Clinical Breast Cancer Supplement April 2005 S5Introduction Breast cancer was demonstrated to be a hormone-re- sponsive disease by Beatson in 1896, when responses in the treatment of premenopausal women with advanced breast cancer were observed following oophorectomy.1Subse- quently, a wide variety of hormonal maneuvers have proven effective in the treatment of breast cancer, with the presence of intratumoral hormone receptors for estrogen and/or progesterone predicting for hormone response.2-4Of the hormonal agents, tamoxifen has been the most widely used and studied in the treatment of breast cancer. Tamoxifen functions as a selective estrogen receptor modulator (SERM) and, as such, has estrogen agonistic, partial agonistic, or antagonistic properties depending upon the species, organ, and endpoint in question.5,6In the treatment of breast cancer, tamoxifen has estrogen antagonistic properties with short- to intermediate-term use but may have estrogen agonistic effects with long- term use.7-9Tamoxifen improves disease-free and overallsurvival in the treatment of hormone receptorpositive breast cancer in the adjuvant setting and is associated with a high rate of response and favorable disease-free survival in patients with recurrent or metastatic disease.10,11The estrogen agonistic properties of tamoxifen are associated with the preservation of bone mineral density in post- menopausal women.12-14 Tamoxifen is also associated with endometrial proliferation and an increased risk of endome- trial carcinoma in postmenopausal women and with an in- creased risk of thromboembolic disease in premenopausal and postmenopausal women.15-17 The adverse impact of the estrogen agonistic effects of tamoxifen, including the increased risk of endometrial car- cinoma and thromboembolic disease, provided the ration- ale for the search for agents with high affinity for the es- trogen receptor and with pure estrogen antagonistic prop- erties regardless of the end organ. From this discovery ef- fort, the pure antiestrogen fulvestrant emerged for further clinical development.Development of Fulvestrant Bucourt et al documented that a decamethylene bridging group could be added in the 7-position of estradiol with- out inhibiting binding to the estrogen receptor.18This led to a systematic medicinal chemistry strategy of identifyingSubmitted: Feb 22, 2005; Revised: Mar 25, 2005; Accepted: Mar 28, 2005Address for correspondence: Robert W. Carlson, MD, Professor of Medicine, Stanford University, 875 Blake Wilbur Dr, Stanford, CA 94305-5826 Fax: 650-498-4696; e-mail: rcarlsonstanford.eduDepartment of Medicine, Stanford University, CAThe History and Mechanism of Action of FulvestrantFulvestrant is a pure antiestrogen that emerged from a systematic medicinal chemistry strategy of modifi- cation of long-chain alkyl substitutes in the 7-position of estradiol. Fulvestrant has no uterotrophic effects on the immature or ovariectomized rat and blocks the agonistic effects of estradiol and tamoxifen in a dose- dependent manner. In in vivo and in vitro breast cancer models, fulvestrant has anticancer activity at least as good as tamoxifen and is superior to tamoxifen in some models. Fulvestrant requires intramuscular ad- ministration in a proprietary formulation of castor oil and alcohols. When fulvestrant binds to estrogen re- ceptor monomers it inhibits receptor dimerization, activating function 1 (AF1) and AF2 are rendered inac- tive, translocation of receptor to the nucleus is reduced, and degradation of the estrogen receptor is accel- erated. This results in pure antiestrogenic effects. There is substantial preclinical evidence that the nons- teroidal hormone-dependent mechanisms of estrogen receptor activation and regulation via growth factor receptors and their signal transduction pathways are important in the development of breast cancer hor- monal resistance. Methods of exploiting the interactions between these nonsteroidal hormone-dependent mechanisms of resistance and hormonal agents such as fulvestrant are an active area for drug develop- ment and clinical investigation.Clinical Breast Cancer, Vol. 6, Suppl. 1, S5-S8, 2005 Key words: Antiestrogen, Estrogen receptor, Hormonal therapyAbstractRobert W. CarlsonElectronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1526-8209, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.S6 Clinical Breast Cancer Supplement April 2005History and Mechanism of Fulvestrant novel pure antiestrogens via modification of long-chain alkyl substitutes in the 7-position of estradiol. These com- pounds were screened for estrogen agonistic and antago- nistic effects via a uterotrophic and antiuterotrophic model in the immature rat