	While the beginnings of endocrine therapy for breast cancer can be traced to the 19th century, 

 the exact mechanisms of tumor response and resistance to endocrine manipulation still remain to be elucidated. The first truly successful targeted therapy against the estrogen receptor (ER) came with the resurrection of the compound ICI 46474, as tamoxifen, after it was initially abandoned in 1972.

 Although several endocrine therapies, including selective ER modulators, aromatase inhibitors (AIs), progestins, androgens, and luteinizing hormone-releasing hormone (LHRH) agonists, are available today, the quest for a better tamoxifen still continues. Many promising agents in the preclinical setting have not proven nearly as effective as tamoxifen in the clinical setting.

	In the early 1990s, a new compound, ICI 182780, a 7 alpha-alkylamide analogue of estradiol with promising preclinical activity, was selected for additional clinical studies under the name of fulvestrant.

 A pure novel antiestrogen, fulvestrant competitively binds to ER and blocks receptor dimerisation. The unstable fulvestrant- ER complex then undergoes accelerated degradation, resulting in downregulation of the ER with subsequent inhibition of ER-DNA binding and abrogation of the expression of genes associated with tumor progression, metastasis, and angiogenesis

 Fulvestrant produces dosedependent reductions in the cellular levels of ERs and progesterone receptors (PGRs), resulting in more profound effects in tumors that express both hormonal receptors.

 Fulvestrant’s distinct mechanism of action ensures a lack of cross-resistance with other hormonal agents and no known estrogen agonist effects.

 Following a pivotal phase III clinical trial,

 fulvestrant 250 mg by monthly intramuscular injection was approved by the FDA in April 2002 for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

	Prior to the fulvestrant era, data on the endocrine treatment of breast cancer favored the use of third-generation AIs over progesterone, tamoxifen, and older AIs.

 Preclinical research and early clinical studies of fulvestrant suggested that it would outperform existing endocrine therapies for hormone receptor-positive breast cancer. So far, however, several randomized clinical trials have shown only comparable efficacy but no obvious superiority of fulvestrant to tamoxifen, anastrazole, or exemestane in postmenopausal women with hormone receptor-positive metastatic breast cancer.

	There are 3 possible explanations for fulvestrant’s lack of superiority compared to other endocrine therapies: 1) a delay in obtaining steady-state levels, 2) the competitive effect from circulating estrogens, and 3) the inability to reach the maximally effective and tolerated dose.

	In most early clinical trials of fulvestrant, the drug was administered as a monthly, slow intramuscular injection of 5 ml of 50 mg/ml solution containing 250 mg of fulvestrant, plus excipients (ethanol 96%, benzyl alcohol, benzyl benzoate, and castor oil). With this so-called approved dose (AD) regimen it can take 3 to 6 months to reach steady-state levels. Early progression of patients on the AD regimen led to the concept of a loading dose (LD) regimen, which consisted of a 500 mg injection on day 1, then 250 mg injections on days 14 and 28, and monthly 250 mg injections of fulvestrant thereafter. The LD regimen produced steady-state plasma fulvestrant concentrations in 28 days as opposed to 3 months with the AD regimen.

 The use of the LD fulvestrant regimen, however, not only failed to prove superior to exemestane in patients who failed prior nonsteroidal AIs, but also was not better than anastrozole monotherapy alone, even when combined with anastrozole.

Competitive Effect from Circulating Estrogens 

	Fulvestrant competes with estradiol for binding at the ER. Preclinical data show that complete estrogen blockade, by downregulating ER and inhibiting estrogen synthesis, has greater effect on tumor growth than either treatment alone.

 Since the major source of estradiol in postmenopausal women is by aromatization of androgens, the combination of AIs with fulvestrant may enhance the efficacy of fulvestrant by reducing plasma estrogen levels.

