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)

Thirty postmenopausal patients who had evaluable estrogen receptor-positive or unknown metastatic breast cancer were treated with cyclic sequential combined hormonal therapy consisting of 50 micrograms of ethinylestradiol orally daily for 7 days followed by 400 mg of medroxyprogesterone acetate orally daily for 21 days, followed in turn by 7 days of rest. Cyclic administration was continued until progressive disease was detected. Patients who had had one previous chemotherapy regimen were included, but 63% of patients were previously untreated. Six patients achieved complete remission and 11, a partial remission, for an overall response rate of 57%. Median remission duration was 22 months; median time to disease progression for all 30 patients was 8 months. Toxicity consisted of cyclic vaginal bleeding, hot flashes, weight gain, irritability, and fluid retention. This cyclic, sequential hormonal regimen was effective and well tolerated.
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PMID:Sequential cyclic combined hormonal therapy for metastatic breast cancer. 252 85

Leuprolide (Lupron, TAP Pharmaceuticals, North Chicago), a gonadotropin-releasing hormone analogue, was administered to 26 premenopausal women with metastatic breast cancer. Of 25 evaluable patients, 11 (44%) had a partial response with a median duration of 39 weeks and five (20%) remained stable. Six patients showed early rapid progression of their disease. Toxicity was mild and included hot flashes, nausea, vomiting, and headache. Leuprolide induced amenorrhea in all patients who received treatment for ten weeks or longer. We conclude that this GnRH analogue provides a safe and effective means of producing medical castration in premenopausal patients with metastatic breast carcinoma.
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PMID:Medical castration produced by the GnRH analogue leuprolide to treat metastatic breast cancer. 392 58

In pre-clinical and limited clinical studies, high doses ( > or = 200 mg/day) of the triphenylethylene derivative toremifene showed activity in estrogen receptor (ER) negative and ER-unknown metastatic breast cancer after progression on tamoxifen, and a mechanism of action independent of hormone receptor binding was speculated. The CALGB conducted a Phase II trial (CALGB 8945) to test the efficacy of high dose toremifene in a population of patients who had hormone receptor-negative, metastatic breast cancer with limited prior chemotherapy exposure, good performance status, and measurable disease. Twenty eligible patients received toremifene at a dose of 400 mg/day orally for 8 weeks. Toxicity was minimal. Nausea was reported by 20% of the patients, lightheadedness by 20%, weight loss by 20%, and hot flashes by 15%. There was no grade 3-4 toxicity. No objective responses were observed, and 5 of 6 patients with stable disease at 8 weeks developed progressive disease at 11 to 33 weeks. High dose toremifene (400 mg/day) is well-tolerated but imparts no detectable activity in hormone receptor-negative, metastatic breast cancer.
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PMID:High dose toremifene for estrogen and progesterone receptor negative metastatic breast cancer: a phase II trial of the Cancer and Leukemia Group B (CALGB). 757 4

Droloxifene (3-hydroxytamoxifen) is a new, nonsteroidal antiestrogen. In comparison with tamoxifen, it has a 10- to 64-fold higher affinity for the estrogen receptor and has shown a lower estrogenic and higher antiestrogenic effect in experimental studies. The objective of this study was to determine the toxicity (and its reversibility) of droloxifene given at different doses to patients with advanced metastatic breast cancer refractory to conventional endocrine therapy and chemotherapy. In this study, 30 patients were treated in groups of 6 at 5 different doses (20, 40, 100, 200, and 300 mg) by mouth once a day. Toxic effects included hot flashes, nausea, and fatigue and were not dose-related. Toxicity did not require any dose reduction or discontinuation of therapy. There was one episode of deep venous thrombosis and pulmonary embolism. There was no complete or partial response in this study, but four patients showed a minor response (13%). These data illustrate that this drug is well tolerated and needs to be further evaluated in phase II and III studies.
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PMID:Phase I trial of droloxifene in patients with metastatic breast cancer. 828 25

We concluded a randomized crossover trial comparing tamoxifen 40 mg daily with ovarian ablation for treatment of metastatic breast cancer in premenopausal women. Objective responses (complete response (CR) plus partial response (PR)) were observed in 5/20 patients treated initially with tamoxifen and in 3/19 patients initially treated with ovarian ablation (p = 0.69). Seven additional patients were stable (SD) on tamoxifen while five additional patients were stable after ovarian ablation, for CR + PR + SD rates of 12/20 (60%) for tamoxifen and 8/19 (42%) for ovarian ablation (p = 0.34). Median time to disease progression was 184 days for tamoxifen and 126 days for ovarian ablation (p = 0.40, logrank test, odds ratio for progression 0.71). Overall survival times were also similar: a median of 2.35 years for tamoxifen and 2.46 years for ovarian ablation (p = 0.98, logrank test, odds ratio for death 1.07). Side effects from tamoxifen included hot flashes and menstrual abnormalities. With one exception, these toxicities were not sufficient to require dose reduction. In this small study, tamoxifen was associated with similar response rates, response durations, and survival times to those observed with ovarian ablation.
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PMID:A randomized crossover trial of tamoxifen versus ovarian ablation for metastatic breast cancer in premenopausal women: a report of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial MA.1. 926

