Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tamoxifen is the most widely prescribed anti-neoplastic drug for the treatment of both localized and metastatic breast cancer. It is also the prototype for a class of drugs that are referred to as selective estrogen receptor modifiers (SERMs), most of which have both estrogenic and anti-estrogenic activity in estrogen target tissues including the breast and endometrium. The underlying mechanisms of action of SERMs in the breast and endometrium that lead to profound differences in the tissue-specific effects of tamoxifen have not yet been elucidated. We have compared the effects of tamoxifen and the pure anti-estrogen ICI 182,780 (Faslodex) in the RUCA-I hormone-responsive rat endometrial cell line in vitro and in vivo. In cell culture, RUCA-I cells responded to both estrogens and anti-estrogens, and the expression of clusterin and complement C3 mRNAs required the presence of estradiol and was repressed in the absence of estradiol or in the presence of the pure anti-estrogen ICI 182,780. Tamoxifen, on the other hand, induced both complement C3 and clusterin mRNA in the absence of estradiol and failed to repress their expression in the presence of estradiol. When grown as subcutaneous xenografts in syngeneic Da/Han rats for 5 weeks, the RUCA-I cells retained their sensitivity to estradiol, as demonstrated by significantly enhanced tumor growth in intact female rats compared with the growth in ovariectomized rats. But neither ICI 182,780 nor tamoxifen had a significant impact on tumor growth in cycling or ovariectomized animals. On the other hand, tamoxifen was potently estrogenic in metastatic lymph nodes, increasing the size of the lymph node tumors almost 6-fold over that seen in the intact cycling animals. In primary tumors, the expression of complement C3 mirrored that seen in vitro, although tamoxifen showed some agonist activity in ovariectomized animals. Tamoxifen also displayed marked agonist activity with respect to clusterin expression and enhanced clusterin mRNA levels and protein in both the primary tumors and lymph metastases in intact and ovariectomized animals. Given the recent demonstration that over-expression of clusterin increases the metastatic potential of breast cancer cells, these data may provide a mechanistic explanation for the increased incidence of endometrial cancer in postmenopausal patients treated with tamoxifen.
 ...
PMID:Tamoxifen exerts agonistic effects on clusterin and complement C3 gene expression in RUCA-I primary xenografts and metastases but not normal uterus. 1561 55

Third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, are active and well tolerated in postmenopausal patients with hormone-sensitive advanced or metastatic breast cancer, as either first- or second-line therapy. These agents are being investigated as neoadjuvant therapy of locally advanced breast cancer and as adjuvant therapy of early breast cancer. In a large neoadjuvant study, letrozole resulted in significantly more responses than tamoxifen, with significantly more patients becoming eligible for breast-conserving surgery. Greater letrozole responses were associated with high and low levels of estrogen receptor expression and with coexpression of ErbB-1 and/or ErbB-2. Neoadjuvant anastrozole, in two studies, was also significantly superior to tamoxifen in rendering patients eligible for breast-conserving surgery. In the adjuvant setting, the Arimidex, Tamoxifen Alone or in Combination trial compared 5 years of anastrozole versus tamoxifen versus the combination. At 47 months' median follow-up, disease-free survival was significantly improved with anastrozole compared with the other arms. In the Intergroup Exemestane Study, switching to exemestane after 2 to 3 years of tamoxifen significantly improved disease-free survival compared with remaining on tamoxifen for 5 years. The MA.17 trial evaluated switching to letrozole versus placebo following 5 years of adjuvant tamoxifen, and letrozole was significantly superior to placebo in disease-free survival. While all three aromatase inhibitors as adjuvant therapy were well tolerated, long-term effects on bone health and lipids are being monitored. Ongoing trials will better define the optimum use of aromatase inhibitors as adjuvant therapy.
 ...
PMID:Aromatase inhibitors in early breast cancer therapy. 1571 96

Endocrine therapy of hormone receptor-positive breast tumors is widely used as palliative therapy for metastatic breast cancer and as adjuvant therapy for early stage breast cancer. Tamoxifen has been the definitive standard of hormonal therapies for the last 30 years because of its documented efficacy and reasonable safety profile. Based on encouraging results from trials utilizing the selective, third generation aromatase inhibitors (AIs) in metastatic breast cancer, a number of trials were designed to examine these agents as adjuvant therapies. Trials directly comparing AIs with tamoxifen have, to date, demonstrated superior disease-free-survival with AIs. Likewise, trials examining the use of AIs after tamoxifen have demonstrated better outcomes compared with tamoxifen alone. Additionally, letrozole has been demonstrated to result in superior disease-free-survival after 5 years of adjuvant tamoxifen, compared with no further therapy. In general, the AIs are tolerated at least as well as tamoxifen but decrease bone mineral density and increase osteoporosis due to their lack of estrogenic effects on bone. Based on the fact that AIs appear more effective at preventing contralateral breast cancers than tamoxifen, they are being examined as breast cancer preventives. Despite available data using the AIs as adjuvant therapies, many questions remain unanswered, and further trials will be needed to address these important issues.
 ...
PMID:Aromatase inhibitors as adjuvant therapy for postmenopausal patients with early stage breast cancer. 1589 Jun 38

