Is fulvestrant (‘‘Faslodex’’) just another selective estrogen receptor modulator? A. HOWELL Cancer Research UK, Department of Medical Oncology, University of Manchester, Christie Hospital NHS Trust, Manchester, United Kingdom Approximately two thirds of all breast tumors express estrogen receptor (ER) and/or progesterone receptors (PgR) and sequential treatment with non-cross- resistant endocrine therapies is often the treatment strategy of choice for patients with these tumors. The antiestrogen tamoxifen was the mainstay of endocrine treatment for breast cancer for many years, although this is now starting to be superseded by third-genera- tion aromatase inhibitors such as anastrozole, letro- zole, and exemestane (1) . Other antiestrogens including newer generation selective estrogen receptor modu- lators (SERMs), such as droloxifene, toremifene, and raloxifene, and the new ER antagonist fulvestrant (‘‘Faslodex’’) that downregulates the ER have also been developed and tested in different breast cancer settings. Important differences exist in the mode of action of these new antiestrogens that may impact on their usefulness in the clinic, particularly in the treat- ment of women with tamoxifen-resistant disease. Fulvestrant: mode of action Fulvestrant is the first in a new class of endocrine agents—an ER antagonist with no agonist effects that binds, blocks, and degrades the ER. Fulvestrant is a steroidal analogue of 17b-estradiol that binds the ER with a 100-fold higher affinity than tamoxifen (2) . Once bound, fulvestrant blocks ER dimerization and nuclea- rization (3) and accelerates ER protein degradation (4) leading to reduced cellular ER levels and inhibition of estrogen-mediated ER signaling (5) . Fulvestrant blocks both activating functions (AFs) of the ER (AF1 and AF2), thereby effectively abrogating estrogen-sensitive gene transcription (Fig. 1). In contrast, tamoxifen blocks only AF2, thus allowing some ER-regulated transcription to occur. This difference in mechanism of action may explain the ‘‘pure’’ estrogen antagonist activity of fulvestrant compared with the mixed estrogen antagonist/agonist activity associated with tamoxifen. The differential effects of fulvestrant and tamoxifen on the ER have been demonstrated in patients receiv- ing short-term endocrine treatment prior to surgery for primary breast cancer. As expected from preclinical studies, all fulvestrant doses (50, 125, and 250 mg) pro- duced statistically significant reductions in ER protein levels compared with placebo. At the higher 250 mg dose, the fulvestrant-induced reduction was also sig- nificantly greater than that observed with tamoxifen (6) . Significant reductions in PgR protein levels were also observed at the fulvestrant 125 and 250 mg doses com- pared with placebo. In contrast, tamoxifen treatment resulted in a significant increase in PgR relative to pla- cebo, a finding attributed to its partial agonist effects (6) . Activity in tamoxifen-resistant disease Although the partial estrogen agonist activity of tamoxifen has beneficial effects on bone mineral den- sity and lipid profiles, it is also associated with an increased risk of endometrial cancer and thromboem- bolic disease. In addition, this agonist activity is also implicated in the development of resistance to tamoxi- fen. Clinical development of later SERMs aimed to identify agents with reduced estrogen agonist effects and improved efficacy compared with tamoxifen. However, all of the first- and second-generation SERMs to date have some level of estrogen agonist ef- fects, and none have demonstrated improved efficacy. In addition, all are cross-resistant with tamoxifen and therefore lack efficacy in tamoxifen-resistant disease. Toremifene has similar efficacy to tamoxifen and has been used as an alternative to this agent in some patients (7) . Address correspondence and reprint requests to: Professor Anthony Howell, Cancer Research UK, Department of Medical Oncology, University of Manchester, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK. Email: maria.parker@ christie-tr.nwest.nhs.uk doi:10.1111/j.1525-1438.2006.00686.x # 2006, Copyright the Authors Journal compilation # 2006, IGCS Int J Gynecol Cancer 2006, 16 (Suppl. 2), 521–523