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PubMed2006

Changes in oestrogen receptor-alpha and -beta during progression to acquired resistance to tamoxifen and fulvestrant (Faslodex, ICI 182,780) in MCF7 human breast cancer cells.

Cell culture models of antioestrogen resistance often involve applying selective pressures of oestrogen deprivation simultaneously with addition of tamoxifen or fulvestrant (Faslodex, ICI 182,780) which makes it difficult to distinguish events in development of antioestrogen resistance from those in loss of response to oestrogen or other components. We describe here time courses of loss of antioestrogen response using either oestrogen-maintained or oestrogen-deprived MCF7 cells in which the only alteration to the culture medium was addition of 10(-6) M tamoxifen or 10(-7) M fulvestrant. In both oestrogen-maintained and oestrogen-deprived models, loss of growth response to tamoxifen was not associated with loss of response to fulvestrant. However, loss of growth response to fulvestrant was associated in both models with concomitant loss of growth response to tamoxifen. Measurement of oestrogen receptor alpha (ERalpha) and oestrogen receptor beta (ERbeta) mRNA by real-time RT-PCR together with ERalpha and ERbeta protein by Western immunoblotting revealed substantial changes to ERalpha levels but very little alteration to ERbeta levels following development of antioestrogen resistance. In oestrogen-maintained cells, tamoxifen resistance was associated with raised levels of ERalpha mRNA/protein. However by contrast, in oestrogen-deprived MCF7 cells, where oestrogen deprivation alone had already resulted in increased levels of ERalpha mRNA/protein, long-term tamoxifen exposure now reduced ERalpha levels. Whilst long-term exposure to fulvestrant reduced ERalpha mRNA/protein levels in the oestrogen-maintained cells to a level barely detectable by Western immunoblotting and non-functional in inducing gene expression (ERE-LUC reporter or pS2), in oestrogen-deprived cells the reduction was much less substantial and these cells retained an oestrogen-induction of both the ERE-LUC reporter gene and the endogenous pS2 gene which could still be inhibited by antioestrogen. This demonstrates that whilst ERalpha can be abrogated by fulvestrant and increased by tamoxifen in some circumstances, this does not always hold true and mechanisms other than alteration to ER must be involved in the development of antioestrogen resistant growth.

Antineoplastic Agents, Hormonal↗

PubMed2004

Impact on estrogen receptor binding and target tissue uptake of [18F]fluorine substitution at the 16alpha-position of fulvestrant (faslodex; ICI 182,780).

Fulvestrant (Faslodex; ICI 182,780) is a pure estrogen receptor (ER) antagonist recently approved for the treatment of hormone-sensitive breast cancer in post-menopausal women with disease progression following antiestrogen therapy. Fulvestrant strongly binds to the ER and its mode of action consists of inhibition of ER dimerization leading to a down regulation of ER protein cellular levels. With the aim to develop a probe for positron emission tomography (PET) imaging capable of predicting the potential therapeutic efficacy of selective ER modulators (SERM), we prepared three new 16alpha-[18F]fluoro-fulvestrant derivatives. These new radiopharmaceuticals were evaluated for their binding affinity to the human ERalpha and for their target tissue uptake in immature female rats. Substitution of one of the side-chain F-atoms of fulvestrant for 18F would have led to a product of low specific activity; instead we selected the 16alpha-position for 18F-labeling, which at least in the case of estradiol (ES) is well tolerated by the ER. Radiochemical synthesis proceeds by stereoselective introduction of the [18F]fluoride at the 16-18F-position of fulvestrant via opening of an intermediate O-cyclic sulfate followed by hydrolysis of the protecting methoxymethyl (MOM) ether and sulfate groups. Three analogs with different oxidation states of the side chain sulfur, i.e. sulfide, sulfone or sulfoxide (fulvestrant) were prepared. Introduction of the 16(18)F-fluorine led to a dramatic decrease of the apparent binding affinity for ER, as reported by Wakeling et al. (Cancer Res. 1991;51:3867-73). Likewise, in vivo ER-mediated uterus uptake values in immature female rats were disappointing. Overall, our findings suggest that these new PET radiopharmaceuticals are not suitable as tracers to predict ER(+) breast cancer response to hormonal therapy with selective ER modulators.

