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)

Tamoxifen is the most widely prescribed anti-neoplastic drug for the treatment of both localized and metastatic breast cancer. It is also the prototype for a class of drugs that are referred to as selective estrogen receptor modifiers (SERMs), most of which have both estrogenic and anti-estrogenic activity in estrogen target tissues including the breast and endometrium. The underlying mechanisms of action of SERMs in the breast and endometrium that lead to profound differences in the tissue-specific effects of tamoxifen have not yet been elucidated. We have compared the effects of tamoxifen and the pure anti-estrogen ICI 182,780 (Faslodex) in the RUCA-I hormone-responsive rat endometrial cell line in vitro and in vivo. In cell culture, RUCA-I cells responded to both estrogens and anti-estrogens, and the expression of clusterin and complement C3 mRNAs required the presence of estradiol and was repressed in the absence of estradiol or in the presence of the pure anti-estrogen ICI 182,780. Tamoxifen, on the other hand, induced both complement C3 and clusterin mRNA in the absence of estradiol and failed to repress their expression in the presence of estradiol. When grown as subcutaneous xenografts in syngeneic Da/Han rats for 5 weeks, the RUCA-I cells retained their sensitivity to estradiol, as demonstrated by significantly enhanced tumor growth in intact female rats compared with the growth in ovariectomized rats. But neither ICI 182,780 nor tamoxifen had a significant impact on tumor growth in cycling or ovariectomized animals. On the other hand, tamoxifen was potently estrogenic in metastatic lymph nodes, increasing the size of the lymph node tumors almost 6-fold over that seen in the intact cycling animals. In primary tumors, the expression of complement C3 mirrored that seen in vitro, although tamoxifen showed some agonist activity in ovariectomized animals. Tamoxifen also displayed marked agonist activity with respect to clusterin expression and enhanced clusterin mRNA levels and protein in both the primary tumors and lymph metastases in intact and ovariectomized animals. Given the recent demonstration that over-expression of clusterin increases the metastatic potential of breast cancer cells, these data may provide a mechanistic explanation for the increased incidence of endometrial cancer in postmenopausal patients treated with tamoxifen.
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PMID:Tamoxifen exerts agonistic effects on clusterin and complement C3 gene expression in RUCA-I primary xenografts and metastases but not normal uterus. 1561 55

It is clear that all available means should be taken to diagnose prostate cancer early and to use efficient therapy immediately in order to prevent prostate cancer from migrating to the bones where treatment becomes extremely difficult and cure or even long-term control of the disease is an exception. The only means of preventing prostate cancer from migrating to the bones and becoming incurable is efficient treatment at the localized stage of the disease. In fact, since radical prostatectomy, radiotherapy and brachytherapy can achieve cure in about 50% of cases, these approaches are all equally valid choices as first treatment of localized prostate cancer. However, in view of the current knowledge and available data, nowadays, androgen blockade should also be considered as first line treatment. While showing the high efficacy of hormonal therapy in localized prostate cancer, present knowledge clearly indicate that long-term treatment with the best available hormonal drugs, somewhat similar to the 5 years of Tamoxifen in breast cancer, is required for optimal control of prostate cancer. It is also clear from the data analyzed that combined androgen blockage alone could well be an efficient therapy of localized prostate cancer while it has already been recognized as the best therapy for metastatic disease. This paper presents and discusses the current knowledge available on the use and results of endocrine therapy in localized prostate cancer.
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PMID:Current status of endocrine therapy in localized prostate cancer: cure has become a strong possibility. 1570 6

Tamoxifen has been the standard of care for adjuvant endocrine therapy of early breast cancer. In postmenopausal women, data now suggest that alternative agents (aromatase inhibitors [AIs]) may have improved long-term risk:benefit profiles and thus have the potential to improve outcome. The 'Arimidex', Tamoxifen, alone or in combination (ATAC) trial has shown that anastrozole provides improved disease-free survival (DFS) and time to recurrence, significantly reduced time to distant metastases and superior overall tolerability compared with tamoxifen when used as initial adjuvant therapy. Results have already led to a reconsideration of current recommendations for adjuvant therapy. Other ongoing trials include studies that are evaluating the benefits of sequencing of endocrine agents both within the standard 5-year adjuvant treatment period and as additional therapy in the post-adjuvant period. Three recently reported trials have suggested that switching from tamoxifen to an AI after 2-3 years of treatment leads to better outcomes than 5 years of tamoxifen. Finally, the NCIC MA 17 trial has shown that switching to an AI after 5 years of tamoxifen improves DFS compared with placebo. These are momentous discoveries that have improved our biological understanding and will inevitably change the management of breast cancer in the near future.
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PMID:Adjuvant endocrine therapy in postmenopausal women with early breast cancer: where are we now? 1604 17

