Endometrial safety: A key hurdle for selective estrogen receptor modulators in development

University of Virginia, Charlottesville, VA, USA.
Menopause (New York, N.Y.) (Impact Factor: 3.36). 05/2010; 17(3):642-53. DOI: 10.1097/gme.0b013e3181c4f1d6
Source: PubMed


Selective estrogen receptor modulators (SERMs) have the ability to provide mixed functional estrogen receptor (ER) agonist or antagonist activity, depending on the target tissue. Tamoxifen, the first SERM available for clinical use, is regarded as a highly effective agent for the prevention and treatment of breast cancer. However, tamoxifen exhibits ER agonist activity in the uterus and is associated with an increased risk of endometrial hyperplasia and malignancy. Endometrial safety has been an important consideration in the clinical development of SERMs, with improved benefit-risk profiles. Raloxifene, which is currently approved for the prevention and treatment of postmenopausal osteoporosis and for the prevention of breast cancer, seems to have neutral effects on the uterus. Promising results have been observed with the targeted development of newer and more tissue-specific SERMs, many of which are under investigation for postmenopausal osteoporosis. Of the newer SERMs in development, lasofoxifene has been shown to reduce fracture risk and decrease the incidence of breast cancer but has been associated with an increased incidence of vaginal bleeding, endometrial thickening, and endometrial polyps. Lasofoxifene and ospemifene have shown beneficial effects on the vaginal epithelium. Phase 3 clinical data have shown that bazedoxifene is effective in preventing and treating postmenopausal osteoporosis, without adverse effects on the endometrium or breast. Arzoxifene has been evaluated in phase 3 trials for postmenopausal osteoporosis and has been studied for the treatment of uterine malignancies but is no longer in clinical development. Further investigation of newer SERMs is warranted to more clearly define the endometrial safety of these agents.

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    • "The lack of estrogen receptor α (ERα) expression in most type II tumors has led to the assumption that these tumors must be “estrogen-independent” and that treatment with antiestrogens (selective estrogen receptor modulators (SERMs) such as tamoxifen and Raloxifene, or pure antagonists/selective estrogen receptor modulators (SERDs) such as ICI182,780/fulvestrant) commonly used in breast cancer treatment, would be ineffectual, a conclusion largely substantiated in a number of clinical trials [5, 6]. In fact, prolonged treatment of breast cancer with SERMs such as tamoxifen leads to an increased incidence of endometrial cancer [7], particularly those of high-risk histologic types [8], resulting in significantly poorer overall survival [9]. The effects of tamoxifen in the uterus have been ascribed to altered expression of nuclear coregulatory proteins in the endometrium compared to the breast, resulting in moderate agonist activity of tamoxifen in the uterus, compared to its antagonistic effects in the breast [10–13]. "
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    ABSTRACT: Breast cancer is one of the most common malignant tumours in women. More than a century ago it was noted that oophorectomy helps some but not all breast cancer patients. Further milestones in the development of endocrine treatment included the discovery of oestrogen receptors in breast tumours, introduction of tamoxifen, pharmacological ovarian ablation, and inhibitors of oestrogen biosynthesis in postmenopausal women. Each of these steps led to improvement in outcomes of breast cancer. However, despite the success of endocrine treatment, resistance remains an important clinical issue. There are no reliable markers for predicting endocrine resistance in ER-positive tumours and there is no rational targeted treatment of tumours, which do not respond (primary resistance) or progress after initial response (secondary resistance).
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