CANCER TREATMENT REVIEWS (2005) 31, S3–S9
www.elsevierhealth.com/journals/ctrv
Clinical development of fulvestrant (‘Faslodex’) Anthony Howell
a,*
, Paul Abram
b
a
CRUK Department of Medical Oncology, University of Manchester, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK b Belvoir Park Hospital, Belfast, UK
KEYWORDS
Summary This paper outlines the development of fulvestrant, the first in a new class of antioestrogen agents with no agonist effects, to be used for the treatment of hormone receptor-positive advanced breast cancer in postmenopausal women. The role of the oestrogen receptor in breast cancer growth and development and the evolution of pharmacological strategies to manipulate it are also discussed. Preclinical and clinical evidence for the efficacy of fulvestrant are also reviewed, along with the tolerability profile of this agent in relation to other endocrine therapies. Further research will define the role of this exciting new agent in the endocrine treatment of breast cancer. c 2005 Elsevier Ltd. All rights reserved.
Advanced breast cancer; Aromatase inhibitors; Clinical trials; Fulvestrant; ‘Faslodex’; Gefitinib; Long-term oestrogen deprivation; Trastuzumab
The role of oestrogens in breast cancer The link between breast cancer growth and oestrogens was first demonstrated by George Beatson in 1896,1 who proposed ovariectomy as a method of shrinking breast tumours. By the mid-1940s, large doses of oestrogen were being used as treatment for breast cancer and synthetic oestrogens, e.g., diethyl stilboestrol (DES),2 were also in use. However, it was not until the 1970s that DES was linked to several reproductive tract neoplasms and other
* Corresponding author. Tel.: +44 161 446 8037; fax: + 44 161 446 8000. E-mail address:
[email protected] (A. Howell).
morbidities, predominantly as a result of in utero exposure. Pregnant women who had been given DES for the prevention of miscarriage were also found to have an increased risk of developing breast cancer.3 DES is still sometimes used in the treatment of advanced breast cancer (ABC), being an alternative to cytotoxic chemotherapy in some patients, following progression on other endocrine agents.4 Antioestrogens were originally developed in the 1950s as emergency contraceptives, but were not effective. During the 1960s, the oestrogen receptor (ER) was isolated and located in tissues of the womb, vagina and also in some breast cancer cells, leading to the use of antioestrogens for breast cancer treatment. However, trials involving some of the early synthetic compounds were disappointing due to poor tolerability.
0305-7372/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2005.08.010
S4
A. Howell, P. Abram
The development of selective ER modulators (SERMs) Tamoxifen is a non-steroidal, triphenylethylene agent (Fig. 1) with partial agonist properties at the ER (antagonist properties in the breast and agonist properties in the endometrium and bone), and is recognised as the first successful SERM. Tamoxifen was developed as a fertility drug in the mid1960s and was trialled for the treatment of ABC in the early 1970s. The favourable efficacy and side-effect profile of tamoxifen led to its UK license for ABC therapy in postmenopausal women in 1973; subsequent investigations into its potential for post-surgical use and breast cancer prevention were then undertaken. Following the success of tamoxifen therapy for breast cancer, several triphenylethylene derivatives were developed in an attempt to increase its efficacy and reduce the partial agonist properties. The partial agonist effect of tamoxifen on the endometrium results in proliferation and is responsible for an increased risk of endometrial cancer with long-term exposure.5 Toremifene, droloxifene and idoxifene are first-generation triphenylethylene SERMs that are structurally similar to tamoxifen, and which in preclinical studies showed potentially improved efficacy and safety over tamoxifen.6–8 However, in both the advanced disease9–11 and adjuvant12 clinical settings, all demonstrated cross-resistance with tamoxifen and none proved to be more effective. Toremifene is still under investigation for the prevention of breast cancer as it has similar efficacy to, but fewer agonist properties than tamoxifen.13,14 The second-generation, ‘fixed-ring’ SERMs developed in the 1980s were structurally similar to raloxifene, a benzothiophene molecule (Fig. 1).
Oestradiol
OH
OH
Fulvestrant
7
HO
HO
Tamoxifen O
(CH2)9SO(CH2)3CF2CF3
Raloxifene NMe2 N O
O OH
HO
Figure 1
S
Structures of oestradiol, SERMs and fulvestrant.
