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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The widespread use of tamoxifen has led to significant improvements in survival for postmenopausal women with early-stage hormone receptor-positive breast cancer; however, approximately 30% of patients die despite receiving tamoxifen as adjuvant treatment. In addition, concerns exist regarding tamoxifen-associated side effects, including endometrial cancer and thromboembolic disease. The development of the third-generation aromatase inhibitors (AIs; anastrozole, exemestane, and letrozole) therefore represented a welcome potential alternative to tamoxifen. Several clinical trials have demonstrated the superiority of AIs over tamoxifen in the adjuvant treatment of postmenopausal women with hormone-sensitive breast cancer, but these trials differ in their design and in the characteristics of their patient populations. This review discusses the different designs of the primary adjuvant, switching, extended adjuvant, and sequencing trials that are investigating the use of AIs in the adjuvant treatment of breast cancer and provides direction regarding how the data from these trials could be used to guide treatment choice. This review also demonstrates why one should not extrapolate results from clinical trials to clinical situations that differ from the clinical trial or from clinical trials investigating a particular AI to clinical situations involving another AI.
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PMID:Defining the roles of aromatase inhibitors in the adjuvant treatment of early-stage breast cancer. 1627 79

Toremifene has been in clinical use for 8 years for the treatment of advanced hormone-sensitive breast cancer and the adjuvant treatment of early breast cancer. More than 350,000 patient treatment years have accumulated, sufficient to allow evaluation of its longer-term safety profile in comparison with tamoxifen and, where possible, with raloxifene and aromatase inhibitors. We reviewed all preclinical and clinical safety data from 1978 to 2004 and comparative clinical safety data between October 1995 and the end of 2004. Secondary endometrial cancer incidence was lower with toremifene than with tamoxifen and was similar to that with raloxifene. It is speculated that toremifene may unmask existing endometrial tumors rather than induce new events. The risk of stroke, pulmonary embolism, and cataract may be lower with toremifene than with tamoxifen and the risk of pulmonary embolism and deep vein thrombosis lower than with raloxifene. Beneficial estrogen agonistic effects were equivalent to those of tamoxifen regarding bone mineral density and superior regarding lipid profiles.
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PMID:Toremifene: an evaluation of its safety profile. 1628 4

Estrogen-dependent endometrial cancer is related to unopposed and prolonged estrogen stimulation. We examined the expression of estrogen-metabolizing enzymes in correlation with the ERalpha and ERbeta estrogen receptors in human endometrial Ishikawa adenocarcinoma cells and in endometrial cancer specimens and adjacent normal endometrium from the same patients. Real-time PCR analysis revealed that both estrogen receptors and selected estrogen-metabolizing enzymes were expressed in the Ishikawa cells and in endometrial tissue. We detected higher expression of ERalpha than ERbeta, higher expression of sulfatase than sulfotransferase and low expression of aromatase in the Ishikawa cells and the tissue, as well as higher levels of type 2 17beta-hydroxysteroid dehydrogenase (17beta-HSD) in normal and diseased tissue than in the Ishikawa cells. When we compared the expression in endometrial cancer samples and in the adjacent normal endometrium, ERalpha and ERbeta, sulfatase and sulfotransferase were seen to be downregulated in the majority of the cancerous tissue specimens.
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PMID:Expression analysis of estrogen-metabolizing enzymes in human endometrial cancer. 1633 31

