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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18 Jun 2014
TL;DR: The data suggest that GP88 prevents apoptosis induced by faslodex and contributes to antiestrogen resistance in human breast cancer.
Abstract: The 88 kDa glycoprotein
known as GP88, Progranulin or PC cell derived growth factor is an autocrine
growth factor with a unique cysteine rich motif that is over expressed in
breast cancer whereas it is negative in normal mammary epithelial cells. It has
been shown to play a major role in estrogen independence, tamoxifen resistance
and tumorigenesis of breast cancer cells. In the present study, we investigated
the effect of GP88 overexpression on the response of the human breast cancer
MCF-7 cells to the pure estrogen receptor antagonist fulvestrant (ICI 182,780).
While fulvestrant effectively inhibited cell proliferation of empty vector
transfected cells, it had no inhibitory effect on the proliferation of GP88
overexpressing breast cancer cells. Mouse xenograft experiments in athymic
ovariectomized nude mice showed that GP88 over expressing cells were
fulvestrant resistant in vivo in contrast to low GP88 expressing
cells. We show that the ability of fulvestrant to induce apoptosis determined
by measuring cleavage of poly (ADP-ribose) polymerase was inhibited by GP88.
Anti-apoptotic activity of GP88 was associated with sustained expression of
bcl-2 and bcl-xL after
fulvestrant treatment. In contrast, fulvestrant was still able to inhibit the
ability of estrogen to stimulate ERE-luciferase reporter gene activity as well
as vEGF expression in GP88 over expressing MCF-7 cells similarly to control
MCF-7 cells. Collectively, our data suggest that GP88 prevents apoptosis
induced by faslodex and contributes to antiestrogen resistance in human breast
cancer.
12 citations
Cites background from "Fulvestrant ('Faslodex')--a new tre..."
...GP88 overexpression of several growth factors or growth factor receptors has been found to be associated with tamoxifen resistance, especially in MCF-7 cells [5]....
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...Fulvestrant (faslodex, ICI 182,780) is a steroidal estrogen receptor (ER) pure antagonist that acts by binding with high affinity to the ER and down-regulating ER expression [4] [5]....
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TL;DR: This developed and validated assay method was successfully employed to characterize the plasma concentration-time profile of fulvestrant after its intramuscular administration in rats at a dose of 10 mg kg−1.
Abstract: A reversed-phase liquid chromatography coupled to tandem mass spectrometry (LC–MS–MS) method was developed and validated for the determination of fulvestrant in rat plasma. Sample preparation involved a liquid-liquid extraction using 1.0 mL of n-hexane–isopropanol (90:10, v/v) to extract the analyte from 0.1 mL of rat plasma. The analytes were separated on a phenyl-based column using the mobile phase consisting of methanol/water containing 5 mM ammonium acetate at the flow rate of 0.3 mL min−1. The analytes were monitored by tandem mass spectrometry under electrospray negative ionization mode. Linear calibration curves were generated over the fulvestrant concentration ranges of 0.05–10.0 ng mL−1 in rat plasma. The accuracy and within- and between-day precisions were within the generally accepted criteria for bioanalytical methods (<15%). This developed and validated assay method was successfully employed to characterize the plasma concentration-time profile of fulvestrant after its intramuscular administration in rats at a dose of 10 mg kg−1.
10 citations
TL;DR: Endocrine and endocrine‐based options, including combinations with targeted agents, for HR+ and human epidermal growth factor receptor 2‐negative (HER2−) ABC are examined, using patient case examples to illustrate how ABC can present and the clinical issues involved in treatment selection.
10 citations
Cites background from "Fulvestrant ('Faslodex')--a new tre..."
...Therefore, fulvestrant, which promotes degradation of the ER, and thereby complete blockade of ER signaling, may be an option in AI-resistant patients.(79)...
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...Fulvestrant also accelerates ER degradation, resulting in complete suppression of the estrogenic effects on breast tissue.(79) Fulvestrant has received United...
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TL;DR: An ER antagonist is screened and identified, CH4893237, which bound to ER with an IC50 value of 1.4 μM and, by oral administration, inhibited estrogen-stimulated uterine growth in ovariectomized mice, indicating an orally active pure anti-estrogen.