The role of anastrozole, a new selective aromatase inhibitor, in treating hormone-responsive metastatic breast cancer is discussed. Treatment options for hormone-dependent breast cancer focus on interfering with the endocrine system in an attempt to modify the effects of estrogen. Tamoxifen is the drug of choice for primary endocrine therapy, but there is a need for agents with similar or greater efficacy and better tolerability. Anastrozole inhibits the conversion of androgens to estrogens by aromatase. Bioavailability studies have demonstrated almost complete absorption of anastrozole after oral administration. The drug's terminal half-life after multiple doses is 50 hours. Anastrozole is cleared principally by the liver. Clinical trials comparing anastrozole with megestrol acetate demonstrated no significant differences in clinical efficacy, although a follow-up study revealed a longer median overall survival rate in patients receiving anastrozole. The drug is well tolerated. Among the most frequently reported adverse effects are asthenia, hot flashes, headache, and back pain. The recommended dosage is 1 mg daily. The average wholesale cost of month's supply of anastrozole is $187.20, compared with approximately $100 for generic megestrol acetate or aminoglutethimide plus hydrocortisone. Although anastrozole will likely become the preferred second-line agent in the treatment of postmenopausal breast cancer in patients with disease progression after tamoxifen therapy, it is not a therapeutic alternative to aminoglutethimide on the basis of approved indications. Anastrozole and other aromatase inhibitors may have multiple applications in treating hormone-responsive breast cancer.
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PMID:Anastrozole: a selective aromatase inhibitor for the treatment of breast cancer. 952 27

One hundred fifty-one postmenopausal women with progressive metastatic breast cancer and no prior hormonal therapy were treated with either diethylstilbestrol (DES) or tamoxifen (TAM). One hundred forty-three eligible patients were followed until death or for a minimum of 14.1 years on the DES arm or 16.7 years on the TAM arm. The overall objective response was 42% for DES and 33% for TAM (p = 0.31) and the median duration of response was 11.8 months for DES and 9.9 months for TAM (p = 0.38). Duration of response and progression-free survival were not found to be significantly different between DES and TAM (p = 0.32 and 0.65, respectively). The median survival was 3.0 years for DES vs. 2.4 years for TAM. The 5-year survival was 35% for the DES arm and 16% for the TAM arm. Survival was significantly better for women on DES than for women on TAM (adjusted p = 0.039). Review of records did not show any difference in pattern of treatment failure or subsequent treatments in the DES and TAM arms. Treatment with DES was more commonly associated with toxicity such as nausea, edema, vaginal bleeding, and cardiac problems, whereas hot flashes were commonly seen with TAM therapy. The initial treatment with DES is associated with increased survival. The basis of this survival advantage is not known. TAM still is the preferred agent in the treatment of metastatic breast cancer, but this trial underscores the fact that estrogens have activity and remain in the armamentarium for treatment of selected patients with metastatic breast cancer.
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PMID:Randomized trial of diethylstilbestrol vs. tamoxifen in postmenopausal women with metastatic breast cancer. An updated analysis. 1042 2

Toremifene is a chlorinated triphenylethylene derivative of tamoxifen approved for use in the treatment of patients with metastatic breast cancer. Toremifene is well tolerated in patients, and common adverse effects of this drug include vasomotor symptoms such as hot flashes and vaginal discharge. This compound is administered to patients orally at a dose of 60 mg/day, although alternative methods of administration have been investigated. Oral bioavailability is estimated to be approximately 100%. At steady state, toremifene and its metabolites are highly protein bound (>95%). Toremifene is metabolised in the liver by cytochrome P450 enzymes, and it is eliminated primarily in the faeces following enterohepatic circulation. The half-life of toremifene is approximately 5 days, and steady state is reached by 6 weeks depending on the dose given. The pharmacokinetics of toremifene have been shown to be altered by certain liver conditions, but age and kidney function do not appear to be as significant.
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PMID:Clinical pharmacokinetics of toremifene. 1110 32

