Fulvestrant ('Faslodex')--a new treatment option for patients progressing on prior endocrine therapy.
TL;DR: Fulvestrant has recently gained US Food and Drug Administration approval for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy and these new hormonal treatments expand the choice of endocrine therapy for women with advanced breast cancer.
Abstract: Since its introduction more than 30 years ago, tamoxifen has been the most widely used endocrine therapy for the treatment of women with advanced breast cancer. More recently, a number of alternative endocrine treatments have been developed, including several selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs) and, most recently, fulvestrant ('Faslodex'). Fulvestrant is an estrogen receptor (ER) antagonist, which, unlike the SERMs, has no known agonist (estrogenic) effect and downregulates the ER protein. Tamoxifen is effective and well tolerated, although the non-steroidal AIs, anastrozole and letrozole, are more effective treatments for advanced disease than tamoxifen. Fulvestrant has recently gained US Food and Drug Administration approval for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. In two global phase III clinical trials fulvestrant was at least as effective and as equally well tolerated as anastrozole for the treatment of postmenopausal women with advanced and metastatic breast cancer. In a retrospective analysis of the combined data from these trials, mean duration of response was significantly greater for fulvestrant compared with anastrozole. These new hormonal treatments expand the choice of endocrine therapy for women with advanced breast cancer and offer new options for sequencing and combining treatments.
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TL;DR: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib significantly delayed the emergence of resistance to both estrogen deprivation and fulvestrant, but reactivation of HER-2/neu and signaling through AKT leads to tumor regrowth.
Abstract: HER-2/neu in breast cancer is associated with tamoxifen resistance, but little data exist on its interaction with estrogen deprivation or fulvestrant. Here, we used an in vivo xenograft model of estrogen receptor (ER)-positive breast cancer with HER-2/neu overexpression (MCF7/HER-2/neu-18) to investigate mechanisms of growth inhibition and treatment resistance. MCF7/HER-2/neu-18 tumors were growth inhibited by estrogen deprivation and with fulvestrant, but resistance developed in 2 to 3 months. Inhibited tumors had reductions in ER, insulin-like growth factor-I receptor (IGF-IR), phosphorylated HER-2/neu (p-HER-2/neu), and phosphorylated p42/44 mitogen-activated protein kinase (p-MAPK). p27 was increased especially in tumors sensitive to estrogen deprivation. Tumors with acquired resistance to these therapies had complete loss of ER, increased p-HER-2/neu, increased p-MAPK, and reduced p27. In contrast, IGF-IR and phosphorylated AKT (p-AKT) levels were markedly reduced in these resistant tumors. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib, which can block EGFR/HER-2/neu signaling, significantly delayed the emergence of resistance to both estrogen deprivation and fulvestrant. Levels of p-MAPK and p-AKT decreased with gefitinib, whereas high ER levels were restored. Eventually, however, tumors progressed in mice treated with gefitinib combined with estrogen deprivation or fulvestrant accompanied again by loss of ER and IGF-IR, increased p-HER-2/neu, high p-MAPK, and now increased p-AKT. Thus, estrogen deprivation and fulvestrant can effectively inhibit HER-2/neu-overexpressing tumors but resistance develops quickly. EGFR/HER-2/neu inhibitors can delay resistance, but reactivation of HER-2/neu and signaling through AKT leads to tumor regrowth. Combining endocrine therapy with EGFR/HER-2/neu inhibitors should be tested in clinical breast cancer, but a more complete blockade of EGFR/HER-2/neu may be optimal.
158 citations
TL;DR: Compelling experimental and clinical evidence suggest that the epidermal growth factor/her2/neu receptor (EGFR/HER2) pathway might play a distinct role in endocrine resistance, and especially in resistance to selective estrogen receptor modulators (SERMs) such as tamoxifen.
