Pure Oestrogen Antagonists for the Treatment of Advanced Breast Cancer
Total Page:16
File Type:pdf, Size:1020Kb
Endocrine-Related Cancer (2006) 13 689–706 REVIEW Pure oestrogen antagonists for the treatment of advanced breast cancer Anthony Howell CRUK Department of Medical Oncology, University of Manchester, Christie Hospital NHS Trust, Manchester M20 4BX, UK (Requests for offprints should be addressed to A Howell; Email: [email protected]) Abstract For more than 30 years, tamoxifen has been the drug of choice in treating patients with oestrogen receptor (ER)-positive breast tumours. However, research has endeavoured to develop agents that match and improve the clinical efficacy of tamoxifen, but lack its partial agonist effects. The first ‘pure’ oestrogen antagonist was developed in 1987; from this, an even more potent derivative was developed for clinical use, known as fulvestrant (ICI 182,780, ‘Faslodex’). Mechanistic studies have shown that fulvestrant possesses high ER-binding affinity and has multiple effects on ER signalling: it blocks dimerisation and nuclear localisation of the ER, reduces cellular levels of ER and blocks ER-mediated gene transcription. Unlike anti-oestrogens chemically related to tamoxifen, fulvestrant also helps circumvent resistance to tamoxifen. There are extensive data to support the lack of partial agonist effects of fulvestrant and, importantly, its lack of cross-resistance with tamoxifen. In phase III studies in patients with locally advanced or metastatic breast cancer, fulvestrant was at least as effective as anastrozole in patients with tamoxifen-resistant tumours, was effective in the first-line setting and was also well tolerated. These data are supported by experience from the compassionate use of fulvestrant in more heavily pretreated patients. Further studies are now underway to determine the best strategy for sequencing oestrogen endocrine therapies and to optimise dosing regimens offulvestrant. At present, and for the foreseeable future, fulvestrant is the only oestrogen antagonist with no agonistic effects licensed for the treatment of advanced breast cancer in postmenopausal women. Other similar oestrogen antagonists are undergoing research and development, with a few currently being evaluated in phase II trials. Endocrine-Related Cancer (2006) 13 689–706 Background use. As such, research has endeavoured to develop The critical role played by oestrogen in breast cancer agents that are at least as effective as tamoxifen but has driven a huge amount of research into the which lack its partial agonist effects. development of hormonal therapies that are able to First-generation selective ER modulators (SERMs, block oestrogen-mediated cell signalling. For more e.g. toremifene, droloxifene and idoxifene) were based than 30 years, tamoxifen, a non-steroidal triphenyl- on the non-steroidal triphenylethylene structure of ethylene derivative (Fig. 1), has been the drug of tamoxifen (Wakeling 2000). These agents have no choice in treating patients with oestrogen receptor efficacy benefits over tamoxifen and also show partial (ER)-positive and/or progesterone receptor (PgR)- agonist activity (Pyrhonen et al. 1994, Lee et al. 2000, positive tumours. Not only is tamoxifen effective in Buzdar et al. 2002), with some studies suggesting there patients with breast cancer, it also reduces the is cross-resistance ‘between’ first-generation SERMs incidence of disease in healthy women at high risk of and tamoxifen (Haarstad et al. 1992, Stenbygaard et al. developing breast cancer (Cuzick et al. 2003). The 1993, Pyrhonen et al. 1994, 1997, 1999, Hayes et al. success of tamoxifen has been achieved despite its 1995, Gershanovich et al. 1997, Lee et al. 2000, partial agonist activity, which is associated with Johnston et al. 2001, MillaSantos et al. 2001). increased risk of endometrial cancer, thromboembolic Disappointing efficacy data for both droloxifene and events and tumour flare, particularly with long-term idoxifene when compared with tamoxifen or when Endocrine-Related Cancer (2006) 13 689–706 Downloaded from Bioscientifica.comDOI: 10.1677/erc.1.00846 at 09/27/2021 10:26:15PM 1351-0088/06/013–689 q 2006 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.orgvia free access A Howell: Pure anti-oestrogens in advanced breast cancer Figure 1 Chemical structures of oestradiol, tamoxifen, fulvestrant and raloxifene. used in tamoxifen-resistant disease have led to their of steroidal 7a-alkylamide analogues of oestradiol. development being halted. Toremifene (chloro-tamox- Of these, ICI 164,384 was the first pure oestrogen ifen), which has similar efficacy but fewer agonist antagonist to be described, completely blocking the properties compared with tamoxifen (Marttunen et al. uterotrophic action of both oestradiol