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 goals of treating patients with metastatic breast cancer are to prolong survival, slow or halt disease progression, and enhance the patient's quality of life. In patients with estrogen receptor (ER)-positive cancers that are not progressing rapidly, endocrine therapy is generally the first treatment option. If a patient initially responds to an endocrine agent and then progresses, another endocrine agent may still provide benefit. Tamoxifen has been used as first-line therapy for metastatic breast cancer for many years. Until recently, no other endocrine agent has shown superiority to tamoxifen in this setting. The nonsteroidal aromatase inhibitors, anastrozole and letrozole, have been widely accepted as second-line therapy after failure of tamoxifen; they have replaced megestrol acetate in this setting. Recently, anastrozole was shown to have at least equivalent efficacy and a superior side effect profile compared with tamoxifen for treating postmenopausal women in the first-line setting. Thus, this aromatase inhibitor has become a viable option for first-line therapy in postmenopausal women. Trials of letrozole in this setting are nearing completion. Exemestane has been shown to be an effective second-line agent and to have at least some efficacy as a third-line agent even after failure of a nonsteroidal aromatase inhibitor. Results are anxiously awaited from trials of new endocrine agents including the first member of a new class of endocrine agent, the estrogen-receptor downregulator class. Semin Oncol 28:291-304.
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PMID:Endocrine therapy in the treatment of metastatic breast cancer. 1140 39

Following the pivotal clinical trials of trastuzumab (Herceptin), further phase II and III studies have been initiated. Preliminary results from a phase II, dose-response study of single-agent trastuzumab in 113 HER2-positive metastatic breast cancer patients without prior chemotherapy for stage IV disease have shown that the overall response rate was 23% (six complete responses and 20 partial responses), with similar results using both standard- and high-dose regimens of trastuzumab. Another phase II study of trastuzumab plus paclitaxel, both given weekly, in 63 HER2-positive and -negative patients with metastatic breast cancer produced an overall response rate of 62% in HER2-positive and 44% in HER2-negative patients. A further phase II study is underway to investigate the combination of trastuzumab plus docetaxel in 30 HER2-positive patients with metastatic breast cancer. Finally, a number of European studies are at an advanced stage of planning or are about to start patient recruitment. These include docetaxel +/- trastuzumab, aromatase inhibitor +/- trastuzumab, CMF (cyclophosphamide, methotrexate, 5-fluorouracil) +/- trastuzumab, vinorelbine + trastuzumab, all in HER2-positive patients, and epirubicin-cyclophosphamide (EC) + trastuzumab in HER2-positive patients vs. EC alone in HER2-negative patients. The results from these trials should be available over the next one to two years.
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PMID:Ongoing trials with trastuzumab in metastatic breast cancer. 1152 25

Anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are members of the third generation of aromatase inhibitors that has now replaced aminoglutethimide (Cytadren), the progestins, and tamoxifen (Nolvadex) as the hormonal therapy of choice in estrogen-receptor-positive, postmenopausal, metastatic breast cancer. This article will review the role of aromatase in the pathogenesis of breast cancer and the results of recent studies that have established the role of its inhibitors in estrogen-receptor-positive breast cancer. We will also briefly outline the rationale and design of ongoing studies.
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PMID:Nonsteroidal and steroidal aromatase inhibitors in breast cancer. 1154 77

Presently, metastatic breast cancer cannot be cured and therefore good palliation of symptoms and longer overall survival make the most important targets, always considering quality of life. In addition to the established hormonal therapies or chemotherapy regimens, several recent advances have accelerated progress in metastatic breast cancer treatment. As demonstrated in recent studies, the third-generation aromatase inhibitors are playing a significant role in the improvement of the therapeutic approach. The development of new drugs with novel mechanisms of action, such as taxanes, used alone in innovative schedules or in association with other drugs (mainly the anthracyclines), vinorelbine and gemcitabine, or capecitabine, which is administered orally, has broadened the scope of metastatic breast cancer chemotherapy. A new investigation field is represented by high-dose chemotherapy with stem cell support, which has provided controversial preliminary results but is also acknowledged to deserve larger and randomized trials. Finally, the emergence of biological therapies such as the anti-HER2 monoclonal antibody Trastuzumab opens new and exciting prospects for the treatment of this disease. Moreover, the present trend is to try to rationalize the therapeutic approach on the basis of biological parameters which are prognostic and predictive of treatment response.
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PMID:Strategies of medical treatment for metastatic breast cancer (Review). 1156 48