In a review of current information on aromatase inhibitors (AIs) and their use in breast cancer treatment and prevention, published reports were obtained through a Medline search. Tamoxifen, a selective estrogen receptor modulator, is approved for use in metastatic breast cancer (MBC), the adjuvant treatment of breast cancer, and the prevention of breast cancer in women at high risk. The 50% reduction in breast cancer incidence seen with tamoxifen is significant for women at increased risk but is accompanied by notable toxicities such as thrombotic events and endometrial cancer. Therefore, the development of other effective agents with less toxicity would be a major advance in breast cancer prevention. Aromatase inhibitors, recently approved for the treatment of MBC and in the adjuvant setting, are proving to be slightly more effective than tamoxifen therapy. These drugs, approved for use in only postmenopausal women, inhibit the enzyme aromatase and thereby lower circulating functional estrogen. To date, the most concerning side effect of these agents is an increase in fracture rate. Compared with tamoxifen, thrombotic events and endometrial cancer rates are much lower. Ongoing data from the Arimidex, Tamoxifen, Alone or in Combination trial continue to favor anastrozole over tamoxifen in the reduction of primary contralateral breast cancers. This information has prompted breast cancer chemoprevention trials with AIs. Although tamoxifen is the gold standard for prevention therapy, results of ongoing studies may indicate a role for AIs in the prevention of breast cancer.
 ...
PMID:Aromatase inhibitors for the treatment and prevention of breast cancer. 1589 70

Tamoxifen is used as adjuvant therapy for prevention and treatment of metastatic breast cancer, whereas raloxifene is approved for osteoporosis and is being investigated for breast cancer prevention. The most important aspects of these therapies are focused on their influence on bone and lipid metabolism. Several studies have reported the effect of tamoxifen and raloxifene on plasma lipids. Approximately 40% of total cholesterol removal occurs by conversion to bile acids, a process that takes place in the liver. The aim of the present study was to evaluate the influence of tamoxifen and raloxifene on the conversion of cholesterol to bile acids in estrogen-deficient in rats. The study included 40 female Wistar rats, divided into four groups: sham-operated controls, ovariectomized controls, ovariectomized rats treated with tamoxifen and ovariectomized rats treated with raloxifene. After 42 days of drug administration, bile was collected under anesthesia following administration of radioactive [4-(14)C]cholesterol and assayed for total (14)C radioactivity; (14)C-labeled bile acids were determined by the use of isotopic techniques after initial separation by thin-layer chromatography. Ovariectomy caused decreased excretion of bile and bile acids. Administration of tamoxifen and raloxifene significantly reduced the excretion of (14)C-labeled bile and bile acids compared with ovariectomized controls. Tamoxifen therapy significantly reduced the excretion of taurocholic acid and glycochenodeoxycholic plus glycodeoxycholic acids, and excretion of cholic, litocholic and chenodeoxycholic plus deoxycholic acids was increased. Raloxifene significantly reduced the excretion of taurocholic, glycocholic and litocholic acids, taurochenodeoxycholic plus taurodeoxycholic acids, as well as chenodeoxycholic plus deoxycholic acids. The results of the present study suggest that tamoxifen and raloxifene did not reverse the changes in bile composition induced by estrogen deficiency. The decreased concentration of trihydroxy bile acids during therapy with raloxifene might decrease the risk of gallstone formation, although this hypothesis requires further investigation.
 ...
PMID:Effect of tamoxifen and raloxifene on cholesterol transformation to bile acids in ovariectomized rats. 1601 79

Toremifene (TOR), a selective estrogen receptor modulator (SERM), showed efficacy equivalent to Tamoxifen (TAM) in terms of the objective response rate, stable disease, time to progression and overall survival in patients with metastatic breast cancer (MBC). High-dose TOR is also effective for patients with TAM-resistant breast cancer. We tried to study retrospectively the efficacy and the safety of high-dose TOR treatment for patients with MBC in our hospital. Ten patients received TOR 120 mg daily. Most of the patients were treated with one or more endocrine agents before high-dose TOR. Objective response and clinical benefits were found in 3 patients (30%) and 7 patients (70%), respectively. Median time to progression and median overall survival were 9 months and 21.5 months, respectively. In our study,we found the efficacy for patients with hormone receptor negative, TAM resistance and aromatase inhibitor (AI)-resistance breast cancer. Adverse events induced by high-dose TOR treatment were tolerable. High-dose TOR may be one of the optional treatments for patients with MBC after TAM and AI treatment.
 ...
PMID:[Experience of high-dose toremifene treatment for postmenopausal women with metastatic breast cancer]. 1622 40

