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)

Randomized clinical trials have established the role of third-generation aromatase inhibitors (AIs) (letrozole, anastrozole, and exemestane) as standard treatment for patients with hormone-sensitive metastatic breast cancer who have experienced disease progression with antiestrogen therapy. Significant gains in clinical efficacy and improved tolerability over progestins (megestrol acetate) and the first-generation AI aminoglutethimide have positioned these agents above previous therapies. Estrogen receptor (ER) status remains the best predictive determinant of endocrine response, and further randomized trials with properly selected patient populations may distinguish individual AIs within this class. A recently completed, randomized, head-to-head phase III trial of letrozole versus anastrozole as second-line endocrine therapy demonstrated a significant difference in objective response rate for letrozole compared with anastrozole (19% versus 12%, respectively; P = 0.014), with similar time to progression. The improved efficacy and safety of AIs as second-line endocrine therapies has spawned trials of their use as first-line endocrine therapy versus tamoxifen for patients with metastatic breast cancer. Based on favorable results from these trials, letrozole and anastrozole have also been approved for use as first-line treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer.
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PMID:A comparison of the efficacy of aromatase inhibitors in second-line treatment of metastatic breast cancer. 1290 72

Preclinical models and clinical studies have shown that aromatase inhibitors (AIs) are powerful inhibitors of estrogen synthesis and significantly suppress estrogen in vivo. For more than 20 years, standard first-line treatment for postmenopausal women with metastatic breast cancer has been the antiestrogen tamoxifen, a selective estrogen receptor modulator (SERM) with differential effects on breast, endometrial, bone, and vascular tissues. The estrogenic activity of tamoxifen is associated with deleterious clinical side effects, including vaginal bleeding, endometrial cancer, and thromboembolism. AIs are established second-line treatments in patients who progress with tamoxifen. Compared with progestins, such as megestrol acetate, or the earlier AIs aminoglutethimide and fadrozole, the new AIs, including exemestane, anastrozole, and letrozole, have increased efficacy and clinical benefit and cause fewer side effects in patients with metastatic breast cancer. Letrozole and anastrozole are approved first-line therapy for patients with metastatic breast cancer and as second-line treatment after tamoxifen failure. Studies in the intratumoral aromatase xenograft preclinical model have shown better responses with AIs than with antiestrogens in first-line therapy, and these data are consistent with the results from clinical trials. This model is now being used to assess whether combined or sequential administration of AIs with other agents may provide additional benefit.
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PMID:Applicability of the intratumor aromatase preclinical model to predict clinical trial results with endocrine therapy. 1290 73

With the development of highly effective, well-tolerated third-generation aromatase inhibitors (AIs), these drugs will probably play an increasingly important role in all phases of breast cancer treatment. As a result, the impact of such hormonal agents on patients' quality of life bears rigorous investigation. In a randomized, multicenter, single-blind cross-over study, the AIs letrozole and anastrozole were evaluated for quality of life, toxicity, and patient preference. A total of 72 patients were enrolled and were treated with each drug for a 4-week period, with a 1-week drug-free washout period before cross-over to the alternate agent. Assessments included the FACT-ES, toxicity, and patient preference. The FACT-ES is a validated questionnaire designed to measure quality of life of women with breast cancer who are being treated with endocrine therapies. Letrozole was superior to anastrozole with respect to both quality of life and toxicity evaluations. In addition, at the conclusion of the trial, reduced nausea, hot flashes, and abdominal discomfort caused almost twice as many patients to prefer to continue with letrozole therapy than with anastrozole. Data from this recent trial indicate that letrozole is better tolerated and provides better quality of life than anastrozole for women with metastatic breast cancer.
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PMID:Examining quality of life issues in relation to endocrine therapy for breast cancer. 1290 76

The aim of this randomised study was to compare the effects of progestins and aromatase inactivators on bone remodelling markers and the components of insulin-like growth factor in patients with metastatic breast cancer. Within the framework of a large (769 patients), randomised double-blind clinical trial comparing exemestane (EXE) with megestrol acetate (MA), serum 17 beta-estradiol (E2), estrone (E1), estrone sulphate (E1S), bone alkaline phosphatase (BAP), carboxy-terminal cross-linking telopeptide of type I collagen (ICTP) and the components of insulin-like growth factor (IGF) family (IGF-1, IGF-2 and IGFBP-3) were determined in 53 patients (24 randomised to EXE and 29 ramdomised to MA). After eight weeks of treatment, both ICTP and BAP increased (p < 0.01) in the EXE group, but only ICTP in the MA group (p < 0.03). The 8-week suppression of E2 and E1S was more pronounced in the EXE group (to, respectively, 11.2% and 9.9% of baseline values) than in the MA group (33.1% and 29.7%). IGF-1 increased (p < 0.01) in both groups, but more so in the patients treated with MA. Estrogen levels negatively correlated with ICTP in both groups, but were not related to BAP in either. IGF-1 negatively correlated with estrogens in both groups. The results of this study indicate that anti-aromatase therapy is associated with increased osteoclast activity, and suggest the existence of possible differential effects of different hormonal therapies on bone remodelling markers regardless of the estrogen suppression induced by EXE.
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PMID:Bone turnover markers and insulin-like growth factor components in metastatic breast cancer: results from a randomised trial of exemestane vs megestrol acetate. 1292 95