Abstract: Tamoxifen has been widely used for the treatment of estrogen receptor (ER)-positive breast cancer, but its partial agonist activity is considered to limit the efficacy, and cause tumor flare and endometrial cancer. Fulvestrant, on the other hand, binds and degrades ER, thereby acting as a pure anti-estrogen without partial agonist activity. However, due to its low oral bioavailability, fulvestrant has to be intramuscularly administered to patients, which limits the convenience of the drug, and causes pain and inflammation at the site of injection. In search of a patient- friendly pure anti-estrogen, we screened and identified an ER antagonist, CH4893237, which bound to ER with an IC50 value of 1.4 muM and, by oral administration, inhibited estrogen-stimulated uterine growth in ovariectomized mice. CH4893237 reduced the amount of ER at the protein level and impaired the nuclear accumulation of ER, indicating an orally active pure anti-estrogen. Furthermore, CH4893237 inhibited the estrogen-stimulated proliferation of MCF-7, ZR-75-1 and BT-474 cells, and caused a marked growth inhibition of the MCF-7 xenograft in vivo. Thus, CH4893237 will provide an additional option for second-line hormone treatment of breast cancer.
10 citations
TL;DR: Fulvestrant up regulates the expression of UDP glucuronosyltransferase 1A4 (UGT1A4) and up regulates multidrug resistance-associated proteins (MRPs) in a time- and concentration-dependent manner, suggesting a clinically significant role for UGT1A 4 and MRP s in drug efficacy.
Abstract: Fulvestrant (Faslodex™) is a pure antiestrogen that is effective in treating estrogen receptor-(ER) positive breast cancer tumors that are resistant to selective estrogen receptor modulators such as tamoxifen. Clinical trials investigating the utility of adding fulvestrant to other therapeutics have not been shown to affect cytochrome P450-mediated metabolism. Effects on phase II metabolism and drug resistance have not been explored. This study demonstrates that fulvestrant up regulates the expression of UDP glucuronosyltransferase 1A4 (UGT1A4) >2.5- and >3.5-fold in MCF7 and HepG2 cells, respectively. Up regulation occurred in a time- and concentration-dependent manner, and was inhibited by siRNA silencing of ERα. Fulvestrant also up regulates multidrug resistance-associated proteins (MRPs). There was an up regulation of MRP 2 (1.5- and 3.5-fold), and MRP 3 (5.5- and 4.5-fold) in MCF7 and HepG2 cell lines, respectively, and an up regulation of MRP1 (4-fold) in MCF7 cells. UGT1A4 mRNA up regulation was significantly correlated with UGT1A4 protein expression, anastrozole glucuronidation, ERα mRNA expression and MRP mRNA expression, but not with ERα protein expression. Genetic variants in the UGT1A4 promoter (-163A, -217G and -219T) reduced the basal activity of UGT1A4 by 40-60%. In silico analysis indicated that transcription factor c-Myb binding capacity may be affected by these variations. Luciferase activity assays demonstrate that silencing c-Myb abolished UGT1A4 up regulation by fulvestrant in promoters with the common genotype (-163G, -217 T and -219C) in MCF7 cells. These data indicate that fulvestrant can influence the disposition of other UGT1A4 substrates. These findings suggest a clinically significant role for UGT1A4 and MRP s in drug efficacy.
10 citations
Cites background from "Fulvestrant ('Faslodex')--a new tre..."
...Fulvestrant shows no estrogen agonist activity, and thus has been regarded as an important improvement in breast cancer therapy (Morris and Wakeling 2002; Howell et al. 2002; Osborne et al. 2002)....
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References
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TL;DR: The FACT-G meets or exceeds all requirements for use in oncology clinical trials, including ease of administration, brevity, reliability, validity, and responsiveness to clinical change.
Abstract: PURPOSEWe developed and validated a brief, yet sensitive, 33-item general cancer quality-of-life (QL) measure for evaluating patients receiving cancer treatment, called the Functional Assessment of Cancer Therapy (FACT) scale.METHODS AND RESULTSThe five-phase validation process involved 854 patients with cancer and 15 oncology specialists. The initial pool of 370 overlapping items for breast, lung, and colorectal cancer was generated by open-ended interview with patients experienced with the symptoms of cancer and oncology professionals. Using preselected criteria, items were reduced to a 38-item general version. Factor and scaling analyses of these 38 items on 545 patients with mixed cancer diagnoses resulted in the 28-item FACT-general (FACT-G, version 2). In addition to a total score, this version produces subscale scores for physical, functional, social, and emotional well-being, as well as satisfaction with the treatment relationship. Coefficients of reliability and validity were uniformly high. The ...