Aromatase inhibition provides both paracrine/intracrine and endocrine treatment. Recent accumulated data clarified that 3rd generation aromatase inhibitors potently suppress intratumoral estrogen synthesis particularly in postmenopausal patients. In the 2nd-line treatment for metastatic breast cancer patients, aromatase inhibitors achieved results antitumor activity at least equal to and sometimes better than that of tamoxifen. In the first-line treatment for metastatic breast cancer patients, a recent pivotal study clearly demonstrated that aromatase inhibitor was superior to tamoxifen. Based upon these results, various adjuvant trials which compare aromatase inhibitors with tamoxifen and attempt to determine optimal combination therapies and treatment periods with aromatase inhibitors are currently being conducted. In addition, preliminary studies conducted in neoadjuvant setting indicated that aromatase inhibitors showed an extremely high response rate, which predicts a future paradigm, that neoadjuvant therapy using aromatase inhibitors singly or in combination may become standard for hormone-responsive and post-menopausal breast cancer patients.
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PMID:Aromatase and aromatase inhibitors. 1179 Nov 26

Letrozole (Femara; Novartis Pharmaceuticals Corp., East Hanover, NJ) is a nonsteroidal inhibitor of aromatase enzyme complex. It inhibits the peripheral conversion of circulating androgens to estrogens. In postmenopausal women, letrozole decreases plasma concentrations of estradiol, estrone, and estrone sulfate by 75-95% from baseline with maximal suppression achieved within 2-3 days of treatment initiation. Suppression is dose related, with doses of >or=0.5 mg giving estrone and estrone sulfate values that were often below assay detection limits. At clinically used dosage, letrozole does not impair adrenal synthesis of glucocorticoids or aldosterone. In 1998, letrozole was approved by the United States Food and Drug Administration (FDA) for the treatment of advanced breast cancer in postmenopausal women, with hormone receptor positive or unknown breast cancer, who had failed one prior antiestrogen treatment (i.e., for "second-line" treatment). Approval was based on two randomized trials comparing tumor RRs of patients receiving 0.5 mg of letrozole, 2.5 mg of letrozole, and either megestrol acetate (MA) or aminoglutethimide. In the megestrol trial, 2.5 mg/day letrozole was superior to 0.5 mg of letrozole and MA (RRs 24, 13, and 16%, respectively), whereas in the aminoglutethimide trial, there was no significant difference in 2.5 mg of letrozole and 0.5 mg of letrozole RRs (20 and 17%). There was a trend toward RR superiority of 2.5 mg of letrozole over aminoglutethimide (P = 0.06). Letrozole (2.5 mg) was the dose chosen for comparison with tamoxifen in the first-line setting. In July 2000, a marketing application for first-line letrozole treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer was submitted to the FDA. A single double-blind, double dummy, randomized, and multicenter trial compared 2.5 mg of letrozole to 20 mg of tamoxifen (456 patients/arm). Letrozole was superior to tamoxifen with regard to time to progression (TTP) and objective response rate (RR). The median TTP for letrozole treatment was 9.9 months [95% confidence interval (CI) 9.1-12.2] versus 6.2 months (95% CI 5.8-8.5) for tamoxifen, P = 0.0001, hazard ratio 0.713, (95% CI 0.61-0.84). RR was 32% for letrozole versus 21% for tamoxifen (odds ratio 1.74, 95% CI 1.29-2.34, P = 0.0003). Preliminary survival data (survival data are still blinded) indicate that letrozole is unlikely to be worse than tamoxifen. Both treatments were similarly tolerated. On the basis of these results, the United States FDA approved letrozole tablets, 2.5 mg/day, for first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer. The manufacturer made a commitment to provide updated information on survival.
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PMID:Approval summary: letrozole in the treatment of postmenopausal women with advanced breast cancer. 1189 93

The traditional hormonal cascade of the 1970s and 1980s used tamoxifen followed by megestrol acetate and subsequently by aminoglutethimide. In the 1990s, however, three trials of third-generation aromatase inhibitors (AIs) compared with megestrol acetate and two trials of third-generation AIs compared with aminoglutethimide showed improved efficacy and decreased toxicity for the newer AIs. Thus, the hormonal cascade changed in the late 1990s, to one in which tamoxifen, followed by a third-generation AI, followed by megestrol acetate, seemed more suitable. Now, however, several trials comparing anastrozole, letrozole, and exemestane to tamoxifen as first-line hormonal agents for metastatic breast cancer have shown that these drugs are at least equivalent and perhaps superior to tamoxifen in that setting in terms of response rate and time to progression. Results from 1021 patients randomized to receive anastrozole versus tamoxifen showed a slightly improved overall response rate (RR; 29% versus 26%), slightly improved clinical benefit (CB; 57% versus 52%), and a significantly improved time to progression (TTP; 8.5 months versus 7.0 months) in favor of anastrozole. In 907 women randomized to treatment with letrozole versus tamoxifen, significantly improved RR (30% versus 20%), CB (49% versus 38%), and TTP (9.4 months versus 6 months) have all been shown for those treated with letrozole. In addition, a randomized Phase II trial of 121 patients has shown nonsignificant benefits in favor of exemestane (RR 41% versus 14%; CB 56% versus 42%; TTP not available). To date, none of these trials has demonstrated any overall survival benefit. Additional follow-up in regard to survival in the trial of tamoxifen versus letrozole and an expanded Phase III trial of tamoxifen versus exemestane are ongoing.
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PMID:The role of tamoxifen and aromatase inhibitors/inactivators in postmenopausal patients. 1191 25