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

A recent National Institutes of Health consensus guideline recommends the general use of adjuvant hormonal therapy for the treatment of early breast cancer in postmenopausal women with estrogen receptor-positive tumors. Standard therapy has been 5 years of tamoxifen, but about 30% of those patients fail to survive 10 years, many as a consequence of tamoxifen resistance. Promising results with the third-generation aromatase inhibitors anastrozole, letrozole, and exemestane in first- and second-line treatment of metastatic breast cancer has prompted their evaluation as adjuvant therapy in patients progressing on tamoxifen or as alternative first-line treatment. Anastrozole has recently achieved significantly longer disease-free survival than tamoxifen in a first-line adjuvant therapy trial, and letrozole is being investigated in several large adjuvant trials. Aromatase inhibitors appear to be well tolerated for long-term adjuvant treatment. In the neoadjuvant setting, letrozole has been especially effective compared with tamoxifen in downstaging primary tumors in postmenopausal women, permitting significantly more breast-conserving surgery.
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PMID:Aromatase inhibitors in early breast cancer treatment. 1451 36

Estrogen is critical in the progression and probably also in the initiation of breast tumors. Two classes of pharmacologic agents currently used in the treatment of estrogen receptor-positive breast tumors are the selective estrogen receptor modulators such as tamoxifen that block the interaction of estrogen with its cognate receptor, and the aromatase inhibitors (AIs) that block the final enzymatic step in the estrogen biosynthetic pathway. Recent data from first-line phase III trials in postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer suggest that AIs are at least equivalent to or more effective than tamoxifen in this setting. As a result AIs are being evaluated in the adjuvant setting and may eventually displace tamoxifen as the endocrine therapy of choice for postmenopausal patients with breast cancer. Among the side effects of therapy that were observed in metastatic trials, AIs have shown less vascular and uterine adverse events than tamoxifen. Some concern exists, however, regarding their effect on lipid metabolism and bone turnover. To be acceptable for adjuvant treatment, AIs will have to show not only an advantage in efficacy, but also that any concerns from potential side effects may be managed appropriately. This article reviews the safety profile of AIs, discussing events related to their chemical structure, their specificity, and the effects of estrogen deprivation on target organs.
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PMID:Origin and characteristics of adverse events in aromatase inhibition therapy for breast cancer. 1451 37

Despite the dramatic fall in plasma estrogen levels at menopause, only minor differences in breast tissue estrogen levels have been reported comparing pre- and postmenopausal women. Thus, postmenopausal breast tissue has the ability to maintain concentrations of estrone (E1) and estradiol (E2) that are 2-10- and 10-20-fold higher than the corresponding plasma estrogen levels. This finding may be explained by uptake of estrogens from the circulation and/or local estrogen production. Local aromatase activity in breast tissue seems to be of crucial importance for the local estrogen production in some patients while uptake from the circulation may be more important in other patients. Beside aromatase, breast tissue expresses estrogen sulfotransferase and sulfatase as well as dehydrogenase activity, allowing estrogen storage and release in the cells as well as conversions between estrone and estradiol. The activity of the enzyme network in breast cancer tissue is modified by a variety of factors like growth factors and cytokines. Aromatase inhibitors have been used for more than two decades in the treatment of postmenopausal metastatic breast cancer and are currently investigated in the adjuvant treatment and even prevention of breast cancer. Novel aromatase inhibitors and inactivators have been shown to suppress plasma estrogen levels effectively in postmenopausal breast cancer patients. However, knowledge about the influence of these drugs on estrogen levels in breast cancer tissue is limited. Using a novel HPLC-RIA method developed for the determination of breast tissue estrogen concentrations, we measured tissue E1, E2 and estrone sulfate (E1S) levels in postmenopausal breast cancer patients before and during treatment with anastrozole. Our findings revealed high breast tumor tissue estrogen concentrations that were effectively decreased by anastrozole. While E1S was the dominating estrogen fraction in the plasma, estradiol was the estrogen fraction with the highest concentration in tumor tissue. Moreover, plasma estrogen levels did not correlate with tissue estrogen concentrations. The overall experience with aromatase inhibitors and inactivators concerning their influences on breast tissue estrogen concentrations is summarized.
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PMID:Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators. 1462 18

There is increasing evidence that endocrine therapy has an important role in patients with oestrogen receptor positive breast cancer. Several large meta-analyses have reinforced the value of both ovarian ablation and tamoxifen in improving survival. Over the past decade, aromatase inhibitors have become the treatment of choice for second-line therapy of metastatic breast cancer, and the third generation inhibitors have now an established reputation for good patient tolerability. Early studies indicated that aminoglutethimide/hydrocortisone could benefit postmenopausal patients with primary breast cancer, and in 2001, the ATAC study showed that the third generation aromatase inhibitor, anastrozole, seemed superior to tamoxifen in that anastrozole-treated patients had a longer disease-free survival. Other studies will report on the relative merits of the steroidal inhibitor exemestane as well as non-steroidal letrozole. The exact duration and sequencing of treatment, together with the long-term effects on bone are at present, unknown.
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PMID:Aromatase inhibitors as adjuvant therapies in patients with breast cancer. 1462 26

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


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