Fulvestrant - A Novel Endocrine Therapy for Breast Cancer

Abstract

Fulvestrant is a novel endocrine therapy for breast cancer, with a unique structure and mode of action. It binds competitively to the oestrogen receptor (ER), with high affinity, and downregulates ER by functional blockade and increased turnover. Fulvestrant has reached the clinic via extensive pre-clinical and clinical trials, which demonstrated fulvestrant's unique characteristics and showed that they translate to equivalent or improved clinical efficacy compared to established endocrine agents. Fulvestrant is currently licensed for use in postmenopausal women with hormone receptor positive advanced breast cancer which has progressed on prior endocrine therapy. As a pure oestrogen antagonist, fulvestrant avoids the risk of detrimental side effects of selective ER modulators such as tamoxifen, which has partial agonist activity. Fulvestrant, the only parenteral agent in this setting, has a good side effect profile and is well tolerated. Due to its unique mode of action, fulvestrant lacks cross-resistance with existing agents. Fulvestrant is the subject of much ongoing research, which utilises knowledge of its novel mechanism and pharmacokinetic profile in order to optimise clinical efficacy and explore new roles, including first-line use in advanced breast cancer, use in combination with existing agents, in males, and in premenopausal women, and use as an adjuvant therapy.

Tetrahydroisoquinoline Phenols: Selective Estrogen Receptor Downregulator Antagonists with Oral Bioavailability in Rat

“…3 A further step change in treatment for hormonally driven breast cancer occurred with development of selective estrogen receptor downregulators (SERDs) such as fulvestrant. 4 These molecules are capable of both antagonizing estrogen receptor driven cell proliferation as well as effecting a conformational change resulting in ubiquitinylation and degradation of the receptor. Although effective, the low oral bioavailability of fulvestrant means that it is therapeutically administered as a monthly intramuscular implant.…”

The Tissue Specific Role of Estrogen and Progesterone in Human Endometrium and Mammary Gland

“…This forces the receptor into conformation that it is recognized as being misfolded, which induces its rapid degradation (Wu et al 2005). Fulvestrant is currently licensed for the use in postmenopausal women with ER-positive recurrent disease (Johnston et al, 2010). However, the lack of agonist activity limits its beneficial effects in bone.…”

Acquired Resistance of ER-Positive Breast Cancer to Endocrine Treatment Confers an Adaptive Sensitivity to TRAIL through Posttranslational Downregulation of c-FLIP

“…Since the introduction of tamoxifen to the clinic nearly 30 years ago, further endocrine agents have been developed, notably the steroidal antiestrogen fulvestrant (Faslodex) that also promotes ER degradation (4), and aromatase inhibitors (AI) that suppress estrogen production in the body (5,6). Although AIs are now the gold-standard endocrine strategy in the ERþve postmenopausal setting (7), tamoxifen remains a pivotal treatment option in ERþve premenopausal breast cancer patients with 67% of patients responding to tamoxifen as first-line therapy (8)(9)(10).…”