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 has been the gold standard of endocrine therapy for postmenopausal patients with hormone receptor-positive breast cancer for over 20 years. The development of the third-generation aromatase inhibitors anastrozole, letrozole, and exemestane is changing the algorithm for the treatment of the disease. Recent clinical trials have shown that all three third-generation aromatase inhibitors present significant advantages over traditional progestins and aminoglutethimide therapy after tamoxifen failure in postmenopausal women. These new agents are now accepted as first choice for second-line treatment of metastatic disease. Since 2000, phase III trials with anastrozole and letrozole have shown that third-generation aromatase inhibitors are at least as effective as tamoxifen in the first-line treatment of postmenopausal women with hormone receptor-positive or -unknown metastatic breast cancer. The first-line phase III trial of letrozole versus tamoxifen which, unlike the anastrozole trials, was prospectively designed to test superiority of the aromatase inhibitor, showed that this agent was superior to tamoxifen in all assessed outcome measures. A first-line phase III trial of exemestane versus tamoxifen in postmenopausal patients with hormone receptor-positive or -unknown advanced breast cancer is ongoing. The data presented in this article suggest that aromatase inhibitors may replace tamoxifen in the first-line hormonal management of this disease in postmenopausal women.
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PMID:The role of aromatase inhibitors in the treatment of metastatic breast cancer. 1451 35

The use of adjuvant endocrine therapy in the treatment of hormone receptor-positive, early breast cancer has become important in both pre- and postmenopausal women. Tamoxifen has been the principal adjuvant hormonal therapy in pre- and postmenopausal women with hormone receptor-positive breast cancer for nearly 20 years. Recent data in premenopausal women suggest benefit from ovarian ablation with or without tamoxifen. Early results from the 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial have demonstrated that the third-generation, selective aromatase inhibitor (AI) anastrozole ('Arimidex') is a suitable alternative adjuvant therapy for postmenopausal women with hormone receptor-positive disease. After recurrence or relapse on adjuvant endocrine therapy, responses to the sequential use of additional endocrine agents are common. The increase in the number of options now available for adjuvant therapy will have important implications for the selection of the optimal sequence of endocrine agents in the treatment of recurrent breast cancer. Menopausal status is an important factor in determining the endocrine therapy that a patient receives. For premenopausal women, tamoxifen and/or a luteinizing hormone-releasing hormone agonist such as goserelin ('Zoladex') are both options for adjuvant endocrine treatment. After progression on adjuvant and first-line tamoxifen, ovarian ablation is an appropriate second-line therapy. For premenopausal women who have undergone ovarian ablation, the use of third-line therapy with an AI becomes possible. For postmenopausal women, a wide choice of endocrine treatment options is available and an optimal sequence has yet to be determined. Options for first-line therapy of metastatic disease include an AI for women who have received adjuvant tamoxifen or tamoxifen for patients who have received adjuvant anastrozole. In addition, data suggest that fulvestrant ('Faslodex'), a novel estrogen receptor (ER) antagonist that downregulates the ER protein and has no known agonist effects, is a promising therapeutic option that has shown efficacy in the treatment of postmenopausal women with advanced breast cancer. Other agents that may be used in the sequence include the steroidal AI exemestane and the progestin megestrol acetate. The widening range of adjuvant endocrine options therefore represents an opportunity to prolong patient benefits in the treatment of hormone receptor-positive breast cancer, and will require the further refinement of the optimal sequence of endocrine agents for the treatment of recurrent breast cancer.
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PMID:Sequential hormonal therapy for metastatic breast cancer after adjuvant tamoxifen or anastrozole. 1453 31

Tamoxifen has contributed to a dramatic reduction in breast cancer mortality and recent results indicate that aromatase inhibitors may further improve survival in some patients. Nevertheless, a substantial proportion of patients become resistant to treatment. To date, with the exception of estrogen receptor (ER) determination by ligand binding or immunohistochemical techniques, there has been no way of predicting which of several therapies is indicated in particular patients. We describe a novel assay using the adenoviral gene delivery system to assess ER function in breast cancer cells derived directly from patients. The purification and short-term culture of these cells has been recently described by our laboratory. Adenovirus containing an estrogen-regulated beta-galactosidase reporter gene (ERE-lacZ) was constructed and used to test ER activity in breast cancer cells derived from 18 patients with primary and 16 patients with metastatic cancer, under varying treatment schedules. The adenoviral assay enabled ER activity to be readily determined in purified cells from primary breast cancers and secondary sites. Breast cancers cells could be categorized on the basis of ER activity in the absence of ligand, the presence of estrogen or anti-estrogens. In primary breast cancers, our results correlated with ER determination by immunohistochemistry in 78% of cases. In patients who had become resistant to tamoxifen, however, we found some in whom reporter activity was stimulated by tamoxifen and others whose tumors were either still estrogen responsive or completely unresponsive, irrespective of the original ER content. Our findings indicate that this reporter assay could be useful in decisions regarding use of adjuvant endocrine therapies in breast cancer.
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PMID:Reporter gene assay demonstrates functional differences in estrogen receptor activity in purified breast cancer cells: a pilot study. 1456 18