Animals↗

PubMed2003

A randomized, placebo-controlled, dose-ranging trial comparing fulvestrant with goserelin in premenopausal patients with uterine fibroids awaiting hysterectomy.

OBJECTIVE: To compare the use of a new antiestrogen fulvestrant with goserelin in reducing uterine fibroid growth before hysterectomy. DESIGN: An international, multicenter, randomized, placebo-controlled study. SETTING: Departments of obstetrics and gynecology. PATIENT(S): Premenopausal women (n = 307) diagnosed with uterine fibroids requiring hysterectomy. INTERVENTION(S): Over a 12-week period, patients received fulvestrant (50 mg, 125 mg, or 250 mg) as an i.m. injection, goserelin (3.6 mg) as a s.c. injection, or an injection-matched placebo once every 4 weeks. Patients underwent a hysterectomy at week 13. MAIN OUTCOME MEASURES: Efficacy endpoints included changes in fibroid growth, endometrial thickness, and uterine volume. The excretion of urinary markers of bone resorption was also examined. RESULT(S): Goserelin significantly reduced fibroid growth and endometrial thickness compared with placebos. Fulvestrant did not significantly alter fibroid volume or endometrial thickness or change endpoints such as endometrial histology or vaginal bleeding. Fulvestrant was associated with fewer postmenopause-related adverse events than goserelin. Goserelin, but not fulvestrant, significantly increased markers of bone resorption. CONCLUSION(S): At doses equivalent to those used for the treatment of breast cancer in postmenopausal women, fulvestrant did not significantly inhibit fibroid growth and, of particular note, did not lead to bone resorption.

Adult↗

PubMed2005

Additive antitumor effect of aromatase inhibitor letrozole and antiestrogen fulvestrant in a postmenopausal breast cancer model.

Blocking estrogen receptors with antiestrogens and blocking estrogen synthesis with aromatase inhibitors are two strategies currently being used for reducing the effect of estrogen in postmenopausal estrogen receptor-positive breast cancer patients. To optimize these treatment strategies, we have investigated whether tumor progression can be delayed by combining the pure antiestrogen fulvestrant with the nonsteroidal aromatase inhibitor letrozole. These studies were done in ovariectomized, athymic mice bearing tumors of estrogen receptor-positive human breast cancer cells stably transfected with the aromatase gene (MCF-7Ca). Groups of mice with equivalent tumor volumes were injected s.c. daily with vehicle (control; n = 6), fulvestrant (1 mg/d; n = 7), letrozole (10 microg/d; n = 18), or letrozole (10 microg/d) plus fulvestrant (1 mg/d; n = 5). All treatments were effective in suppressing tumor growth compared with controls (P < 0.001). Tumor volumes of the fulvestrant-treated group had doubled in 10 weeks. After 19 weeks of letrozole (10 microg/d) treatment when tumors had nearly doubled in volume, mice (n = 18) were assigned to second-line therapy with letrozole (100 microg/d; n = 6), tamoxifen (100 microg/d; n = 6), or remained on letrozole treatment (10 microg/d; n = 6). However, tumors continued to increase in volume in these groups. Tumors of animals treated with the combination of letrozole plus Faslodex regressed over 29 weeks of treatment by 45%. Thus, the combination of letrozole plus fulvestrant was more effective in suppressing tumor growth than either letrozole or fulvestrant alone or sequential therapies with tamoxifen or a higher dose of letrozole (100 microg/d).

Animals↗

PubMed2006

Fulvestrant: pharmacologic profile versus existing endocrine agents for the treatment of breast cancer.

