Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over the last 20 years tamoxifen, a selective estrogen receptor modulator, has been shown to be of clinical benefit to patients with advanced and resected hormone receptor-positive breast cancer. Tamoxifen has also been evaluated as a risk-reducing agent among patients at a high risk for the development of breast cancer and found to be effective, although it is associated with untoward adverse events (ie, stroke, venous thrombosis, and endometrial cancer). Recent analysis of National Surgical Adjuvant Breast and Bowel Project tamoxifen trials confirms that an increased risk for developing various endometrial malignancies exists across these protocols. Raloxifene, a selective estrogen receptor modulator available to treat osteoporosis, may also reduce the risk for developing breast cancer. The National Surgical Adjuvant Breast and Bowel Project is now comparing the risk-reducing activities of tamoxifen and raloxifene in women considered to be at a high risk for developing breast cancer. As newer potential risk-reducing agents are identified and placed into clinical prevention trials, patient selection, trial implementation methods, and accrual strategies must be developed to insure both that appropriate accrual targets are achieved and that women at clinically significant risk levels are accrued.
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PMID:A review of selective estrogen receptor modulators and national surgical adjuvant breast and bowel project clinical trials. 1461 21

Breast cancer remains the most common malignancy in women worldwide. Oestrogen levels appear to be associated with an increased risk for the development of breast cancer. The Early Breast Cancer Trialists' Cooperative Group reported in a 1998 meta-analysis of 37000 breast cancer patients in 55 randomized adjuvant trials that tamoxifen, a selective oestrogen receptor modulator, reduced the incidence of contralateral breast cancers by 47% at 5 years. Tamoxifen has been shown in numerous prevention studies to decrease the incidence of breast cancer in high-risk women. Overall, the tamoxifen prevention trials showed a 38% reduction in the incidence of breast cancer (95% CI 28-46; P<0.0001). In the largest risk-reduction trial, the Breast Cancer Prevention Trial conducted by the National Surgical Adjuvant Breast and Bowel Project, tamoxifen reduced the risk of invasive breast cancer by 49% (two-sided P<0.00001), and non-invasive breast cancer by 50% (P<0.002). The occurrence of oestrogen receptor-(OR)-positive tumours decreased by 69%. Tamoxifen reduces the risk of developing oestrogen receptor-positive tumours, but OR-negative tumours are not affected. Rare but life-threatening side-effects of tamoxifen include endometrial carcinoma, thromboembolic events and cerebrovascular events. Less serious side-effects include cataracts, vasomotor instability, nausea and vaginal discharge. Raloxifene, a second-generation selective oestrogen receptor modulator, is approved for treatment of osteoporosis in post-menopausal women in the USA but it is not currently approved for breast cancer prevention outside of a clinical trial. Prevention studies involving raloxifene and aromatase inhibitors are currently being conducted.
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PMID:Endocrine prevention of breast cancer using selective oestrogen receptor modulators (SORMs). 1468

Raloxifene (Evista, Eli Lilly), a selective estrogen receptor modulator (SERM) and ligand for the estrogen receptor (ER), competes with endogenous estrogen for ER binding. Raloxifene is approved for the prevention and treatment of osteoporosis, and shows promise as a breast cancer prevention drug. Raloxifene may be a preferred agent over tamoxifen due to its side-effect profile; in particular, it does not stimulate the endometrium and is not associated with endometrial cancer. The mechanisms for the differential tissue effects of raloxifene compared with other SERMs are not completely understood; the roles of ERalpha and -beta, classic and alternative signaling pathways, and drug conformation are discussed in this review. The utility of raloxifene will depend on the outcome of trials that are now underway, as well as acceptance by high-risk women and their healthcare practitioners.
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PMID:Raloxifene and its role in breast cancer prevention. 1527 Jun 57

The Multiple Outcomes of Raloxifene Evaluation (MORE) Trial enrolled 7,705 women with osteoporosis, defined by prevalent vertebral fractures and/or a bone mineral density (BMD) T score at -2.5 or below, who were treated with placebo or raloxifene at a dosage of 60 or 120 mg/day for 3 years. Raloxifene hydrochloride therapy significantly reduces the risk for vertebral fractures at 3 and 4 years administration group. The fact that Raloxifene administration causes the significant 25% reduction in overall risks in postmenopausal women indicate a favorable risk-benefit profile. These data suggested that raloxifene is effective to protect from the occurrence of bone fracture without causing increases of breast cancer and endometrial cancer, and improve overall health conditions in postmenopausal women.
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PMID:[SERM & bone metabolism: protective effects of SERM against fracture risk and its long-term beneficial effects]. 1557 28