5,232 citations
"Fulvestrant ('Faslodex')--a new tre..." refers background in this paper
...The Functional Assessment of Cancer Therapy – Breast (FACT-B) questionnaire (Cella et al. 1993) is a sensitive measure for evaluating physical, functional, social and emotional well-being of the patient....
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TL;DR: Anastrozole is an effective and well tolerated endocrine option for the treatment of postmenopausal patients with hormone-sensitive early breast cancer and longer follow-up is required before a final benefit:risk assessment can be made.
1,905 citations
Journal Article•
TL;DR: The properties of ICI 182,780 identify this pure antiestrogen as a prime candidate with which to evaluate the potential therapeutic benefits of complete estrogen withdrawal in endocrine-responsive human breast cancer.
Abstract: Previous studies from this laboratory have described a series of 7 alpha-alkylamide analogues of estradiol with pure antiestrogenic activity, exemplified by ICI 164,384. A new compound, 7 alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10 )- triene-3,17 beta-diol (ICI 182,780) has now been identified which has significantly increased antiestrogenic potency and retains pure estrogen antagonist activity. The antiuterotrophic potency of ICI 182,780 in the immature rat was more than 10-fold greater than that of ICI 164,384 (50% effective doses of 0.06 and 0.9 mg/kg, respectively). This order of magnitude increase of in vivo potency was also reflected, in part, by intrinsic activity at the estrogen receptor. The relative binding affinities of ICI 182,780 and ICI 164,384 were 0.89 and 0.19, respectively, compared with that of estradiol (1.0). Similarly, the in vitro growth-inhibitory potency of ICI 182,780 exceeded that of ICI 164,384 in MCF-7 human breast cancer cells, where 50% inhibitory concentrations of 0.29 and 1.3 nM, respectively, were recorded. ICI 182,780 was a more effective inhibitor of MCF-7 growth than 4'-hydroxytamoxifen, producing an 80% reduction of cell number under conditions where 4'-hydroxytamoxifen achieved a maximum of 50% inhibition. This increased efficacy was reflected by a greater reduction of the proportion of cells engaged in DNA synthesis in ICI 182,780-treated cell cultures compared with tamoxifen-treated cells. Sustained antiestrogenic effects, following a single parenteral dose of ICI 182,780 in oil suspension, were apparent in both rats and pigtail monkeys. In vivo, antitumor activity of ICI 182,780 was demonstrated with xenografts of MCF-7 and Br10 human breast cancers in nude mice. A single injection of ICI 182,780 provided antitumor efficacy equivalent to that of daily tamoxifen treatment for at least 4 weeks. The properties of ICI 182,780 identify this pure antiestrogen as a prime candidate with which to evaluate the potential therapeutic benefits of complete estrogen withdrawal in endocrine-responsive human breast cancer.
1,158 citations
"Fulvestrant ('Faslodex')--a new tre..." refers background in this paper
...In pigtailed monkeys, sustained antiestrogenic effects were apparent following a single parenteral dose of fulvestrant (Wakeling et al. 1991)....
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...Like tamoxifen, fulvestrant competitively binds to the ER but with a much greater affinity than tamoxifen – approximately 89% that of estradiol, compared with 2.5% for tamoxifen (Wakeling & Bowler 1987, Wakeling et al. 1991)....
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...Further observations from this study showed that the oral antiuterotropic activity of fulvestrant was one order of magnitude less than its parenteral potency (Wakeling et al. 1991)....
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...Similar reductions of tumor growth were seen in the Br10 human tumor model (Wakeling et al. 1991)....
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TL;DR: Risk of endometrial cancer increases following tamoxifen therapy for invasive breast cancer; however, net benefit greatly outweighs risk, and tamoxIFen treatment for breast cancer should continue.