The indolent nature of estrogen-dependent breast cancer is the most important obstacle for development of new adjuvant endocrine treatments. Clinical trials require thousands of study participants and at least a decade of clinical investigation. How can we be sure that a new endocrine agent warrants this extraordinary level of investment? Traditionally, we have relied on advanced breast cancer trials to determine which drugs are suitable for adjuvant studies. However, with endocrine agents the high incidence of resistance in metastatic breast cancer may mask important advances in efficacy. Recent clinical results with the aromatase inhibitor letrozole suggest that neoadjuvant endocrine therapy is a highly informative additional approach to consider when planning adjuvant studies. In this report, new neoadjuvant endocrine therapy study designs are discussed that address the following issues: (a) the scientific opportunities afforded by gene microarray studies and other genetic technologies to investigate the molecular basis of estrogen-dependent breast cancer; (b) studies that address critical drug development questions as a prelude to adjuvant studies; and (c) the conduct of randomized trials that compare neoadjuvant chemotherapy with neoadjuvant aromatase inhibitor therapy to establish a place for neoadjuvant endocrine therapy in routine clinical practice.
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PMID:Neoadjuvant endocrine therapy for breast cancer: medical perspectives. 1191 29

Although SERMs are currently being evaluated and are approved for breast cancer prevention in several countries, aromatase inhibitors and inactivators may represent interesting options in this setting. The encouraging results revealing these drugs to be superior to conventional therapy in metastatic breast cancer confirm their therapy efficacy and suggest that they may also have a role in adjuvant therapy and even for breast cancer prevention. Secondly, whereas the bulk of "high-risk" breast cancer patients with confirmed founder mutations in the BRCA1 or BRCA2 genes develop their cancers earlier in life (during the premenopausal period), 75-80% of all breast cancers, in general, develop in postmenopausal women. Thus, in considering prevention of breast cancer in moderate-risk groups, strategies for prevention in postmenopausal women may play an important role. Also, among high-risk patients who have not developed breast cancer by the time of the menopause, aromatase inhibition could be a feasible option. Considering the potential hazards of long-term use of SERMs, switching to an aromatase inhibitor or inactivator in this setting may be beneficial. Finally, the observation that postmenopausal estrogen levels are related to subsequent risk of breast cancer in the general population underlines the potential for estrogen suppression as a preventive strategy. Results from ongoing studies examining the toxicity of aromatase inhibitors and inactivators in postmenopausal women will set the stage for future trials that explore them as preventive treatment options.
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PMID:The potential for aromatase inhibition in breast cancer prevention. 1191 35

Tamoxifen has dominated endocrine treatment of breast cancer for over two decades. It is useful in metastatic breast cancer, adjuvant therapy, preoperative treatment, ductal carcinoma-in-situ and chemoprevention. However, breast cancer may be refractory to tamoxifen or develop resistance to it with ongoing treatment. This resistance involves several mechanisms including receptor mutation causing 'estrogen hypersensitivity' and an increasing agonist effect of tamoxifen. Megestrol (megestrol acetate), in North America, and aminoglutethimide, in Europe, have been the traditional second line therapies after tamoxifen in advanced breast cancer. Aromatase (estrogen synthetase) inhibitors are a logical alternative to tamoxifen to antagonise the effects of estrogen on breast cancer. The third-generation non-steroidal aromatase inhibitors anastrozole, letrozole and vorozole, and the steroidal inhibitor exemestane, have been studied after tamoxifen versus either megestrol or aminoglutethimide. They showed enhanced efficacy and significantly superior toxicity profiles. Compliance with the inhibitors was also significantly better than with the traditional treatments. Aromatase inhibitors have most recently been shown to be superior to tamoxifen as initial therapy and are being extensively tested in the adjuvant setting after, or instead of, tamoxifen. Pilot studies of chemoprevention are also being undertaken. The aromatase inhibitors are an important new addition to the armamentarium of breast cancer therapy.
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PMID:Tamoxifen resistant and refractory breast cancer: the value of aromatase inhibitors. 1192 41


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