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 third generation of aromatase inhibitors and inactivators, such as anastrozole (Arimidex), letrozole (Femara) and exemestane (Aromasin), have become available for treatment of postmenopausal breast cancer patients. Several clinical trials have demonstrated that these new drugs can achieve better treatment results than megestrol acetate (Megace) and may replace tamoxifen for the first-line hormonal therapy for metastatic breast cancer patients. In fact, these drugs are now used in many hospitals and clinics for patients with metastatic breast cancer who were previously given tamoxifen as adjuvant treatment. However, the primary concern is whether they can be used as first-line agents for adjuvant treatment of primary breast cancer or are suitable for breast cancer prevention in view of possible adverse side effects. Recently, the Arimidex and Tamoxifen Alone or in Combination trial demonstrated the superiority in terms of disease-free survival of anastrozole over tamoxifen in adjuvant use for postmenopausal patients with Stage I and II primary breast cancer. The results of this report indicate the potential of anastrozole as an alternative drug in the adjuvant setting, although the mean follow-up time is so far only 47 months. Additional data regarding survival resulting from comparative trials of letrozole and tamoxifen and of exemestane and tamoxifen are expected to be available in a few years. However, limited information is available regarding adverse events caused by long-term administration of aromatase inhibitors. Longer follow-up is needed to determine the efficacy and safety of these new aromatase inhibitors when used for adjuvant treatment of postmenopausal patients with breast cancer.
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PMID:Aromatase inhibitors for treatment of postmenopausal patients with breast cancer. 1272 79

The treatment of postmenopausal women with breast cancer presents a number of challenges. Tamoxifen has had a substantial impact on mortality in women with early-stage, estrogen-receptor-positive tumors. Despite the improvement in the treatment of breast cancer, many patients will ultimately experience a recurrence. Present treatment approaches can provide effective palliation in the advanced disease setting, but, at best, there has been a modest impact on survival. Numerous options are now available to provide effective palliation for patients with advanced disease. These options include antiestrogens, pure antiestrogens, aromatase inhibitors and progestins and LHRH agonists. Recently, several studies have reviewed the efficacy of aromatase inhibitors as first-line agents in postmenopausal women. Anastrozole and letrozole have recently been approved as first-line agents in women with metastatic breast cancer. In addition to their role in metastatic breast, trials investigating the potential of aromatase inhibitors in the early breast cancer, both in the adjuvant and neoadjuvant setting are underway.
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PMID:Hormonal therapy in postmenopausal women with breast cancer. 1275 23

For the past 25 years, the estrogen antagonist tamoxifen has been the hormonal treatment of choice for postmenopausal patients with hormone-sensitive metastatic and early breast cancer (EBC). However, tamoxifen is associated with certain tolerability and safety concerns. In addition, the hormonal options after progression are limited, and thus, alternative endocrine treatments have been developed. This review provides a synopsis of the newer alternatives in endocrine therapy of breast cancer: the aromatase inhibitors (AIs) and fulvestrant Faslodex), the estrogen receptor antagonist that downregulates estrogen and progesterone receptors and has no known agonist activity. The third-generation AIs, anastrozole and letrozole, have been shown to be as effective or more effective than megestrol acetate and tamoxifen as second- and first-line therapies for the treatment of postmenopausal patients with metastatic breast cancer, and exemestane has been approved for second-line use. Fulvestrant has been shown to be as effective as anastrozole as second-line therapy for metastatic breast cancer and has been approved in the U.S. for the treatment of postmenopausal women with hormone-receptor-positive metastatic breast cancer following progression on antiestrogen therapy. Anastrozole is the only AI with published clinical trial data and U.S. Food and Drug Administration approval for adjuvant therapy of postmenopausal women with EBC. The 'Arimidex,' Tamoxifen, Alone or in Combination (ATAC) trial, a double-blind, multicenter trial with 9,366 patients, compared tamoxifen with anastrozole, alone and in combination, as adjuvant endocrine treatment for postmenopausal patients with operable, invasive, EBC. The first analysis (at a median follow-up of 33.3 months) showed longer disease-free survival and, in general, better tolerability with anastrozole than with tamoxifen. This pattern was maintained at later analyses with a median follow-up of 47 months for efficacy and 37 months for safety and tolerability. Although longer follow-up is warranted, anastrozole appears to be a well-documented choice of endocrine adjuvant therapy for postmenopausal women with hormone-responsive breast cancer.
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PMID:Advances in endocrine treatments for postmenopausal women with metastatic and early breast cancer. 1289 30

