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)

Fulvestrant (Faslodex) is a novel estrogen receptor (ER) antagonist that competitively binds to the ER with a much greater affinity than that of tamoxifen. The downregulation of cellular levels of the ER protein results in complete abrogation of estrogen-sensitive gene transcription. This distinct mechanism of action ensures a lack of cross resistance with other hormonal agents and, in contrast to tamoxifen, fulvestrant has no known estrogen-agonist effects. Fulvestrant is administered via monthly intramuscular injections (250mg) and is recommended for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. The efficacy of fulvestrant was similar to that of the aromatase inhibitor anastrozole (1 mg/day) in two, well designed studies in postmenopausal women with locally advanced or metastatic breast cancer that had progressed during prior antiestrogen therapy. Time to disease progression (primary endpoint) and treatment failure, rates of objective response and clinical benefit, overall survival and quality of life were similar in patients treated with fulvestrant or anastrozole. In retrospective noninferiority analyses, fulvestrant was at least as effective as anastrozole in all randomised patients, and in those with or without visceral metastases. Fulvestrant is generally well tolerated and was tolerated as well as anastrozole in clinical trials. Treatment-related adverse events were mostly mild to moderate and led to treatment withdrawal in about 1% of patients who received fulvestrant or anastrozole. The main adverse effects associated with therapy are nausea, asthenia, pain, vasodilation and headache.In conclusion, monthly intramuscular injections of fulvestrant are at least as effective and as well tolerated as oral anastrozole once daily in the treatment of postmenopausal women with advanced breast cancer that has progressed on prior antiestrogen therapy. Because of a different mode of action to that of other hormonal agents, fulvestrant is effective in the treatment of tamoxifen-resistant disease and, unlike tamoxifen, has no known estrogen agonist effects. Thus, fulvestrant provides an effective and well tolerated option for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.
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PMID:Fulvestrant: a review of its use in hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. 1501 96

Breast cancer represents a major health problem, with more than 1,000,000 new cases and 370,000 deaths yearly worldwide. In the last decade, in spite of an increasing incidence, breast cancer mortality has been declining in the majority of developed countries. This is the combined result of better education, widespread screening programmes and more efficacious adjuvant treatments. Better knowledge of breast cancer biology now allows the cosmetic, physical and psychological consequences of radical mastectomy to be spared in the majority of breast cancer patients. Use of the sentinel node technique is rapidly expanding and this will further reduce the extent and the consequences of surgery. Several clinico-pathological factors are used to discriminate between patients at low (<10%), average (10-40%) and high risk of relapse. Nodal status, tumour size, tumour grade and age are accepted universally as important factors to define risk categories. Newer factors such as uPA/PAI-1, HERer2-neu, proliferative indices and gene expression profile are promising and will allow better discrimination between patients at different risk. Endocrine manipulation with tamoxifen, ovarian ablation or both is the preferred option in the case of endocrine-responsive tumours. Tamoxifen administered for 5 years is the standard treatment for postmenopausal patients; tamoxifen plus ovarian ablation is more effective than tamoxifen alone for premenopausal women. Recent data demonstrate that, for postmenopausal patients, the aromatase inhibitors are superior to tamoxifen, with a different safety profile. At present, anastrozole can be used in the adjuvant setting in cases of tamoxifen intolerance or toxicity. Chemotherapy is the treatment of choice for steroid receptor-negative tumours. Polychemotherapy is superior to single agents and anthracycline-containing regimens are superior to CMF. Six courses of FEC or FAC or the sequential administration of four doses of anthracycline followed by four of CMF are the recommended regimens. New regimens including the taxanes have produced a further improvement in risk reduction and are reasonable therapeutic options. The taxanes have been approved for adjuvant therapy in the USA, while European approval is pending. Combined endocrine-chemotherapy is the standard adjuvant treatment in high-risk patients with endocrine-responsive tumours. Endocrine manipulation is usually administered after completion of the chemotherapy programme. For HER2-neu overexpressing tumours, several rapidly accruing trials are exploring the potential additive effect of trastuzumab, a monoclonal antibody directed against the extramembrane portion of the HER2 receptor. Primary chemotherapy is increasingly used in the treatment of locally advanced and operable breast cancer, with increased rates of breast-conserving surgery. A proportion of patients achieve a pathological complete response and these patients have significantly better long-term outcomes. Twenty-five to forty percent of breast cancer patients develop distant metastases. At this stage the disease is incurable; however, treatments can assure a significant prolongation of survival, symptomatic control and maintenance of quality of life. In the case of hormone receptor positivity and in the absence of visceral, life-threatening disease, endocrine manipulation is the treatment of choice. Active treatments include tamoxifen, ovarian ablation, aromatase inhibitors, pure anti-oestrogens and progestins. Aromatase inhibitors are the most active agents, but the choice and the sequence of endocrine therapies are also dictated by prior adjuvant treatment. Chemotherapy has to be preferred in cases of receptor-negative tumours, acquired resistance to hormones and aggressive visceral disease. Combination regimens are usually associated with higher response rates and sometimes survival prolongation, and this approach should be recommended in young patients with good performance status and visceral disease. On the other hand, single agents have a better tolerability profile and should be tand should be the treatment of choice when a careful balance between activity and tolerability is needed. For HER2-neu positive tumours, the combination of trastuzumab and chemotherapy is significantly superior to chemotherapy alone in terms of both response rates and survival. Other useful palliative treatments include bisphosphonates for the control of metastatic bone disease and radiotherapy for painful bone lesions or local relapses.
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PMID:The curability of breast cancer and the treatment of advanced disease. 1510 48

