Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aromatase activity was measured in 104 primary and 24 metastatic breast cancer patients. The assay employed quantitates the production of 3H water release from 1 beta-[3H]androstenedione after aromatization. Of 104 human primary breast tumors studied, 64 contained measurable aromatase activity, ranging from 5-70.5 pmol estrone formed/g protein/hour. In primary breast cancers there was no difference in levels of aromatase activity when analyzed by menstrual status or age by decade. Aromatase activity was similar in small and large primary tumors. The median aromatase activity of primary breast tumors (8.6 pmol/g/h) was similar to that found in metastatic breast cancer deposits (12.0 pmol/g/h). Aromatase activity did not correlate with either estrogen (ER) or progesterone (PR) receptor concentration in the tissues assayed. In this regard there were 33 ER- PR- tumor biopsies. Twelve of these 33 tumors contained aromatase activity greater than 10 pmol/g/hour.
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PMID:Aromatase activity in primary and metastatic human breast cancer. 380 35

Hormonal therapy for breast cancer began more than a century ago with the observation that bilateral oophorectomy caused tumor regression in selected premenopausal patients. In the first half of this century, besides extending ablation of ovarian function to photon irradiation, surgical adrenalectomy and hyophysectomy were introduced, and hormonal additive therapy was established. Regression rates for advanced breast cancer with all types of endocrine therapy at this point did not exceed 35%. The demonstration that adjuvant systemic therapy can prolong the disease-free interval and improve overall survival has been a major advance in the management of breast cancer, the rationale was to control or eliminate micrometastases before tumor recurrence. The nonsteroidal antiestrogen tamoxifen was chosen for the majority of studies since the mid-1970s. Since the first report of successful treatment of metastatic breast cancer, the number of treated women worldwide has reached over 3,000,000. Objective response rate (CR+PR following UICC) in unselected patients is 34%. Tamoxifen has been used successfully to treat both pre- and postmenopausal women with all stages of the disease. In an overview analysis of 30,000 patients from 40 trials of adjuvant tamoxifen, a significant increase was found in both disease-free and overall survival. When patients were separated by nodal status, statistically significant increases were observed in disease-free and overall survival for both node-positive and node-negative patients. Women over 50 appear to benefit most from tamoxifen treatment experiencing highly significant increases in disease-free and overall survival regardless of nodal status. However, since tamoxifen primarily acts as a cytostatic and not cytotoxic agent, most patients ultimately experience disease recurrence or progression during or after therapy. Newer antiestrogens include trioxifene, toremifene, and droloxifene (3-OH-tamoxifen). Randomized, prospective studies are still under way to establish their clinical superiority (or lack of it). Progestins exert direct antiproliferative effects on human breast cancer cell lines. They may also exert direct antiestrogenic action by increasing the oxidative activity of 17 beta-hydroxy-steroid-dehydrogenase, thereby facilitating the conversion of estradiol to estrone. Progestins may exert additional antiestrogenic effects by suppressing estrogen receptor levels. As they also cause estrogen deprivation indirectly through suppression of pituitary ACTH secretion, resulting in reduced production of adrenal androgen precursors, both low- and high-dose regimens have been studied. Aromatase inhibition in premenopausal women interrupts estrogen biosynthesis; the reflex rise in FSH then stimulates production of new aromatase enzyme, and the LH increment results in enhanced ovarian steroidogenesis, counteracting the inhibitory action of aromatase-blocking drugs on the ovary.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Endocrine management of breast cancer. 787 88

Aromatase inhibitors are a new class of agents that are of considerable interest for potential use as palliative therapy for hormone-dependent metastatic breast cancer in postmenopausal women. In the postmenopausal or castrate female, the process of aromatization accounts for the majority of circulating, biologically active estrogens. This report presents a clinical perspective on some of the most recent information concerning the biology and pharmacology of the aromatase enzyme and highlights the development of newer aromatase inhibitors with important therapeutic potential. Clinical questions addressed include the selection of aromatase inhibitors, the selection of the most appropriate patients for therapy with these new agents, and the positioning of these new agents with respect to other forms of endocrine therapy for breast cancer. Finally, we shall consider areas for future investigation of possible new indications for these agents in clinical medicine.
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PMID:Aromatase inhibitors in clinical practice: current status and a look to the future. 882 63