However, neither raloxifene nor arzoxifene proved to have greater clinical efficacy than tamoxifen in the treatment of ABC, and both agents also lacked efficacy in tamoxifen-resistant disease.15,16 Results from the Study of Tamoxifen And Raloxifene (STAR), which is investigating the use of these agents for the prevention of breast cancer in highrisk women, are expected in 2006. Current evidence suggests that the third-generation SERM, ERA-923, has no trophic effects on the uterus,17 and investigation continues into its clinical potential.
The search for more potent antioestrogens In the search for novel agents that would completely block ER signalling, oestradiol was used as a starting point for the development of a series of steroidal 7a-alkylamide analogues. ICI 164384 was the first pure oestrogen antagonist to be described, and this was shown to block the uterotrophic action of both oestradiol and tamoxifen in studies in rats.18 Further research improved the potency of this compound, resulting in the discovery of ICI 182780 (fulvestrant; ‘Faslodex’; Fig. 1). Fulvestrant has an affinity for the ER that is almost equal to that of oestradiol, and far higher than that of tamoxifen. The ER binding affinities of fulvestrant and tamoxifen are 89% and 2.5% of the binding affinity of oestradiol at this receptor, respectively.19 The mode of action of fulvestrant is also different from that of SERMs. Briefly, oestradiol-mediated ER activation consists of dimerisation of the receptor, followed by translocation of the dimer complex to the cell nucleus. The recruitment of co-activator and co-repressor proteins at two activating sites on the ER dimer then enables gene expression. SERMs permit receptor dimerisation but enable co-activator recruitment at only one activating site, leading to reduced gene expression. The residual expression of oestrogenresponsive genes accounts for the oestrogenagonist activity of SERMs in certain tissues. Fulvestrant, however, impairs dimerisation and translocation of the ER and blocks cofactor recruitment at both activating sites. The ER–fulvestrant complex is unstable and is rapidly degraded, leading to a reduction of cellular ER protein, and the negation of oestrogen signalling through the ER.19 The extent of ER blockade and reduction in oestrogen signalling produced by fulvestrant is unique to this agent and differentiates it from the SERM class of therapies.
Clinical development of fulvestrant (‘Faslodex’)
Fulvestrant – preclinical and early clinical investigations
S5 a 120
p = 0 .0001 p = 0.0006 p = 0.026 NS
Absence of uterotrophic effects An important aspect of the development of more useful antioestrogens is the elimination of partial agonist effects alongside the tumour cell growth implications of their antagonist properties. In vivo studies in immature or ovariectomised rats showed that fulvestrant inhibits the uterotrophic effects of oestradiol and tamoxifen.19 In ovariectomised monkeys, fulvestrant blocked oestrogen-associated endometrial growth, demonstrating that it has no agonist activity at this site.27 This effect has been replicated in humans in phase I investigations, where fulvestrant did not increase endometrial thickness in healthy volunteers.28 Furthermore, fulvestrant significantly reduced endometrial stim-
Mean ± 1SEM
p = 0.024 80 60 40 20 0 Placebo 50 mg 125 mg 250 mg Tamoxifen (n = 29) Fulvestrant Fulvestrant Fulvestrant (n = 25) (n = 31) (n = 32) (n = 32) Overall treatment effect p = 0.0003
b
p = 0.0001 p = 0.0001 p = 0.0001
100 80 Mean ± 1SEM
It has been demonstrated in vitro that fulvestrant effectively inhibits the growth of ER-positive MCF-7 breast cancer cells,20 and also that it is a more effective growth inhibitor than tamoxifen.21 Fulvestrant also reduced cellular levels of ER in this system,22 and was shown to inhibit the expression of other oestrogen-regulated proteins such as progesterone receptor (PgR), pS2 and cathepsin D to a greater extent than tamoxifen.23 Tamoxifen also reverses the loss of ER protein and downregulation of PgR induced by fulvestrant, an observation that indicates the contrasting mechanisms of action of these drugs.24 Similarly, studies in MCF-7 tumour xenografts have shown that fulvestrant effectively suppresses oestradiol-mediated tumour growth19 and reduces cellular levels of ER protein.19,25 The continued sensitivity of tamoxifen-resistant tumours in nude mice to fulvestrant has also been demonstrated.25 Thus, the different mechanisms of action of tamoxifen and fulvestrant prevent extensive cross-resistance between these agents, and as we will see later in this paper, this principle has been borne out in the clinic. Suppression of ER and PgR protein has been replicated in postmenopausal women with primary breast tumours given a single neoadjuvant dose of fulvestrant prior to surgery of curative intent.26 Fulvestrant 50, 125 and 250 mg reduced the expression of these proteins in a dose-dependant manner. Fulvestrant 250 mg produced a significant reduction in ER and PgR compared with tamoxifen, while tamoxifen increased the expression of PgR as a result of its partial agonist action (Fig. 2).
