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

The clinical development of aromatase inhibitors in recent years represents a significant addition to our armamentarium for the treatment of postmenopausal patients with hormone receptor-positive breast cancer--both for metastatic disease and in the adjuvant setting. In patients with metastatic disease, third-generation aromatase inhibitors have shown significantly superior efficacy over tamoxifen as first-line hormone therapy. In the adjuvant setting, preliminary results with the use of aromatase inhibitors in ongoing large clinical trials indicate significant gains in disease-free survival rates and in the occurrence of contralateral breast cancer, either alone for 5 years or sequentially after tamoxifen for 2-3 or 5 years. While tamoxifen monotherapy continues to be standard adjuvant therapy for patients with low risk primary breast cancer, postmenopausal patients with higher risk hormone-positive primary breast cancer should also be offered an aromatase inhibitor. Aromatase inhibitors are also prescribed for patients with contraindications to tamoxifen. The optimal sequence and duration of aromatase inhibitor adjuvant therapy as well as its long-term impact on overall survival remain to be established. In general, aromatase inhibitors have a good toxicity profile. Long-term effects such as the risk of osteoporosis need to be better defined.
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PMID:The emerging role of the new aromatase inhibitors in the treatment of breast cancer. 1584 8

Fulvestrant, an estrogen receptor antagonist with no known agonist effects, is effective and well tolerated in the treatment of hormone-sensitive breast cancer after antiestrogen failure in postmenopausal women. Numerous phase II and III clinical trials of fulvestrant that are designed to build on its efficacy in breast cancer and explore its value in other tumors are ongoing or in the final planning stage. Favorable safety, dose-response, and pharmacokinetic data led to the initiation of clinical trials to evaluate loading and higher doses with the aim of building on the well-defined efficacy of fulvestrant. Recently reported results of phase II trials by the North Central Cancer Treatment Group and the Swiss Group for Clinical Cancer Research support the clinical activity of fulvestrant after recurrence or progression on a nonsteroidal aromatase inhibitor, and 2 international phase III trials are ongoing in this setting. As a first-line treatment for metastatic disease, fulvestrant is currently being evaluated in combination with anastrozole versus anastrozole alone in 2 phase III trials, 1 by the Southwest Oncology Group and the other being conducted mainly in Scandinavia. Preclinical data have also led to randomized phase II trials of fulvestrant in combination with the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib, and the HER2/neu-targeted antibody trastuzumab. Additional phase II and III trials are currently evaluating fulvestrant plus tipifarnib, Theratope vaccine, or the dual kinase inhibitor, GW572016. Although fulvestrant is undergoing robust clinical development as a treatment for breast cancer, investigation of this agent in other types of solid tumors has only just begun.
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PMID:Current and future perspectives on fulvestrant. 1586 48

For more than twenty years, tamoxifen represents the gold standard treatment in adjuvant setting for breast cancer patients. However, the tamoxifen activity remains complex, with its agonist effects, sometimes a poor tolerance and a certain number of patients become refractory to treatment. The aromatase inhibitors, such as progestatifs, were developed to challenge tamoxifen efficacy, along with improved tolerability. The third generation of aromatase inhibitors seems to provide significant gains in efficacy over tamoxifen for postmenopausal patients with hormone receptor positive breast cancer and they have already been approved in patients with metastatic disease. We review, in this article, the rationale for using IA in patients with breast cancer and, across the different clinical trials results already published, their current major role they are playing in adjuvant setting for menopausal hormonal receptor-positive breast cancer patient. One of the main issues using the third generation of IA is their long-term side effects, especially bone turnover and lipid metabolism.
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PMID:[Aromatase inhibitors in adjuvant setting in breast cancer]. 1589 15

Thirty years after the introduction of tamoxifen, which was expanded from palliation of metastatic cancer to recent application for chemoprevention, the primacy of this drug as the mainline pharmacological intervention is currently being challenged by the third generation aromatase inhibitors and inactivators. In contrast to the oestrogen receptor blockade provided by tamoxifen, aromatase inhibitors result in deprivation of oestrogens in postmenopausal women both through paracrine/intracrine and endocrine modulation. Experimental evidence has shown a significant (97-99%) reduction of in vivo aromatase activity and an equal or sometimes better antitumour activity compared with megestrol acetate when these drugs are used as second-line treatment for metastatic breast cancer. Recent pivotal studies in first-line settings comparing tamoxifen for metastatic breast cancer and preliminary results from the neoadjuvant trials demonstrate that third generation aromatase inhibitors are superior to tamoxifen. With a better understanding of local tissue production of oestrogen through oestrone sulfatase, which hydrolyses oestrone sulfate to oestrone, and 17-beta-hydroxysteroid dehydrogenase Type 1, which in turn catalyses the reduction of oestrone to oestradiol, more powerful tactics for oestrogen starvation of cancer may be realised in future.
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PMID:Aromatase inhibitors and other novel agents in breast cancer treatment. 1598 53

