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)

The pharmacologic inhibition of aromatase activity has been the focus of clinical trials in patients with advanced stage breast cancer. Recent developments with imidazole compounds that inhibit aromatase activity suggest their clinical use as potent inhibitors of estrogen biosynthesis in postmenopausal breast cancer patients. In this Phase I, open-label, dose-range finding study, we examined the inhibitory potency of CGS 20267 on blood and urine levels of estradiol, estrone and estrone sulfate in 8 patients with metastatic breast cancer. Studies included evaluation of adrenal and thyroid function to look for evidence of general hydroxylase inhibition at dose levels effective for aromatase blockade. Patients were administered CGS 20267 at doses of 0.1 and 0.25 mg, once a day in ascending doses over a 12-week period. Preliminary data reveal that CGS 20267 elicits a striking suppression in plasma estradiol, estrone and estrone sulphate which was observed in some patients as quickly as within 24 h of the first dose. Estrogen suppression of over 90% was achieved within 2 weeks of therapy. No alterations in either baseline or ACTH (cortrosyn) stimulated cortisol and aldosterone levels were observed through the 12 weeks of therapy. In addition, 24 h urine sodium and potassium values were not appreciably altered during therapy. We conclude that CGS 20267 is a potent, specific inhibitor of estrogen biosynthesis in postmenopausal patients with metastatic breast cancer and effectively reduces blood and urine estrogens to undetectable levels.
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PMID:The efficacy of CGS 20267 in suppressing estrogen biosynthesis in patients with advanced stage breast cancer. 847 85

Hormones of the hypothalamic-pituitary-adrenal system were studied in 31 patients with early stage breast cancer and patients with metastatic breast cancer. Both groups received tamoxifen as first-line treatment. As a control group 15 age-matched healthy women participated in the study. The results showed that breast cancer patients had significant elevations in basal cortisol levels compared to controls. Metastatic breast cancer patients had higher cortisol levels than early stage breast cancer patients. No significant differences between breast cancer patients and controls were found in basal plasma ACTH and prolactin levels. These data provide evidence that breast cancer is associated with a hyperactive adrenal gland, which may be due to the physiological stress associated with the presence of (micro)metastases or tumor cells in the circulation, in combination with administration of tamoxifen. In response to a behavioral challenge increases were observed in plasma ACTH and prolactin. Metastatic breast cancer patients had a faster prolactin response to acute stress than healthy women. However, metastatic breast cancer patients showed a blunted ACTH response compared to healthy women. Stress-induced ACTH responses and basal cortisol levels were negatively correlated in the metastatic group only. Thus, the blunted ACTH response to the behavioral challenge might be related to hypercortisolemia suggesting that the pituitary corticotroph cell in metastatic cancer is appropriately restrained possibly by the negative feedback effects of chronic cortisol elevations. Interestingly, the behavioral challenge induced decreases in cortisol levels in all three groups. However, metastatic breast cancer patients had a faster cortisol decline compared to healthy women. We hypothesize that this is caused by increased metabolic clearance of cortisol due to increased utilization of metabolic substrates often observed in the presence of a tumor.
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PMID:Elevated basal cortisol levels and attenuated ACTH and cortisol responses to a behavioral challenge in women with metastatic breast cancer. 884 75

Breast carcinoma is a rare cause of ectopic ACTH syndrome. There are only two previously reported cases in which ACTH secretion is documented. We describe the case of a 56-year-old woman who presented with clinical and biochemical features of ectopic ACTH syndrome in the setting of metastatic breast carcinoma. Despite aggressive management of her ectopic ACTH syndrome, her course was complicated by opportunistic infection, respiratory failure and death. Immunostaining of the breast metastases for ACTH was positive and in situ hybridization revealed proopiomelanocortin gene expression. This is the first reported case of ectopic ACTH syndrome associated with metastatic breast cancer in which the technique of in situ hybridization has been used to confirm the breast cancer metastases as the source of ectopic ACTH secretion.
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PMID:Cushing's syndrome secondary to ectopic ACTH secretion from metastatic breast carcinoma. 1046 35

Recent clinical trials indicate that the third-generation aromatase inhibitors may be more effective than tamoxifen as first line endocrine therapy in ER+ metastatic breast cancer in postmenopausal women. This review will focus exclusively on the pharmacology of the non-steroidal inhibitor letrozole. Aromatase derived from a variety of sources is inhibited at low nM concentrations of the drug. In non-cellular systems, letrozole is 2-5 times more potent than anastrozole and exemestane in its inhibition of aromatase, whilst in cellular systems it is 10-20 times more potent. Anti-tumour effects of letrozole have been demonstrated in several animal models. In postmenopausal women, letrozole commonly suppresses circulating concentrations of estrone and estradiol to below the sensitivity limit of the assays used to measure them. In a recent randomized cross-over study, letrozole (2.5mg daily) achieved a significantly greater suppression of the plasma concentrations of both estrone and estrone sulphate than anastrozole (1mg daily) and a greater inhibition of in vivo aromatization. Letrozole appears to have a small effect on adrenal steroidogenesis such that a small number of patients exhibit an abnormal response to synthetic ACTH during letrozole therapy. This is unlikely to have any clinical significance. In short-term studies letrozole has been shown to increase markers of bone resorption indicating the need to monitor bone integrity when the drug is used for extended periods of time. A consistent effect of letrozole on serum lipids has not been demonstrated.
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PMID:The pharmacology of letrozole. 1463 89

The normal diurnal cortisol cycle has a peak in the morning, decreasing rapidly over the day, with low levels during the night, then rising rapidly again to the morning peak. A pattern of flatter daytime slopes has been associated with more rapid cancer progression in both animals and humans. We studied the relationship between the daytime slopes and other daytime cortisol responses to both pharmacological and psychosocial challenges of hypothalamic-pituitary-adrenal (HPA) axis function as well as DHEA in a sample of 99 women with metastatic breast cancer, in hopes of elucidating the dysregulatory process. We found that the different components of HPA regulation: the daytime cortisol slope, the rise in cortisol from waking to 30 min later, and cortisol response to various challenges, including dexamethasone (DEX) suppression, corticotrophin releasing factor (CRF) activation, and the Trier Social Stress Task, were at best modestly associated. Escape from suppression stimulated by 1mg of DEX administered the night before was moderately but significantly associated with flatter daytime cortisol slopes (r=0.28 to .30 at different times of the post DEX administration day, all p<.01). Daytime cortisol slopes were also moderately but significant associated with the rise in cortisol from waking to 30 min after awakening (r=.29, p=.004, N=96), but not with waking cortisol level (r=-0.13, p=.19). However, we could not detect any association between daytime cortisol slope and activation of cortisol secretion by either CRF infusion or the Trier Social Stress Task. The CRF activation test (following 1.5mg of DEX to assure that the effect was due to exogenous CRF) produced ACTH levels that were correlated (r=0.66, p<.0001, N=74) with serum cortisol levels, indicating adrenal responsiveness to ACTH stimulation. Daytime cortisol slopes were significantly correlated with the slope of DHEA (r=.21, p=.04, N=95). Our general findings suggest that flatter daytime cortisol slopes among metastatic breast cancer patients may be related to disrupted feedback inhibition rather than hypersensitivity in response to stimulation.
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PMID:Stress sensitivity in metastatic breast cancer: analysis of hypothalamic-pituitary-adrenal axis function. 1708


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