NS
100
Effects on tumour cell growth
60
p = 0 .0002 p = 0.003 NS
40 20 0 Placebo 50 mg 125 mg 250 mg Tamoxifen (n = 28) Fulvestrant Fulvestrant Fulvestrant (n = 21) (n = 29) (n = 29) (n = 29)
Overall treatment effect p = 0.0001
Figure 2 Cellular levels of (a) ER and (b) PgR protein following treatment with fulvestrant or tamoxifen. Reproduced with Permission of the American Association for Cancer Research.26
ulation when given with ethinyloestradiol, compared with those receiving unopposed oestradiol (P = 0.0001).28 These findings further demonstrate the lack of agonist activity with this type of antioestrogen.
Effects on bone, lipid levels and brain function Preclinical data on the effect of fulvestrant on bone have been a little conflicting, but in essence suggest that this agent is bone-neutral. One study reported that fulvestrant reduced the cancellous bone volume in intact adult female rats but had no effect on the growth plate and peristeum, whereas a second study found no overall effect on bone density.29 Clinical data on the effects of fulvestrant on bone density are needed to clarify these results. No effects of fulvestrant on serum lipids,30,31 body fat or brain function32 have been
S6 noted in preclinical or clinical studies. In line with this, there are data to suggest that fulvestrant does not cross the blood–brain barrier.
Fulvestrant – phase III clinical trials in ABC Efficacy of fulvestrant Phase III clinical data indicate that fulvestrant is an effective therapy for hormone-responsive ABC in postmenopausal women.33 The combined analysis of data from two trials conducted in North America, Europe, South Africa and Australia compared the efficacy of fulvestrant (250 mg intramuscular injection monthly) with that of the third-generation aromatase inhibitor (AI) anastrozole (1 mg daily), in 851 postmenopausal women who had progressed on prior antioestrogen therapy (mostly tamoxifen). The estimated median time to progression (TTP) was 5.5 months for patients receiving fulvestrant (n = 428) compared with 4.1 months for patients receiving anastrozole [n = 423; hazard ratio (HR) 0.95; 95.14% confidence interval (CI) 0.82, 1.10; P = 0.48; Fig. 3]. Clinical benefit (CB; objective response (OR) + stable disease P 24 weeks) rates at a median follow-up of 15.1 months were comparable between treatment groups (43.5% and 40.9% for fulvestrant and anastrozole, respectively), with OR rates of 19.2% and 16.5% in the fulvestrant and anastrozole groups, respectively. In those patients who responded to either treatment, further follow-up (median 22.1 months) revealed a median duration of response of 16.7 months and 13.7 months in patients receiving fulvestrant compared with those receiving anastrozole. Based on the combined analysis data it was concluded that fulvestrant was at least as effective as anastrozole in the second-line treatment of
A. Howell, P. Abram postmenopausal women with hormone-responsive ABC.33 This evidence has led to its regulatory approval in a number of countries including the USA, Brazil and the European Union. A separate retrospective analysis of these combined data considered patients with (n = 381) or without (n = 470) visceral metastases. OR and CB rates were found to be similar for both treatments, even though visceral metastases are often regarded as more difficult to treat than non-visceral metastases.34 A combined