Aromatase inhibitors (AIs) have been approved as second-line treatment for estrogen receptor-positive (ER+) metastatic breast cancer after first-line treatment with the selective estrogen receptor modulator (SERM) tamoxifen. Anastrozole and letrozole have also recently been widely approved as first-line endocrine therapy for postmenopausal women with hormone receptor-positive metastatic breast cancer. The three third-generation selective oral AIs approved for use in the United States include two nonsteroidal agents, anastrozole (Arimidex) and letrozole (Femara), and the irreversible steroidal inhibitor exemestane (Aromasin). Several major ongoing clinical trials with a variety of treatment regimens are comparing the relative efficacy of tamoxifen with the steroidal and nonsteroidal AIs in the adjuvant setting. The first strategy compares an AI against tamoxifen directly. Among these are the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial (anastrozole), the BIG FEMTA (Femara-Tamoxifen Breast International Group) trial (letrozole), and the EXEM and TEAM (exemestane) trials. A second strategy is examining the use of an AI as an extension after the initial 5 years of tamoxifen. Examples of this trial design are the MA-17 (letrozole) and the National Surgical Adjuvant Breast and Bowel Project (NSABP B-33, exemestane) trials. A third approach is the use of these agents in sequence with tamoxifen as therapy within the initial 5 postoperative years. Examples of this approach are the International Collaboration Cancer Group trial (tamoxifen for 2-3 years followed by either tamoxifen or exemestane for the remainder of the 5-year period), the BIG FEMTA trial (patients are crossed over from tamoxifen to Ietrozole or letrozole to tamoxifen), and the Arimidex-Nolvadex (ARNO) trial (patients receiving tamoxifen are randomized either to continue with tamoxifen or to switch to anastrozole). A single trial is comparing tamoxifen and anastrozole as initial 5-year therapy, or a combination of the two. The study addressing this design is the ATAC trial. Finally, a small trial in Norway is comparing 2 years of an AI versus a placebo in very low-risk patients with receptor-positive breast tumors. Most adjuvant trials have companion studies associated with the main protocol. These are to determine the end-organ effects of the inhibitors and include measurements of quality of life, bone and lipid metabolism, and endometrial effects. This review addresses the clinical implications of these studies of AIs.
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PMID:Emerging role of aromatase inhibitors in the adjuvant setting. 1290 74

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

The goal of endocrine therapy in breast cancer is to block the action of estrogen on the tumor cells either by inhibiting estrogen from binding to the specific estrogen receptor or by inhibiting its synthesis. Tamoxifen, a selective estrogen receptor modulator, is the standard endocrine treatment for hormone receptor-positive breast cancer, both in the adjuvant and metastatic settings. Tamoxifen inhibits the binding of estrogen to the receptor, resulting in inhibition of hormone action. However, as tamoxifen is also weakly estrogenic, it may not be optimally effective and increases the risk of endometrial cancer and stroke. Furthermore, patients may be refractory or may become resistant to tamoxifen treatment. Since aromatase inhibitors (AI) block the synthesis of estrogen and have no intrinsic estrogenic activity, they have the potential to be more effective than tamoxifen. Their different mechanism of action and chemical structures may also circumvent tamoxifen resistance. Consequently, AIs are currently being evaluated as an alternative to tamoxifen treatment. A preclinical model has recently been developed to compare the efficacy of AIs and antiestrogens in different treatment schemes and to assist in the design of clinical trials. Current studies with the MCF-7Ca xenograft model are exploring the effects of combination and sequential therapy on tumor growth. The efficacy of AIs in the treatment of hormone receptor-positive breast cancer was first demonstrated in five multicenter second-line trials enrolling several hundreds of postmenopausal patients with metastatic breast cancer who had failed tamoxifen treatment. More recently, anastrozole demonstrated efficacy at least equivalent to that of tamoxifen in first-line randomized, phase III clinical trials in postmenopausal women with hormone receptor-positive or unknown metastatic breast cancer, whereas letrozole demonstrated superiority. The steroidal AI exemestane is currently under evaluation. Letrozole is the only AI to have been studied in a randomized, phase III trial in the neoadjuvant setting. In this trial, more patients underwent breast-conserving surgery with letrozole than with tamoxifen. Smaller phase II studies also suggest that both anastrozole and exemestane are active in the neoadjuvant setting. Because neoadjuvant trials permit temporal sampling of breast tissue, substudies in the phase III trial with letrozole have examined the impact of such biomarkers as estrogen receptor, progesterone receptor and epidermal growth factor receptor family members, HER-1 and HER-2, on patient response. AIs are currently under evaluation in the adjuvant setting, and preliminary results of the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial have been reported. AIs have proven as safe as tamoxifen in trials in patients with metastatic breast cancer. Ongoing clinical trials in the adjuvant setting include companion studies of end-organ effects, particularly bone metabolism and lipid metabolism evaluations. Quality-of-life assessments are also parts of major clinical trials. A head-to-head quality-of-life assessment of anastrozole compared with letrozole demonstrated patient preference for letrozole. These assessments also clearly indicated the eagerness of patients to participate actively in treatment decisions
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PMID:Challenges in the endocrine management of breast cancer. 1465 38