OBJECTIVE: To compare the pharmacologic profile of fulvestrant with that of tamoxifen and the aromatase inhibitors with respect to the choice of treatment for advanced breast cancer (ABC). DATA SOURCES: Principal literature and review articles were obtained from MEDLINE (1991-March 2006). Key search terms included fulvestrant, tamoxifen, aromatase inhibitors, pharmacology, and breast cancer. Further data sources were identified from the bibliographies of selected articles. STUDY SELECTION AND DATA EXTRACTION: English-language preclinical and clinical research and review articles reporting pharmacologic and safety data for fulvestrant, tamoxifen, and the aromatase inhibitors were evaluated to identify relevant information. Randomized clinical trial data were preferred over preclinical or Phase I and II trial data. DATA SYNTHESIS: A total of 52 clinical papers (including 10 reviews) and 17 clinical abstracts were evaluated reporting results from controlled Phase I-III studies and pilot studies. Eleven preclinical papers (including 2 reviews) and 6 preclinical abstracts were also included. Fulvestrant has little effect on sex hormone endocrinology, bone metabolism, and lipid biochemistry and appears unlikely to be the subject or cause of CYP3A4-mediated drug interactions. Tamoxifen has a protective effect on bone (due to its partial estrogen agonist activity) and reduces plasma low-density lipoprotein cholesterol but increases triglyceride levels. The aromatase inhibitors have variable effects on lipid profiles and sex hormone endocrinology but have detrimental effects on bone due to inhibition of estrogen synthesis. Drug interactions have been noted between tamoxifen and anticoagulants and tamoxifen and aromatase inhibitors, which may be due to CYP-mediated mechanisms. CONCLUSIONS: Fulvestrant appears to have little effect on sex hormone endocrinology, bone metabolism, and lipid biochemistry and is unlikely to be subject to or the cause of CYP3A4-mediated drug-drug interactions. As such, fulvestrant represents a valuable new endocrine therapy for the treatment of ABC and broadens the options available to clinicians in the treatment of this disease.

Antineoplastic Agents, Hormonal↗

PubMed2005

The history and mechanism of action of fulvestrant.

Fulvestrant is a pure antiestrogen that emerged from a systematic medicinal chemistry strategy of modification of long-chain alkyl substitutes in the 7a-position of estradiol. Fulvestrant has no uterotrophic effects on the immature or ovariectomized rat and blocks the agonistic effects of estradiol and tamoxifen in a dose-dependent manner. In in vivo and in vitro breast cancer models, fulvestrant has anticancer activity at least as good as tamoxifen and is superior to tamoxifen in some models. Fulvestrant requires intramuscular administration in a proprietary formulation of castor oil and alcohols. When fulvestrant binds to estrogen receptor monomers it inhibits receptor dimerization, activating function 1 (AF1) and AF2 are rendered inactive, translocation of receptor to the nucleus is reduced, and degradation of the estrogen receptor is accelerated. This results in pure antiestrogenic effects. There is substantial preclinical evidence that the nonsteroidal hormone-dependent mechanisms of estrogen receptor activation and regulation via growth factor receptors and their signal transduction pathways are important in the development of breast cancer hormonal resistance. Methods of exploiting the interactions between these nonsteroidal hormone-dependent mechanisms of resistance and hormonal agents such as fulvestrant are an active area for drug development and clinical investigation.

Animals↗

PubMed2006

Time to response: comparison of fulvestrant and oral endocrine agents.