Abstract: Estrogen receptor (ER), mediating estrogen-signaling stimuli, is a dominant regulator and a key therapeutic target in breast cancer etiology and progression. Endocrine therapy, blocking the ER pathway, is one of the most important systemic therapies in breast cancer management, but de novo and acquired resistance is still a major clinical problem. New research highlights the role of both genomic and nongenomic ER activities and their intimate molecular crosstalk with growth factor receptor and other signaling kinase pathways in endocrine resistance. These signaling pathways, when overexpressed and/or hyperactivated, can modulate both activities of ER, resulting in endocrine resistance. Thus, these signal transduction receptors and signaling molecules may serve as both predictive markers and novel therapeutic targets to circumvent endocrine resistance. Compelling experimental and clinical evidence suggest that the epidermal growth factor/HER2/neu receptor (EGFR/HER2) pathway might play a distinct role in endocrine resistance, and especially in resistance to selective estrogen receptor modulators (SERMs) such as tamoxifen. Results from preclinical studies of treatment combinations with various endocrine therapy drugs together with several potent anti-EGFR/HER2 inhibitors are very promising, and clinical trials to see whether this new strategy is effective in patients are now ongoing.
146 citations
Cites background from "Fulvestrant ('Faslodex')--a new tre..."
...estrogen receptor modulators (SERMs) such as arzoxifene, with more favorable tissue-specific ER effects than tamoxifen [59], as well as selective ER downregulators (SERDs) such as the potent antiestrogen fulvestrant (Faslodex, ICI 182,780), which target and degrade the ER [60, 71], are already in clinical use or at the final stages of clinical development....
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TL;DR: The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described.
Abstract: The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced estrogen receptor (ER) positive breast cancer.
143 citations
TL;DR: A crucial role for p72 is highlighted in ERα co-activation and oestrogen-dependent cell growth and evidence in support of distinct but important roles for both p68 and p72 in regulating ERα activity in breast cancer is provided.
Abstract: The DEAD-box RNA helicases p68 (DDX5) and p72 (DDX17) have been shown to act as transcriptional co-activators for a diverse range of transcription factors, including oestrogen receptor-alpha (ERalpha). Here, we show that, although both proteins interact with and co-activate ERalpha in reporter gene assays, small interfering RNA-mediated knockdown of p72, but not p68, results in a significant inhibition of oestrogen-dependent transcription of endogenous ERalpha-responsive genes and oestrogen-dependent growth of MCF-7 and ZR75-1 breast cancer cells. Furthermore, immunohistochemical staining of ERalpha-positive primary breast cancers for p68 and p72 indicate that p72 expression is associated with an increased period of relapse-free and overall survival (P=0.006 and 0.016, respectively), as well as being inversely associated with Her2 expression (P=0.008). Conversely, p68 shows no association with relapse-free period, or overall survival, but it is associated with an increased expression of Her2 (P=0.001), AIB-1 (P<0.001) and higher tumour grade (P=0.044). Our data thus highlight a crucial role for p72 in ERalpha co-activation and oestrogen-dependent cell growth and provide evidence in support of distinct but important roles for both p68 and p72 in regulating ERalpha activity in breast cancer.
101 citations
Cites background from "Fulvestrant ('Faslodex')--a new tre..."
...These tumours often remain ERa positive and may respond to an alternative endocrine agent, showing ERa-dependence for the continued growth of these tumours (Buzdar and Howell, 2001; Morris and Wakeling, 2002), and indicating altered ERa function as a possible mechanism underlying treatment failure....
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...…tumours often remain ERα positive and may respond to an alternative endocrine agent, demonstrating ERα-dependence for the continued growth of these tumours (Buzdar and Howell, 2001; Morris and Wakeling, 2002), and indicating altered ERα function as a possible mechanism underlying treatment failure....
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TL;DR: The molecular mechanisms through which ER activates transcription of target genes and through which available anti-estrogens mediate their therapeutic effects are reviewed.
Abstract: Evidence for a role of ovarian factors in the growth of metastatic breast cancer was first recognized over 100 years ago. Today, anti-estrogens are central to the treatment of breast cancer of all stages. We now understand that the action of estrogen is mediated by the estrogen receptors (ER) which are members of the nuclear receptor family of ligand-regulated transcription factors. In this article we review the molecular mechanisms through which ER activates transcription of target genes and through which available anti-estrogens mediate their therapeutic effects. We discuss possible mechanisms of failure of treatment with current anti-estrogens and how newer anti-estrogens under development attempt to address these problems. In addition an expanded view of the molecular mechanisms of estrogen action is leading to the development of novel selective ER modulators or SERMs.
