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)

During the past year there have been a number of important advances in the area of systemic therapy for breast cancer. Combined chemoendocrine therapy has been shown to be more effective than tamoxifen alone in the adjuvant therapy of node-negative estrogen receptor-positive breast cancer. Preliminary results of a randomized trial suggest that the addition of paclitaxel to adjuvant AC (Adriamycin and Cytoxan) improves survival in patients with operable node-positive disease. In the treatment of metastatic disease, preliminary results of a randomized trial have shown docetaxel to be superior to doxorubicin in response rate. In hormonal therapy, third generation aromatase inhibitors have replaced megestrol acetate as second-line hormonal therapy in receptor-positive disease. There are promising recent data about anti-HER-2 antibody therapy and other new approaches. This article reviews these and other recent advances in the systemic therapy of breast cancer.
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PMID:Recent advances in systemic therapy for breast cancer. 981 30

Recent trials comparing single-agent vs combination therapy in metastatic breast cancer suggest that it may be time to reconsider the belief that combination chemotherapy is the gold standard of treatment. Based on the limited randomized trial data available to date, high-dose chemotherapy with stem-cell rescue should not be viewed as "state-of-the art" treatment for metastatic disease and should be used only in the context of clinical trials. Recent trials have explored the optimal dosing and scheduling of the taxanes, as well as the possible role of these agents in combination regimens. Capecitabine (Xeloda), a new oral fluoropyrimidine, appears to be comparable in efficacy to CMF (cyclophosphamide, methotrexate, and fluorouracil), and preclinical data suggest possible synergy between this agent and the taxanes. Other promising agents under study include liposome-encapsulated doxorubicin (TLCD-99), an immunoconjugate linking a chimeric human/mouse monoclonal antibody to doxorubicin molecules; MTA (LY231514), a multitargeted antifolate; and marimistat, a broad-spectrum matrix metalloproteinase inhibitor. Tamoxifen (Nolvadex) remains the most important hormonal agent, but new antiestrogens and selective estrogen receptor modulators (SERMs) may provide alternatives. The potential role of new aromatase inhibitors as first-line hormonal agents requires further study. Finally, the possible synergy between trastuzumab (Herceptin), a recombinant humanized monoclonal antibody to the HER-2/neu protein, and paclitaxel (Taxol) is being studied in two clinical trials.
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PMID:Update on the management of advanced breast cancer. 1035 85

In spite of major advances in early detection and adjuvant therapy, metastatic breast cancer remains a major clinical problem affecting a significant number of patients. Metastatic disease is generally considered incurable and conventional therapy is used mainly with palliative intent. Therefore, the choice of appropriate therapeutic approach requires a reasoned evaluation of the likelihood of benefit from therapy balanced with the impact of therapy on the patient's quality of life. The estimated aggressiveness of the tumour and indicators of response to therapy (e.g. the status of hormonal receptors) are useful parameters to take into account before selecting a given treatment. Endocrine therapy is an important option in the management of stage IV disease, with tamoxifen the most widely used first-line drug in postmenopausal women. For progressing patients, the third generation of aromatase inhibitors (letrozole, anastrazole) are considered good second-line endocrine agents. The LH-RH agonists represent the initial choice in premenopausal patients candidate to receive hormonal therapy, with the use of tamoxifen as a valuable alternative. Combination chemotherapy regimens (e.g. CMF or CAF) are usually used for first-line treatment of patients with aggressive, steroid receptor-negative disease. Recently, several relatively new agents have shown significant activity in metastatic breast cancer. In particular, the taxanes (paclitaxel and docetaxel) are particularly promising as single agents but also in combination with other drugs, especially anthracyclines. Finally, another class of agents, the d mention because they represent an important new treatment modality in the management of metastatic.
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PMID:[Treatment of metastatic breast carcinoma]. 1046 41

This phase II study of liarozole fumarate (R85246, liarozole), a novel imidazole with retinomimetic and aromatase inhibitory effects, was designed to determine the efficacy and tolerability in postmenopausal women with advanced breast cancer in progression, to correlate these effects with hormonal levels, and to evaluate quality of life. Twenty-nine women with ER-positive or unknown metastatic disease who received > or = 2 prior hormonal therapies were treated with 150-300 mg liarozole twice daily until disease progression. All patients were evaluable for toxicity and 25 for response. Four patients (16.0%, 95% CI 5.3-37.4%) had partial remission (PR) of their disease for a median of 7.4 months (range 1.2-12.9) and 7 (28%) had disease stabilization for a median of 4.8 months (1.6-16.0). Estradiol decreased from pre-treatment levels of 9.2-52 pM (mean 17.1) to below detection (9.2 pM, p = 0.0005) after 1 month. Similarly estrone levels fell from 14-307 pM (mean 92.7) to below detection (9.2 pM, p = 0.0001). The most common toxicity was dermatological (96.6%) with features compatible with hypervitaminosis A syndrome such as rash, pruritus, dry skin, and brittle nails. The majority of these were mild to moderate in severity. No significant improvement in quality of life scores (FLI-C) were noted. Liarozole is an active new treatment for breast cancer in patients heavily pre-treated with hormone therapies. Further studies are needed to confirm its relative efficacy in both receptor positive and negative postmenopausal breast cancer.
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PMID:Liarozole fumarate (R85246): a novel imidazole in the treatment of receptor positive postmenopausal metastatic breast cancer. 1075 80

