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: A phase II study compared droloxifene in dosages of 20, 40, and 100 mg daily in postmenopausal women with metastatic, or inoperable recurrent, or primary locoregional breast cancer who had not received prior hormonal therapy.
Abstract: Droloxifene, a new antiestrogen, has theoretical advantages over tamoxifen based on preclinical data. These include higher affinity to the estrogen receptor, higher antiestrogenic to estrogenic ratio, and more effective inhibition of cell growth and division in ER positive cell lines, as well as less toxicity, including reduced carcinogenicity in animal models. Droloxifene also exhibits more rapid pharmacokinetics, reaching peak concentrations and being eliminated much more rapidly than tamoxifen. A phase II study compared droloxifene in dosages of 20, 40, and 100 mg daily in postmenopausal women with metastatic, or inoperable recurrent, or primary locoregional breast cancer who had not received prior hormonal therapy. Of 369 patients randomized, 292 were eligible and 268 evaluable for response. Response rates (CR + PR) were 30% in the 20 mg group, 47% in the 40 mg group, and 44% in the 100 mg group (40 mg vs 20 mg, p = 0.02; 100 mg vs 20 mg, p = 0.04; pooled 40 + 100 mg vs 20 mg, p = 0.01). Median response duration also favoured the higher dosages (20 mg group = 12 months; 40 mg group = 15 months; 100 mg group = 18 months). When adjusted for prognostic factors, time to progression was significantly better for the 100 mg (p = 0.01) and the 40 mg (p = 0.02) group compared to the 20 mg group. Droloxifene increased SHBG and suppressed FSH at all dosages and suppressed LH at the 40 and 100 mg dosages. These hormonal effects increased with increasing dosage. Shortterm toxicity was generally mild, and similar to that seen with other antiestrogens. Droloxifene appears active and tolerable. It may have a particular role in situations in which rapid pharmacokinetics, or an increased antiestrogenic to estrogenic ratio, are required.
79 citations
"Fulvestrant ('Faslodex')--a new tre..." refers background in this paper
...…estrogen receptor modulators Toremifene (Hayes et al. 1995), raloxifene (Thiebaud & Secrest 2001), idoxifene (Dowsett et al. 2000), and droloxifene (Rauschning & Pritchard 1994) are all antiestrogens that, like tamoxifen, compete with estrogen for the ER and have been collectively termed SERMs....
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TL;DR: Fulvestrant is at least as effective as anastrozole, providing a valuable treatment option for advanced breast cancer in postmenopausal women with visceral metastases who have failed on prior endocrine therapy.
73 citations
"Fulvestrant ('Faslodex')--a new tre..." refers background in this paper
...These data indicate that patients with visceral metastases derived a similar benefit from endocrine therapy to those without visceral metastases (CB 47.6% vs 43.8%; OR 21.9% vs 19.3% for fulvestrant and anastrozole respectively) (Mauriac et al. 2002)....
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TL;DR: The ability to block estrogen biosynthesis peripherally and locally within the breast provides new options for the treatment of hormone-sensitive breast cancers in postmenopausal women.
69 citations
"Fulvestrant ('Faslodex')--a new tre..." refers background in this paper
...…to tamoxifen (Dhingra 2001), non-steroidal and steroidal aromatase inhibitors (AIs) that inhibit the synthesis of estrogen in postmenopausal women (Miller & Dixon 2000), and most recently, fulvestrant (‘Faslodex’) a new ER antagonist that downregulates cellular levels of the ER (Howell et al.…...
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TL;DR: Effectiveness of the calusterone has prompted a dose-response study by the CBCG to determine the most effective dose of this androgen for use in treatment of breast cancer.
Abstract: A randomized clinical trial of calusterone and testolactone according to the protocol of the Cooperative Breast Cancer Group (CBCG) produced objective remissions of advanced breast cancer in 28% of women receiving calusterone and 18% of those given testolactone. Effectiveness of the calusterone has prompted a dose-response study by the CBCG to determine the most effective dose of this androgen for use in treatment of breast cancer.
68 citations
"Fulvestrant ('Faslodex')--a new tre..." refers background in this paper
...Over the past 60 years, androgens, progesterones and pharmacological doses of estrogens have been used to treat breast malignancies (Goldenberg et al. 1973, Pritchard & Sutherland 1989, Espie 1994)....
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TL;DR: Blocking of c‐erbB‐2 receptor with a humanized monoclonal antibody, 4D5 (HerceptinTM), or of EGFR with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI), ZD1839 (IressaTM), would decrease epithelial proliferation in DCIS.
Abstract: Background:
Ductal carcinoma in situ (DCIS) expresses c-erbB-2 receptor and epidermal growth factor receptor (EGFR). The aim of this study was to determine whether blocking of c-erbB-2 receptor with a humanized monoclonal antibody, 4D5 (HerceptinTM), or of EGFR with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), ZD1839 (IressaTM), would decrease epithelial proliferation in DCIS.
Methods:
DCIS tissue from 18 women undergoing surgery was implanted into 16 to 20 athymic nude mice per experiment (eight xenografts per mouse). Treatment commenced 2 weeks after implantation and consisted either of twice-weekly intraperitoneal injections of 4D5 10 mg/kg or of daily gavage with ZD1839 at 100–200 mg/kg for 14 days; appropriate controls were included. Xenografts were removed on days 14, 21 and 28. Proliferation was assessed by counting 1000 epithelial cells after Ki67 immuno- staining.
Results:
ZD1839 inhibited proliferation compared with that in controls after 14 days (P < 0·01), whereas 4D5 did not.
Conclusion:
Proliferation in DCIS was decreased by EGFR tyrosine kinase inhibition but not by c-erbB-2 receptor blockade. ZD1839, an orally active and selective EGFR-TKI, has potential as adjuvant therapy in DCIS. © 2001 British Journal of Surgery Society Ltd
66 citations
"Fulvestrant ('Faslodex')--a new tre..." refers background in this paper
...These cells are highly sensitive to growth inhibition by the EGFRtyrosine kinase inhibitor (EGFR-TKI) gefitinib (‘Iressa’ ZD1839), an effective inhibitor of cell proliferation (Chan et al. 2001)....
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