Aromatase inhibitors are proving to be more effective than tamoxifen for postmenopausal patients with breast cancer. Estrogen concentrations in the breast are similar in both premenopausal and postmenopausal women, and several fold higher than circulating levels in postmenopausal women. In order to investigate the importance of intratumoral aromatase in stimulating the proliferation of the tumor, we used immunocytochemistry to determine the extent of aromatase expression in relationship to the response of the patient to aromatase inhibitor treatment. The relationship between positive staining for aromatase in the primary tumor and response to treatment with an aromatase inhibitor was investigated in a retrospective study of 102 patients with advanced breast cancer. Immunohistochemical staining using a monoclonal antibody against aromatase was performed on paraffin embedded tumor tissue. Response was evaluated using UICC criteria. Nine out of 13 patients with objective response to treatment stained positive and 49 of 89 patients with stable or progressive disease stained positive. No significant relationship between positive staining and objective response to treatment could be found. When patients with 'clinical benefit' (i.e. objective response plus prolonged stable disease of at least 6 months) were considered, also no relationship could be found. Further analysis of subgroups with positive hormone receptors, treatment with newer generation aromatase inhibitors, single metastatic site, non-visceral metastases and previous treatment only with tamoxifen did not show any relationship. Tumor aromatase expression did not correlate with response of patients with advanced breast cancer to aromatase inhibitor treatment. Most patients had relapsed from other treatments before receiving an aromatase inhibitor. It seems likely that many of these patients had tumors that may have progressed to hormone independence at this stage of the disease. Research in patients who have received treatment with aromatase inhibitors in earlier stages of disease (first line and adjuvant treatment) may provide further information on the relationship between tumor aromatase, steroid receptors and response to inhibitor treatment.
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PMID:The relationship between aromatase in primary breast tumors and response to treatment with aromatase inhibitors in advanced disease. 1467 35

Tumors that have spread to the liver or lungs (visceral metastases) are associated with a worse prognosis than tumors in soft tissue and bone only. Here we review available efficacy data to address whether or not anastrozole, a non-steroidal aromatase inhibitor (AI), is effective in postmenopausal patients with advanced breast cancer (ABC) and visceral metastases. We include data from Phase III clinical trials, comparing clinical benefit (CB) with anastrozole versus tamoxifen as a first-line treatment, and versus megestrol acetate (MA) or fulvestrant as a second-line therapy. Patients in these trials had adequate organ function and the volume of disease had to be minimal or moderate for them to be eligible for inclusion. First-line treatment of patients with or without visceral metastases in the overall population resulted in CB rates of 49.5 and 62.3%, respectively, for anastrozole and 46.9 and 55.9%, respectively, for tamoxifen. In patients with confirmed hormone receptor (HR)-positive tumors, the CB rate was 51.9 and 65.7%, respectively, for anastrozole and 41.6 and 58.7%, respectively, for tamoxifen. In patients with or without visceral metastases, second-line treatment with anastrozole resulted in a CB rate of 31.4 and 51.8%, respectively, compared with 31.9 and 47.1%, respectively, for those treated with MA. Patients in the overall population with and without visceral metastases treated with anastrozole obtained a CB rate of 37.4 and 43.8%, respectively, while those treated with fulvestrant obtained a CB rate of 38.2 and 47.6%, respectively. In patients with confirmed HR-positive tumors, CB was seen in 37.6 and 41.5%, respectively, of patients treated with anastrozole and in 37.3 and 47.0%, respectively, of patients treated with fulvestrant. The results reveal anastrozole to be an effective and valuable first- and second-line therapy in postmenopausal women with ABC and visceral metastases, showing similar CB to other endocrine therapies.
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PMID:A review of the efficacy of anastrozole in postmenopausal women with advanced breast cancer with visceral metastases. 1470 69

Metastatic breast cancer is considered an incurable disease. The choice of drug or drug combination in palliative therapy is determined by the subjective symptoms of the patient and by the more objective parameters age and general health status, localization of metastases and aggressiveness of the disease, which is described by the necessity to achieve remission. The relation between the effectiveness aimed for and the subjective quality of life is described by the term 'therapeutic index'. With receptor-positive tumours and under low remission pressure, endocrine therapy is the method of choice when considering sustaining the quality of life--here aromatase inhibitors have replaced the former gold standard anti-estrogen tamoxifen. With receptor-negative tumors or under high remission pressure the therapy decision is far more difficult. The cytostatic therapy can be performed as mono- or polychemotherapy. In both cases taxanes show a higher effectiveness when compared to standard therapies, with Docetaxel giving the highest response rate and (as shown in a recent Cochrane analysis) increasing overall survival with a HR of 0.88. We describe taxane-containing therapy regimes in the context of modern therapy options. Current data presented by 4 chosen studies are described, as well as AGO recommendations on palliative therapy.
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PMID:[Palliative therapy of breast cancer]. 1471 35