BACKGROUND: The different pharmacokinetic profiles of the intramuscularly administered antioestrogen fulvestrant and oral endocrine treatments have led to speculation among some physicians that this could result in a delayed time to response (TTR) with fulvestrant. PATIENTS AND METHODS: An analysis of TTR was performed on data from 2 phase III trials comparing fulvestrant and anastrozole as second-line treatments for postmenopausal women with advanced-stage, tamoxifen-resistant breast cancer. RESULTS: In a combined analysis of the data from these trials, median TTR was 3.1 months (range, 0.9-33.1 months) for fulvestrant and 3 months (range, 0.7-20.2 months) for anastrozole, although responses were still being noted after 2-3 years of stable disease in some patients. Data were subsequently analyzed from 3 other randomized phase III trials of fulvestrant, anastrozole, and tamoxifen in postmenopausal women. Time to response was also similar between the 3 treatments in these additional analyses. CONCLUSION: Time to response is similar between fulvestrant and oral endocrine treatments, despite pharmacokinetic differences.

Administration, Oral↗

PubMed2003

Dehydroepiandrosterone sulfate causes proliferation of estrogen receptor-positive breast cancer cells despite treatment with fulvestrant.

HYPOTHESIS: Dehydroepiandrosterone sulfate (DHEA-S) causes a proliferation of estrogen receptor (ER)-positive breast cancer cells, even with tamoxifen citrate blockade. The ER antagonist ICI 182780 (fulvestrant) will more effectively stop the proliferative effect of DHEA-S on breast cancer cells. DESIGN: Examination of in vitro breast cancer cell growth in the presence of fulvestrant and DHEA-S. SETTING: Surgical oncology research laboratory. INTERVENTIONS: The ER-positive and ER-negative breast cancer cells were pretreated with fulvestrant and stimulated with 900 microg/dL (22.8 micromol/L) of DHEA-S. MAIN OUTCOME MEASURES: Assays using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, thiazolyl blue, were performed on the third, fifth, and seventh days poststimulation and permitted the calculation of growth percent change. RESULTS: The ER-positive and progesterone receptor-positive cells demonstrated universal proliferation of 107% by day 7 when treated with fulvestrant, regardless of the dose. The ER-negative and progesterone receptor-negative cells demonstrated growth inhibition. CONCLUSIONS: The DHEA-S circumvented fulvestrant inhibition and caused ER-positive breast cancer cell growth.

Breast Neoplasms↗

PubMed2005

The future of fulvestrant ("Faslodex").

Changes in clinical practice regarding favoured first-line and adjuvant treatments for postmenopausal women with advanced breast cancer (ABC) mean that it is becoming increasingly important to identify agents that are effective following aromatase inhibitor (AI) failure as well as tamoxifen failure. Fulvestrant ("Faslodex") is a new oestrogen receptor (ER) antagonist with no agonist effects that binds, blocks and degrades the ER. Fulvestrant is at least as effective as anastrozole following tamoxifen failure and also shows activity after progression on AIs. Its very good tolerability profile and novel mode of action, might offer potential for the use of fulvestrant in combination regimens, and there is also scope for investigating the use of loading and higher dose regimens in an attempt to further enhance efficacy. Here, the rationale and evidence for the efficacy of fulvestrant following AI failure and its combination with AIs and novel agents such as gefitinib and trastuzumab will be reviewed. The ongoing clinical development programme for fulvestrant will more fully the role of this valuable new agent in the treatment of postmenopausal ABC.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Emerging principles for the development of resistance to antihormonal therapy: implications for the clinical utility of fulvestrant.

