merit of evaluating simultaneous blockade of the HER-2 and IGF-IR pathways using combination therapy with rhIGFBP-3 plus Herceptin in human clinical trials of patients with HER-2-positive breast cancer.
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PMID:Recombinant human insulin-like growth factor binding protein 3 inhibits growth of human epidermal growth factor receptor-2-overexpressing breast tumors and potentiates herceptin activity in vivo. 1684 73

In 1985, a growth factor pathway that depends on the presence of a tyrosine kinase transmembrane receptor present on the surface of 20-25% of breast cancer cells was discovered. The receptor is called human epidermal growth factor receptor (HER)-2 and the prognosis of those patients whose tumors overexpress it is poor. In the 1980s, a monoclonal antibody against this receptor, trastuzumab, was developed and, in 1998, approved for the treatment of metastatic breast cancer. In 2005, the results of five trials evaluating trastuzumab in the adjuvant setting, involving more than 10,000 women, were presented. Despite differences in design and having a short follow-up (between 1 and 2 years), these studies show the same astonishing results that adjuvant trastuzumab therapy halves the recurrence rate and reduces mortality by 30% in those trials mature enough to show survival gains. This benefit is, on average, higher than that of adjuvant chemotherapy and similar to that seen with adjuvant hormonal therapy. The main setback of trastuzumab is its potential for cardiotoxicity, although benefits seem to outweigh risks and the ensuing congestive heart failure is generally reversible. Today, the evaluation of HER-2 expression should be mandatory in every early breast cancer patient, since without it, there is the risk that access to this highly effective drug will be denied for women belonging to this unfavorable subgroup of patients.
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PMID:Use of trastuzumab for the treatment of early stage breast cancer. 1692 82

Human epidermal growth factor receptor (HER)-2 is a member of the HER tyrosine kinase family, which regulates cell growth and proliferation. HER-2 is overexpressed in 20% to 30% of breast cancers and has been associated with an aggressive phenotype and a poorer prognosis, making it an appealing therapeutic target. Since 1998, the anti-HER-2 antibody trastuzumab has been used for the treatment of women with HER-2-positive metastatic breast cancer. Results from large trials have established a role for trastuzumab in the adjuvant setting for the treatment of high-risk primary breast cancer as well. Tyrosine kinase inhibitors that target HER-2 are also very promising therapies and are likely to be incorporated into clinical practice in the near future. HER-2-targeted therapies represent a major step forward in achieving our goal of delivering individualized targeted therapy for breast cancer. However, there are many unanswered questions about the optimal use of these agents. Ongoing research will better elucidate the best combination therapies to overcome resistance to HER-2-targeted agents and will help identify patients at high enough risk to warrant their toxicity.
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PMID:Advances in targeting human epidermal growth factor receptor-2 signaling for cancer therapy. 1708 41

In recent years, antiangiogenic therapy with the monoclonal antibody bevacizumab has demonstrated significant activity in patients with metastatic breast cancer. Bevacizumab is targeted against vascular endothelial growth factor (VEGF), a primary mediator of angiogenesis. Research is ongoing to define the mechanism of action of anti-VEGF treatment in order to predict who will respond to treatment and to monitor responses to treatment at the molecular level. The initial randomized phase III trial of bevacizumab evaluated capecitabine with bevacizumab versus capecitabine alone in patients with heavily pretreated metastatic breast cancer. The addition of bevacizumab to capecitabine did not improve progression-free survival in these patients. However, in the subsequent Eastern Cooperative Oncology Group 2100 trial of patients with previously untreated metastatic breast cancer, bevacizumab combined with paclitaxel doubled progression-free survival compared to paclitaxel alone. Based on these encouraging findings, current studies are evaluating bevacizumab in the adjuvant setting. The oral tyrosine kinase inhibitor sunitinib has shown activity in metastatic breast cancer, and additional agents are being investigated. Combination therapy consisting of antiangiogenic agents with chemotherapy, hormone therapy, or other agents is also being evaluated in hopes of improving treatment options for these patients.
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PMID:The role of angiogenesis inhibition in the treatment of breast cancer. 1713 44