and tamoxifen in 1998, 2001), remains in clinical development in the rats (Wakeling & Bowler 1987). Following this, a far breast cancer prevention setting. more potent pure oestrogen antagonist was developed, Structurally distinct second- and third-generation ICI 182,780, which is now known as fulvestrant SERMs (‘fixed-ring’ benzothiophene derivatives (‘Faslodex’) (Fig. 1)(Wakeling et al. 1991). At present (Fig. 1)) such as raloxifene, arzoxifene and ERA- (and for the foreseeable future), fulvestrant, an 923 were then developed. Most of these have oestrogen antagonist with no agonist effects, is licensed demonstrated anti-tumour activity in breast cancer for the treatment of advanced breast cancer in but also have some partial agonist activity (Buzdar postmenopausal women. Therefore, this paper will et al. 1988, Gradishar et al. 2000, Munster et al. 2001, describe in detail the mode of action of fulvestrant, Buzdar et al. 2003). Results from the Study of and explore how this underlies its clinical efficacy, Tamoxifen and Raloxifene (STAR) trial, one of the tolerability and safety profile in the treatment of largest breast cancer prevention studies, which has advanced breast cancer. In considering the future recruited 19 000 postmenopausal women at risk of directions for oestrogen-antagonistic agents, ongoing breast cancer, are expected in 2006. Based on its clinical trials with fulvestrant will be reviewed. The partial oestrogen agonist effects (Delmas et al. 1997), current status of other ‘pure’ oestrogen antagonists in raloxifene is also currently being used for the preclinical and clinical development will also be prevention and treatment of osteoporosis and breast described. cancer. Arzoxifene showed promising initial results in a phase II study in advanced breast cancer, although its efficacy was greater in tamoxifen-sensitive than Mode of action tamoxifen-resistant disease (Buzdar et al. 2003). Results from a phase I study suggest that ERA-923 ER-mediated signalling has no trophic effects on the uterus (Cotreau et al. The biological actions of oestrogen are mediated by 2002), and its role in patients with breast cancer is two subtypes of ER, ERa and ERb. Both receptors currently being investigated. belong to a family of ligand-activated nuclear The search for novel agents that would completely transcription factors (Evans 1988) and share a high block all ER signalling led to the synthesis of a series degree of homology in their DNA binding domains Downloaded from Bioscientifica.com at 09/27/2021 10:26:15PM via free access 690 www.endocrinology-journals.org Endocrine-Related Cancer (2006) 13 689–706 (Kuiper et al. 1996). However, they differ considerably to promoters of responsive genes. Genes that are in their N-terminal regions, which contain the ligand- regulated by oestrogen but do not have an ERE include independent transcription activation function, AF1 cyclin D1, p21 and the PgR (Shupnik 2004). Many (Kuiper et al. 1996). These differences suggest that such genes are regulated via ER interactions with ERa and ERb could have distinct functions in terms of stimulating protein 1 (Sp1), the signal transducers and gene regulation and may contribute to the selec- activators of transcription (STAT) family of transcrip- tive action of oestradiol in different target tissues tion factors and transcription factors associated with (Gustafsson & Warner 2000). There is evidence from activating protein 1 (AP1) sites. The AP1 transcription in vitro studies to suggest that imbalanced ERa/ERb factors are a family of homo- and heterodimers expression may be a feature of oestrogen-dependent composed of proteins that belong to the Jun, Fos, tumour progression and that ERb has a key role in Maf and ATF subfamilies that bind to 12-0-tetra- providing protection against ERa-induced hyperproli- decanoylphorbol-13-acetate (TPA) response elements feration (Bardin et al. 2004). It has also been suggested (TRE) or cAMP response elements (CRE) in target that ERb may be a dominant regulator of oestrogen genes (Chinenov & Kerppola 2001). The c-Jun signalling as it causes a dose-dependent reduction homodimer is the most potent transcriptional activator in ERa-mediated transcription when coexpressed with in the AP1 family (Matthews et al. 2006). ERa (Lindberg et al. 2003). While both ERa and ERb can bind oestradiol and activate transcription through an ERE, they have Classical pathway of ER signalling differential transcriptional activities at Sp1 and AP1 sites. Only ERa can stimulate genes via the Sp1 In classical ER signalling, unbound ER can be nuclear pathway and the two isoforms are differentially localised and bound loosely to the oestrogen response regulated by oestrogens and antioestrogens at AP1 elements (ERE) (Kumar & Chambon 1988, Reese & sites (Shupnik