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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Breast cancer is the most common malignancy in woman in the USA. Metastasis is a major cause of morbidity and mortality in breast cancer patients. Total incidence of brain metastases of breast cancer is about 30%. Because of the improvements in control of systemic disease, for example the successful use of Trastuzumab, and the consequent prolonged life span, the incidence of brain metastases is increasing in breast cancer patients. The progressive neurological disabilities not only impair the quality of life, but also decrease the survival in patients. However, current treatments are of limited effectiveness. This is partially caused by the unique structure of the blood brain barrier. So far very little is known about the mechanisms how breast cancer metastizes to the brain. Some studies showed that ErbB2 overexpression is associated with the brain metastatic phenotype. Other molecules, like vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs) and chemokine receptor CXCR4 are also involved in the metastasis of breast cancer cell to the brain. The current review will briefly overview the clinical features of brain metastasis of breast cancer and discusses the relationship of blood brain barrier and ErbB2 signal pathway to brain metastasis in breast cancer.
Cancer Metastasis Rev 2007 Dec
PMID:Breast cancer brain metastases. 1771 35

Overexpression of the epidermal growth factor receptor family member HER2 is found in approximately 30% of breast cancers and is a target for immunotherapy. Trastuzumab, a humanized monoclonal antibody against HER2, is cytostatic when added alone and highly successful in clinical settings when used in combination with other chemotherapeutic agents. Unfortunately, HER2 tumors in patients develop resistance to trastuzumab or metastasize to the brain, which is inaccessible to antibody therapy. Previously, we showed that the green tea polyphenol epigallocatechin-3 gallate (EGCG) inhibits growth and transformed phenotype of Her-2/neu-driven mouse mammary tumor cells. The different modes of action of EGCG and trastuzumab led us to hypothesize that EGCG will inhibit HER2-driven breast cancer cells resistant to trastuzumab. We studied trastuzumab-resistant BT474 human breast cancer cells, isolated by chronic trastuzumab exposure, and JIMT-1 breast cancer cells, derived from a pleural effusion in a patient who displayed clinical resistance to trastuzumab therapy. EGCG treatment caused a dose-dependent decrease in growth and cellular ATP production, and apoptosis at high concentrations. Akt activity was suppressed by EGCG leading to the induction of FOXO3a and target cyclin-dependent kinase inhibitor p27Kip1 levels. Thus, EGCG in combination with trastuzumab may provide a novel strategy for treatment of HER2-overexpressing breast cancers, given that EGCG can cross the blood-brain barrier.
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PMID:Trastuzumab-resistant HER2-driven breast cancer cells are sensitive to epigallocatechin-3 gallate. 1790 3

A few years back, the survival benefit of trastuzumab in HER 2 positive breast cancer patients presenting with metastatic disease was proven in a randomized setting. Recently a number of randomized trials have reported their results in the adjuvant setting in HER 2 positive patients. These trials have been considered by some as a landmark in the evolution of breast cancer management. Although the data is encouraging, it need to be seen in a proper perspective keeping in mind the limitations and the side effects reported. This article stresses the use of Herceptin in carcinoma breast patients in adjuvant setting with a cautionary eye.
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PMID:Trastuzumab: is the new evidence revolutionary? 1799 95

Trastuzumab is the first of the monoclonal antibodies to be used in the treatment of those patients who have HER2-positive metastatic breast cancer. It is most effective when combined with cytotoxics, such as the taxanes and vinorelbine. It is well-tolerated but associated cardiotoxicity makes use with anthracyclines and in patients with cardiac dysfunction problematic. A further adverse observation is that the rate of development of cerebral metastases is 2.8-times higher in patients who have received trastuzumab as part of their treatment regimens. Trastuzumab has been combined with cytotoxics, hormones, other monoclonal antibodies, such a pertuzumab and bevacizumab, and targeted small molecules such as lapatinib, and it can be conjugated with cytotoxics to deliver them to cancer cells. The dosage, duration of therapy and optimal combinations in advanced and early stage breast cancer and use after relapse are still being defined.
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PMID:Trastuzumab as the lead monoclonal antibody in advanced breast cancer: choosing which patient and when. 1824 Oct 7