Five years of adjuvant endocrine therapy with the antiestrogen tamoxifen has been shown to significantly reduce the risk of recurrence in women with early breast cancer and has thus been the standard of adjuvant therapy for this malignancy over the last two decades. Tamoxifen has also been used for the first-line treatment of advanced or metastatic breast cancer, and it was studied in the neoadjuvant setting to promote breast-conserving surgery in those patients who may be otherwise ineligible. However, comparative clinical trials involving the more recently approved third-generation aromatase inhibitor drugs (anastrozole, letrozole, and exemestane) have challenged tamoxifen as first-line therapy in advanced/metastatic breast cancer as well as in the neoadjuvant setting. Although trials with other AIs have shown improved efficacy and better tolerability over tamoxifen, letrozole has consistently demonstrated superiority over tamoxifen when used as first-line treatment for advanced/metastatic breast cancer or as neoadjuvant therapy. The efficacy of letrozole in the neoadjuvant setting further extends to those tumors with positive human epidermal growth factor receptor (HER1) and/or HER2 expression, which are often less responsive to tamoxifen. The encouraging results of such trials identify letrozole as a better alternative to tamoxifen in improving responses rates in the treatment of advanced breast cancer and as neoadjuvant therapy, which allows breast-conserving surgery in women with inoperable breast cancer or who were not candidates for breast-conserving surgery.
 ...
PMID:Review of the development of letrozole and its use in advanced breast cancer and in the neoadjuvant setting. 1650 Feb 35

Tamoxifen has been a standard adjuvant therapy, despite its limited 5-year efficacy window and risk of thromboembolism and endometrial malignancy. The potent aromatase inhibitor letrozole (Femara) has emerged as a viable alternative to tamoxifen for the treatment of advanced, metastatic breast cancer, as well as in the neoadjuvant and extended adjuvant settings. Here we describe the first efficacy and safety analysis of BIG 1-98, a large, randomized, independently conducted clinical trial designed specifically to assess and compare the efficacy of sequential or up-front use of letrozole and/or tamoxifen as adjuvant therapy for patients with early breast cancer. The analysis reported here combined the monotherapy arms of letrozole and tamoxifen with the truncated sequential arms. Patients randomized to letrozole had a 19% reduction in the risk of a disease-free survival event (hazard ratio 0.81; P=0.003), especially reducing distant metastases (hazard ratio 0.73; P=0.0012). These results establish letrozole as part of standard adjuvant therapy for postmenopausal women with endocrine-responsive breast cancer.
 ...
PMID:The evolving role of letrozole in the adjuvant setting: first results from the large, phase III, randomized trial BIG 1-98. 1650 Feb 37

The majority of breast cancers in male patients are hormone receptor positive. Tamoxifen has proven to be successful in both adjuvant and metastatic settings and remains the standard of care. Given the improved outcomes in female patients with aromatase inhibitors (AI), these drugs have become a potential therapeutic tool for male patients. Preliminary data show effective suppression of oestradiol levels in males treated with AI and some reports have demonstrated objective responses. Here we report a case of a male patient with metastatic breast cancer treated with letrozole who achieved clinical response associated with a decrease in blood oestradiol levels.
 ...
PMID:Aromatase inhibitors and male breast cancer. 1740 31

A retrospective analysis was performed on 31 consecutive locally advanced or metastatic breast cancer patients who commenced exemestane 25mg/d orally following previous treatment with Tamoxifen and a non-steroidal third-generation aromatase inhibitor (AI). Patients were seen 3 monthly until clinical or radiological disease progression. Median age was 64 years (range 34-90 yrs). The average number of recurrences before starting exemestane was three (range 1-6). There were two complete responses (CR), four partial responses (PR), 12 with stable disease (SD) and 12 with progressive disease (PD). Objective response rate (CR+PR) was 19.4% and overall clinical benefit (CR+PR+SD >or= 24 weeks) was 54.8%. The median durations of objective response and overall clinical benefit were 18 and 14 months, respectively. This data support the anti-tumour activity of exemestane 25mg daily in patients with locally advanced and/or metastatic breast cancer who have been previously exposed to non-steroidal AIs and Tamoxifen.
 ...
PMID:Exemestane after non-steroidal aromatase inhibitors for post-menopausal women with advanced breast cancer. 1741 75


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>