Over the last few decades, there have been unprecedented advances in the multidisciplinary management of breast cancer. Surgical principles have shifted away from the Halstedian concept of radical surgery towards more cosmetic breast-conserving procedures, and advances have been made in terms of oncologic and plastic surgical techniques for those opting for mastectomy and reconstruction. Sentinel lymph node biopsy has revolutionized the evaluation of patients' nodal status and has become widely accepted as "state of the art." Medical oncology has made tremendous advances and is no longer relegated to the patients with metastatic disease. It is well accepted that chemotherapy may play a role even in patients with small tumors. Certainly the impact of neoadjuvant chemotherapy for downsizing tumors and making them amenable for breast conservation is also widely accepted. The advent of anthracyclines and, more recently, taxane-based regimens has had a substantial impact on the management of breast cancer. In addition, newer hormonal therapies such as the aromatase inhibitors have rivaled the classic cornerstone of tamoxifen. Radiation therapy has evolved from the era of cobalt-based therapy to newer, less morbid, techniques. In addition to advances in external beam radiation, the concept of accelerated partial breast irradiation and intraoperative radiation therapy is evolving and continues to be the focus of research endeavors. The unparalleled advances in the management of breast cancer in the fields of surgical, medical, and radiation oncology over the last half century continue today with ongoing research and clinical trials. As we enter the new millennium, breast cancer management will continue to evolve.
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PMID:Advances in the management of localized breast cancer: an overview. 1548 7

Several studies have suggested that cyclooxygenase-2 (COX-2) expression is associated with parameters of aggressive breast cancer, including large tumor size, positive axillary lymph node metastases, and HER2-positive tumor status. Studies of mammary tumors in mice and rats have indicated that moderate to high COX-2 expression is related to the genesis of mammary tumors that are sensitive to treatment with nonspecific and specific COX-2 inhibitors. Moreover, these studies also suggest that mammary tumors are associated with high prostaglandin levels and induction of aromatase, a cytochrome P450 enzyme that catalyses estrogen production. Mechanistically, lack of apoptosis and increased angiogenesis and invasiveness have been implicated as mechanisms of tumor growth in COX-2-dependent mammary tumors. Based on these observations, clinical trials are evaluating adjunctive therapy with a selective COX-2 inhibitor, celecoxib, in combination with several regimens used in the metastatic and adjuvant or neoadjuvant settings of breast cancer. In addition, proof-of-principle trials are being conducted to ascertain the effects of celecoxib on known markers of proliferation, angiogenesis, and apoptosis. Finally, based on the apparent synergy between celecoxib and the aromatase inhibitor exemestane, the National Cancer Institute of Canada Clinical Trials Group is launching a phase III trial comparing exemestane with or without celecoxib against placebo in postmenopausal women with elevated risk of breast cancer. Results of these trials will help to define the role of celecoxib in the management and prevention of breast cancer. Epidemiologic evidence suggests the incidence of breast, colon, and lung cancers is inversely related to the use of aspirin and nonsteroidal anti-inflammatory drugs, which are nonspecific inhibitors of COX. COX-1 and COX-2 are enzymes that generate prostaglandins and thromboxanes from free arachidonic acid. Genetic approaches pursued in animal models and biochemical evidence obtained from human tumor cell lines have strongly implicated COX-2, an inducible enzyme, in many preinvasive and invasive human tumors. In this article we will first review data that point to COX-2 as an important indicator in the genesis of breast cancer and discuss planned and ongoing clinical trials evaluating specific COX-2 inhibitors in the treatment and prevention of breast cancer.
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PMID:The role of COX-2 inhibition in breast cancer treatment and prevention. 1517 21