Tamoxifen is one of the most effective treatments for breast cancer through its ability to antagonize estrogen-dependent growth by binding estrogen receptors (ERs) and inhibiting proliferation of breast epithelial cells. However, tamoxifen has estrogenic agonist effects in other tissues such as bone and endometrium due to liganded ER activating target genes in these different types of cell. Several novel anti-estrogen compounds have been developed which have a reduced agonist profile on breast and gynaecological tissues. These compounds offer the potential for enhanced efficacy and reduced toxicity compared with tamoxifen. In advanced breast cancer clinical data exist for two groups of agents: the selective estrogen receptor modulators (SERMs), further divided into "tamoxifen-like" (e.g. toremifene, droloxifene and idoxifene) and "fixed ring" compounds (e.g. raloxifene, arzoxifene and EM-800), and the selective estrogen receptor down-regulators (SERDs; e.g. fulvestrant (ICI 182780), SR 16234 and ZK 191703) also termed "pure anti-estrogens". In phase II trials in tamoxifen-resistant metastatic breast cancer the SERMs show low objective response rates (range 0-15%), suggesting cross resistance with tamoxifen. Randomized phase III trials for toremifene and idoxifene in over 1500 patients showed no significant difference compared with tamoxifen. Fewer clinical data exist for the "fixed ring" SERMs and it remains unclear whether any clinical advantage exists for the "fixed ring" SERMs over tamoxifen as first-line therapy. The main advantage for SERMs such as tamoxifen and raloxifene probably remains in early-stage disease (adjuvant therapy or prevention). Fulvestrant and the other SERDs have a high affinity for the estrogen receptor (ER) compared to tamoxifen, but none of its agonist activities. Of the SERDs, only fulvestrant has entered the clinic and this new agent is showing promising clinical activity in the treatment of advanced breast cancer. Recently published phase III studies have shown fulvestrant to be at least as effective as the third-generation aromatase inhibitor anastrozole in patients whose disease has relapsed or progressed on prior endocrine therapy. Surprisingly, however, in a phase III trial versus tamoxifen for the first-line therapy of advanced breast cancer fulvestrant did not attain the requirements for equivalence to tamoxifen, and in terms of time-to-treatment failure was inferior (5.9 versus 7.8 months for fulvestrant and tamoxifen, respectively; P=0.029). Future clinical studies will evaluate fulvestrant in the neoadjuvant setting together with its optimal sequencing in relation to tamoxifen and other endocrine therapies in advanced disease.
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PMID:The use of selective estrogen receptor modulators and selective estrogen receptor down-regulators in breast cancer. 1468 97

