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)

Aromatase activity has been measured in human breast cancers by incubating tumour minces with [7 alpha-3H]testosterone and characterizing purified oestradiol (E2) fractions by chemical derivative formation. Of 247 primary tumours, 178 showed evidence of oestrogen biosynthesis, levels varying between 0.5 and 12.5 fmol E2 produced/h/g tissue. These values were quantitatively small but at least comparable with those in other peripheral tissues. There was no correlation between presence or level of aromatase activity and the histopathology of the tumours although oestrogen biosynthesis was more likely to be present in more cellular tumours. Aromatase activity was also unrelated to age, menopausal status, lymph node status and T stage of the patient from which the tumour was derived. In a subgroup of patients presenting without clinical evidence of distant metastatic disease, no significant relation was detected between tumour aromatase and disease-free interval, but tumours without aromatase activity were associated with increased survival at 36 months after primary treatment. A statistically significant correlation was also detected between the presence of tumour aromatase and oestrogen receptors. Furthermore, in small subgroups of patients with "advanced" breast cancer tumour aromatase was related to response to aminoglutethimide but not tamoxifen therapy. Whilst these results do not conclusively define a role for local synthesis of oestrogen in the progression of breast cancer, this possibility still exists and further studies on tumour aromatase are warranted.
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PMID:Relationship between tumour aromatase activity, tumour characteristics and response to therapy. 228 81

The axillary lymph-node-status is the most important prognostic factor in breast cancer patients without distant metastases. The proportion of node positive axillae depends on the number of histologically documented nodes (at least 6 according to TNM recommendations). The prognostic significance of solitary micro-metastases and of metastases detected only by serial sectioning or by immunocytochemistry is not yet established. An important prerequisite for successful conserving breast-cancer treatment is patient selection. Selection leads to a high proportion of patients with favourable prognosis: primary tumors less than 3 cm in diameter, at least 2/3 without axillary lymph-node-metastases, at least 1/3 less than 50 years old. That means attribution of prognostically less favourable patients to mastectomy. Tumor diameter and grading are established prognostic parameters of the primary. The significance of grading is independent of the system used and also independent of the reproducibility by different investigators. Measurement of tumor cell ploidy, proliferation and of epidermal growth factor-receptor content may add to the safety of prognosis prediction. Steroid hormone receptor content, eventually also Somatostatin-receptor and Aromatase activity in the tumor tissue can influence the therapeutic decisions.
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PMID:[Pathologic-anatomic parameters for the prognosis of invasive breast cancer following amputation or saving the breast]. 266 53

Aromatase inhibitors are a useful therapeutic option in the management of endocrine-dependent advanced breast cancer. Formestane (Lentaron) is the first irreversible aromatase inhibitor to be extensively investigated. In a phase II study to determine the effects of formestane on serum estradiol and urinary 17-hydroxycorticosteroid (17-OHCS) levels and to evaluate its clinical activity, 72 postmenopausal patients with advanced breast cancer were given formestane 250 mg intramuscularly every 2 weeks. Of 66 patients fully evaluable, 56 were estrogen receptor (ER) positive, and 43 had a disease-free interval > or = 2 years. Metastases were assessable in soft tissue (53%), bone (53%) and viscera (47%); 34 patients had 1, 32 had > or = 2 metastatic lesions. Serum estradiol levels fell significantly (p < 0.01) after 2 weeks and remained unchanged thereafter, whereas urinary 17-OHCS levels did not change during treatment. Objective responses were obtained in 19 patients (29%), of whom 8 had complete response. In relation to disease sites, similar responses were obtained in soft tissue (33%) and viscera (30%), whereas response in bone was 18%. The overall tolerability of formestane was satisfactory, and only two patients complained of local side effects. We conclude that formestane is an effective aromatase inhibitor in postmenopausal patients with hormone-dependent breast cancer, and does not interfere with adrenal steroidogenesis.
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PMID:Formestane: effective therapy in postmenopausal women with advanced breast cancer. 787 56