There are important surgical issues related to the use of the third generation aromatase inhibitors in both the neoadjuvant and adjuvant settings. Neoadjuvant hormone therapy is effective at downstaging tumours, particularly large tumours initially thought to be inoperable or requiring mastectomy. Randomised trials have shown that the newer aromatase inhibitors letrozole and anastrozole increase the numbers of women who are suitable for breast-conservation compared with tamoxifen, and that letrozole is superior to tamoxifen in terms of clinical response. Aromatase inhibitors are most effective in ER-rich tumours and are clinically and biologically effective in both HER2 positive and negative tumours, whereas HER2 positive tumours show a level of resistance to tamoxifen. In neoadjuvant studies comparing aromatase inhibitors with tamoxifen, the duration of use has been 3-4 months, by which time any response is usually evident but longer treatment periods produce continued shrinkage and response. The re-excision rate following breast conservation surgery after neoadjuvant hormone therapy is favourable compared with the rates following immediate wide local excision. Local recurrence rates are acceptable in patients undergoing neoadjuvant therapy and breast-conserving surgery providing post-operative radiotherapy is given. Adjuvant aromatase inhibitors, as well as having an effect on metastatic disease and survival, reduce local and regional recurrence.
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PMID:Surgical issues surrounding use of aromatase inhibitors. 1602 54

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

The aromatase enzyme catalyses the last step in estrogen biosynthesis. There are two classes of third-generation aromatase inhibitors: irreversible steroidal inhibitors (e.g. exemestane) and reversible non-steroidal inhibitors (e.g. anastrozole, letrozole). All three agents have been found to be equivalent or superior to megestrol acetate as second-line therapy for metastatic breast cancer. In the first-line setting, large phase III trials have shown that all three are equivalent or superior to tamoxifen in women with metastatic disease. Several large trials with varying study designs have been launched to analyse their role in the adjuvant setting. The four that have reported found longer average disease-free survival for women who received an aromatase inhibitor than for those who did not. In addition, one trial, MA.17, has shown a survival advantage associated with the use of an aromatase inhibitor in node-positive patients. Guidelines produced by the American Society of Clinical Oncology suggest that adjuvant therapy for postmenopausal women with hormone-receptor-positive breast cancer should include an aromatase inhibitor. However, the long-term consequences of estrogen deprivation in postmenopausal women remain uncertain, particularly with regard to bone and cardiovascular health. The advantages and disadvantages of different hormonal strategies should therefore be carefully considered in each individual case.
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PMID:Recent advances in the use of aromatase inhibitors for women with postmenopausal breast cancer. 1615

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

Hormonal manipulations have been used for more than 100 years for the treatment of metastatic breast cancer and after definition of the concept of micro-metastases also in the adjuvant setting. In the postmenopausal population, tamoxifen has played the most important role for almost four decades. Progestins or the first generation of aromatase inhibitors (AIs) were only marginally used in the adjuvant setting due to their prohibitive toxicity. The new generation of anti-estrogen compounds, the selective estrogen receptor down-regulators (SERDs) like fulvestrant have a higher affinity for the estrogen receptor than tamoxifen, but none of its agonist activities, and have shown promising clinical activity in the treatment of advanced breast cancer. The third generation of AIs investigated in six large trials has been reported to be superior to tamoxifen in terms of disease-free survival, but not in terms of survival. These trials will be discussed in terms of results in different subpopulations and of toxicity.
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PMID:Adjuvant endocrine therapies for postmenopausal women with early breast cancer: standards and not. 1618 42

Fulvestrant is a new oestrogen receptor (ER) antagonist that is licensed for the treatment of postmenopausal women with advanced breast cancer progressing following antioestrogen treatment and may also be effective in those progressing after non-steroidal aromatase inhibitors. The use of fulvestrant in a Compassionate Use Programme (CUP) in a "real-life" setting has permitted its activity and tolerability profile in patients with different disease characteristics to be observed. Here, we present five case reports of fulvestrant use in postmenopausal women with advanced breast cancer progressing after prior endocrine therapy. Clinical experience from the CUP supports the published clinical trial data and suggests that fulvestrant is a valuable new treatment for postmenopausal women with advanced breast cancer, including those with visceral metastases and human epidermal growth factor receptor 2-positive disease.
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PMID:Case studies of fulvestrant ("Faslodex") in postmenopausal women with advanced breast cancer. 1619 28


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