Hormonal therapy and chemotherapy play a major role in the management of advanced or recurrent endometrial cancer. Progesterone therapy obtains overall response rates ranging from 11% to 25% in patients with endometrioid-type tumours, and oral medroxyprogesterone acetate 200mg daily appears to be a reasonable therapeutic option for those lesions that are well differentiated and/or have a high progesterone receptor (PgR) content. However, the activity of progestins is often compromised by the down-regulation of PgR within the target tissues, and therefore therapeutic strategies designed to enhance PgR expression are warranted. Little data are currently available about the new aromatase inhibitors and selective estrogen receptor modulators. As for chemotherapy, the combination of doxorubicin [DOX]+cisplatin [CDDP] achieves overall response rates ranging from 34% to 60%, and the addition of paclitaxel (TAX) seems to improve response rates, progression-free survival and overall survival, but to worsen toxicity profile. A phase III study is currently comparing TAX+DOX+CDDP versus the less toxic combination of TAX+carboplatin. Chemotherapy is active against both endometrioid-type carcinoma and uterine serous papillary carcinoma. However, this latter endometrial malignancy is less chemosensitive than the histologically similar high-grade serous ovarian carcinoma. Interesting fields of research are represented by investigational agents directed against specific intracellular signal transduction pathways involved in the proliferation, invasiveness and metastatic spread of endometrial cancer. Mammalian target of the rapamycin (mTOR) inhibitors, epidermal growth factor receptor inhibitors (gefitinib, erlotinib, lapatinib, the monoclonal antibody cetuximab), imatinib, the monoclonal antibody trastuzumab, and the Clostridium perfrigens enterotoxin are currently under evaluation as molecularly targeted therapies for endometrial cancer. Further investigations addressed to better understand the signal transduction pathways that are disregulated in endometrial carcinogenesis could identify novel biological targets suitable for tailored therapies.
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PMID:Old and new perspectives in the pharmacological treatment of advanced or recurrent endometrial cancer: Hormonal therapy, chemotherapy and molecularly targeted therapies. 1643 30

Generally, estrogens are considered to be involved in the neoplastic transformation of endometrium. After the menopause these estrogens mainly originate from conversion of adrenal androgens by aromatization in body fat. However, in case of stromal hyperplasia of the ovaries, it cannot be excluded that production of aromatizable androgens by postmenopausal ovaries leads to increased availability of androgen precursors for intratumoral estrogen synthesis in the endometrial tissue as well. The local presence of androgens and the local expression and activity of aromatase is considered important for this steroidogenesis. In this review, we will discuss the available evidence that androgens, produced in hyperplastic ovarian stroma or body fat tissues, play a role in the development of endometrial cancer through conversion into estrogens, a reaction catalyzed in the endometrium by the enzyme aromatase cytochrome P450. As the presence of aromatase appeared to be a pathophysiological factor in the formation of breast cancer, the latter will be evaluated in relation to the development of endometrioid endometrial cancer as well, since both disorders appear partly estrogen dependent. As treatment with aromatase inhibitors appeared feasible in breast cancer, current knowledge of comparable treatment modalities in hormone dependent endometrial cancer will be reviewed.
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PMID:Aromatase in the context of breast and endometrial cancer. A review. 1649 63

Breast cancer remains a leading cause of cancer death in women worldwide, and the risk for disease recurrence continues despite improvements in screening and treatment and the use of prophylactic estrogen-inhibiting therapies such as tamoxifen. A number of long-term studies now indicate a significant risk for breast cancer recurrence among patients who have undergone the currently recommended five years of tamoxifen adjuvant therapy following successful treatment of their initial disease. This ongoing recurrence risk extends even to patients commonly considered at low risk for relapse, that is, those with low-grade, small tumors, and/or node-negative disease. Treatment with tamoxifen for more than five years appears detrimental rather than beneficial and, therefore, tamoxifen is not indicated for use beyond the initial five years. Endometrial cancer and thromboembolism are among the serious adverse events that have been observed with long-term tamoxifen treatment. The aromatase inhibitors are able to reduce overall estrogen levels and appear to be better tolerated over a long term. Letrozole is the most potent aromatase inhibitor and has been available in Europe since 1996 and in the United States since 1997. Letrozole has been approved for first-line treatment of postmenopausal women with hormone-receptor-positive or hormone-receptor-unknown, advanced or metastatic breast cancer in the United States and Europe, as well as for neoadjuvant treatment (primary systemic therapy) of early breast cancer prior to surgery in many countries. The results of the pivotal MA-17 trial demonstrate that letrozole is unique in its ability to improve disease-free survival in breast cancer patients who have undergone tamoxifen therapy for five years. The MA-17 results indicate that extended adjuvant therapy with letrozole reduces risk of recurrence in this setting by 42%, reduces risk of distant recurrence (metastasis), and may improve patient survival in the node-positive patient population. The results also show letrozole to be well tolerated and safe over the length of follow-up. The trial outcomes have led to the approval of letrozole for the extended adjuvant indication in more than 40 countries worldwide. Re-randomization of letrozole-treated patients from this pivotal trial is underway to investigate if ten years of extended adjuvant endocrine therapy leads to further improvement, and the results of this extension study should aid in resolving several open questions regarding extended adjuvant therapy, including who should be treated and for how long.
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PMID:Extended breast cancer treatment with an aromatase inhibitor (Letrozole) after tamoxifen: why, who and how long? 1662 Dec 29