The introduction of the nonsteroidal aromatase inhibitor (NS-AI) anastrozole as an alternative to tamoxifen for adjuvant therapy of women with resected hormone receptor-positive breast cancer has added a management category into which patients presenting with metastatic disease can be placed. There are now essentially three such categories: (a) tamoxifen sensitive (no prior AI); (b) tamoxifen resistant (no prior AI); and (c) NS-AI resistant (no prior tamoxifen). Well-conducted Phase III trials provide evidence for choosing first-line therapy for advanced disease in categories a and b. In tamoxifen-sensitive patients, one can choose either NS-AI, anastrozole, or letrozole. In tamoxifen-resistant patients, one can choose either of the NS-AIs, the steroidal AI exemestane, or the estrogen receptor down-regulator fulvestrant. The situation is quite different for patients in category c. There are no Phase III trials of agents in patients who have experienced disease progression on a NS-AI. Phase II data are available for exemestane and high-dose estrogens, and retrospective data are available for tamoxifen and fulvestrant. Additional clinical trials are needed to determine an optimal sequencing strategy.
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PMID:Sequencing of endocrine therapy in postmenopausal women with advanced breast cancer. 1473 92

Aromatase inhibitors and inactivators are playing an increasing greater role in breast cancer treatment. Exemestane, a highly specific, steroidal aromatase inactivator, is the newest agent in this class. The drug is highly specific, and inhibits the in vivo conversion of androstenedione to oestrone (aromatization) by a mean of 97.9%. Exemestane has shown good efficacy and tolerability in multiple clinical trials among patients with metastatic breast cancer who have failed one or more previous hormonal therapies. Exemestane 25 mg/day slows disease progression and reduces tumour-related signs and symptoms and the drug exhibits a partial lack of cross-resistance with the non-steroidal aromatase inhibitors. Response rates to exemestane of 14% to 29% were observed including patients with visceral metastases, who have historically proven difficult to treat. In a large phase III trial, exemestane was found to be superior to megestrol acetate with respect to time to progression and overall survival. In addition, exemestane is currently under investigation as first-line therapy in metastatic disease and in sequence with tamoxifen in the adjuvant setting. Adverse events include low-grade hot flashes, nausea, and fatigue--mostly of mild to moderate intensity--and treatment-related discontinuations are rare. In conclusion, exemestane represents a novel and interesting drug for the treatment of advanced breast cancer, with exciting prospects for use in adjuvant therapy and, potentially, breast cancer prevention.
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PMID:Exemestane: a review of its clinical efficacy and safety. 1496 85

The clinical benefits of endocrine therapy for patients with hormonosensitive breast cancer remains perfectly established. For instance, tamoxifen, the gold standard of the adjuvant treatment, has largely contributed of the effectiveness of such a therapy. The recent development of new endocrine agents (the third-generation aromatase inhibitors, selective estrogen receptors modulators), provides to physicians the opportunity of a more effective and tolerable therapeutic approach, in the metastatic disease setting or likely in adjuvant setting for breast cancer patients. Preoperative therapy has been widely used for the treatment of initially inoperable locally advanced breast cancers with the main objective of breast-conserving surgery. The benefits of neoadjuvant chemotherapy has widely been demonstrated; however, the success of neoadjuvant endocrine therapy is much recent. The clinical and pharmacological data of the main published studies using neoadjuvant hormonotherapy are presented herein this review. Therefore, clinical and histologic assessments of response brings essential informations about the breast cancer hormonal sensitivity, but may also be predictor of the future (adjuvant or metastatic) treatment responsiveness.
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PMID:[Neoadjuvant endocrine therapy for breast cancer: an overview]. 1497 5

Major advances have been made in the treatment of postmenopausal women with hormone-sensitive breast cancer. Although tamoxifen has been the standard endocrine therapy for the past twenty years, the development of a third generation of aromatase inhibitors (Als), which effectively inhibit estrogen synthesis in extragonadal sites, gives us a wider range of choices in endocrine therapy. However, many questions remain with respect to the optimal use of Als. Differences between Als and tamoxifen as well as non-steroidal and steroidal Als in their long-term adverse effects on bone demineralization and lipid metabolism are only starting to emerge. The preferable orders for use of non-steroidal and steroidal Als, Als and pure anti-estrogen in patients with metastatic disease are emerging subjects to be examined, following several studies that showed non-cross reactivity between these types of drug. Neo-adjuvant endocrine therapy is now attempting to apply breast conserving surgery in larger numbers of elderly patients who are not suitable for neo-adjuvant chemotherapy. Moreover, many investigators are currently searching for surrogate markers in neo-adjuvant endocrine treatment that can predict the responsiveness and prognosis with adjuvant endocrine therapy. Further research concomitant with clinical trials may lead to a more reliable endocrine therapy modality in the treatment of breast cancer.
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PMID:[Controversies in endocrine therapy for breast cancer]. 1499 48


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