Introduction Trastuzumab is a highly effective therapy for the treatment of HER-2/neu positive breast cancer. To maximize benefit and minimize unnecessary toxicity, patient selection is essential. Currently HER-2/neu analysis is routinely performed only for primary invasive breast cancers, and trastuzumab therapy is recommended based on primary analysis only. Methods Using immunohistochemistry, we performed a retrospective study comparing HER-2/neu expression in original primary to subsequent metastatic breast cancers. Results Tumors from 382 patients with metastatic breast cancer were studied. In 254 cases (66%) both primary and metastatic lesions were concordant. In 90 cases the primary lesion was HER-2/neu positive with the metastatic lesion negative; whereas, in 37 cases the primary lesion was HER-2/neu negative and the metastatic lesion positive. Primary HER-2/neu immunostaining was associated with a negative predictive value of 35.7%. Although all four groups were similar at diagnosis, survival differences were noted with the best survival experienced by patients with initial primary lesions HER-2/neu negative and subsequent metastatic lesions positive. Patients with hormone receptor and HER-2/neu positive primary lesions who received tamoxifen were more likely to have HER-2/neu positive metastasis. Conclusions The significant discordance between HER-2/neu expression in primary and metastatic tumors suggests that determination of HER-2/neu status in metastatic disease should be attempted.
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PMID:HER-2/neu expression in primary and metastatic breast cancer. 1827

The HER2/neu (HER2) gene is a member of a family of genes which has been implicated in cancer. These four genes, HER1/EGFR, HER2, HER3 and HER4 encode for transmembrane proteins that are involved in the regulation of cell proliferation, differentiation and survival. Amplification of HER2 occurs in 20%-25% of breast cancers and is associated with an aggressive tumor phenotype and poor prognosis. Results from five randomized, phase III clinical trials have recently demonstrated that trastuzumab (Herceptin) significantly improves disease free survival and overall survival when used in conjunction with chemotherapy for early stage HER2-positive breast cancer. Despite adjuvant trastuzumab, approximately 15% of patients with early stage disease recur, and those with metastatic disease eventually become resistant to therapy. Novel treatment approaches are needed for patients who have either intrinsic or acquired resistance to trastuzumab. This article reviews the role of trastuzumab in managing early and advanced stage HER2-positive disease, the role of lapatinib (Tykerb) in trastuzumab resistant disease, and the novel agents in development targeting mechanisms of trastuzumab resistance.
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PMID:Targeting the human epidermal growth factor receptor 2 (HER2) in the treatment of breast cancer: recent advances and future directions. 1847 95

Breast cancer is the second leading cause of cancer-related death in women in the United States, and for nearly all with metastatic disease at presentation or relapse it will be incurable. The goals of therapy are to optimize quality of life and, if possible, prolong time to progression of disease and death. For a select group of patients an aggressive surgical approach may be considered. Initial palliation with endocrine therapy should be the primary consideration for patients with metastatic hormone receptor-positive tumors. Cytotoxic chemotherapy is appropriate for those with hormone-refractory disease, rapidly progressive visceral disease, or early relapse after adjuvant therapy. If a tumor overexpresses HER2, targeted treatment with trastuzumab (Herceptin) or lapatinib (Tykerb) is possible. Consequently, accurate determination of the status of these predictive markers in tissue (possibly from a recurrence site) is key. Other novel agents are adding to the wide choices of standard chemotherapies already available. This review offers an approach to the selection of individualized and rational therapies for patients with metastatic breast cancer.
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PMID:Therapeutic options in the management of metastatic breast cancer. 1856 51