The incidence of newly diagnosed breast cancer cases world-wide is expected to double by 2020. Risk-reducing strategies for breast cancer include lifestyle modifications, chemoprevention and surgery (bilateral mastectomy and/or oophorectomy). Lifestyle modifications include avoidance of postmenopausal obesity and hormone replacement therapy (HRT), regular physical activity, and restriction of alcohol and animal fat intake. Tamoxifen is a selective estrogen receptor modulator (SERM) shown in randomized controlled trials to reduce the incidence of estrogen receptor (ER)-positive breast cancer in high-risk healthy women. However, its routine use cannot be recommended for breast cancer prevention in healthy women due to its significant adverse effects, specifically in terms of endometrial carcinoma and thromboembolism. On the other hand, tamoxifen may be used for chemoprevention in women at high risk of developing ER-positive breast cancer and at low risk of developing complications. Raloxifene, another SERM, also appears to be effective in reducing breast cancer risk, and lacks the unwanted stimulatory effect on the uterus. Other promising chemopreventive agents currently under investigation include cyclo-oxygenase 2 (COX-2) inhibitors, fenretinide, aromatase inhibitors, and goserelin. Prophylactic mastectomy can reduce breast cancer risk by 90% in high-risk women. Bilateral oophorectomy has the potential of reducing the risk of both breast and gynecologic cancer in women carrying BRCA-1 or BRCA-2 mutations. Further research is required to identify novel strategies to prevent ER-negative breast cancer, minimize the adverse effects of tamoxifen and other SERMs, and evaluate the role of mammary ductal lavage and ductoscopy in guiding risk-reducing strategies.
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PMID:Risk-reducing strategies for breast cancer--a review of recent literature. 1564 97

In the United States, an estimated 211,240 new cases of breast cancer were diagnosed in 2005 and approximately 40,410 deaths occurred. In recent years, a number of randomized prospective trials have investigated the use of antiestrogens as a means to reduce the incidence of breast cancer. We aim to describe the results of these trials as they pertain to postmenopausal women. In the Breast Cancer Prevention Trial and the International Breast Cancer Intervention Study-I, tamoxifen reduced the risk of invasive breast cancer by 55% and 30%, respectively, among older participants. However, tamoxifen is associated with adverse events including thromboembolic disease and endometrial cancer. The Multiple Outcomes of Raloxifene Evaluation, aimed primarily at evaluating the use of raloxifene for the prevention of osteoporosis, demonstrated a 72% decreased breast cancer risk. Side effects of raloxifene include thromboembolic events, but not endometrial cancer. Results from the Study of Tamoxifen and Raloxifene trial comparing these two agents are expected in mid-2006. Ongoing chemoprevention trials are evaluating the use of the aromatase inhibitors. At present, tamoxifen is the only FDA-approved agent for breast cancer risk reduction. Decisions regarding its use must remain highly individualized, involving careful consideration of its risks versus benefits.
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PMID:Chemoprevention of breast cancer in postmenopausal women. 1691 41

In 1998, the concept of breast cancer prevention became a reality with the approval of tamoxifen to reduce the risk of developing breast cancer in women at increased risk for the disease. This approval was based on decades of research on selective estrogen receptor modulators providing an understanding of the role of the estrogen receptor in breast cell growth, and an appreciation of the carcinogenic process. Although results from the Breast Cancer Prevention Trial demonstrated a 49% reduction in breast cancer in women at increased risk, there were associated toxicities related to the estrogenic effects of tamoxifen; that is, deep vein thrombosis, pulmonary embolism, and endometrial cancer. In an effort to improve its benefit-risk profile, tamoxifen is now being compared with raloxifene, a selective estrogen receptor modulator approved for the treatment and prevention of osteoporosis. This equivalency prevention Study of Tamoxifen and Raloxifene completed accrual of 19 747 high-risk postmenopausal women in November 2004. Meanwhile, another class of estrogen-directed drugs, the aromatase inhibitors, have shown efficacy in breast cancer adjuvant trials, spawning a number of prevention trials that have recently been initiated. As with breast cancer the hormonal contribution to prostate carcinogenesis was the basis for the Prostate Cancer Prevention Trial which showed that finasteride, an androgen antagonist, reduces the incidence of prostate cancer compared to placebo.
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PMID:Hormonal interventions to prevent hormonal cancers: breast and prostate cancers. 1741 94