A series of 1-imidazolyl(alkyl)-substituted quinoline, isoquinoline, naphthalene, benzo[b]furan, and benzo[b]thiophene derivatives was synthesized as dual inhibitors of thromboxane A(2) synthase (P450 TxA(2)) and aromatase (P450 arom). Dual inhibition of these enzymes could be a novel strategy for the treatment of mammary tumors and the prophylaxis of metastases. The most potent dual inhibitors, 5-(2-imidazol-1-ylethyl)-7,8-dihydroquinoline (31) (P450 TxA(2): IC(50) = 0.29 microM; P450 arom: IC(50) = 0.50 microM) and its 5, 6-saturated analogue 30 (P450 TxA(2): IC(50) = 0.68 microM; P450 arom: IC(50) = 0.38 microM), showed a stronger inhibition of both target enzymes than the reference compounds (dazoxiben: IC(50) = 1.1 microM; aminoglutethimide: IC(50) = 18.5 microM). For the determination of the in vivo activity, the influence of selected compounds on serum TxB(2) concentration was examined in rats. Compound 30 (8.5 mg/kg body weight) led to a reduction of the TxB(2) serum level of 78%, 71%, and 51% after 3, 5, and 8 h, respectively (dazoxiben: 60%, 34%, and 36%). Selectivity was studied toward some enzymes of the steroidogenic and eicosanoid pathways. P450 17 was inhibited by selected compounds only at high concentrations. Compound 30 inhibited P450 scc by 13% (25 microM). Compound 31 did not affect cyclooxygenase and lipoxygenase.
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PMID:1-imidazolyl(alkyl)-substituted di- and tetrahydroquinolines and analogues: syntheses and evaluation of dual inhibitors of thromboxane A(2) synthase and aromatase. 1079

In addition to ovarian ablation by means of surgery or irradiation, a wide variety of endocrine agents are now available for the management of breast cancer, in both the metastatic and adjuvant settings. Currently available endocrine agents include antiestrogens, progestational drugs, and aromatase inhibitors. Randomized trials and meta-analyses have greatly clarified the specific roles of the more established of these agents in both premenopausal and postmenopausal women. However, the exact combination and sequence of these drugs are still under investigation. The addition of the bisphosphonates has also helped improve the quality of life of patients with metastatic disease. Among new endocrine agents currently under development are the pure antiestrogens, selective estrogen receptor modulators (SERMs), and a group of drugs with effects intermediate between the two.
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PMID:Endocrine therapy for breast cancer. 1082 11

Complete estrogen blockade has long been sought as a more effective means of controlling breast cancer compared with single agent endocrine therapy. This approach may be accomplished through the use of agents which reduce estrogen production combined with agents that prevent the activity of estrogen at the cellular level. For prostate cancer, another hormonally responsive malignancy, this approach has not been successful at improving survival compared with that achieved with single agent therapy. Preclinical information is contradictory for many promising combinations and may not reflect the true nature of in vivo interaction between agents. For premenopausal patients with metastatic breast cancer, the combination of a luteinising hormone-releasing hormone (LHRH) agonist and tamoxifen is clearly effective, but whether the combination is more effective than either single agent is still controversial. Similar response rates and overall survival were reported with goserelin or goserelin plus tamoxifen by Jonat et al. in 1 randomised, prospective study, but the addition of tamoxifen improved time to progression. A second trial comparing buserelin plus tamoxifen with either single agent reported superior efficacy in terms of response rates, disease-free survival and overall survival with combination therapy. A meta-analysis of 4 randomised trials making similar comparisons, demonstrated significant improvement in median overall survival, progression-free survival, response rate, and duration of response with the combination of a LHRH agonist (goserelin or buserelin) and tamoxifen in premenopausal breast cancer patients with metastatic disease. For postmenopausal women with metastatic breast cancer, the addition of an aromatase inhibitor to tamoxifen has yet to be prospectively compared to single agent therapy. Use of endocrine combinations in the treatment of early stage breast cancer is under investigation. Preliminary results of some of the ongoing adjuvant therapy trials indicate that the combination of a LHRH agonist and tamoxifen may have similar efficacy to cyclophosphamide, methotrexate, and fluorouracil chemotherapy in premenopausal women with estrogen receptor-positive tumour. Addition of LHRH agonist therapy in premenopausal patients with estrogen receptor-positive tumour who had maintained the ovarian function following chemotherapy [cyclophosphamide, doxorubicin (adriamycin), fluorouracil, and tamoxifen], also led to a reduction in the risk of recurrence. These studies have identified a sub-population of patients who may benefit from the addition of combination endocrine therapy. Overall, the issue is quite complex and the data from many ongoing trials are still awaited with anticipation to further delineate the role of complete estrogen deprivation in this disease.
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PMID:Complete estrogen blockade for the treatment of metastatic and early stage breast cancer. 1087 21