analysis of overall survival data from these trials was conducted at an extended median follow-up of 27.0 months.35 At this analysis, 74.5% and 76.1% of patients in the fulvestrant and anastrozole groups, respectively, had died. Median time to death was not significantly different between treatments (27.4 months versus 27.7 months for the fulvestrant and anastrozole groups, respectively; HR 0.98; 95% CI 0.84, 1.15; P = 0.81). A study involving 587 postmenopausal women investigated the efficacy of fulvestrant compared with tamoxifen for the treatment of women with ABC who had received no prior endocrine treatment or chemotherapy for advanced disease.36 Approximately 25% of patients in the trial had received tamoxifen as adjuvant therapy. At a median follow-up of 14.5 months, there was no statistically significant difference between treatments in TTP (median 6.8 months and 8.3 months for the fulvestrant and tamoxifen groups, respectively; HR 1.18; 95% CI 0.98, 1.44; P = 0.088). In this trial the between-group differences in efficacy favoured tamoxifen and the statistical non-inferiority of fulvestrant could not be demonstrated. In the prospectively defined, clinically relevant sub-population of patients with ER-positive and/ or PgR-positive disease (n = 247 (78.8%) in the fulvestrant group and n = 212 (77.4%) in the tamoxifen group), median TTP was 8.2 months and 8.3 months, respectively (HR 1.10; 95% CI 0.89, 1.36; P = 0.388). In a retrospective analysis of patients with both ER-positive and PgR-positive tumours, median TTP was also comparable between treatments (11.4 months and 8.5 months for fulvestrant and tamoxifen, respectively; HR 0.85; 95% CI 0.63, 1.15; P = 0.306).36
Fulvestrant in the endocrine treatment sequence Figure 3 Time to progression for patients receiving fulvestrant or anastrozole (combined analysis of two Phase III trials). Reprinted with Permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.33
In a phase II evaluation of the efficacy of fulvestrant in patients who have progressed following benefit from both tamoxifen and an AI, 19 of 68 (28%) patients gained CB from fulvestrant.37 A
Clinical development of fulvestrant (‘Faslodex’) similar phase II study investigating response to fulvestrant following progression on an AI and up to one other endocrine therapy (mainly tamoxifen) has reported 25 of 77 (33%) patients gained CB.38,39 These data suggest fulvestrant may also be effective following AI failure. Furthermore, retrospective, questionnaire-based analyses of responses from patients progressing on fulvestrant during clinical trials have demonstrated continued sensitivity to other endocrine therapies.40,41 Trials comparing fulvestrant with tamoxifen, and fulvestrant with anastrozole indicated that approximately half of the patients receiving subsequent treatment with AIs, tamoxifen and progestins, experienced CB irrespective of their response to fulvestrant. Ongoing phase III trials are further evaluating the efficacy of fulvestrant following AI failure and in combination with other agents and these trials are reviewed in the final paper of this supplement.35 In conjunction, these findings indicate that fulvestrant is effective after prior endocrine treatment and does not preclude the use of further endocrine therapy, demonstrating the value of fulvestrant in the treatment sequence for patients with hormone-sensitive ABC.