98 citations
References
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TL;DR: Fulvestrant was at least as effective as anastrozole, with efficacy end points slightly favoring fulvestrant, and represents an additional treatment option for postmenopausal women with advanced breast cancer whose disease progresses on tamoxifen therapy.
Abstract: PURPOSE: To compare the efficacy and tolerability of fulvestrant (formerly ICI 182,780) with anastrozole in the treatment of advanced breast cancer in patients whose disease progresses on prior endocrine treatment. PATIENTS AND METHODS: In this double-blind, double-dummy, parallel-group study, postmenopausal patients were randomized to receive either an intramuscular injection of fulvestrant 250 mg once monthly or a daily oral dose of anastrozole 1 mg. The primary end point was time to progression (TTP). Secondary end points included objective response (OR) rate, duration of response (DOR), and tolerability. RESULTS: Patients (n = 400) were followed for a median period of 16.8 months. Fulvestrant was as effective as anastrozole in terms of TTP (hazard ratio, 0.92; 95.14% confidence interval [CI], 0.74 to 1.14; P = .43); median TTP was 5.4 months with fulvestrant and 3.4 months with anastrozole. OR rates were 17.5% with both treatments. Clinical benefit rates (complete response + partial response + stable ...
605 citations
"Fulvestrant ('Faslodex')--a new tre..." refers background in this paper
...%) greater for fulvestrant than for anastrozole (ratio of average response durations = 1.30; 95% CI 1.13 to 1.50; P > 0.01) (Parker & Webster 2002)....
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TL;DR: Although ligand binding is not required by the estrogen receptor to undergo nucleocytoplasmic shuttling, this process can be disrupted by the binding of a pure antiestrogen.
Abstract: The mouse estrogen receptor was shown to be constantly shuttling between the nucleus and cytoplasm although under steady-state conditions it is detected predominantly in the cell nucleus in both the absence and presence of estradiol. Shuttling was demonstrated by monitoring the transfer of protein between nuclei in heterokaryons and by examining the subcellular distribution of mutant receptors. In the presence of the partial antiestrogen 4-hydroxytamoxifen the receptor was retained in the nucleus whereas it accumulated in the cytoplasm when cells were treated with the pure antiestrogen ICI 182780. The effect of the pure antiestrogen was to inhibit nucleocytoplasmic shuttling of the receptor by blocking its nuclear uptake. Thus although ligand binding is not required by the estrogen receptor to undergo nucleocytoplasmic shuttling, this process can be disrupted by the binding of a pure antiestrogen.
524 citations
"Fulvestrant ('Faslodex')--a new tre..." refers background in this paper
...These include inhibition of ER dimerization (Fawell et al. 1990), and reduced shuttling of the ER from the cytoplasm to the nucleus (Dauvois et al. 1993)....
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...1990), and reduced shuttling of the ER from the cytoplasm to the nucleus (Dauvois et al. 1993)....
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TL;DR: A phase III, double-blind, randomized, multicenter study evaluated the efficacy, pharmacodynamics, and safety of the oral aromatase inactivator exemestane (EXE) versus megestrol acetate (MA) in postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen as discussed by the authors.
Abstract: PURPOSE: This phase III, double-blind, randomized, multicenter study evaluated the efficacy, pharmacodynamics, and safety of the oral aromatase inactivator exemestane (EXE) versus megestrol acetate (MA) in postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen. PATIENTS AND METHODS: A total of 769 patients were randomized to EXE 25 mg/d (n = 366) or MA (n = 403) 40 mg four times daily. Tumor response, duration of tumor control, tumor-related signs and symptoms (TRSS), quality of life (QOL), survival, and tolerability were evaluated. RESULTS: Overall objective response (OR) rates were higher in patients treated with EXE than in those treated with MA (15.0% v 12.4%); a similar trend was noted in patients with visceral metastases (13.5% v 10.5%). Median survival time was significantly longer with EXE (median not reached) than with MA (123.4 weeks; P = .039), as were the median duration of overall success (OR or stable disease ≥ 24 weeks; 60.1 v 49.1 weeks; P = .025)...