Significant progress has been made in the last 30 years in the adjuvant hormonal and chemo-therapeutic treatments of breast cancer. Currently, several cytotoxic agents are available for use including anthracyclines, taxanes, and cyclophosphamide, methotrexate and 5-fluorouracil (CMF) and a new class of hormonal agents, aromatase inhibitors were introduced. A greater than 50% improvement in risk of relapse and 25% absolute overall survival advantage is presently realistic for many women with lymph node-positive breast cancer who receive adjuvant therapy. Aromatase inhibitors (AI) now constitute a superior alternative to tamoxifen as adjuvant hormonal therapy in postmenopausal women with hormone receptor-positive breast cancer. Extended hormonal therapy with letrozole after completion of five-years of tamoxifen has been shown to improve survival and reduce late relapses. It has also been established that anthracycline containing combination chemotherapy is superior to CMF if the number of cycles is kept the same. Inclusion of a taxane in an anthracycline-based regimen has further improved efficacy. The schedule of administration of drugs, particularly of paclitaxel, also appears to have an impact on efficacy. On the other hand, increasing the dose of cyclophosphamide or anthracyclines above the standard dose do not appear to improve the efficacy of these regimens, whereas substandard dose are clearly inferior. Currently there are several highly effective adjuvant chemotherapy regimens, however there is no single best treatment, let alone a universally effective one. Tamoxifen was the first truly molecularly targeted agent to be used in the treatment of cancer though it took some time to understand that its benefits are restricted to hormone receptor-positive cancers only. Clinical experience shows that similar principals apply to adjuvant chemotherapy as well. Only a subset of patients with micro-metastatic disease benefit from cytotoxic therapy. A major current research effort is focused on the discovery of molecular markers that could predict who will benefit from what particular type of chemotherapy. In the near future, important clinical advances will come from the incorporation of trastuzumab into adjuvant chemotherapy regimens for patients with HER-2 amplified tumors. Results from several large randomized studies are expected shortly and will define the use of trastuzumab in this clinical setting.
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PMID:Adjuvant therapy for breast cancer. 1616 38

Nuclear metastasis-associated 1(MTA1) protein is an estrogen receptor co-repressor that regulates transcription via chromatin remodeling, and MTA1 messenger ribonucleic acid (mRNA) levels are elevated in several kinds of locally advanced and metastatic tumors relative to non-metastatic tumors. Previous studies in our laboratory mapped MTA1 into a region showing significantly lower LOH (loss of heterozygosity) in primary breast cancers with metastases compared to node-negative tumors, suggesting that epigenetic alterations of MTA1 affect metastatic potential. The present study examined immunohistochemical expression of the MTA1 protein in treated and untreated primary human breast cancers to study the relationship between MTA1 expression and clinical outcome. Node-negative tumors that overexpress MTA1 protein had recurrence risks similar to node-positive tumors. In multivariate analysis of untreated node-negative tumors, highest expression of MTA1 was associated with increased relapse risk (hazard ratio (HR)=2.72, p=0.0003 for multivariate analysis). Tamoxifen and/or anthracylcene-based chemotherapies eliminated all MTA1 associations with clinical outcome, suggesting MTA1 overexpression predicts early disease relapse, but sensitizes breast tumors to systemic therapies.
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PMID:Breast tumors that overexpress nuclear metastasis-associated 1 (MTA1) protein have high recurrence risks but enhanced responses to systemic therapies. 1624 88

Tamoxifen has been a standard adjuvant therapy, despite its limited 5-year efficacy window and risk of thromboembolism and endometrial malignancy. The potent aromatase inhibitor letrozole (Femara) has emerged as a viable alternative to tamoxifen for the treatment of advanced, metastatic breast cancer, as well as in the neoadjuvant and extended adjuvant settings. Here we describe the first efficacy and safety analysis of BIG 1-98, a large, randomized, independently conducted clinical trial designed specifically to assess and compare the efficacy of sequential or up-front use of letrozole and/or tamoxifen as adjuvant therapy for patients with early breast cancer. The analysis reported here combined the monotherapy arms of letrozole and tamoxifen with the truncated sequential arms. Patients randomized to letrozole had a 19% reduction in the risk of a disease-free survival event (hazard ratio 0.81; P=0.003), especially reducing distant metastases (hazard ratio 0.73; P=0.0012). These results establish letrozole as part of standard adjuvant therapy for postmenopausal women with endocrine-responsive breast cancer.
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PMID:The evolving role of letrozole in the adjuvant setting: first results from the large, phase III, randomized trial BIG 1-98. 1650 Feb 37