Trastuzumab is a monoclonal antibody that targets the extracellular domain of HER2, a member of the epidermal growth factor receptor (EGFR) family. Trastuzumab is currently approved for the treatment of breast cancer overexpressing HER2, given alone or in combination with paclitaxel or docetaxel. Trastuzumab pharmacokinetics are characterized by a low systemic clearance, a low volume of distribution (4l) and a very long half-life (28 days) comparable to that of endogenous immunoglobulins G. The elimination pathways are not yet defined and the clinical relevance of trastuzumab kinetic variability is unknown. Whether exposure might correlate with toxic effects or inadequate response has not been explored. No drug-drug interactions have been reported. This is not surprising because based on the current knowledge, no monoclonal antibody (including trastuzumab) has been found to interact with major molecular pharmacokinetic determinants such enzymes, drug transporters or orphan nuclear receptors. Dosage regimens of trastuzumab are similar either it is used in the adjuvant setting (postoperative) or in metastatic disease. According to the official labelling, trastuzumab is given by intravenous perfusion at a dose based on body weight, weekly (metastatic, adjuvant) or 3-weekly (adjuvant). The schedule also includes a loading dose at the initiation of the treatment. The recommended duration of treatment is currently one year (adjuvant) or until the progression of the disease (metastatic). Regarding the adjuvant setting, different dosage regimens have been tested (from 9 weeks to 2 years) but the optimal duration of treatment is unknown. The short course of trastuzumab (9 weeks) appears promising in terms of activity, tolerance and cost but should be compared to 1 or 2-years treatments. In addition, dosing regimens might be optimized by integrating pharmacokinetic elements. In the adjuvant setting, given the more favorable kinetic situation (absence of tumor penetration), a less intense dosage regimen might be appropriate when compared with that used in metastatic disease. Further body weight is weakly related to trastuzumab exposure and it is not proven that it significantly affects clinical activity. These pharmacokinetic considerations may support the use of fixed doses given monthly, on short periods, for the treatment of early breast cancer.
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PMID:Clinical pharmacology of trastuzumab. 1869 Aug 78

Current techniques to assess lymph node metastases in cancer patients include lymphoscintigraphy after administration of a nonspecific radiocolloid in order to locate and resect lymph nodes for pathological examination of harbored cancer cells. Clinical trials involving intradermal or subcutaneous injection of antibody-based nuclear imaging agents have demonstrated the feasibility for target-specific, molecular imaging of cancer-positive lymph nodes. The basis for employing near-infrared (NIR) optical imaging for assessing disease is evidenced by recent work showing functional lymph imaging in mice, swine, and humans. We review antibody-based immunolymphoscintigraphy with an emphasis on the use of trastuzumab (or Herceptin) to target human epidermal growth factor receptor-2 (HER2) overexpressed in some breast cancers. Specifically, we review in vitro and preclinical imaging data from our laboratory that show how the dual-labeled agent ((111)In-DTPA)(n)-trastuzumab-(IRDye800)(m) utilizes the high photon count provided by an NIR fluorescent dye, IRDye 800CW, and the radioactive signal from a gamma emitter, Indium-111, for possible detection of HER2 metastasis in lymph nodes. We show that the accumulation and clearance of ((111)In-DTPA)(n)-trastuzumab-(IRDye800)(m) from the axillary nodes of mice occurs 48 h after intradermal injection into the dorsal aspect of the foot. The requirement for long clearance times from normal, cancer-negative nodes presents challenges for nuclear imaging agents with limited half-lives but does not hamper NIR optical imaging.
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PMID:Near infrared fluorescent optical imaging for nodal staging. 1902 20

HER2 positive breast cancers are characterized by their aggressive course of disease. Treatment with trastuzumab has significantly improved survival of patients with these cancers. Trastuzumab has few side effects, although in 10-15% of cases it is necessary to interrupt therapy because of cardiotoxicity, in most cases temporarily. It has become clear that patients receiving trastuzumab more frequently develop brain metastases than patients with a HER2 negative tumor. It is important to realize that patients with brain metastases from a HER2 positive breast tumor have a more favorable prognosis than patients with brain metastases from a HER2 negative tumor. Continuation of treatment with trastuzumab should be considered, next to the surgical intervention and/ or radiotherapy. Recently, lapatinib, a tyrosine kinase inhibitor, was registered by EMEA for patients with a HER2 positive tumor after previous treatment with anthracyclines, taxanes and trastuzumab. In combination with capacitabine, this agent leads to partial responses of cerebral metastases. More HER2 targeting drugs are expected to be introduced.
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PMID:[Brain metastases in breast cancer: a special disease course for HER2 positive tumors]. 1919 81


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