	Several small-size studies of AI and fulvestrant have been reported. Massarweh and colleagues

 conducted a phase II trial to evaluate the efficacy of anastrozole/ fulvestrant/gefitinib as initial therapy in postmenopausal women with locally advanced or metastatic breast cancer. While the planned sample size was 60 patients, the trial was closed after 15 patients due to poor accrual. Of the 15 patients entered into the trial, 3 patients withdrew. Of the remaining 12 patients, 2 had a compete response, 5 had a partial response, 5 had stable disease, and 2 had progressive disease. Mrozek and colleagues

 reported preliminary results of an ongoing phase II trial evaluating the combination of fulvestrant and exemestane in postmenopausal women with hormone receptorpositive advanced breast cancer previously treated with chemotherapy, tamoxifen, or nonsteroidal AIs in the adjuvant or advanced disease setting. Patients received exemestane 25 mg starting on day 1, with fulvestrant 250 mg monthly added on day 8. At the time of the report, 19 women had been enrolled. Nine patients had a progression-free survival (PFS) of more than 6 months (range: 6-20 months), with 8 of these patients still receiving treatment. An additional 8 patients had progression prior to 6 months. Accrual to this trial is ongoing.

	At the Saint Francis Cancer Treatment Center in Grand Island, Nebraska, we evaluated the combination of letrozole and fulvestrant in 32 postmenopausal patients with hormone receptor-positive metastatic breast cancer who had prior chemotherapy and/or non-AI endocrine therapy. Letrozole was given 2.5 mg daily along with monthly fulvestrant 250 mg given via intramuscular injection. Overall clinical benefit rate was 71%, with a mean clinical benefit duration of 15 months. Eight patients progressed under therapy. Older age, less than 4 prior lines of therapy, and expression of both ER and PGR were predictive of clinical benefit.

	In the large open-label randomized FACT (Fulvestrant and Anastrozole in Combination Trial) study, the combination of the fulvestrant LD regimen plus anastrozole versus anastrozole alone at first relapse in patients with hormone receptor-positive metastatic breast cancer showed similar time to progression and overall survival rates.

 Two other large phase III trials, Southwest Oncology Group (SWOG) SO226 and SOFAE (Study of Faslodex vs Exemestane with/without Arimidex), in postmenopausal women with metastatic breast cancer following progression on nonsteroidal AIs are currently ongoing and their results are eagerly awaited. Both studies are utilizing the fulvestrant LD regimen.

Inability to Reach Maximally Effective and Tolerated Doses 

	The short-term biological and dose-response effects of fulvestrant was first evaluated by Robertson and colleagues.

 Fourteen to 21 days prior to surgery, a single-dose intramuscular administration of fulvestrant at 50 mg, 125 mg, or 250 mg produced a dose-dependent reduction in both ER and PGR expression in resected hormone receptor-positive breast cancer specimens from postmenopausal women. There was no plateau in the decrease of ER in response to administered fulvestrant doses. In another study, the administration of fulvestrant doses up to 750 mg in premenopausal women were shown to be biologically active and well tolerated, other than injection-site reactions.

 There has been increasing interest in administering fulvestrant at doses in excess of the currently labeled amounts, up to and including as much as 1 gram per month. To do so with current formulations would require considerably larger volumes than could be injected intramuscularly at any 1 time, or would require administration at multiple sites or at multiple times throughout the month. Thus, the search continues for injectable formulations of fulvestrant that can deliver more than 250 mg in less than 5 ml or that can be administered by transdermal or topical route.

 Finding the maximally effective and tolerated dose and route of administration remains an elusive pharmacological and clinical challenge.

	The most recent important contribution to the field of endocrine therapy of breast cancer comes from the CONFIRM (Comparison of Faslodex in Recurrent or Metastatic Breast Cancer) trial. Di Leo and colleagues

 compared the clinical benefit of the fulvestrant HD regimen versus the AD regimen in postmenopausal women with ER-positive tumors who were previously exposed to at least 1 endocrine therapy. The fulvestrant HD regimen consisted of a 500 mg injection on day 1, day 14, and day 28, followed by monthly 500 mg injections thereafter. Compared to the fulvestrant AD regimen, the fulvestrant HD regimen was associated with a statistically significant and clinically relevant increase in PFS corresponding to a 20% reduction in the risk of progression. Two similar prior studies—1 in a Japanese patient population (FINDER1) and the other in a white patient population (FINDER2)&mdash;of postmenopausal women with ER-positive, locally advanced/ metastatic breast cancer have also been reported.

 In these 2 studies, the pharmacokinetics, efficacy, and tolerability of fulvestrant in 3 different dose regimens—HD, LD, and AD&mdash;were compared as opposed to 2 dose regimens in the CONFIRM study (ie, HD vs AD). The fulvestrant HD regimen produced steady-state concentrations within 1 month that were approximately double of those seen with the fulvestrant LD or AD regimens.