Tolerability of fulvestrant Fulvestrant is a well-tolerated treatment, with a side-effect profile similar to that of other endocrine therapies. In the combined analysis of trials of fulvestrant and anastrozole for second-line ABC therapy, reported adverse events (AEs) were predominantly of mild-to-moderate intensity and of comparable incidence in the fulvestrant and anastrozole arms (46% versus 40%, respectively, for drug-related AEs).29 The incidence of pre-defined AEs [gastrointestinal disorders, hot flushes, joint disorders, thromboembolic disease, urinary tract infections, vaginitis and weight gain] was also low
S7 for both drugs although the incidence of joint disorders was significantly lower in patients receiving fulvestrant compared with those receiving anastrozole (P = 0.0036) (Table 1). In the fulvestrant group, the incidence of injection-site reactions was low, and only two patients (0.5%) discontinued treatment as a result of such events. Overall, approximately 1% of patients in each group withdrew due to treatment-related AEs.33 In the trial of first-line ABC therapy comparing fulvestrant with tamoxifen, the incidence of drug-related AEs was comparable in patients receiving fulvestrant (42%) and those receiving tamoxifen (51%).36 There were no significant differences between treatment groups for the incidence of pre-defined AEs [gastrointestinal disturbance (37.1% versus 43.2%), hot flushes (17.7% versus 24.7%), vaginitis (3.9% versus 6.3%), thromboembolic disease (5.8% versus 3.3%)], although the incidence of hot flushes was lower in the fulvestrant group compared with the tamoxifen group (P = 0.0501). Injection-site reactions also occurred in similar proportions of patients receiving fulvestrant (7.1%) and a placebo injection (8.1%). Three patients receiving fulvestrant (1.0%) withdrew as a result of treatment-related AEs (cerebrovascular accident, deep vein thrombophlebitis, and pulmonary embolus), and there were no such withdrawals from the tamoxifen group. Overall, fulvestrant has a favourable tolerability profile compared with other endocrine treatments. The reduced incidence of joint disorders observed with fulvestrant compared with anastrozole may be advantageous in certain patient populations, and it is also associated with a lower incidence of hot flushes compared with tamoxifen. Furthermore, indirect comparisons also suggest that it may offer tolerability benefits over exemestane in terms of weight gain, diarrhoea and other gastrointestinal disturbances,33,42,43 although randomised trials are required to confirm this observation.
Table 1 Pre-defined adverse events reported in the combined analysis of trials involving fulvestrant and anastrozole Event Gastrointestinal disturbances Hot flushes Joint disorders Thromboembolic disease Urinary tract infection Vaginitis Weight gain
a
Fulvestrant (n = 423) n (%)
Anastrozole (n = 423) n (%)
P value
196 (46.3) 89 (21.0) 23 (5.4) 15 (3.5) 31 (7.3) 11 (2.6) 4 (0.9)
185 (43.7) 87 (20.6) 45 (10.6) 17 (4.0) 18 (4.3) 8 (1.9) 7 (1.7)
0.53 0.91 0.0036 0.68 0.06 0.51 0.35
Reprinted with Permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.33 a Including anorexia, constipation, diarrhoea, nausea and emesis.
S8
Summary Fulvestrant was discovered as a product of research intended to improve upon the utility of SERMs in breast cancer by increasing the extent of their ER antagonism and decreasing associated side effects, which are caused mainly by their partial agonist properties. Fulvestrant has demonstrated good efficacy and tolerability in the treatment of ABC and this along with its lack of agonist activity and lack of cross-resistance with existing endocrine treatments including the SERMs, suggests that it will be valuable new agent in the sequential treatment of breast cancer. As such, fulvestrant represents a significant improvement on the SERM class of agents and is the first drug in a new class of ER antagonists with no agonist properties to become licensed for breast cancer treatment. Continued experience from the Compassionate Use Programme and data from ongoing randomised clinical trials will further define the role of fulvestrant in the treatment of women with hormone-sensitive breast cancer.
References 1. Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Lancet 1896;2: 105–7. 2. Dodds EC, Golberg L, Lawson W, Robinson R. Oestrogenic activity of certain synthetic compounds. Nature 1938;141:247–8. 3. Schrager S, Potter BE. Diethylstilbestrol exposure. Am Fam Physician 2004;69:2395–400. 4. Lonning PE, Taylor PD, Anker G, et al. High-dose estrogen treatment in postmenopausal breast cancer patients heavily exposed to endocrine therapy. Breast Cancer Res Treat 2001;67:111–6. 5. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials, . Lancet 1998;351:1451–67. 6. Hasmann M, Rattel B, Loser R. Preclinical data for droloxifene. Cancer Lett 1994;84:101–16. 7. Johnston SR, Riddler S, Haynes BP, et al. The novel antioestrogen idoxifene inhibits the growth of human MCF-7 breast cancer xenografts and reduces the frequency of acquired anti-oestrogen resistance. Br J Cancer 1997;75:804–9. 8. Robinson SP, Parker CJ, Jordan VC. Preclinical studies with toremifene as an antitumor agent. Breast Cancer Res Treat 1990;16(Suppl.):S9–S17. 9. Stenbygaard LE, Herrstedt J, Thomsen JF, Svendsen SA, Engelholm SA, Dombernowsky P. Toremifene and tamoxifen in advanced breast cancer – a double-blind cross-over trial. Breast Cancer Res Treat 1993;25: 57–63. 10. Buzdar A, Hayes D, et al. Phase III randomized trial of droloxifene and tamoxifen as first-line endocrine treatment of ER/PgR-positive advanced breast cancer. Breast Cancer Res Treat 2002;73:161–75.
