Estrogen receptors tamoxifen therapy

EM-800 is a pure estrogen receptor antagonist that has recently been used clinically for breast cancer patients who have failed tamoxifen therapy. 

The presence of estrogen receptors (ER) in biopsies of breast cancers is a good predictor of responsiveness to tamoxifen therapy 60% of women with ER-positive tumors will have a remission, as opposed to fewer than 10% with ER-negative tumors. Overall, 35 to 40% of women with breast cancer will respond to some degree, with antitumor effects lasting an average of 9 to 12 months. Complete remissions may occur in 10 to 15% of patients and may last several months to a few years. Therapy should be continued for at least 6 weeks to establish efficacy. 

Estrogen receptor-positive breast cancer in premenopausal and postmenopausal women responds equally to tamoxifen therapy (see Chapter 58). In addition, daily tamoxifen administration for 5 years is a successful therapy for the prevention of breast cancer in the contralateral breast in women who have already had one episode of breast cancer. 

Tamoxifen is a competitive partial agonist inhibitor of estradiol at the estrogen receptor and is extensively used in the palliative treatment of advanced breast cancer in postmenopausal women. It is a nonsteroidal agent (see structure below) that is given orally. Peak plasma levels are reached in a few hours. Tamoxifen has an initial half-life of 7-14 hours in the circulation and is predominantly excreted by the liver. It is used in doses of 10-20 mg twice daily. Hot flushes and nausea and vomiting occur in 25% of patients, and many other minor adverse effects are observed. Studies of patients treated with tamoxifen as adjuvant therapy for early breast cancer have shown a 35% decrease in contralateral breast cancer. However, adjuvant therapy extended beyond 5 years in patients with breast cancer has shown no further improvement in outcome. Toremifene is a structurally similar compound with very similar properties, indications, and toxicities. 

A key clinical classification of breast cancer tumors is estrogen receptor (ER) expression. The more ERs are present on tumor cells, the more likely an anti-estrogen therapy such as tamoxifen can be successfully applied. Classification of each tumor is important, as only about 60%) of breast cancers are ER-positive. Initial studies set out to demonstrate that breast cancers with distinct pathological features could be separated by microarrays. Several groups demonstrated that supervised data analysis could be used to distinguish ER-positive from ER-negative tumors (74—76). 

Introduced into the clinic some 30 years ago, tamoxifen selectively modulates estrogen receptors and thus can be considered as one of the first examples of targeted anticancer therapy, years before the era of TKIs described in Section 2. This largely justifies that a section of the present review is devoted to tamoxifen, especially in... 

Although raloxifene is not approved for prevention or treatment of breast cancer, a 4-year trial of raloxifene in women with osteoporosis (not at increased risk for breast cancer) showed a 76% risk reduction for estrogen-receptor-positive breast cancer" (relative risk 0.24, 95% Cl 0.13-0.44). Furthermore, the CORE trial, a study evaluating the efficacy of an additional 4 years of raloxifene therapy in women with osteoporosis, showed that the reduction in estrogen-receptor positive breast cancer incidence continues for up to 8 years" " (hazard ratio 0.24, 95% Cl 0.15-0.40) (see Table 80-9). Raloxifene does not increase breast density. A trial comparing raloxifene with tamoxifen is underway. 

Cui, Y., Osborne, C.K. and Fuqua, S.A. (2004) Low levels of estrogen receptor p protein predict resistance to tamoxifen therapy in breast cancer. Clinical Cancer Research, 10, 7490-7499. 

Fisher, B., Dignam, J., Bryant, J., DeCillis, A., Wickerham, D.L., Wolmark, N., Costantino, J., Redmond, C., Fisher, E.R., Bowman, D.M., Deschenes, L., Dimitrov, N.V., Margolese, R.G., Robidoux, A., Shibata, H., Terz, J., Paterson, A.H., Feldman, M.I., Farrar, W., Evans, J. and Lickley, H.L. (1996) Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. Journal of the National Cancer Institute, 88, 1529-1542. 

Ellis MJ, Coop A, Singh B, et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer Evidence from a phase 111 randomized trial. / Clin Oncol. 2001 19 3808-3816. 

The anti-estrogen, tamoxifen, is the most commonly used hormonal therapy for breast cancer and has demonstrated positive effects on the cardiovascular and skeletal systems of postmenopausal women but is associated with an increased risk of uterine cancer. Tamoxifen is described as a SERM, a selective estrogen receptor modulator with a tissue selective profile that is caused by the different distribution of the a- and /3-subtypes of the estrogen receptor (ERa and ER/3) that activate and inhibit transcription respectively (77). These selective effects have been ascribed to differential interactions with gene promotor elements and coregulatory proteins depending on whether the ERa interacts directly, or in a tethered manner with DNA (78). In uterine tissue, tamoxifen interacts with a specific coactivator, SRCl, that is abundant in uterine tissue. 

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