Patients with hormone-sensitive breast cancer who have responded to tamoxifen may receive additional benefit from a second endocrine agent following progression or relapse after tamoxifen therapy. Fulvestrant (Faslodex((R)), ICI 182780, AstraZeneca Pharmaceuticals; Wilmington, Delaware) is a selective antagonist of estrogen designed to have no estrogenic effects. Lack of aqueous solubility led to the development of a parenteral formulation for monthly intramuscular administration. Fulvestrant has been shown to inhibit the proliferative effects of estrogen on sensitive tissues in vitro and in vivo, and is without apparent measurable estrogenic activity. The data upon which marketing approval for fulvestrant was based are summarized below. Eight hundred fifty-one postmenopausal women with advanced breast cancer were enrolled in two phase III studies, 400 in a North American double-blind study and 451 in a European open-label study, comparing the efficacy and safety of fulvestrant with anastrozole. Four hundred twenty-eight patients were randomized to receive fulvestrant 250 mg monthly by intramuscular injection and 423 patients were to receive anastrozole 1 mg daily. Patients were considered hormone sensitive either by receptor status or previous response to endocrine therapy. Over 96% of patients had previously received tamoxifen, either in the adjuvant setting or as treatment for metastatic disease. The primary study end points were response rate and time to progression. Response rates for patients treated with fulvestrant were 17% and 20% in the North American and European trials, respectively, compared with 17% and 15% in the anastrozole treatment arms. There were no statistically significant differences in response rates, time to progression, or survival between treatment arms in either study. The most common adverse events attributed to the treatment (>10%) were injection-site reactions and hot flashes. Common events (1%-10%) included asthenia, headache, and gastrointestinal disturbances (nausea, vomiting, and diarrhea), as well as rash and urinary tract infections. A small increase in joint disorders was reported in the anastrozole-treated patients. On April 25, 2002, fulvestrant 250 mg by monthly intramuscular injection was approved by the U.S. Food and Drug Administration for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. Approval was based on similarity of response rates and time to progression between fulvestrant and anastrozole.
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PMID:FDA drug approval summaries: fulvestrant. 1249 Jul 35

The role of hormonal therapy for the treatment of patients with early stage breast cancer has been evaluated in many studies. The results of these studies establish tamoxifen as the gold standard of hormonal therapy for the adjuvant treatment of hormone receptor-positive invasive breast cancer in pre- and postmenopausal women. Studies show tamoxifen reduces the risk of invasive breast cancer in women at increased risk for the disease, including women with ductal carcinoma in situ. Tamoxifen has adverse effects such as hot flashes, increased risk of uterine cancer in postmenopausal women, and rare occurrence of thromboembolic disease. Despite the multiple therapeutic roles of tamoxifen, alternatives are needed. Aromatase inhibitors (AI) are drugs with antiestrogenic activity. AIs function by inhibiting the peripheral conversion of adrenally synthesized androstenedione to estradiol through inhibition of the aromatase enzyme. AIs do not suppress estradiol synthesis by the ovary adequately. Therefore, AIs are effective in reducing circulating estradiol levels in postmenopausal women, but not premenopausal women. Selective nonsteroidal AIs, including anastrozole (Arimidex; AstraZeneca, Wilmington, DE) and letrozole (Femara; Novartis, East Hanover, NJ), and the steroidal AI exemestane (Aromasin; Pharmacia, Peapack, NJ) have been associated with increased specificity and improved therapeutic index compared to nonselective AIs such as aminoglutethamide. Nonsteroidal and steroidal AIs have demonstrated to be superior to megestrol acetate in second-line therapy of postmenopausal women with metastatic breast cancer, and selective nonsteroidal AIs have shown to be superior to tamoxifen in first-line therapy of postmenopausal women with metastatic breast cancer. The ATAC (Arimidex, tamoxifen, alone, or in combination) trial is the only published randomized trial comparing the efficacy of an AI to tamoxifen for the adjuvant treatment of women with early breast cancer. This large study showed that at a median follow-up time of 33 months, anastrozole alone results in significant improvement in disease-free survival rates, reduction in contralateral breast cancers, and increased tolerability, compared to tamoxifen in postmenopausal women. Although the long-term effects of AIs are not known, the early positive results of the ATAC trial led to the approval of anastrozole by the US Food and Drug Administration for use as adjuvant hormonal therapy for postmenopausal women with hormone receptor-positive invasive breast cancer. Thus, there is an alternative to tamoxifen for postmenopausal women with relative/absolute contraindications to tamoxifen use or patients who choose not to take tamoxifen because of its side-effect profile. New AIs may challenge the position of tamoxifen as the gold standard for the treatment of early stage breast cancer in postmenopausal women.
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PMID:The role of aromatase inhibitors in early breast cancer. 1259 39


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