Breast cancer is the most frequently diagnosed and the second cause of cancer death in women, thus making breast cancer a most feared disease. Since breast cancer metastasizes early and it is unlikely that improvements in the treatment of metastatic disease could permit a cure in most cases in the foreseeable future, it is clear that prevention is essential in order practically to eliminate deaths from breast cancer. Tamoxifen is the only selective estrogen receptor modulator (SERM) currently registered for use in breast cancer prevention; the tamoxifen versus raloxifene study should indicate the efficacy of this compound compared with raloxifene. The recent benefits of aromatase inhibitors over tamoxifen indicate the advantages of a blockade of estrogens more complete than the one achieved with tamoxifen, a SERM having some estrogenic activity in the mammary gland and an even higher estrogenic action in the uterus. However, it is unlikely that the general estrogen ablation achieved with aromatase inhibitors will be acceptable for the long-term use required for prevention. It is thus important to develop SERMs with highly potent and pure antagonistic activity in the mammary gland and uterus while possessing estrogen-like activity in tissues of particular importance for women's health, namely the bones and the cardiovascular system. However, it is expected that a SERM alone will not meet all the requirements of women's health at the postmenopause when ovarian estrogen secretion has ceased and peripheral formation of androgens and estrogens from DHEA by intracrine mechanisms is decreased by 60% or more. One possibility is to combine a SERM with DHEA, a precursor of sex steroids that permits, somewhat like SERMs, tissue-specific formation of androgens and/or estrogens according to the level of expression of the steroidogenic and steroid-inactivating enzymes. DHEA could thus compensate for the important loss of androgens that accompanies aging and could also permit sex steroid formation and action in the brain while breast cancer prevention would be achieved by the SERM.
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PMID:Future perspectives of selective estrogen receptor modulators used alone and in combination with DHEA. 1672 67

Aggressive fibromatoses, also known as desmoid tumours, are rare fibrous tissue proliferations with a tendency for slow, local infiltrative growth. There is an association with Gardner's syndrome and familial adenomatous polyposis. Histologically they are fairly bland with no abnormal mitoses or necrosis. They do not metastasize, but can cause significant morbidity through their locally destructive effects. Magnetic resonance imaging is the method of choice for diagnosis, pre-treatment planning and post-treatment follow-up. Surgical excision with a wide margin is the treatment of choice. However, there is a tendency for local recurrence and repeated excision may result in a poor functional or cosmetic outcome. Radiotherapy is used to reduce local recurrence rates after excision and is also used to treat inoperable tumours. Long-lasting remissions can be obtained. Treatment is now planned using modern three-dimensional conformal techniques, similar to those used in soft tissue sarcoma management. There is no definite dose-response relationship, but doses of 50-60 Gy in 1.8-2 Gy fractions are recommended. Systemic therapy has been used for lesions not controlled by surgery or radiotherapy, or less commonly, as a primary treatment. Tamoxifen and non-steroidal anti-inflammatory agents are used most often as they are relatively non-toxic, but there is limited experience with cytotoxic chemotherapy and biological agents. There are no randomised trials to help guide the management of this locally aggressive 'benign' tumour and treatment decisions are best made by the local soft tissue sarcoma multidisciplinary team.
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PMID:Fibromatosis: benign by name but not necessarily by nature. 1741 39

The Stockholm Breast Cancer Study Group conducted a randomized trial during 1976 through 1990 comparing adjuvant tamoxifen versus control. A total of 2,738 postmenopausal women with invasive, early stage disease were randomised between tamoxifen for 2 or 5 years, or no adjuvant endocrine therapy. Among high-risk patients the treatment was given against a background of either postoperative, locoregional radiation or CMF-type chemotherapy. The median follow up was 18 years (range 11-25 years). There was a statistically significant (p =0.001) interaction between ER status and tamoxifen with no treatment benefit among receptor negatives. PgR-status had little additional predictive value. Among ER-positive patients tamoxifen reduced locoregional recurrences by 48%, contralateral breast cancers by 54%, distant metastases by 28%, and all events by 24% (p <0.001). On the other hand, there was a substantial increase of endometrial cancer associated with tamoxifen. There was no effect of tamoxifen on intercurrent mortality whereas breast cancer deaths were reduced by 31% (p <0.001) and overall mortality by 15% (p =0.01). Tamoxifen produced long-term benefits among estrogen receptor positive patients in terms of breast cancer-related events, but also an increased incidence of endometrial cancer. Despite long-term follow-up we observed no benefit with tamoxifen in terms of cardiovascular mortality.
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PMID:Long-term follow-up of the randomized Stockholm trial on adjuvant tamoxifen among postmenopausal patients with early stage breast cancer. 1745 61

State of the art hormonal therapy for women with breast cancer has evolved over the last few years. Tamoxifen used to be the gold standard for adjuvant treatment of postmenopausal women with hormone-sensitive early breast cancer and also for patients with metastatic disease in whom hormonal manipulation was considered, but the introduction of third generation aromatase inhibitors has changed this concept. This article discusses the clinical implications of recent trials with one of the aromatase inhibitors letrozole, including pharmacokinetic and pharmacodynamic data as well as recent data on relative benefits and side effects compared with other available hormonal agents. Relevant ongoing clinical-translational trials evaluating this agent are also discussed.
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PMID:Letrozole: present and future role in the treatment of breast cancer. 1769 97


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