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PubMed2002

Fulvestrant: a review of its development, pre-clinical and clinical data.

Hormone therapy is the most important systemic treatment of hormone receptor-positive breast cancer at all stages. Selective oestrogen receptor modulators (SERMs), such as tamoxifen, the mainstay of hormone receptor positive breast cancer manipulation for many years, are limited by their agonist actions. Oestrogen-like activity of these drugs may stimulate cancer growth such as in the endometrium and is a mechanism of resistance in breast cancer. Fulvestrant, the first of a new class of drugs, an oestrogen receptor down regulator, may have advantages over tamoxifen in the treatment of oestrogen-dependent disease. The pre-clinical development and early clinical data of fulvestrant are reviewed. Fulvestrant was as effective as the aromatase inhibitor anastrazole in second-line advanced breast cancer. The phase III trial of fulvestrant versus tamoxifen, as first-line treatment for metastatic breast cancer, has completed accrual and is maturing. Fulvestrant has useful activity against breast cancer as well as a favourable side-effect profile and is likely to represent a useful addition to the fight against hormone dependent breast cancer. Its place will be better defined by ongoing clinical trials.

Animals↗

PubMed2004

Understanding the biologic mechanisms responsible for breast-cancer progression during tamoxifen or fulvestrant treatment.

BACKGROUND: Dehydroepiandosterone sulfate (DHEAS) causes breast-cancer proliferation, even during tamoxifen or fulvestrant blockade. The purpose of this study was to determine possible mechanisms for this treatment failure. METHODS: T-47D cells (estrogen receptor [ER] and progesterone receptor [PR] positive) were treated with fulvestrant (10 micromol/L), tamoxifen (10 mmol/L or 0.0001 nmol/L), or vehicle and stimulated with DHEAS. Gene expression of ER, PR, insulin-like growth factor (IGF)-1 and -2, and insulin-like growth-factor binding protein (IGFBP)-1 through -4 was determined. RESULTS: ER and PR gene expression decreased by 1.3- and 4-fold with fulvestrant and DHEAS. ER expression decreased by 2.7-fold with 0.0001 nmol/L tamoxifen and DHEAS. ER and PR expression were unchanged by 10 nmol/L tamoxifen. IGF-1 and IGF-2 were not expressed. IGFBP-2 and -4 expression decreased by 1.9- and 1.6-fold after DHEAS stimulus, although this was not statistically significant. CONCLUSIONS: DHEAS exposure, even in the presence of tamoxifen and fulvestrant, induces changes in ER and PR gene expression that may be partially responsible for breast cancer progression.

Antineoplastic Agents, Hormonal↗

PubMed2005

Case studies of fulvestrant ("Faslodex") in postmenopausal women with advanced breast cancer.

Fulvestrant is a new oestrogen receptor (ER) antagonist that is licensed for the treatment of postmenopausal women with advanced breast cancer progressing following antioestrogen treatment and may also be effective in those progressing after non-steroidal aromatase inhibitors. The use of fulvestrant in a Compassionate Use Programme (CUP) in a "real-life" setting has permitted its activity and tolerability profile in patients with different disease characteristics to be observed. Here, we present five case reports of fulvestrant use in postmenopausal women with advanced breast cancer progressing after prior endocrine therapy. Clinical experience from the CUP supports the published clinical trial data and suggests that fulvestrant is a valuable new treatment for postmenopausal women with advanced breast cancer, including those with visceral metastases and human epidermal growth factor receptor 2-positive disease.

Adult↗

PubMed2004

Clinical experience with fulvestrant ('Faslodex'): a nurse's perspective.

Following the recent approval of fulvestrant ('Faslodex', 250 mg/month) for the treatment of postmenopausal women with advanced or metastatic breast cancer in the European Union, its use in the clinic will increase. The breast cancer nurse specialist and/or the oncology nurse will be the health care professional who administers fulvestrant to patients, and this manuscript aims to describe my experiences and the practicalities of using this new treatment. Faslodex is a viscous solution that is slowly administered intramuscularly (250 mg/5 mL) into the upper outer quadrant of the buttock, with patients positioned either on their side, prone or standing up. Injection-site reactions are infrequent and most patients do not find the injection painful. To highlight the use of fulvestrant in the clinical setting, four case histories of patients who have received fulvestrant in my centre are described.

Aged↗

PubMed2005

Aromatase inhibitors: combinations with fulvestrant or signal transduction inhibitors as a strategy to overcome endocrine resistance.