It is desirable to identify the most effective sequence of endocrine therapies for the treatment of postmenopausal women with advanced, hormone-responsive breast cancer. In a retrospective analysis of two large, randomized, comparative Phase III trials in this patient population, the Tamoxifen or 'Arimidex' Randomized Group Efficacy and Tolerability (TARGET) trial and the North American trial, we ascertained that tumors responding to anastrozole as first-line therapy may subsequently respond to tamoxifen as second-line therapy. In a double-blind cross-over trial, the SAKK 21/95 sub-trial (including patients from the Swiss centres in the TARGET trial), we further investigated the clinical impact of anastrozole followed by tamoxifen compared with that of tamoxifen followed by anastrozole. Patients with locally advanced or metastatic breast cancer who had continued on randomized treatment until objective disease progression and were still considered suitable for endocrine therapy, could continue on blinded therapy crossing-over to the alternative treatment. They were assessed for time to progression (TTP) from treatment randomization, TTP after crossing-over treatments, time from randomization to progression after crossing-over treatments and overall survival. Median TTP from randomization for patients receiving first-line treatment with anastrozole (n = 31) and tamoxifen (n = 29) was 11.3 and 8.3 months, respectively, p = 0.75. Median TTP from treatment cross-over was 6.7 months for tamoxifen after progression on anastrozole (n = 19) and 5.7 months for anastrozole after progression on tamoxifen (n = 18), while median time from randomization to second progression was 28.2 and 19.5 months, respectively. Overall survival from randomization for the anastrozole-tamoxifen sequence and the tamoxifen-anastrozole sequence was 69.7 versus 59.3 months, respectively, p = 0.10. The relative risk of death was higher for the tamoxifen followed by anastrozole sequence (1.63; 95% confidence interval [CI] 0.89-2.98). Tamoxifen is an effective second-line therapy after anastrozole. Our data, together with the better tolerability profile of anastrozole compared with tamoxifen, support the use of anastrozole as first-line therapy for advanced breast cancer in postmenopausal women with hormone receptor-positive tumors. Treatment with tamoxifen may still be useful upon subsequent progression.
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PMID:Anastrozole ('Arimidex') versus tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer: results of the double-blind cross-over SAKK trial 21/95--a sub-study of the TARGET (Tamoxifen or 'Arimidex' Randomized Group Efficacy and Tolerability) trial. 1511 63

The prognosis of patients with de novo stage IV breast cancer seems to be similar to that of patients with metastatic disease. Because these patients have not been exposed to prior therapy, the use of high dose chemotherapy (HDCT) may be beneficial. Twenty-four newly diagnosed (median age 42) responding metastatic breast cancer patients underwent HDCT (Stamp V) and stem cell support as their initial treatment. The predominant sites of metastatic disease were bone (12), lung (5), liver (2), lymph nodes (6), marrow (4), and soft-tissue (1). Estrogen/progesterone receptors were positive in 35%, negative in 45%, and unknown in 20%. Before transplantation, 10 patients were in complete remission (CR), 6 were in partial remission (PR), and 8 were inevaluable. Radiotherapy was administered to sites of documented metastatic disease. Tamoxifen was given to patients with receptor positive and unknown tumor status. After a median follow-up of 60 months from diagnosis (range 42 to 96 months), 15 patients have relapsed and 10 died. Mean and median progression free survival from transplant are 53 (SE 6.6, CI 40-66) and 60 (SE 18, CI 25-96) months, respectively. The median survival has not yet been achieved (>6 years). There was no treatment-related mortality. The use of HDCT in patients with chemosensitive, de novo metastatic breast cancer is safe and well tolerated. Overall clinical outcome is good; however, this study cannot determine whether this was due to treatment or selection bias.
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PMID:High-dose chemotherapy and autologous stem cell transplant in women with de novo chemosensitive metastatic breast cancer. 1517 Jan 43

Tamoxifen, an anti-estrogen, has been used for a long time as an adjuvant therapy in cases of estrogen receptor positive breast cancer. Tamoxifen also demonstrates some weak estrogenic activity. A small increase in serum triglycerides is commonly found after tamoxifen administration. Herein we report 3 cases of sever hypertriglyceridemia due to tamoxifen. Case 1 recovered with tamoxifen withdrawal. Tamoxifen was replaced with toremifene in case 2. The level of triglyceride decreased significantly after the change of agent. Tamoxifen was discontinued and anastrozole administration was started in the third patient. Her triglyceride levels improved. Tamoxifen-induced severe hypertriglyceridemia seen in these patients was an effect of its estrogen action. Anastrozole has been used to treat postmenopausal metastatic breast cancer, and several clinical trials in the adjuvant setting are ongoing. Anastrozole does not affect lipid metabolism. Therefore, anstrozole might be safe for patiens with abnormal triglyceride profiles during tamoxifen treatment. We recommended that a periodic serum triglyceride check is needed for patients treated with tamoxifen.
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PMID:[Tamoxifen-induced severe hypertriglyceridemia--report of 3 cases]. 1527 96


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