We seek to evaluate the clinical consequences of resistance to antihormonal therapy by studying analogous animal xenograft models. Two approaches were taken: (1) MCF-7 tumors were serially transplanted into selective estrogen receptor modulator (SERM)-treated immunocompromised mice to mimic 5 years of SERM treatment. The studies in vivo were designed to replicate the development of acquired resistance to SERMs over years of clinical exposure. (2) MCF-7 cells were cultured long-term under SERM-treated or estrogen withdrawn conditions (to mimic aromatase inhibitors), and then injected into mice to generate endocrine-resistant xenografts. These tumor models have allowed us to define Phase I and Phase II antihormonal resistance according to their responses to E(2) and fulvestrant. Phase I SERM-resistant tumors were growth stimulated in response to estradiol (E(2)), but paradoxically, Phase II SERM and estrogen withdrawn-resistant tumors were growth inhibited by E(2). Fulvestrant did not support growth of Phases I and II SERM-resistant tumors, but did allow growth of Phase II estrogen withdrawn-resistant tumors. Importantly, fulvestrant plus E(2) in Phase II antihormone-resistant tumors reversed the E(2)-induced inhibition and instead resulted in growth stimulation. These data have important clinical implications. Based on these and prior laboratory findings, we propose a clinical strategy for optimal third-line therapy: patients who have responded to and then failed at least two antihormonal treatments may respond favorably to short-term low-dose estrogen due to E(2)-induced apoptosis, followed by treatment with fulvestrant plus an aromatase inhibitor to maintain low tumor burden and avoid a negative interaction between physiologic E(2) and fulvestrant.

Animals↗

PubMed2004

Additive antitumour effect of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839) and the antioestrogen fulvestrant (Faslodex, ICI 182,780) in breast cancer cells.

A high expression level of epidermal growth factor receptor (EGFR)/HER1 has been suggested to lead to a shorter survival time and resistance to endocrine therapy in patients with breast cancer. To test the hypothesis that inhibition of the EGFR signalling pathway affects the antitumour effect of endocrine therapy, an EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib, and an oestrogen receptor (ER) antagonist, fulvestrant, were administered to human breast cancer cells. A total of five human breast cancer cell lines were used. The effects of single or combined treatments with gefitinib and/or fulvestrant on cell growth, cell cycle progression and apoptosis were analysed. Changes in the expression levels of cyclin-dependent kinase inhibitors, p21 and p27, an antiapoptotic factor, Bcl-2, and a proapoptotic factor, Bax, were also investigated. All cell lines tested were sensitive to gefitinib (50% growth inhibitory concentration, 10-28.5 microM). Breast cancer cell lines with a high expression level of HER1 or HER2 were more sensitive to gefitinib than the others. Gefitinib induced a significant G1-S blockade in ER-positive KPL-3C cells. Gefitinib induced significant apoptosis in HER1-overexpressing MDA-MB-231 cells. Gefitinib additively increased the antitumour effect of fulvestrant in all three ER-positive cell lines in a medium supplemented with 17beta-oestradiol. The combined treatment promoted cell cycle retardation in KPL-3C cells, which is associated with an upregulation of p21 by fulvestrant and gefitinib, respectively. Apoptosis was associated with downregulation of Bcl-2 by gefitinib in MDA-MB-231 cells. These results suggest an additive interaction between the EGFR-TKI gefitinib and the antioestrogen fulvestrant in ER-positive breast cancer cells.

Antineoplastic Agents↗

PubMed2006

Clinical benefit of fulvestrant in postmenopausal women with advanced breast cancer and primary or acquired resistance to aromatase inhibitors: final results of phase II Swiss Group for Clinical Cancer Research Trial (SAKK 21/00).

BACKGROUND: The aim of this study was to evaluate the efficacy and tolerability of fulvestrant, an estrogen receptor antagonist, in postmenopausal women with hormone-responsive tumors progressing after aromatase inhibitor (AI) treatment. PATIENTS AND METHODS: This is a phase II, open, multicenter, noncomparative study. Two patient groups were prospectively considered: group A (n=70) with AI-responsive disease and group B (n=20) with AI-resistant disease. Fulvestrant 250 mg was administered as intramuscular injection every 28 (+/-3) days. RESULTS: All patients were pretreated with AI and 84% also with tamoxifen or toremifene; 67% had bone metastases and 45% liver metastases. Fulvestrant administration was well tolerated and yielded a clinical benefit (CB; defined as objective response or stable disease [SD] for >or=24 weeks) in 28% (90% confidence interval [CI] 19% to 39%) of patients in group A and 37% (90% CI 19% to 58%) of patients in group B. Median time to progression (TTP) was 3.6 (95% CI 3.0 to 4.8) months in group A and 3.4 (95% CI 2.5 to 6.7) months in group B. CONCLUSIONS: Overall, 30% of patients who had progressed following prior AI treatment gained CB with fulvestrant, thereby delaying indication to start chemotherapy. Prior response to an AI did not appear to be predictive for benefit with fulvestrant.