Endocrine therapy represents a mainstay of effective, minimally toxic, palliative treatment for metastatic breast cancer. Research focusing on the mechanism of action of endocrine agents will provide new insights leading to new hormonal approaches in breast cancer treatment. Development of new agents, especially the 'pure' antiestrogens, is of great interest. Combining endocrine therapy with biologic agents, especially antiproliferative compounds, may lead to more effective treatment in the adjuvant as well as the advanced setting. Tables 4 and 5 summarize response rates to the different groups of endocrine agents used in metastatic breast cancer and doses of commonly used agents, respectively. At present, tamoxifen is the drug of choice as first-line endocrine therapy for metastatic breast cancer with no or minimal symptoms in premenopausal or postmenopausal women. Second-line therapy usually consists of megace. Aromatase inhibitors may be used as second- or third-line therapy in postmenopausal women. In premenopausal women, LHRH analogues are a reasonable choice. The other hormonal agents may be beneficial as salvage therapy. More effective endocrine approaches are under development.
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PMID:Endocrine therapy in metastatic breast cancer. 958 91

Aromatase inhibitors were first reported in the early 1970s and have been used to treat breast cancer since that time. Until recently, essentially the only agent available in this class was aminoglutethimide, a nonspecific inhibitor with multiple adverse effects and drug interactions. Selective and potent aromatase inhibitors are now available (formestane, exemestane, fadrozole, anastrozole and letrozole), and we review the risks and benefits of these agents in order to assist clinicians in making treatment decisions. Formestane is an injectable steroidal aromatase inhibitor with significant activity against metastatic breast cancer. It has been shown to have similar efficacy and superior tolerability compared with megestrol, and is similar to tamoxifen in the metastatic setting. Exemestane is an oral steroidal aromatase inhibitor. It has been shown to be effective third-line therapy after tamoxifen and megestrol in postmenopausal patients with metastatic breast cancer. All the nonsteroidal (imidazole/triazole) aromatase inhibitors are orally available. Fadrozole has similar activity to megestrol and tamoxifen in the setting of metastasis, but has been shown in phase II trials to inhibit cortisol and aldosterone production. Anastrozole and letrozole have similar toxicity profiles. Compared with megestrol, anastrozole improves overall survival and has superior tolerability. Letrozole is superior to megestrol and aminoglutethimide in terms of overall survival and time to progression, and is also better tolerated. Although there is a strong rationale for using these agents in the treatment of breast cancer, the information presently available is insufficient to recommend any one agent over another. Direct comparative studies are lacking, and comparing agents across studies is limited by many biases and may not be valid. Formestane is only available as an injection and exemestane is not commercially available in many countries, making these agents more difficult to recommend over the other 3 agents. Fadrozole is less potent and less selective in inhibiting aromatase than letrozole. The efficacies of fadrozole, megestrol and tamoxifen appear to be similar; however, comparative data show no advantage of fadrozole over letrozole. Anastrozole and letrozole are generally considered to be similar agents. The clinical future of the selective aromatase inhibitors is promising, and these agents may change the way postmenopausal breast cancer is treated at all stages of the disease.
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PMID:Risks and benefits of aromatase inhibitors in postmenopausal breast cancer. 1051 21

Aromatase, a cytochrome P-450 enzyme that catalyzes the conversion of androgens to estrogens, is the major mechanism of estrogen synthesis in the post-menopausal woman. We review some of the recent scientific advances which shed light on the biologic significance, physiology, expression and regulation of aromatase in breast tissue. Inhibition of aromatase, the terminal step in estrogen biosynthesis, provides a way of treating hormone-dependent breast cancer in older patients. Aminoglutethimide was the first widely used aromatase inhibitor but had several clinical drawbacks. Newer agents are considerably more selective, more potent, less toxic and easier to use in the clinical setting. This article reviews the clinical data supporting the use of the potent, oral competitive aromatase inhibitors anastrozole, letrozole and vorozole and the irreversible inhibitors 4-OH androstenedione and exemestane. The more potent compounds inhibit both peripheral and intra-tumoral aromatase. We discuss the evidence supporting the notion that aromatase inhibitors lack cross-resistance with antiestrogens and suggest that the newer, more potent compounds may have a particular application in breast cancer treatment in a setting of adaptive hypersensitivity to estrogens. Currently available aromatase inhibitors are safe and effective in the management of hormone-dependent breast cancer in post-menopausal women failing antiestrogen therapy and should now be used before progestational agents. There is abundant evidence to support testing these compounds as first-line hormonal therapy for metastatic breast cancer as well as part of adjuvant regimens in older patients and quite possibly in chemoprevention trials of breast cancer.
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PMID:Use of aromatase inhibitors in breast carcinoma. 1073 91