The role of adjuvant tamoxifen therapy has gone unchallenged until recently. With the introduction of the selective aromatase inhibitors (AIs), the paradigm for treatment of hormone receptor-positive breast cancer in postmenopausal women is changing. New data from randomized clinical trials have shown the impact of the use of an AI compared with tamoxifen or in sequence with tamoxifen. This review will emphasize some of the highlights from these data sets and the limitations of our current knowledge. Finally, we will discuss the implications of the use of nonselective AIs in the adjuvant setting for the patient who develops recurrent metastatic disease.
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PMID:Implications of first-line adjuvant treatment with aromatase inhibitors in recurrent metastatic breast cancer. 1534 36

Enhancement of the therapeutic effect of conventional drugs is currently an active treatment strategy for breast cancer, as shown in the clinical application of trastuzumab with chemotherapeutic agents, which prolonged survival even for metastatic disease. Cyclo-oxygenase 2(COX-2)inhibitors, which are chemoprevention agents for familial polyposis coli, are now contributing to this strategy in combination with chemotherapeutic and endocrine drugs. As an endocrine application, overexpression of COX-2 contributes to increased expression of aromatase in the breast tumor. In addition, it is also known to promote rich micro-vessels within the tumor through up-regulation of prostaglandin E2(PGE2), which can induce vascular endothelial growth factor(VEGF)and basic fibroblast growth factor(bFGF)in cancer cells, and can directly modulate endothelial cell proliferation. Since both rich vasculature and accelerated estrogen synthesis are thought to contribute to unfavorable conditions for the response to endocrine therapy, inhibiting COX-2 with COX-2 inhibitors is a promising strategy to potentiate endocrine therapy.
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PMID:Novel sensitizing agents: potential contribution of COX-2 inhibitor for endocrine therapy of breast cancer. 1555 Aug 58

Fulvestrant ('Faslodex') is a new estrogen receptor (ER) antagonist that has no agonist effects. It binds, blocks and accelerates degradation of the ER, leading to a complete abrogation of estrogen-sensitive gene transcription. In postmenopausal women with advanced breast cancer progressing on prior endocrine therapy, fulvestrant is at least as effective as the third-generation aromatase inhibitor (AI) anastrozole. In this single-center experience, 42 postmenopausal patients with metastatic breast cancer who had been heavily pretreated with prior endocrine therapy and chemotherapy were treated with fulvestrant. Prior endocrine therapies included selective ER modulators (including tamoxifen and toremifene), AIs, megestrol acetate, and high-dose estrogens. In total, eight patients (19%) achieved stable disease (SD) for > or =24 weeks, including two patients with SD for 2 years and one with SD for 14 months. Fulvestrant was well tolerated with the majority of adverse events related to the site of metastatic disease. These data demonstrate that fulvestrant is a well tolerated and effective endocrine therapy for postmenopausal women with metastatic breast cancer who have been heavily pretreated with prior therapies. The novel mechanism of action of fulvestrant reduces the likelihood of cross-resistance with other endocrine therapies and therefore this agent may be active in patients who have proved to be resistant to treatments such as tamoxifen or AIs. The use of fulvestrant earlier in the sequence of endocrine treatments may achieve better responses than observed in this heavily pretreated patient population.
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PMID:Response to fulvestrant in heavily pretreated postmenopausal women: a single-center experience. 1556 93

