Pure oestrogen antagonists for the treatment of advanced breast cancer

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 of fulvestrant. 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.

Selective recruitment of breast cancer anti-estrogen resistance genes and relevance for breast cancer progression and tamoxifen therapy response

“…Our observations that the mechanisms underlying resistance against diverse anti-estrogens differ are in line with previous observations in breast cancer cell models (Soulez & Parker 2001, Faridi et al 2003, Frasor et al 2004, Martin et al 2005, Fan et al 2006, Kuske et al 2006, Scafoglio et al 2006, Shaw et al 2006, Osipo et al 2007. Accordingly, patients with breast tumors failing on tamoxifen have been shown to respond to the pure anti-estrogen fulvestrant (Howell et al 2002, Osborne et al 2002, Howell 2006, indicating subtle differences in the underlying mechanisms of tumor growth control. High throughput extension of these screens may help to elucidate the mechanistic differences between the diverse anti-estrogen agents used against breast cancer.…”

Antiestrogens: structure-activity relationships and use in breast cancer treatment

“…However, despite the pure antiestrogenic character of fulvestrant, it did not compare advantageously with tamoxifen when used as a first-line therapy for advanced or metastatic breast cancer (Howell et al . 2004 a , Howell 2006). The poor pharmacokinetic properties of ICI 182,780 may limit its effectiveness in the clinic; indeed, increasing monthly intra-muscular injections of fulvestrant from 250 mg to 500 mg led to significant gains in overall survival in metastatic patients having recurred or progressed after prior endocrine therapy in the CONFIRM study and resulted in subsequent adoption of this regimen in the clinic (Di Leo et al .…”

“…All these compounds possess a strong agonist activity in bones. However, these drugs are neither more efficacious than tamoxifen for breast cancer treatment nor do they circumvent resistance to tamoxifen in patients (Howell 2006, Ali et al . 2011, Martinkovich et al .…”

“…The lack of systematic cross-resistance to pure AEs observed in tumors that have progressed under treatment with tamoxifen, or in cell lines that have gained the capacity to grow in the presence of SERMs, suggested that pure AEs and SERMs have different mechanisms of action (Howell 2006, Ali et al . 2011).…”

Breast Cancer, Estrogen Receptor and Ligands

“…SERMs such as tamoxifen and RAL, pure anti-estrogens such as fulvestrant and other steroid hormones have been largely investigated and reported [11,15,106,107,108], and got interpreted above. Hence, we will limit this section to some new potential estrogens or lead structures, which may be also developed into SERMs or pure anti-estrogens by introduction of an appropriate active group onto a suitable position [109].…”