Adult↗

PubMed2003

Paradoxical action of fulvestrant in estradiol-induced regression of tamoxifen-stimulated breast cancer.

BACKGROUND: Long-term tamoxifen treatment of breast cancer can result in tamoxifen-stimulated breast cancer, in which estrogen inhibits tumor growth after tamoxifen withdrawal. We investigated the molecular mechanism(s) of estradiol-induced tumor regression by using an in vivo model of tamoxifen-stimulated human breast cancer. METHODS: Growth of parental estradiol-stimulated MCF-7E2 and long-term tamoxifen-stimulated MCF-7TAMLT xenografts in athymic mice was measured during treatment with vehicle, estradiol, estradiol plus tamoxifen, tamoxifen alone, estradiol plus fulvestrant, or fulvestrant alone. Apoptosis was detected by the terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. Protein expression was assessed by western blot analysis. mRNA expression was assessed by real-time reverse transcription-polymerase chain reaction. All statistical tests were two-sided. RESULTS: MCF-7E2 tumor growth was stimulated by estradiol (cross-sectional area at week 13 = 1.06 cm2, 95% confidence interval [CI] = 0.82 to 1.30 cm2; P<.001) compared with control (0.06 cm2, 95%CI = -0.02 to 0.14 cm2), but tumor growth was inhibited by tamoxifen or fulvestrant. MCF-7TAMLT tumor growth was stimulated by tamoxifen) cross-sectional area at week 10 = 0.60 cm2, 95% CI = 0.50 to 0.70 cm2; P<.001) compared with control (0.02 cm2, 95% CI = 0.00 to 0.04 cm2). For MCF-7TAMLT tumors that were initially 0.35 cm2, estradiol-induced regression to 0.18 cm2 (95% CI = 0.15 to 0.21 cm2; P<.001), and tamoxifen or estradiol plus fulvestrant enhanced tumor growth to 1.00 cm2 (95% CI = 0.88 to 1.22 cm2). Estradiol increased the number of apoptotic cells in tumors by 23% (95% CI = 20% to 26%; P<.001) compared with all other treatments, decreased estrogen receptor alpha(ERalpha) protein expression, increased the expression of Fas mRNA and protein, decreased the expression of HER2/neu mRNA and protein and nuclear factor kappaB (NF-kappaB) protein but did not affect Fas ligand protein expression compared with control. Paradoxically, fulvestrant reversed this effect and stimulated MCF-7TAMLT tumor growth apparently through ERalpha-mediated regulation of Fas, HER2/neu, and NF-kappaB. CONCLUSION: Physiologic levels of estradiol induced regression of tamoxifen-stimulated breast cancer tumors, apparently by inducing the death receptor Fas and suppressing the antiapoptotic/prosurvival factors NF-kappaB and HER2/neu.

Animals↗

PubMed2005

Inactivation of the pure antiestrogen fulvestrant and other synthetic estrogen molecules by UDP-glucuronosyltransferase 1A enzymes expressed in breast tissue.