In patients with metastatic breast cancer, second-line therapy with aromatase inhibitors can improve survival in comparison with megestrol. We conducted a meta-analysis to assess the effectiveness of aromatase inhibitors versus megestrol. After a Medline search, three trials (evaluating letrozole, anastrozole or exemestane versus megestrol) were included in the survival meta-analysis. Our methodology retrieved patient-level information on survival. In comparison with megestrol, aromatase inhibitors prolonged survival at levels of statistical significance (relative death risk for oral aromatase inhibitors=0.79, 95% confidence interval 0.69-0.91; p=0.0011). A lifetime analysis of the pooled survival curves of aromatase inhibitors versus megestrol found a mean survival gain of 4.1 months per patient. Aromatase inhibitors confer a significant survival benefit to patients with metastatic breast cancer as compared with megestrol. A preliminary calculation of the cost per life year gained shows that the pharmacoeconomic profile of these drugs is favorable.
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PMID:Survival in patients with metastatic breast cancer: analysis of randomized studies comparing oral aromatase inhibitors versus megestrol. 1112 31

Aromatase inhibition provides both paracrine/intracrine and endocrine treatment. Recent accumulated data clarified that 3rd generation aromatase inhibitors potently suppress intratumoral estrogen synthesis particularly in postmenopausal patients. In the 2nd-line treatment for metastatic breast cancer patients, aromatase inhibitors achieved results antitumor activity at least equal to and sometimes better than that of tamoxifen. In the first-line treatment for metastatic breast cancer patients, a recent pivotal study clearly demonstrated that aromatase inhibitor was superior to tamoxifen. Based upon these results, various adjuvant trials which compare aromatase inhibitors with tamoxifen and attempt to determine optimal combination therapies and treatment periods with aromatase inhibitors are currently being conducted. In addition, preliminary studies conducted in neoadjuvant setting indicated that aromatase inhibitors showed an extremely high response rate, which predicts a future paradigm, that neoadjuvant therapy using aromatase inhibitors singly or in combination may become standard for hormone-responsive and post-menopausal breast cancer patients.
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PMID:Aromatase and aromatase inhibitors. 1179 Nov 26

Tamoxifen has dominated endocrine treatment of breast cancer for over two decades. It is useful in metastatic breast cancer, adjuvant therapy, preoperative treatment, ductal carcinoma-in-situ and chemoprevention. However, breast cancer may be refractory to tamoxifen or develop resistance to it with ongoing treatment. This resistance involves several mechanisms including receptor mutation causing 'estrogen hypersensitivity' and an increasing agonist effect of tamoxifen. Megestrol (megestrol acetate), in North America, and aminoglutethimide, in Europe, have been the traditional second line therapies after tamoxifen in advanced breast cancer. Aromatase (estrogen synthetase) inhibitors are a logical alternative to tamoxifen to antagonise the effects of estrogen on breast cancer. The third-generation non-steroidal aromatase inhibitors anastrozole, letrozole and vorozole, and the steroidal inhibitor exemestane, have been studied after tamoxifen versus either megestrol or aminoglutethimide. They showed enhanced efficacy and significantly superior toxicity profiles. Compliance with the inhibitors was also significantly better than with the traditional treatments. Aromatase inhibitors have most recently been shown to be superior to tamoxifen as initial therapy and are being extensively tested in the adjuvant setting after, or instead of, tamoxifen. Pilot studies of chemoprevention are also being undertaken. The aromatase inhibitors are an important new addition to the armamentarium of breast cancer therapy.
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PMID:Tamoxifen resistant and refractory breast cancer: the value of aromatase inhibitors. 1192 41

Aromatase inhibitors and inactivators are increasingly important to the therapy of advanced breast cancer in postmenopausal women. These compounds are also currently being evaluated in the adjuvant setting and may have potential in breast cancer prevention. In addition to the recent clinical results, experimental research with development of aromatase 'knockout' mice as well as certain clinical observations in individuals lacking this enzyme have deepened our understanding of estrogens outside of the field of reproduction. Such information should help us to further develop this type of therapy in breast cancer and, in particular, extend our understanding of the lack of complete cross-resistance between aromatase inhibitors and inactivators. Clinically, third-generation aromatase inhibitors and inactivators have shown superiority compared with conventional treatment in advanced postmenopausal breast cancer with respect to second-line (tamoxifen failures) as well as first-line therapy. The fact that tamoxifen is noncurative in metastatic disease but improves long-term survival in the adjuvant setting suggests that even modest improvements in therapy of advanced disease may be translated into survival benefits in patients with early disease. In addition, these novel compounds with lack of complete cross-resistance extend the scope of using sequential treatment options to maximise the duration of optimal endocrine therapy in metastatic breast cancer disease.
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PMID:Aromatase inhibitors and inactivators for breast cancer therapy. 1203 79


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