Aromatase inhibitors are known to be effective in the treatment of advanced postmenopausal breast cancer. To assess the efficacy of the aromatase inhibitor 4-hydroxyandrostenedione (4-OHA) as first-line treatment in patients who were either resistant to or had relapsed after adjuvant therapy, 50 eligible patients received intramuscular 4-OHA either 250 mg or 500 mg fortnightly until disease progression or severe adverse events. Of the 43 patients evaluable for clinical response (UICC criteria), 15 (36%) showed objective response (CR+PR), 6 (14%) stable disease (SD). In relation to disease site, objective responses were obtained in 55% of cases with soft tissue metastases (16/29); in 33% with visceral metastases (8/24), and in 24% with bone involvement (5/21). In relation to previous adjuvant treatment, there were eight objective responses among the 17 patients treated with chemotherapy (47%), and seven objective responses among the 24 treated with tamoxifen (29%). The treatment was well tolerated. These results support the hypothesis that adjuvant therapy, whether hormonal or chemotherapy, may make patients less responsive to subsequent treatment.
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PMID:Efficacy and tolerability of 4-hydroxyandrostenedione (4-OHA) as first-line treatment in postmenopausal patients with breast cancer after adjuvant therapy. 848 32

Tamoxifen as adjuvant systemic treatment after first isolated locoregional recurrence of breast cancer has been shown to decrease the subsequent locoregional relapse rate, but it affects neither distant metastases nor survival. In metastatic disease, tamoxifen has not improved response when added to ablation of ovarian function. The cyclical sequential use of tamoxifen with megestrol acetate has not increased the response over tamoxifen alone. Aromatase inhibitors are an expanding field; formestane and vorozole are effective agents, and letrozole shows promise. In chemotherapy, major interest has focused on the use of taxoids, with high activity being reported for both paclitaxel and docetaxel, the latter being particularly effective as a second-line treatment. Reports continue to reaffirm the effectiveness of vinorelbine. The in vitro ability of quinidine to reverse resistance to anthracyclines has not been repeatable in a clinical setting. The evaluation of high-dose chemotherapy with bone marrow support continues to be explored, but this approach has thus far not been demonstrated to improve clinical outcome in advanced disease. The intra-arterial administration of chemotherapy appears to have a useful palliative role in selected patients with locoregional disease.
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PMID:Metastatic breast cancer. 854

Aromatase inhibition is now an acknowledged second line treatment modality for advanced breast cancer in postmenopausal women. Aminoglutethimide is an inhibitor of adrenal steroid biosynthesis and blocks the conversion of cholesterol to pregnenolone, and therefore reduces levels of adrenal androgens, which are a source of estrogens in both premenopausal and postmenopausal women. Aminoglutethimide has produced antitumor response rates of 35% in unselected patients, most of whom have undergone prior therapy with either chemotherapy or hormonal manipulation. As is true of other hormonal responses, high response rates of up to 70% are observed in patients who are ER and/or PR positive. The reason why these drugs are currently used after tamoxifen is mainly due to the side effects of aminoglutethimide, which impairs the mineralocorticoid and glucocorticoid synthesis. New, less toxic compounds appear, which block the conversion of androstenedione to estrone and efficiently suppress plasma estrogen levels., e.g. formestane, anastrozole and letrozole. Aromatase inhibitors are now being compared to tamoxifen as first-line endocrine treatment in relapsing patients. If these trials confirm a similar or better response rate to new aromatase inhibitors compared to tamoxifen, the time will come to study them as the first line adjuvant treatment in non-metastatic disease.
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PMID:[Aromatase inhibitors--new possibilities in treatment of breast carcinoma]. 962 25

Hormone therapy of breast cancer has been dominated for a very long time by a single class of drugs, the antiestrogens, and especially tamoxifen. Tamoxifen has been the standard treatment in the adjuvant, neoadjuvant, and metastatic contexts. Ten years ago a new generation of aromatase inhibitors became available that was more selective than previous generations. They form two groups that are quite distinct from a pharmacological standpoint: type II non-steroid inhibitors and type I steroid inhibitors or rather steroid "aromatase inactivators". Aromatase inhibitors are prescribed to menopausal women. They are active in patients with tamoxifen-resistant metastatic cancer. They are a potential alternative to tamoxifen in first-line therapy of women with metastatic cancer. They have been proven useful as neoadjuvant therapy. They are under study in several trials in an adjuvant context. Many issues still remain outstanding.
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PMID:[Aromatase inhibitors: therapeutic outlook]. 1125 Jun 7

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

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

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


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