There is an increasing rationale for effective combinations of endocrine therapy with novel drugs that target aberrant signal transduction pathways in estrogen receptor (ER) positive breast cancer. Prolonged endocrine therapy can be associated with an acquired increase in peptide growth factor signaling (EGFR, HER2), together with cross-talk activation of ER-dependent gene transcription and cell growth that leads to endocrine resistance. Current approaches to target these pathways include both the selective ER downregulator fulvestrant, and various signal transduction inhibitors (STIs). Fulvestrant can overcome resistance to tamoxifen (TAM-R) and long-term estrogen deprivation (LTED-R) in experimental models by reducing ER expression, and represents a current option for post-menopausal women with endocrine resistant ER+ve breast cancer. Emerging data suggest that fulvestrant's effect may be greater when combined with estrogen deprivation, and several phase III trials are assessing fulvestrant combined with aromatase inhibitors (AIs). Small molecule STIs such as tyrosine kinase inhibitors (TKIs), farnesyltransferase inhibitors (FTIs) and mTOR antagonists are also active in breast cancer. Pre-clinical data suggest that combined endocrine/STI therapy may result in greater growth inhibition than either therapy alone, and thus delay emergence of resistance. Several clinical trials are now examining STIs combined with AIs both in the tamoxifen-resistant and first-line advanced breast cancer setting, while pre-surgical studies are investigating the efficacy of combined endocrine/STI therapy utilising biological primary endpoints. This article reviews the pre-clinical rationale for this strategy and the clinical trials in this area.

Antineoplastic Agents, Hormonal↗

PubMed2006

Estrogen induces death of tamoxifen-resistant MCF-7 cells: contrasting effect of the estrogen receptor downregulator fulvestrant.

A common problem in breast cancer therapy is resistance to the antiestrogen tamoxifen. However, tamoxifen-resistant breast tumors can still respond to other hormonal therapies. In animal models of tamoxifen-resistant breast cancer cells, physiological levels of estrogen can induce tumor regression. Recently, the estrogen receptor downregulator fulvestrant was shown to promote tumor growth of tamoxifen-resistant cells when added in combination with physiological levels of estrogen. Here, we show, using a cell culture model, that continuous exposure of tamoxifen-resistant cells to physiological levels of estrogen leads to cell death. Addition of the estrogen receptor downregulator fulvestrant prevents estrogen-induced death in a dose-dependent manner. Our data indicate that endogenous levels of estrogen affect the response of tamoxifen-resistant cells to fulvestrant. These results suggest that failure of fulvestrant to inhibit tumor growth in some tamoxifen-resistant patients may be due to endogenous estrogen levels. Moreover, these studies support short-term treatment with estrogen as a second-line hormonal therapy for tamoxifen-resistant breast cancer.

Apoptosis↗

PubMed2006

Fulvestrant: a further treatment option for patients with metastatic uterine cancer?

BACKGROUND: Metastatic uterine cancer is notoriously difficult to treat, presenting a poor prognosis and a median survival time of less than 1 year. We present the successful use of the antiestrogen fulvestrant in an endocrine therapy-naive patient with advanced uterine cancer. CASE REPORT: A 64-year-old female presented with advanced uterine cancer 7.0 x 6.0 x 5.5 cm in size, with infiltration of the bladder. Previous chemotherapy and radiotherapy had been unsuccessful in preventing disease progression, and the patient developed hepatic metastases. As the tumor expressed a high level of estrogen receptor, treatment with fulvestrant 250 mg/month was initiated. RESULTS: 25 months after commencing fulvestrant treatment, the tumor had decreased in size to 4.8 x 3.5 x 3.2 cm, and the hepatic metastases were no longer detectable. Throughout treatment, the patient maintained a Karnofsky performance index of 90%. CONCLUSION: We suggest that fulvestrant may be an active and well-tolerated treatment option for patients with estrogen receptor- positive advanced uterine cancer.

Antineoplastic Agents, Hormonal↗

PubMedDate not supplied

Hormonal therapy for breast cancer: focus on fulvestrant.

Fulvestrant, the first drug of the pure estrogen antagonists to be approved for clinical use, is a new therapeutic option for metastatic breast cancer. Fulvestrant offers a unique metastatic breast cancer treatment option because its mechanism of action is the destruction, rather than the blockade, of estrogen receptors. No known agonistic activity exists, limiting potential side effects and receptor exhaustion. The side effect profile of fulvestrant is related to its antiestrogen effect and includes gastrointestinal disturbance, urinary tract infection, and vaginitis. Suggestions for managing the side effects of fulvestrant are described, and a case study is provided as an illustrative aid in understanding the role of this new hormonal agent.