Abstract: BACKGROUND Tamoxifen is advantageous in treating all stages of breast cancer. However, studies have suggested that incidence and severity of endometrial cancer increase in women treated with tamoxifen. PURPOSE We compared rates of endometrial and other cancers in tamoxifen- and non-tamoxifen-treated patients and described the pathologic characteristics of the endometrial cancers. METHODS Data were analyzed on 2843 patients with node-negative, estrogen receptor-positive, invasive breast cancer randomly assigned to placebo or tamoxifen (20 mg/d) and on 1220 tamoxifen-treated patients registered in NSABP B-14 subsequent to randomization. Average time on study is 8 years for randomly assigned patients and 5 years for registered patients. RESULTS The incidence rates of liver, gastrointestinal, urinary tract, and nonuterine genital tumors were not increased by tamoxifen treatment. Twenty-five endometrial cancers were originally reported, one of which was reclassified after subsequent review. Two cases occurred in the placebo group in patients whose medical status subsequent to random assignment had required tamoxifen treatment. Twenty-three occurred in the tamoxifen groups. Twenty-one of the 24 originally reported endometrial cancers were FIGO stage 1; 18 of 23 gradable cases were of good to moderate histologic grade. Four tamoxifen-treated women died of uterine cancer. The average annual hazard rate of endometrial cancer as a first event within the first 5 years of follow-up in the randomized, tamoxifen-treated group was 1.2/1000 patient-years; the cumulative hazard rate was 6.3/1000. Findings for the registered, tamoxifen-treated group were similar. Including all originally reported endometrial cancers, the annual hazard rate through all follow-up was 0.2/1000 in the placebo group and 1.6/1000 in the randomized, tamoxifen-treated group; the relative risk of endometrial cancer for the latter versus the former group was 7.5. Again for the latter group, using population-based rates of endometrial cancer from SEER data and information from another NSABP (B-06) trial, relative risks were 2.2 and 2.3, respectively. The 5-year cumulative hazard rate for disease-free survival in the randomized tamoxifen group was 38% less than that in the placebo group. Some data in this paper were provided by an investigator who submitted fraudulent data to the NSABP [see the "News" section]; therefore, the reader must read the entire text including Table 10 and the Editor's notes. In brief, data on 182 of the 2843 randomly assigned patients and 37 of the 1220 registered patients were provided by the investigator in question. After review, 24 of the 182 records showed falsification, all involving characteristics of patients prior to random assignment. Of the 37 registered-patient records, 8 showed falsification. CONCLUSIONS Risk of endometrial cancer increases following tamoxifen therapy for invasive breast cancer; however, net benefit greatly outweighs risk. Endometrial cancers occurring after tamoxifen therapy do not appear to be of a different type with a worse prognosis than are such tumors in non-tamoxifen-treated patients. IMPLICATIONS Tamoxifen treatment for breast cancer should continue. In addition, the relative risk of endometrial cancer observed in B-14 tamoxifen-treated patients is consistent with the twofold relative risk used in the initial risk-benefit computation for the NSABP breast cancer prevention trial.
1,149 citations
TL;DR: Letrozole was significantly superior to tamoxifen in TTP, TTF, ORR, and clinical benefit rate, and its results support its use as first-line endocrine therapy in postmenopausal women with advanced breast cancer.
Abstract: PURPOSE: To compare the efficacy and tolerability of tamoxifen with that of letrozole, an oral aromatase inhibitor, with tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: Nine hundred seven patients were randomly assigned letrozole 2.5 mg once daily (453 patients) or tamoxifen 20 mg once daily (454 patients). Patients had estrogen receptor– and/or progesterone receptor–positive tumors, or both receptors were unknown. Recurrence during adjuvant antiestrogen therapy or within the following 12 months or prior endocrine therapy for advanced disease precluded enrollment. One prior chemotherapy regimen for metastatic disease was allowed. The primary end point was time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, rate and duration of clinical benefit, time to treatment failure (TTF), overall survival, and tolerability. RESULTS: TTP was significantly longer for letrozole than for tamoxifen (median,...
997 citations
"Fulvestrant ('Faslodex')--a new tre..." refers background in this paper
...Both the third-generation, non-steroidal AIs, anastrozole (‘Arimidex’) and letrozole, have efficacy advantages over tamoxifen in postmenopausal patients as first-line therapy (Bonneterre et al. 2000, Nabholtz et al. 2000, Mouridsen et al. 2001)....
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