	With its larger patient population than the FINDER1 and FINDER2 studies, the CONFIRM trial may have provided valuable pharmacokinetic data if it were available. In the FINDER1 and FINDER2 trials, while there appeared to be a trend toward improved efficacy, no statistically significant differences could be shown in terms of efficacy between the HD and LD regimens compared to the AD fulvestrant regimen, as was shown in the CONFIRM trial. Although the results of the CONFIRM trial suggest that the fulvestrant HD regimen should replace the AD regimen, the following important questions remain unanswered:

		If there was a loading-dose arm in the CONFIRM trial, would the results be different?

		Considering that the data from the FACT study indicates that combining the fulvestrant LD regimen plus an AI is not superior to AI alone, should the dose of fulvestrant be changed from LD to HD in the 2 ongoing, large combination trials (ie, SOFEA and SWOG SO226) of fulvestrant with AIs?

		Knowing that higher doses of fulvestrant (750 mg) can be safely delivered and effective even in premenopausal women,24 should we pursue a maximally effective and tolerable dose concept and focus our research efforts on finding the optimum delivery systems for fulvestrant?

		Should the patients who have failed a prior AD or LD fulvestrant regimen be rechallenged with an HD fulvestrant regimen in clinical practice?

		Should we be more selective in choosing patients for fulvestrant therapy (ie, both ER- and PGR-positive patients as opposed to ER- and/or PGR—positive or unknown)?

		Finally, has the time come for exploring the combination of fulvestrant with biologics and signal transduction inhibitors along with AIs?

	While endocrine therapy of breast cancer remains a highly important and effective strategy for the treatment of hormone receptor-positive disease, the longstanding quest for a perfect endocrine therapy remains out of reach. Questions concerning the optimal endocrine agent with its optimal setting, sequence, and combination with other agents still remain unanswered. If a maximally effective and tolerated dose and delivery system could be established for fulvestrant, there seems to be a great potential for the use of this novel and versatile drug. Fulvestrant’s possibilities might include first-line and subsequent use in the premenopausal/ postmenopausal metastatic hormone receptor-positive breast cancer setting; adjuvant endocrine treatment of premenopausal/postmenopausal hormone receptor-positive breast cancer; and in combination regimens with other existing endocrine therapies or biologics and with signal transduction inhibitors to overcome endocrine resistance in the metastatic, adjuvant premenopausal/postmenopausal settings. Results of several ongoing clinical trials addressing some of these possibilities are eagerly awaited, as are the new clinical trials of fulvestrant.

Angela Mae Obermiller, PharmD, is the pharmacy supervisor, and Mehmet Sitki Copur, MD, is the medical director of oncology and at Saint Francis Cancer Treatment Center in Grand Island, Nebraska.

The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Mehmet Sitki Copur, MD, Department of Medical Oncology, Saint Francis Cancer Treatment Center, 2116 W Faidley Ave, Grand Island, NE 68802-9804, or e-mail 

Love RR, Philips J. Oophorectomy for breast cancer: history revisited. J Natl Cancer Inst. 2002;94:1433-1434.

Jordan VC. Tamoxifen: a most unlikely pioneering medicine. Nat Rev Drug Discovery. 2003;2:205-213.

Silverman SL. New selective estrogen receptor modulators (SERMs) in development. Curr Osteoporos Rep. 2010;8:151-153.

Lee JW, Lee YS, Yoo KH, et al. LY-6K gene: A novel molecular marker for human breast cancer. Oncol Rep. 2006;16:1211-1214.

Johnston SJ, Cheung KL. Fulvestrant—a novel endocrine therapy for breast cancer. Curr Med Chem. 2010; 17:902-914.

Wakeling AE, Dukes M, Bowler J. A potent specific pure antiestrogen with clinical potential. Cancer Res. 1991;51:3867-3873.

Dodwell D, Wardley A, Johnston S. Postmenopausal advanced breast cancer: options for therapy after tamoxifen and aromatase inhibitors. Breast. 2006;15:584-594.

Dowsett M. Preoperative models to evaluate endocrine strategies for breast cancer. Clin Cancer Res. 2003;9:502S-510S.