Antineoplastic Agents, Hormonal↗

PubMed2006

Fulvestrant in women with advanced breast cancer after progression on prior aromatase inhibitor therapy: North Central Cancer Treatment Group Trial N0032.

PURPOSE: Fulvestrant is an antiestrogen that leads to estrogen receptor degradation and has demonstrated efficacy in breast cancer patients who have had disease recurrence or progression after tamoxifen. This study was designed to examine the efficacy and toxicity of fulvestrant in patients with disease progression on a third-generation aromatase inhibitor (AI). PATIENTS AND METHODS: A one-stage phase II trial was conducted in postmenopausal women with measurable disease by Response Evaluation Criteria in Solid Tumors criteria who experienced disease progression after treatment with a third-generation AI and, at most, one additional hormonal agent. Tumors must have been estrogen receptor and/or progesterone receptor positive. The primary end point was objective response rate, and secondary end points were time to disease progression, survival, duration of response, and toxicity. RESULTS: Eighty patients were enrolled, and three were ineligible. Characteristics of the 77 eligible patients included median age of 68 years, performance score of 0 or 1 in 91% of patients, visceral dominant disease in 88% of patients, two prior hormonal treatments in 73% of patients, and prior chemotherapy for metastatic disease in 32% of patients. Eleven patients (14.3%) achieved a partial response, and 16 patients (20.8%) had stable disease for at least 6 months, for a clinical benefit rate of 35%. Antitumor activity seemed to be higher in women with prior treatment with AI alone compared with women whose prior treatment also included tamoxifen. Median time to progression was 3 months, and median survival time was 20.2 months. Fulvestrant was well tolerated. CONCLUSION: Fulvestrant is a well-tolerated treatment and has efficacy against breast cancers that have progressed after therapy with a third-generation AI.

Aged↗

PubMedDate not supplied

[Fulvestrant: a new agent in endocrine treatment for breast cancer].

Tamoxifen is considered to be the gold standard in hormonotherapy of patients with estrogen dependent breast cancer (estrogen receptor (ER) and/or progesterone receptor (PR) positive tumors). However, because tamoxifen's beneficial effects diminish after 5 years of use in adjuvant setting and because of its partial agonistic effects and its resistence to tamoxifen in some breast carcinoma, there is a need for new antiestrogens. One of these antiestrogens is fulvestrant which, unlike tamoxifen, has no partial agonistic effects. Its efficacy has been confirmed in preclinical and in recent phase III clinical studies in postmenopausal patients. In disease recurrence after adjuvant tamoxifen or progressive disease on-first-line tamoxifen treatment fulvestrant is comparable with (similar to) anastrozole. When compared with tamoxifen as first-line treatment in patients with advanced cancer, only in patients with ER and/or PR positive tumors similar results have also been obtained. In both trials tolerance to fulvestrant has been good. Following the results of these clinical studies fulvestrant has already been licenced in the USA and EU for the treatment of postmenopausal women with advanced breast cancer who had progressed on prior anti-estrogen therapy.

Antineoplastic Agents, Hormonal↗

PubMed2003

Differential effects of raloxifene, tamoxifen and fulvestrant on a murine mammary carcinoma.

The purpose of this study was to evaluate the effect of the selective estrogen receptor modulators raloxifene and tamoxifen and of the pure antiestrogen fulvestrant on tumor growth and progesterone receptor (PR) expression in an experimental model of breast cancer. The effects of these compounds on cell proliferation were studied in primary cultures of a progestin-dependent mammary carcinoma tumor line, in the presence of medroxyprogesterone acetate (MPA) or 17-beta-estradiol (E2). In in vivo studies the tumor was inoculated subcutaneously in BALB/c female mice treated with 20 mg MPA depot. Raloxifene (12.5 mg/kg) or tamoxifen (5 mg/kg) were administered in daily doses or E2 silastic pellets (5 mg) were implanted. When the tumors reached about 25-50 mm2 MPA was removed in half of the animals. E2 induced complete tumor regressions, tamoxifen inhibited tumor growth in vivo while raloxifene disclosed proliferative effects in animals in which MPA had been removed. In vitro, E2 inhibited cell proliferation at concentrations higher than 10(-14)M. Raloxifene and fulvestrant, but not tamoxifen, partially reverted E2-induced inhibition. Fulvestrant and tamoxifen inhibited MPA-induced cell proliferation while raloxifene had a stimulatory effect. Tamoxifen and E2 increased, raloxifene induced no effect, and fulvestrant significantly decreased PR expression. In this study we provide evidence for differential effects of tamoxifen and raloxifene on experimental mammary tumors. Since raloxifene is under evaluation for use in breast cancer prevention, these results may have important clinical implications.