Metastasis, the main reason for high mortality of cancer, is a multistep process. One important step in this process is the adhesion of tumor cells to vascular endothelium at sites distant from primary tumors during hematogenous dissemination. In order to investigate and quantify the adhesion of tumor cells to endothelial cells we developed an in vitro model using MCF-7 breast cancer cells and monolayers of human umbilical vein endothelial cells (HUVEC). The tumor cells were specifically labeled with a fluorescent dye for quantification; for increasing the amount of adherent cells, HUVEC monolayers were stimulated with phorbol ester before the addition of the tumor cells. Due to previous reports that products of several P450 enzymes contribute to the progression of certain kinds of cancer, inhibitors of CYP5 (thromboxane A(2) synthase), CYP17 (17alpha-hydroxylase-C17, 20-lyase), and CYP19 (aromatase) were tested in this in vitro model for their potency to reduce cancer cell adhesion. Within each series of P450 inhibitors, compounds with high inhibitory activity on tumor cell adhesion were identified. At an initial concentration of 100 microM, BW26, a potent inhibitor of CYP5, reduced tumor cell adhesion of MCF-7 to HUVECs to 15%, BW40 (CYP17) to 29%, and SU5a (CYP19) to 11% of the corresponding controls (no inhibitor). Reduction of tumor cell adhesion was shown to occur in a concentration-dependent manner. In addition to these inhibitors of CYP5, CYP17, and CYP19, liarozole, known to be a potent inhibitor of CYP26 (retinoic acid-4-hydroxylase) and ATRA (all-trans-retinoic acid) metabolism, was able to reduce tumor cell adhesion to 51% of the initial rate. Experiments elucidating the mode of action of these compounds revealed that inhibition of the mentioned CYP enzymes is not responsible for their ability to reduce tumor cell adhesion.
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PMID:Discovery of inhibitors of MCF-7 tumor cell adhesion to endothelial cells and investigation on their mode of action. 1559 2

The standard adjuvant endocrine treatment for postmenopausal women with hormone-receptor-positive localised breast cancer is 5 years of tamoxifen, but recurrences and side-effects restrict its usefulness. The aromatase inhibitor anastrozole was compared with tamoxifen for 5 years in 9366 postmenopausal women with localised breast cancer. After a median follow-up of 68 months, anastrozole significantly prolonged disease-free survival (575 events with anastrozole vs 651 with tamoxifen, hazard ratio 0.87, 95% CI 0.78-0.97, p=0.01) and time-to-recurrence (402 vs 498, 0.79, 0.70-0.90, p=0.0005), and significantly reduced distant metastases (324 vs 375, 0.86, 0.74-0.99, p=0.04) and contralateral breast cancers (35 vs 59, 42% reduction, 12-62, p=0.01). Almost all patients have completed their scheduled treatment, and fewer withdrawals occurred with anastrozole than with tamoxifen. Anastrozole was also associated with fewer side-effects than tamoxifen, especially gynaecological problems and vascular events, but arthralgia and fractures were increased. Anastrozole should be the preferred initial treatment for postmenopausal women with localised hormone-receptor-positive breast cancer.
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PMID:Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. 1581 48

The development of the novel third-generation aromatase inhibitors and inactivators for breast cancer treatment is one of the most successful contemporary achievements in cancer therapy. Parallel to studies evaluating toxicity and clinical efficacy in metastatic disease, the endocrine effects of multiple compounds were evaluated, leading to the identification of the highly potent third-generation aromatase inhibitors based on estrogen deprivation and aromatase inhibition in vivo. Thus, translational studies have been of vital importance identifying the unique characteristics of these compounds. Whereas first- and second-generation aromatase inhibitors inhibit estrogen synthesis in vivo by up to 90%, the third-generation compounds anastrozole, exemestane, and letrozole were found to cause > or =98% aromatase inhibition. This article summarizes and discusses the "translational research" that provided the background for the implementation of the third-generation aromatase inhibitors and inactivators into large clinical trials. The need for future translational research exploiting the mechanisms of resistance to these compounds for future improvement of endocrine therapy is emphasized.
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PMID:Aromatase inhibition: translation into a successful therapeutic approach. 1583 28


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