Robertson JF, Nicholson RI, Bundred NJ, et al. Comparison of the short term biological effects of 7alpha-(9-(4,4,5,5,5- pentafluoropentylsulfinyl)-nonyl-estra-1,3,5(10)triene-3, 17beta-diol (Faslodex) versus tamoxifen in postmenopausal women with breast cancer. Cancer Res. 2001;61:6739-6746.

McKeage K, Curran MP, Plosker GL. Fulvestrant: a review of its use in hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. Drugs. 2004;64:633-648.

Robertson JFR, Osborne CK, Howell A, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women; a prospective combined analysis of 2 multicentre trials. Cancer. 2003;98:229-238.

Bross PF, Cohen MH, Williams GA, et al. FDA drug approval summaries: fulvestrant. Oncologist. 2002;7:477-480.

Mauri D, Pavlidis N, Polyzos NP, et al. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: Meta-analysis. J Natl Cancer Inst. 2006;98:1285-1291.

Howell A, Robertson JF, 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;22:1605-1613.

Howell A, Robertson JF, Quaresma Albano J, et al. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002;20:3396-3403.

Osborne CK, Pippen J, Jones SE, et al. Double-blind randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine therapy: Results of a North American trial. J Clin Oncol. 2002;20:3386-3395.

Chia S, Gradishar W, Mauriac L, et al. Double-blind randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor positive advanced breast cancer; results from EFFECT. J Clin Oncol. 2008;26:1664-1670.

Bergh J, Jonsson PE, Lidbrink E, et al. First results from FACT— An open-label randomized phase III study investigating loading dose of fulvestrant combined with anastrozole versus anastrozole at first relapse in hormone receptor positive breast cancer [abstract 23a]. Presented at: San Antonio Breast Cancer Symposium; December 2009; San Antonio, TX.

Macedo LF, Sabnis GJ, Goloubeva OG, Brodie A. Combination of anastrozole with fulvestrant in the intratumoral aromatase xenograft model. Cancer Res. 2008;68:3516-3522.

Jelovac D, Macedo L, Goloubeva OG, et al. Additive antitumor effect of aromatase inhibitor letrozole and antiestrogen fulvestrant in a postmenopausal breast cancer model. Cancer Res. 2005;65:5439-5444.

Massarweh SA, Tham YL, Weis H, et al. A phase II study of anastrozole and fulvestrant in combination with gefitinib in patients with newly diagnosed ER-positive breast cancer [abstract 1050]. Presented at: American Society of Clinical Oncology Meeting; June 1-5, 2007; Chicago, IL.

Mrozek E, Schaaf LJ, Ramaswamy B, et al. Phase II trial of exemestane in combination with fulvestrant in postmenopausal women with hormone responsive advanced breast cancer: no evidence of a pharmacokinetic interaction between exemestane and fulvestrant [abstract 6131]. Presented at: San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, TX.

Obermiller AM, Copur MS, Bolton M, et al. Letrozole(L)/ Fulvestrant(F) combination in second line or more for estrogen receptor (ER) positive ( ) metastatic breast cancer (MBC): efficacy and predictive factors of response. Submitted to be presented at American Society of Clinical Oncology Meeting; June 2011; Chicago, IL.

Young OE, Renshaw L, Macaskill S, et al. Effects of fulvestrant 750 mg in premenopausal women with estrogen-receptor-positive primary breast cancer. Eur J Cancer. 2008;44:391-399.

Intellectual Property Library. Fulvestrant formulations. US 2009/0227549 A1. September 10, 2009;1-11.

Shravani P, Vinod KR, Teja BB, et al. Designing and characterization of reservoir type transdermal formulation of fulvestrant. Int J Pharm Sci Rev Res. 2010;5:59-63.

Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2010;Oct 20(28):4594-4600.

Ohno S, Rai Y, Iwata H, et al. Three dose regimens of fulvestrant in postmenopausal Japanese women with advanced breast cancer: results from a double-blind phase II comparative study (FINDER1). Ann Oncol (Epub ahead of print; April 21, 2010).

Pritchard KI, Rolski J, Papai Z, et al. Results of a phase II study comparing three dosing regimens of fulvestrant in postmenopausal women with advanced breast cancer (FINDER2). Breast Cancer Res Treat. 123:453-461.2010.

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