Animals↗

PubMed2005

Endocrine treatment options for advanced breast cancer--the role of fulvestrant.

For many years, tamoxifen has been the 'gold standard' amongst anti-oestrogen therapies for breast cancer. However, the selective aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, have demonstrated advantages over tamoxifen as first-line treatments for advanced disease. Anastrozole is also more effective as an adjuvant treatment in early, operable breast cancer and is being increasingly used in the adjuvant setting. Generally, the selective oestrogen receptor modulators (SERMs), such as toremifene, droloxifene, idoxifene, raloxifene, and arzoxifene, show minimal activity in tamoxifen-resistant disease and show no superiority over tamoxifen as first-line treatments. In addition to these agents, other treatment options for advanced disease include high-dose oestrogens and progestins. Response rates for high-dose oestrogens and tamoxifen are similar, but the use of oestrogens is limited by their toxicity profile. Consequently, there is a need for new endocrine treatment options for breast cancer, particularly for use in disease that is resistant to tamoxifen or AIs. Fulvestrant ('Faslodex') is a new type of steroidal oestrogen receptor (ER) antagonist that downregulates cellular levels of the ER and progesterone receptor and has no agonist activity. This paper reviews the key efficacy and tolerability data for fulvestrant in postmenopausal women in the context of other endocrine therapies and explores the potential role of fulvestrant within the sequencing of endocrine therapies for advanced breast cancer.

Anastrozole↗

PubMed2004

Fulvestrant ('Faslodex')--a new hormonal treatment for advanced breast cancer.

In patients with hormone receptor-positive advanced breast cancer (ABC), endocrine therapy is as effective as cytotoxic chemotherapy but is better tolerated. Most breast cancers are hormone responsive, but eventually develop resistance to individual endocrine agents. However, changing to a different type of endocrine therapy when resistance develops can circumvent this problem and delay the need for cytotoxic chemotherapy. Such chemotherapy can have a major impact on patient's quality of life, and for this reason is generally considered to be a last option for breast cancer patients. Fulvestrant ('Faslodex') is a new type of endocrine therapy with a different mode of action to existing treatments. It is at least as effective as the third-generation aromatase inhibitor (AI) anastrozole or letrozole in the treatment of postmenopausal women with advanced, tamoxifen-resistant breast cancer. Fulvestrant also appears to be effective after treatment with non-steroidal AIs. Fulvestrant is well tolerated and provides a further option in the endocrine treatment of ABC.

Adult↗

PubMed2005

Durable response of metastatic endometrial carcinoma to treatment with fulvestrant (Faslodex) after prior progestin and anastrozole therapy.

BACKGROUND: Patients with metastatic endometrial carcinoma may respond to hormonal therapy with progestins. There is a need for new therapies for hormone-responsive disease. CASE: We report a patient with metastatic endometrial carcinoma to the lungs, who after progressing on progestin therapy, had a lengthy remission with anastrozole; upon further progression, fulvestrant (Faslodex) was instituted, with a resultant partial remission, which has been sustained for almost 3 years. CONCLUSION: In this case, fulvestrant therapy was successful even in the face of prior anastrozole and megestrol. The activity of fulvestrant in patients with metastatic endometrial carcinoma should be further explored, especially in situations in which the tumor is well differentiated and/or expresses hormone receptors.

Aged↗

PubMed2003

Fulvestrant (Faslodex) versus anastrozole for the second-line treatment of advanced breast cancer in subgroups of postmenopausal women with visceral and non-visceral metastases: combined results from two multicentre trials.

The efficacy of fulvestrant (Faslodex), a novel oestrogen receptor (ER) antagonist that downregulates the ER and has no known agonist effects, was compared with the aromatase inhibitor anastrozole (Arimidex) for the second-line treatment of advanced breast cancer in postmenopausal women with visceral and non-visceral metastases. Assessment was by means of a retrospective subgroup analysis of combined data from two randomised, phase III trials. Objective response (OR) rates were similar in patients treated with fulvestrant and anastrozole, respectively (21.9% versus 19.3%-patients with no visceral metastases; 15.7% versus 13.2%-all of the patients with visceral metastases; 18.8% versus 14.0%-patients with visceral metastases only). The proportion of patients with clinical benefit (CB) was also similar between treatments and between subgroups with and without visceral disease. 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.