Tamoxifen and raloxifene are both selective estrogen receptor modulators (SERMs). The medicines can block estrogen mediated breast cancer growth and development but will also maintain bone density in postmenopausal women and lower circulating cholesterol. Tamoxifen has remained the antihormonal therapy of choice for the treatment of ER positive breast cancer for the last 30 years. However, although adjuvant tamoxifen produces profound increases in disease-free and overall survival in patients with ER positive breast cancer, concerns about drug resistance, blood clots and endometrial cancer have resulted in a change to the use of aromatase inhibitors for the treatment of postmenopausal women. Nevertheless, tamoxifen remains the antihormonal treatment of choice for premenopausal women with ER positive breast cancer and for risk reduction in premenopausal women who are at high risk for developing breast cancer. The risk of endometrial cancer and thromboembolic disorders during tamoxifen therapy is not elevated in premenopausal women. It is important to note that aromatase inhibitors or raloxifene should not be used in premenopausal women. Raloxifene is used to prevent osteoporosis in postmenopausal women and, unlike tamoxifen, does not increase the risk of endometrial cancer. However, raloxifene does reduce breast cancer risk by 50-70% in both low risk and high risk postmenopausal women. Comparisons of raloxifene with tamoxifen show equal efficacy as a chemopreventive for breast cancer but there is a reduction in thromboembolic disorders, fewer endometrial cancers, hysterectomies, cataracts and cataract surgeries in women taking raloxifene. Overall, SERMs continue to fulfill their promise as appropriate medicines that target specific populations for the treatment and prevention of breast cancer.
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PMID:SERMs for the treatment and prevention of breast cancer. 1744 Aug 19

Selective estrogen-receptor (ER) modulators (SERMs) are synthetic nonsteroidal compounds that switch on and switch off target sites throughout the body. Tamoxifen, the pioneering SERM, blocks estrogen action by binding to the ER in breast cancers. Tamoxifen has been used ubiquitously in clinical practice during the last 30 years for the treatment of breast cancer and is currently available to reduce the risk of breast cancer in high-risk women. Raloxifene maintains bone density (estrogen-like effect) in postmenopausal osteoporotic women, but at the same time reduces the incidence of breast cancer in both high- and low-risk (osteoporotic) postmenopausal women. Unlike tamoxifen, raloxifene does not increase the incidence of endometrial cancer. Clearly, the simple ER model of estrogen action can no longer be used to explain SERM action at different sites around the body. Instead, a new model has evolved on the basis of the discovery of protein partners that modulate estrogen action at distinct target sites. Coactivators are the principal players that assemble a complex of functional proteins around the ligand ER complex to initiate transcription of a target gene at its promoter site. A promiscuous SERM ER complex creates a stimulatory signal in growth factor receptor-rich breast or endometrial cancer cells. These events cause drug-resistant, SERM-stimulated growth. The sometimes surprising pharmacology of SERMs has resulted in a growing interest in the development of new selective medicines for other members of the nuclear receptor superfamily. This will allow the precise treatment of diseases that was previously considered impossible.
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PMID:Selective estrogen-receptor modulators and antihormonal resistance in breast cancer. 1789 78

Raloxifene (RAL) significantly reduced the incidence of breast cancer in women at high risk of developing the disease. Unlike tamoxifen (TAM), an increased incidence of endometrial cancer was not observed in women treated with RAL. However, RAL, having two hydroxyl moieties, can be conjugated rapidly through phase II metabolism and excreted, making it difficult to achieve adequate bioavailability by oral administration in humans. As a result, higher doses must be administered to obtain an efficacy equivalent to that achieved with TAM. To improve oral bioavailability and antitumor potential, RAL diphosphate was prepared as a prodrug. RAL diphosphate showed several orders of magnitude lower binding potential to both ER alpha and ER beta and weak antiproliferative potency on cultured human MCF-7 and ZR-75-1 breast cancer cells, as compared to RAL. However, RAL diphosphate has a much higher bioavailability than RAL, endowing it with higher antitumor potential than RAL against both 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats and human MCF-7 breast cancer implanted in athymic nude mice. The RAL prodrug may provide greater clinical benefit for breast cancer therapy and prevention.
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PMID:Increased antitumor potential of the raloxifene prodrug, raloxifene diphosphate. 1818 87


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