Identification of genes/proteins that are differentially expressed in HER2 (erbB-2) oncogene-dependent breast carcinomas is essential in elucidating the mechanistic basis of their increased metastastic potential and resistance to several anti-cancer therapies. We here applied human cytokine antibody arrays with the goal of identifying a unique HER2-induced 'cytokine signature' in breast cancer. Human Cytokine Array III (RayBiotech, Inc.), which simultaneously detects 42 cytokines and growth factors on one membrane, was used to determine the profile of cytokines in conditioned media obtained from MCF-7/Her2-18 cells, a MCF-7-derived clone engineered to stably express the full-length human HER2 cDNA controlled by a SV40 viral promoter, and from the MCF-7/neo control sub-line. We identified two inflammatory and pro-angiogenic CXC chemokines with at least a 10-fold increased expression in HER2-overexpressing MCF-7/Her2-18 transfectants when compared to matched control MCF-7/neo cells: CXCL8 (IL-8; Interleukin-8) and CXCL1 and (GRO; Growth-related oncogene). HER2-induced differential overexpression of IL-8 and GRO was validated by ELISA and further confirmed by switching off the HER2 signalling. Treatment with the tyrosine kinase inhibitor gefitinib (Iressa) returned the expression levels of IL-8 and GRO back to the baseline observed in MCF-7 breast cancer cells, which express physiological levels of HER2. To evaluate the diagnostic utility of these findings, cytokine-specific antibody arrays were incubated with sera retrospectively collected from metastatic breast cancer patients. This approach revealed a high similarity between the 'cytokine signature' observed in serum samples and that obtained in media conditioned by breast cancer-derived cell lines. Thus, IL-8 and GRO circulating levels were significantly higher in HER2-positive breast cancer patients compared with HER2-negative patients. These findings reveal for the first time that: a) Enhanced synthesis and secretion of members of the IL-8/GRO chemokine family, which have recently been linked to oestrogen receptor (ER) inaction, increased cell invasion and angiogenesis, may represent a new pathway involved in the metastatic progression and endocrine resistance of HER2-overexpressing breast carcinomas, and b) Circulating levels of IL-8 and GRO cytokines may represent novel biomarkers monitoring breast cancer responses to endocrine treatments and/or HER2-targeted therapies.
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PMID:Protein array technology to detect HER2 (erbB-2)-induced 'cytokine signature' in breast cancer. 1737 3

Aberrant activation of some members of human epidermal growth factor receptor (HER) family plays a key role in breast carcinogenesis. Lapatinib is an oral dual tyrosine kinase inhibitor selective for inhibition of epidermal growth factor receptor (EGFR/ErbB1) and HER2/ErbB2. Having more targets, probably its antitumor activity could be more efficient. Clinical data have shown that lapatinib is active in HER2-positive breast cancer as monotherapy, in combination with trastuzumab, and in trastuzumab-resistant patients. Phase I clinical trials have shown also that lapatinib is well tolerated, with mild diarrhea and skin rush as common toxic effects and low incidence of cardiotoxicity. Phase II and III clinical trials' data provide encouraging evidence of the clinical effectiveness of lapatinib in advanced or metastatic breast cancer and for its potential in patients with brain metastases. Interim results from the large, phase III trial in 392 patients showed that in combination with capecitabine lapatinib almost doubled time to progression when compared with capecitabine alone. Several clinical trials that explore the efficacy of lapatinib in combination with conventional chemotherapeutic agents [paclitaxel (Taxol), capecitabine and platinoids], hormonotherapy and other target therapies are ongoing in advanced breast cancer or in neo-adjuvant and adjuvant settings. Our improved understanding of the biology of breast cancer and the use of biomarkers for identification of specific subtypes are allowing us to bring patient-specific novel therapies such as lapatinib to the clinic.
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PMID:Lapatinib in breast cancer. 1759 27

Both HER-2 and EGFR are expressed in breast cancer and are implicated in its development and progression. The discovery of the association between HER-2 gene amplification and poor prognosis in breast cancer led to the development of HER-2 targeted therapies. Trastuzumab, a monoclonal antibody to HER-2, has significantly improved the prognosis for HER-2-positive breast cancer patients. It is now approved for the treatment of both HER-2-positive metastatic breast cancer and early stage HER-2-positive breast cancer. Recent results from trials of the dual HER-2 and EGFR tyrosine kinase inhibitor, lapatinib, also show very promising results in HER-2-positive breast cancer. A number of EGFR inhibitors have been tested in breast cancer clinical trials, but with limited effect. This may be due to difficulty in selecting the appropriate patient population, caused by the lack of definitive predictive markers for response to EGFR inhibition.
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PMID:EGFR and HER-2 antagonists in breast cancer. 1759 21

Targeted therapies against the human epidermal growth factor receptor HER2, have led to revolutionary strides in breast cancer research and treatment. Clinical therapeutic decisions in the treatment of patients with HER2 positive metastatic breast cancer are based on appropriate patient selection, the clinical situation, and data related to the available therapeutic agents trastuzumab and lapatinib. Trastuzumab was the first agent tested and approved in 1996 as single agent for patients with chemotherapy-refractory disease, and in combination with paclitaxel as first-line treatment. This intravenous humanized monoclonal antibody is directed against the extracellular domain of the HER2 protein. Lapatinib, an oral small molecule tyrosine kinase inhibitor has more recently become available (in 2007), approved for used in combination with capecitabine for patients with HER2 positive metastatic disease that has progressed on trastuzumab. Important questions and controversies still remain and are reviewed, including patient selection for anti-HER2 treatment of metastatic disease based on HER2 testing, dose scheduling of trastuzumab, duration of therapy, tolerability, role of lapatinib and clinical significance of trastuzumab resistance and efficacy. Ongoing trials designed to maximize the therapeutic ratio of these agents, are also discussed.
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PMID:Issues and controversies in the treatment of HER2 positive metastatic breast cancer. 1765 58

This review addresses molecular targeted therapies for metastatic breast cancer. As the complex cellular aberrations inherent to cancer cells continue to be revealed, new therapies to target specific cellular pathways are being developed, and several are currently in clinical trials. The most promising of these new agents are discussed focusing on monoclonal antibodies and tyrosine kinase inhibitors to human epidermal growth factor receptors (HER) and vascular endothelial growth factor (VEGF).
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PMID:[Molecular targeted therapies for metastatic breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors]. 1787 54


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