Anastrozole↗

PubMed2004

Fulvestrant: pharmacokinetics and pharmacology.

Fulvestrant is a new type of oestrogen receptor (ER) antagonist with no agonist activity and a novel pharmacological profile. Fulvestrant has been shown to significantly reduce cellular levels of the ER and progesterone receptor in both preclinical studies and in clinical trials of postmenopausal women with primary breast cancer. This paper reviews the pharmacokinetics and metabolism of fulvestrant, which support the rationale for drug delivery as a single, once-monthly intramuscular injection, and show that this agent has minimal potential to be the subject, or cause, of significant cytochrome p450-mediated drug interactions.

Animals↗

PubMed2006

Diverse gene expression and DNA methylation profiles correlate with differential adaptation of breast cancer cells to the antiestrogens tamoxifen and fulvestrant.

The development of targeted therapies for antiestrogen-resistant breast cancer requires a detailed understanding of its molecular characteristics. To further elucidate the molecular events underlying acquired resistance to the antiestrogens tamoxifen and fulvestrant, we established drug-resistant sublines from a single colony of hormone-dependent breast cancer MCF7 cells. These model systems allowed us to examine the cellular and molecular changes induced by antiestrogens in the context of a uniform clonal background. Global changes in both basal and estrogen-induced gene expression profiles were determined in hormone-sensitive and hormonal-resistant sublines using Affymetrix Human Genome U133 Plus 2.0 Arrays. Changes in DNA methylation were assessed by differential methylation hybridization, a high-throughput promoter CpG island microarray analysis. By comparative studies, we found distinct gene expression and promoter DNA methylation profiles associated with acquired resistance to fulvestrant versus tamoxifen. Fulvestrant resistance was characterized by pronounced up-regulation of multiple growth-stimulatory pathways, resulting in estrogen receptor alpha (ERalpha)-independent, autocrine-regulated proliferation. Conversely, acquired resistance to tamoxifen correlated with maintenance of the ERalpha-positive phenotype, although receptor-mediated gene regulation was altered. Activation of growth-promoting genes, due to promoter hypomethylation, was more frequently observed in antiestrogen-resistant cells compared with gene inactivation by promoter hypermethylation, revealing an unexpected insight into the molecular changes associated with endocrine resistance. In summary, this study provides an in-depth understanding of the molecular changes specific to acquired resistance to clinically important antiestrogens. Such knowledge of resistance-associated mechanisms could allow for identification of therapy targets and strategies for resensitization to these well-established antihormonal agents.

Breast Neoplasms↗

PubMed2006

Prognostic value of monitoring tumour markers CA 15-3 and CEA during fulvestrant treatment.

BACKGROUND: At many centres tumour markers are used to detect disease recurrence and to monitor response to therapy in patients with advanced disease, although the real value of serial observation of marker levels remains disputed. In this study, we evaluated the prognostic value of tumour markers for predicting response (partial response [PR], stable disease [SD] > or = 6 months), de novo disease progression (PD) and secondary PD in patients receiving fulvestrant ('Faslodex') 250 mg/month for the treatment of metastatic breast cancer (MBC). METHODS: Changes in cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) were prospectively monitored (monthly) and were also evaluated for the 3 months preceding secondary PD. Data from 67 patients with previously treated MBC participating in a Compassionate Use Programme were analysed. RESULTS: In patients with a PR (n = 7 [10.4%]), a non-significant increase in CA 15-3 occurred during the first 6 months of treatment; CEA was significantly reduced (P = 0.0165). In patients with SD >/= 6 months (n = 28 [41.8%]), both CA 15-3 (P < 0.0001) and CEA (P = 0.0399) levels increased significantly after 6 months treatment. In those experiencing de novo PD (n = 32 [47.8%]), CA 15-3 increased significantly (P < 0.0001) after 4 months; CEA also increased significantly (P = 0.0002) during the same time period. Both CA 15-3 (P < 0.0001) and CEA (P < 0.0001) increased significantly in the 3 months preceding secondary PD. CONCLUSION: CA 15-3 increases in patients progressing on fulvestrant but may also increase in those experiencing clinical benefit; this should not be taken as a sign of PD without verification. Overall, both CA 15-3 and CEA appear to be poor prognostic markers for determining progression in patients receiving fulvestrant.

Adult↗