A. Howell, P. Abram 11. Lee ES, Schafer JM, Yao K, et al. Cross resistance of triphenylethylene-type antiestrogens but not ICI 182,780 in tamoxifen-stimulated breast tumors grown in athymic mice. Clin Cancer Res 2000;6:4893–9. 12. Holli K, Valavaara R, Blanco G, et al. Safety and efficacy results of a randomized trial comparing adjuvant toremifene and tamoxifen in postmenopausal patients with nodepositive breast cancer. Finnish Breast Cancer Group. J Clin Oncol 2000;18:3487–94. 13. Marttunen MB, Hietanen P, Tiitinen A, Ylikorkala O. Comparison of effects of tamoxifen and toremifene on bone biochemistry and bone mineral density in postmenopausal breast cancer patients. J Clin Endocrinol Metab 1998;83:1158–62. 14. Marttunen MB, Cacciatore B, Hietanen P, et al. Prospective study on gynaecological effects of two antioestrogens tamoxifen and toremifene in postmenopausal women. Br J Cancer 2001;84:897–902. 15. Gradishar WJ, Glusman JE, Vogel C, et al. Raloxifene HCI, a new endocrine agent, is active in estrogen receptor positive (ER+) metastatic breast cancer. Breast Cancer Res Treat 1997;20(Suppl.):53. abstract 209. 16. Munster PN, Buzdar A, Dhingra K, et al. Phase I study of a third-generation selective estrogen receptor modulator, LY353381.HCL, in metastatic breast cancer. J Clin Oncol 2001;19:2002–9. 17. Cotreau MM, Stonis L, Dykstra KH, et al. Multiple-dose, safety, pharmacokinetics, and pharmacodynamics of a new selective estrogen receptor modulator, ERA-923, in healthy postmenopausal women. J Clin Pharmacol 2002;42:157–65. 18. Wakeling AE, Bowler J. Steroidal pure antioestrogens. J Endocrinol 1987;112:R7–R10. 19. Wakeling AE, Dukes M, Bowler J. A potent specific pure antiestrogen with clinical potential. Cancer Res 1991;51:3867–73. 20. Osborne CK. Steroid hormone receptors in breast cancer management. Breast Cancer Res Treat 1998;51:227–38. 21. Hu XF, Veroni M, De Luise M, et al. Circumvention of tamoxifen resistance by the pure anti-estrogen ICI 182,780. Int J Cancer 1993;55:873–6. 22. McClelland RA, Gee JM, Francis AB, et al. Short-term effects of pure anti-oestrogen ICI 182780 treatment on oestrogen receptor, epidermal growth factor receptor and transforming growth factor-alpha protein expression in human breast cancer. Eur J Cancer A 1996;32:413–6. 23. Nicholson RI, Gee JM, Francis AB, Manning DL, Wakeling AE, Katzenellenbogen BS. Observations arising from the use of pure antioestrogens on oestrogen-responsive (MCF-7) and oestrogen growth-independent (K3) human breast cancer cells. Endocr Relat Cancer 1995;2:115–21. 24. Muller V, Jensen EV, Knabbe C. Partial antagonism between steroidal and nonsteroidal antiestrogens in human breast cancer cell lines. Cancer Res 1998;58:263–7. 25. Osborne CK, Jarman M, McCague R, Coronado EB, Hilsenbeck SG, Wakeling AE. The importance of tamoxifen metabolism in tamoxifen-stimulated breast tumor growth. Cancer Chemother Pharmacol 1994;34:89–95. 26. Robertson JF, Nicholson RI, Bundred NJ, et al. Comparison of the short-term biological effects of 7alpha-9-(4,4,5, 5,5-pentafluoropentylsulfinyl)-nonylestra-1,3,5,(10)-triene3,17beta-diol (Faslodex) versus tamoxifen in postmenopausal women with primary breast cancer. Cancer Res 2001;61:6739–46. 27. Dukes M, Waterton JC, Wakeling AE. Antiuterotrophic effects of the pure antioestrogen ICI 182,780 in adult female monkeys (Macaca nemestrina): quantitative magnetic resonance imaging. J Endocrinol 1993;138:203–10.
