Experimental Disease Models

The experimental disease models for estrogen-responsive tissues will be discussed in the section on current treatment, below.

7.07.4 Clinical Trial Issues

While the estrogen receptor is expressed in most breast cancer, endocrine therapy by treating with tamoxifen is not effective in all estrogen receptor-positive breast cancer patients, i.e., in a random population of patients with metastatic breast cancer, 30-35% will respond positively, whereas 55-60% of patients with tumors known to be estrogen receptor-positive will respond positively. In addition to this intrinsic form of resistance to endocrine therapy, there is an acquired resistance that occurs following a tumor response when the disease subsequently progresses despite continued treatment.

One of the most significant current clinical trials involving the endocrine modulation of breast cancer is the Study of Raloxifene and Tamoxifen, or STAR. This is a large phase III, double-blind trial in which postmenopausal women are assigned to take tamoxifen (20mgday_ or raloxifene (60mgday_ for 5 years. The primary aim of this trial is to compare these two selective estrogen receptor modulators (SERMs) directly for efficacy and safety parameters with respect to breast cancer, coronary heart disease, and osteoporosis. In particular, the effects of long-term raloxifene therapy on preventing the occurrence of invasive breast cancer in postmenopausal women who are identified as being at risk for the disease will be investigated.

Other trials include the study of SERMs combined with aromatase inhibitors to determine if health outcomes can be improved by combining these two therapies.

7.07.5 Current Treatment

Endocrine therapy has been practiced since the turn of the twentieth century. Pioneering studies by George Beatson in 1896 showed that surgical removal of the ovaries, the primary source of endogenous estrogen, from premenopausal women with metastatic breast cancer could cause tumor regression and improve clinical outcomes.2 Beatson's landmark study provided the critical link between a steroid hormone, estrogen, and cancer (breast) regulation. Remarkably, Beatson's findings significantly predate the discovery of both estrogen and the estrogen receptor by decades. The Estrogen Receptors and Endocrine Modulation of Breast Cancer

The interaction of the estrogen receptor with its natural ligand, 17^-estradiol (E2), mediates a number of fundamental physiological processes, including regulation of the female reproductive system and the maintenance of skeletal and cardiovascular health. Pharmacological modulation of the estrogen receptor with the estrogens found in hormone replacement therapy (HRT) provides important clinical benefits in women for the treatment of hot flashes and osteoporosis. However, the increased risk of breast, uterine, and cardiovascular side effects that is associated with estrogen therapies has led to the development of ligands with improved risk-to-benefit ratios. These SERMs, such as tamoxifen and raloxifene, have demonstrated the ability to mimic estrogen in some tissues (bone, liver, and the cardiovascular system) while suppressing the effects of estrogen in other tissues (breast, uterus: Figure 1). This unique tissue-selective profile has proven beneficial for the prevention and treatment of breast cancer as well as osteoporosis. Tamoxifen and other triphenylethylenes

Tamoxifen is currently approved by the US Food and Drug Administration for the treatment of breast cancer in postmenopausal women, estrogen receptor-positive, metastatic breast cancer in premenopausal women, and metastatic breast cancer in men. Tamoxifen is also approved for adjuvant therapy, either alone or following chemotherapy for early-stage, estrogen receptor-positive, breast cancer in pre- and postmenopausal women. Adjuvant therapy with tamoxifen is approved for 5 years of treatment.

Tamoxifen belongs to a class of nonsteroidal estrogen receptor modulators that are termed triphenylethylenes (TPEs). In recent years, the estrogen agonist activities of these compounds in the skeletal and cardiovascular systems have been described. Although they partially antagonize the effects of estrogen on the uterus, evidence to date suggests that, in the absence of estrogen, the members of this structural class also tend to induce some level of uterine stimulation, hence their classification here as partial agonists.

One of the first TPEs to achieve clinical significance was clomiphene,3 available as a one-to-one mixture of doublebond isomers. Paradoxically, although developed as a contraceptive, it has been mainly utilized for the induction of ovulation in anovulatory women.4 Estrogen agonist effects of clomiphene in skeletal tissue have been reported in an ovariectomized (OVX) rat model of postmenopausal osteoporosis.5'6 Clomiphene has also been reported to inhibit bone resorption in vitro and to decrease serum markers of bone resorption in menopausal/castrated women.7,8 In the rat



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