491 citations
TL;DR: This report presents the results of a survival update based on the combined data from two studies that compared the efficacy and tolerability of anastrozole (1 or 10 mg once daily) and megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma whose disease had progressed after treatment with tamoxifen.
Abstract: BACKGROUND. This report presents the results of a survival update based on the combined data from two studies that compared the efficacy and tolerability of anastrozole (1 or 10 mg once daily), a selective, nonsteroidal aromatase inhibitor administered orally, and megestrol acetate (40 mg 4 times daily) in the treatment of postmenopausal women with advanced breast carcinoma whose disease had progressed after treatment with tamoxifen. METHODS. Two randomized, parallel-group, multicenter trials were conducted, involving a total of 764 patients. The two trials were identical in design; both were double blind for anastrozole and open label for megestrol acetate. Overview analyses were conducted with the intent of strengthening the interpretation of results from each trial. The median follow-up duration for this survival update was 31 months. RESULTS. At the clinical dose of 1 mg daily, anastrozole demonstrated a statistically significant survival advantage over megestrol acetate, with a hazard ratio of 0.78 (P , 0.025)(0.60 , 97.5% confidence interval [CI] ,1.0). The 1 mg anastrozole group also had a longer median time to death (26.7 months) compared with 22.5 months for the megestrol acetate group. The 10 mg anastrozole group also had a survival benefit over the megestrol acetate group, with a hazard ratio of 0.83 (P 5 0.09, not significant)(0.64 , 97.5% CI , 1.1). Higher 2-year survival rates were observed for both anastrozole treatment groups than for the megestrol acetate group (56.1%, 54.6%, and 46.3% for the groups given 1 mg anastrozole, 10 mg anastrozole, and megestrol acetate, respectively).
450 citations
"Fulvestrant ('Faslodex')--a new tre..." refers background in this paper
...These AIs are more effective than megestrol acetate after progression on tamoxifen (Buzdar et al. 1998, Dombernowsky et al. 1998)....
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TL;DR: It is shown that the "pure" antiestrogen ICI 164,384 inhibits mouse estrogen receptor-DNA binding in vitro, and it is proposed that ICI164,384 reduces DNA binding by interfering with receptor dimerization.
Abstract: Many estrogen-antagonist and -agonist ligands have been synthesized, some of which have proved clinically important in the treatment of hormone-dependent breast tumors and endocrine disorders. Here we show that the "pure" antiestrogen ICI 164,384 inhibits mouse estrogen receptor-DNA binding in vitro. The effects of this steroid on DNA binding can be overcome by addition of anti-receptor antibody whose epitope lies N-terminal to the receptor DNA-binding domain. Since this antibody is also capable of restoring DNA-binding activity to receptor mutants that either lack the dimerization domain or bear deleterious mutations within it, we propose that ICI 164,384 reduces DNA binding by interfering with receptor dimerization. In contrast, when complexed with the antagonist/partial agonist tamoxifen, the estrogen receptor is capable of binding to DNA in vitro, but tamoxifen does not promote the agonist-induced conformational change obtained with estradiol. The implications of these data are discussed in relation to the in vivo properties of these drugs.
403 citations
"Fulvestrant ('Faslodex')--a new tre..." refers background in this paper
...The fulvestrant–ER complex is also thought to be highly labile, leading to its rapid degradation and hence a marked loss of cellular ER (Fawell et al. 1990)....
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...These include inhibition of ER dimerization (Fawell et al. 1990), and reduced shuttling of the ER from the cytoplasm to the nucleus (Dauvois et al. 1993)....
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...These include inhibition of ER dimerization (Fawell et al. 1990), and reduced shuttling of the ER from the cytoplasm to the nucleus (Dauvois et al....
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