Fulvestrant (Faslodex) is administered by intramuscular injection and is converted into ketone, sulfate, sulfone and glucuronide metabolites. Glucuronidation, catalyzed by 18 members of the UDP-glucuronosyltransferase (UGT) enzyme family, plays a major role in the elimination of natural estrogens. The present study was aimed at identifying and characterizing human UGT enzymes involved in the glucuronidation of this antiestrogen as well as other synthetic estrogen derivatives with aliphatic chains on the E2 molecule. In contrast to E2, which is conjugated by UGT1A1, -1A3, -1A8, -1A10, and -2B7, fulvestrant is glucuronidated by UGT1A1, -1A3, -1A4, and -1A8. The four UGT1A-fulvestrant conjugating enzymes glucuronidate this substrate at position 3, whereas only UGT1A8 also produces fulvestrant-17-glucuronide. For E2, only UGT1A3 and UGT2B7 are capable to conjugate at 17-hydroxyposition. These observations indicate that addition of an aliphatic chain to the E2 molecule modifies the specificity of the UGT enzymes toward the C18 molecules. To further investigate the specificity of these enzymes, a series of E2 derivatives with aliphatic or phenyl chains at position 2, 7alpha, and 11beta was also tested for its conjugation with human UGT enzymes. It was observed that, in addition to UGT1A3, UGT1A1 and UGT1A8 also played important roles for the glucuronidation of these compounds. This suggests that the basic structure of E2 is one of the major determinants for the glucuronidation catalyzed by this group of enzymes. Considering the high level of UGT1A3 and -1A4 expression in the gastrointestinal tract and mammary gland, our results suggest that fulvestrant can be inactivated both in intestine and in its target tissue.

Breast↗

PubMed2004

Fulvestrant: a new type of estrogen receptor antagonist for the treatment of advanced breast cancer.

Postmenopausal women with hormone receptor- positive tumors are candidates for endocrine treatment. Current treatment options include the selective estrogen receptor modulators (e.g., tamoxifen and toremifene), which inhibit estrogen receptor signaling, and the aromatase inhibitors (e.g., anastrozole and letrozole), which prevent the conversion of androgens into estrogen in postmenopausal women. As most patients eventually become resistant to endocrine agents, there is a need for new treatments that are effective, well tolerated and lack cross-resistance with currently available therapies. This review describes the development of fulvestrant (Faslodex), a new type of endocrine agent, which is an estrogen receptor antagonist with no agonist effects. Phase III clinical trials have found that fulvestrant is as effective and well tolerated as anastrozole for treating postmenopausal patients with advanced breast cancer who have progressed on one prior endocrine therapy. In addition, fulvestrant has first-line efficacy similar to that of tamoxifen in patients with estrogen receptor-positive and/or progesterone receptor-positive breast cancer. Moreover, in a compassionate-use program, it has become clear that fulvestrant is not cross-resistant with other therapies. Therefore, fulvestrant is a versatile new treatment option for postmenopausal women with advanced breast cancer who have progressed on prior endocrine therapy.

Animals↗

PubMed2005

Fulvestrant in the treatment of postmenopausal women with advanced breast cancer.

Fulvestrant is a new type of estrogen receptor antagonist with no agonist effects, and represents a valuable addition to the range of endocrine treatments available to treat postmenopausal women with advanced breast cancer. Fulvestrant binds, blocks and degrades the estrogen receptor, thereby retarding growth and progression of hormone-sensitive tumors. Two Phase III trials have demonstrated that fulvestrant is at least as effective as the third-generation aromatase inhibitor anastrozole in the treatment of advanced breast cancer following progression on antiestrogen therapy. In addition, a Phase III trial comparing fulvestrant with tamoxifen in postmenopausal women with advanced breast cancer showed similar efficacy and tolerability. Clinical trials are ongoing to evaluate different endocrine sequence options for postmenopausal women with breast cancer, and to evaluate the efficacy of fulvestrant in combination with anticancer agents that target other signaling pathways.

Aged↗

PubMed2002

Fulvestrant ('Faslodex')--a new treatment option for patients progressing on prior endocrine therapy.

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.

Animals↗

PubMed2006

Mechanisms of tumor regression and resistance to estrogen deprivation and fulvestrant in a model of estrogen receptor-positive, HER-2/neu-positive breast cancer.

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.

Animals↗