Endogenous estrogen exposure is an important determinant of endometrial cancer risk. The CYP 17 and CYP 19 genes encode 17alphahydroxylase/17,20-lyase and aromatase, respectively, both involved in sex hormone synthesis. The genes CYP17 and CYP19 are polymorphic and gene variability could contribute to the level of protein biosynthesis. In the present work the distribution of genotypes and frequency of alleles of the C/T polymorphism in promoter region of CYP17 and G/A polymorphism at position Val80 in CYP19 in subjects with endometrial cancer were investigated. Paraffin embedded tumor tissues were obtained from 100 women with endometrial cancer. DNA from normal endometrial tissue (n=106) served as control. The polymorphisms were determined by PCR-RFLP. The distribution of the genotypes of the C/T polymorphism of CYP17 and G/A polymorphism of CYP19 in both control and patients did not differ significantly (p>0.05) from those predicted by the Hardy-Weinberg distribution. There were no significant differences (p>0.05) in genotype distributions and allele frequencies between subgroups assigned to histological stage. The results suggest that the C/T polymorphism of CYP17 gene as well as G/A polymorphism of CYP19 may not be linked with appearance and development of endometrial cancer.
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PMID:The polymorphisms of the CYP17 and CYP19 genes in endometrial cancer patients. 1673 81

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

Tamoxifen has provided the mainstay of endocrine therapy for more than 20 years. However, the development of the third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, has provided an alternative strategy for managing hormone-responsive breast cancer in postmenopausal women. The efficacy of the AIs as first- and second-line treatment for advanced disease has been demonstrated in several double-blind, randomised trials and they are now widely accepted in this setting. More recently evidence has emerged supporting the role of aromatase inhibitors in early breast cancer, either as 5 years of initial adjuvant therapy or following 2.5 or 5 years of tamoxifen as part of a switching strategy. Controversy remains over which is the optimal treatment strategy, due to a lack of trials directly comparing initial adjuvant therapy with switching. Nevertheless, the data indicate that the third-generation AIs provide superior recurrence benefits to tamoxifen in the adjuvant setting. In addition, the tolerability profiles of the AIs appear to be more acceptable than tamoxifen, with a reduction in serious adverse events such as endometrial cancer and thromboembolic events associated with the AIs compared with tamoxifen. Ongoing trials aim to clarify the role of the AIs in preoperative treatment and chemoprevention.
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PMID:Aromatase inhibitors: changing the face of endocrine therapy for breast cancer. 1691 43

Endocrine therapy that targets the estrogen receptor (ER) is a standard of care for the treatment of postmenopausal women with ER-positive breast cancer. The selective ER modulator (SERM) tamoxifen has been in use for the treatment of advanced breast cancer for more than 30 years and is currently a treatment option for all stages of ER-positive disease. Tamoxifen blocks the action of estrogen by binding to the ER, and possesses both ER-agonist and antagonist properties. Unfortunately, long-term use of tamoxifen is associated with several important concerns including an increased risk of endometrial cancer and thromboembolic complications. In addition, many patients who initially respond to tamoxifen eventually relapse with resistant disease. New treatment approaches are therefore required. A number of alternative SERMs have been tested as substitutes for tamoxifen. These include; toremifene, droloxifene, idoxifene, and keoxifene. Unfortunately, the SERMs have not proved to be more effective than tamoxifen for the treatment of advanced breast cancer and have shown a high level of cross-resistance with tamoxifen. The subsequent development of the aromatase inhibitors (AIs) is an important therapeutic advance by creating a "no estrogen" environment. Another approach is the development of pure antiestrogens. Fulvestrant is a novel ER antagonist that destroys the ER and its signaling pathway and is not associated with tamoxifen-like agonist effects. It produces high response rates compared with other SERMs and is not cross-resistant to tamoxifen or aromatase inhibitors and is equally as effective as the AI anastrozole in the treatment of postmenopausal women with advanced breast cancer who have progressed on prior adjuvant tamoxifen therapy. This review article discusses the significant and continuing value of SERMs for the treatment of postmenopausal ER-positive breast cancer.
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PMID:Treatment of Postmenopausal Breast Cancer with Selective Estrogen Receptor Modulators (SERMs). 1691 42


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