The efficacy of combined endocrine therapy with tamoxifen (TAM), aminoglutethimide (AG), and hydrocortisone (H) or tamoxifen and fluoxymesterone (FLU) was evaluated against treatment with tamoxifen alone in 311 patients above 65 years of age with a first recurrence of a metastatic breast cancer. A total of 279 patients were eligible. The response rates were assessed for 258 fully evaluable patients and were the following for the TAM (N = 94), the TAM+AG+H (N = 83), and the TAM+FLU (N = 81) groups, respectively, PR: 14, 18, and 21%, and CR: 20, 11, and 23%. The overall response rates are not statistically different (p = 0.30). The 95% CL of difference in response rates for TAM vs. TAM+AG+H are -9-19% and for TAM vs. TAM+FLU -4-25%. Time to treatment failure was comparable with median values of 9.2, 7.7, and 9.2 months in the TAM, TAM+AG+H, and TAM + FLU group, respectively (p = 0.17). The corresponding figures for survival are median times of 22.0, 24.1, and 21.1 months with a p-value of 0.62. Toxicity was more pronounced in both the combined treatment groups, and could in most instances be attributed to treatment with either AG+H or FLU. Currently, new specific aromatase inhibitors with lesser toxicity than AG are being evaluated in combination with TAM for treatment of primary and metastatic breast cancer. In conclusion, the simultaneous use of TAM and AG +H or FLU does not seem to improve the therapeutic efficacy in elderly postmenopausal patients with metastatic disease. So far, combined endocrine therapy in this group of patients should only be used in the context of clinical trials.
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PMID:Combined endocrine treatment of elderly postmenopausal patients with metastatic breast cancer. A randomized trial of tamoxifen vs. tamoxifen + aminoglutethimide and hydrocortisone and tamoxifen + fluoxymesterone in women above 65 years of age. 1094 95

New aromatase inhibitors are an exciting treatment option for postmenopausal women with hormone sensitive breast cancer. They have been shown to reduce tumors in a significant number of patients, and exhibit definite antitumor activity at a relatively low daily dose, and are highly potent, highly selective, and well-tolerated. Results from recent clinical phase III studies have confirmed their efficacy and the key role they have in the therapy for advanced breast cancer in postmenopausal women. The agents available for clinical use are: letrozole, anastrozole, and exemestane. These drugs have demonstrated high activity in women failing tamoxifen in locally advanced or metastatic disease. This communication reviews the clinical use of aromatase inhibitors, particularly in second and first line hormonal treatment of advanced breast cancer.
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PMID:New aromatase inhibitors in the treatment of advanced breast cancer. 1102 10

Since the introduction of the first generation aromatase inhibitor, aminoglutethimide, for breast cancer treatment 30 years ago, we now have at hand novel, potent and well-tolerated steroidal and non-steroidal compounds, allowing near complete inhibition of oestrogen synthesis. The third-generation aromatase inhibitor, or more accurately termed inactivator, exemestane, is a potent suppressor of oestrogen synthesis and is shown to be an effective antitumour agent in postmenopausal breast cancer patients. Exemestane has been shown to be effective in patients failing multiple endocrine regimens. A large randomised study has revealed that exemestane improves time-to-disease progression as well as overall survival compared with megestrol acetate as second-line therapy in patients failing tamoxifen. In current studies, exemestane is compared with tamoxifen as first-line therapy for metastatic disease. Sequential therapy with tamoxifen followed by exemestane is also being compared with tamoxifen monotherapy in the adjuvant setting. In addition, the drug may have potential for breast cancer prevention.
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PMID:Pharmacology and clinical experience with exemestane. 1106 Jul 85


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