Clinical development of fulvestrant (‘Faslodex’) 28. Addo S, Yates RA, Laight A. A phase I trial to assess the pharmacology of the new oestrogen receptor antagonist fulvestrant on the endometrium in healthy postmenopausal volunteers. Br J Cancer 2002;87:1354–9. 29. Howell A, Osborne CK, Morris C, Wakeling AE. ICI 182,780 (Faslodexä): development of a novel, ‘‘pure’’ antiestrogen. Cancer 2000;89:817–25. 30. Howell A, DeFriend DJ, Robertson JF, et al. Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti-oestrogen ICI 182780 in women with advanced breast cancer. Br J Cancer 1996;74:300–8. 31. Lundeen SG, Carver JM, McKean M-L, Winneker RC. Characterization of the ovariectomized rat model for the evaluation of estrogen effects on plasma cholesterol levels. Endocrinology 1997;138:1552–8. 32. Wade GN, Blaustein JD, Gray JM, Meredith JM. ICI 182,780: a pure antiestrogen that affects behaviors and energy balance in rats without acting in the brain. Am J Physiol 1993;265(6 Pt 2):R1392–8. 33. Robertson JF, Osborne CK, Howell A, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women – a prospective combined analysis of two multicenter trials. Cancer 2003;98:229–38. 34. Mauriac L, Pippen JE, Quaresma Albano J, Gertler SZ, Osborne CK. Fulvestr ant (Faslodex) versus anastrozole for the second-line treatment of advanced breast cancer in subgroups of postmenopausal women with visceral and nonvisceral metastases: combined results from two multicentre trials. Eur J Cancer 2003;39:1228–33. 35. Howell A, Pippen J, Elledge R, et al. Fulvestrant versus anastrozole for the treatment of advanced breast cancer: a prospectively planned combined survival analysis of two multicenter trials. Cancer 2005;104:236–9. 36. Howell A, Robertson JFR, Abram P, et al. Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol 2004;22:1605–13.
S9 37. Perey L, Paridaens R, Nole ´ F, et al. Fulvestrant (Faslodexä) as hormonal treatment in postmenopausal patients with advanced breast cancer (ABC) progressing after treatment with tamoxifen and aromatase inhibitors: update of a phase II SAKK trial. Breast Cancer Res Treat 2004;88(Suppl. 1): S236. abstract 6048. 38. Ingle JN, Rowland KM, Suman VJ, et al. Evaluation of fulvestrant in women with advanced breast cancer and progression on prior aromatase inhibitor therapy: a phase II trial of the North Central Cancer Treatment Group. In: Poster presentation at the San Antonio breast cancer symposium, 8–11 December, San Antonio, TX, USA; 2004 poster 409. 39. Ingle JN, Rowland KM, Suman VJ, et al. Evaluation of fulvestrant in women with advanced breast cancer and progression on prior aromatase inhibitor therapy: a phase II trial of the North Central Cancer Treatment Group. Breast Cancer Res Treat 2004;88(Suppl. 1):S38. abstract 409. 40. Robertson JFR, Howell A, Gorbunova VA, Watanabe T, Pienkowski T, Lichinitser MR. Sensitivity to further endocrine therapy is retained following progression on first-line fulvestrant. Breast Cancer Res Treat 2005;92:169–74. 41. Vergote I, Robertson JFR, Kleeberg U, Burton G, Osborne L, Mauriac L. Postmenopausal women who progress on fulvestrant (‘Faslodex’) remain sensitive to further endocrine therapy. Breast Cancer Res Treat 2003; 79:207–11. 42. Paridaens R, Dirix L, Lohrisch C, et al. Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. Ann Oncol 2003;14:1391–8. 43. Kaufmann M, Bajetta E, Dirix LY, et al. Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. J Clin Oncol 2000;18: 1399–1411.
