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Pharmacokinetic Profile of the Fulvestrant Loading Dose Regimen in Postmenopausal Women with Hormone Receptor–Positive Advanced Breast Cancer
original contribution Pharmacokinetic Profile of the Fulvestrant Loading Dose Regimen in Postmenopausal Women with Hormone Receptor–Positive Advanced Breast Cancer Peter McCormack, Francisco Sapunar Abstract Purpose: Fulvestrant is at least as effective as anastrozole in the treatment of postmenopausal women with advanced breast cancer whose disease has previously progressed or recurred on antiestrogen therapy. Pharmacokinetic data have shown that, at the approved dose (250 mg/month), it takes approximately 3-6 months for fulvestrant to reach steady-state levels. Theoretically, a more rapid attainment of steady state might reduce the number of early progressions. A pharmacokinetic model simulating plasma concentrations expected to be achieved with a fulvestrant loading dose (LD) regimen suggested that steady state might be achieved earlier with the LD. The aim of this study was to characterize the pharmacokinetics of the fulvestrant LD regimen. This pharmacokinetic substudy was conducted within a phase III trial, EFECT (Evaluation of Fulvestrant versus Exemestane Clinical Trial), comparing fulvestrant with exemestane in postmenopausal women with hormone-sensitive advanced breast cancer whose disease had progressed or recurred following nonsteroidal aromatase inhibitor treatment. Patients and Methods: Patients received fulvestrant intramuscularly using a LD regimen of 500 mg on day 0, 250 mg on days 14 and 28, and then 250 mg each month thereafter. Blood samples were collected throughout the first month and on day 28 of each subsequent month. Plasma fulvestrant concentrations were determined by highperformance liquid chromatography–mass spectrometry, and pharmacokinetic parameters were estimated with nonlinear mixed-effects modeling. Results: Thirty-seven patients receiving fulvestrant were enrolled into the pharmacokinetic substudy, and 269 fulvestrant plasma concentrations were recorded. Maximum fulvestrant concentration (19.7 ng/mL) was observed at an average of 12 days within the first month and maintained at 12-15 ng/mL throughout the remainder of the dosing period. Conclusion: Steady-state plasma levels were attained within the first month of treatment with fulvestrant LD, in line with the predictions of the pharmacokinetic model. Clinical Breast Cancer, Vol. 8, No. 4, 347-351, 2008; DOI: 10.3816/CBC.2008.n.040 Keywords: Anastrozole, Aromatase inhibitor, Ki-67, Steady-state
Introduction Fulvestrant is an estrogen receptor (ER) antagonist licensed for the treatment of postmenopausal women with hormone receptor (HR)– positive advanced breast cancer whose disease has progressed or recurred during previous antiestrogen therapy. Unlike the selective ER modulator tamoxifen, which displays mixed antagonist/agonist properties, fulvestrant has no agonist effects.1,2 Fulvestrant has a different mechanism of action compared with tamoxifen; it binds, blocks, and increases degradation of the ER, leading to an inhibition of estrogen signaling.3 This AstraZeneca Pharmaceuticals, Macclesfield, Cheshire, UK Submitted: Nov 21, 2007; Revised: Mar 26, 2008; Accepted: Apr 10, 2008 Address for correspondence: Peter McCormack, PhD, Department of Clinical Pharmacology, AstraZeneca R&D Alderley Park, Parklands, Macclesfield, Cheshire, SK10 4TG, U Fax: 44-0-1625-517428; e-mail: [email protected]
distinctive mode of action offers the potential to overcome tumor resistance to previous endocrine agents.4 In addition, increased degradation of the ER by fulvestrant might limit cross-talk between growth factor receptor– and ER-mediated signaling pathways and thus increase the duration of response observed with fulvestrant treatment.5-7 In 2 similarly designed phase III studies, both with time to progression (TTP) as the primary efficacy endpoint, fulvestrant (250 mg per month, intramuscular [IM] injection) was shown to be at least as effective and well tolerated as the aromatase inhibitor (AI) anastrozole (1 mg per day, orally) in the treatment of postmenopausal women with advanced, tamoxifen-resistant breast cancer (Trial 0020 conducted in Europe, South Africa, and Australia; Trial 0021 in North America).8,9 Pharmacokinetic data, conducted within the context of these phase III clinical trials, showed that fulvestrant took approximately 3-6 months to reach steady-state levels with this approved dosing (AD) regimen.10 In a phase III trial for the first-line treatment of postmenopausal women with advanced breast cancer (Trial 0025 conducted in 26 coun-
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1526-8209, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Clinical Breast Cancer August 2008 • 347
Pharmacokinetic Profile of the Fulvestrant Loading Dose Regimen Figure 1 Fulvestrant Loading Dose and Approved Dose Regimens 500 mg (Via 2 x Fulvestrant 250 mg) LD
Fulvestrant AD
250 mg
250 mg
Day 0
Day 14 Month 1
250 mg
250 mg
250 mg
250 mg
Day 28 Day 56 Month 2 Onward
Abbreviations: AD = approved dose; LD = loading dose
tries), fulvestrant (250 mg per month) was not shown to be superior to tamoxifen (20 mg per day) for the primary endpoint of TTP.11 This was unexpected because fulvestrant is comparable with anastrozole in the second-line setting,8 and anastrozole is superior to tamoxifen in the first-line setting.12 It was hypothesized that earlier progressions observed in some patients during fulvestrant treatment in Trial 002511 might have been a result of the delay in achieving steady-state and potentially therapeutic fulvestrant levels with the AD regimen. As a result of this hypothesis, pharmacokinetic simulations of the time to reach steady state with different fulvestrant dosing regimens were developed13 using the data derived from previous fulvestrant trials.10 These modeling data predicted that steady-state fulvestrant levels should be attained sooner (within 1 month) by using a loading dose (LD) regimen of 500 mg on day 0, 250 mg on days 14 and 28, and 250 mg monthly thereafter. The aim of the present study, conducted within the context of the phase III EFECT (Evaluation of Fulvestrant versus Exemestane Clinical Trial; 9238IL/0048), was to characterize the pharmacokinetic profile of a fulvestrant LD regimen and assess the time taken to achieve steady-state plasma levels.
Patients and Methods EFECT recruited postmenopausal women with HR-positive locally advanced or metastatic breast cancer whose disease had progressed while receiving treatment with a nonsteroidal AI or recurred while receiving (or within 6 months of discontinuation of) a nonsteroidal AI as adjuvant therapy. Patients who were currently receiving hormone replacement therapy or had received any intercurrent hormonal therapy after previous nonsteroidal AI therapy for advanced breast cancer were excluded from the study as were patients with severe/ uncontrolled systemic disease or hepatic impairment (total bilirubin > 1.5 times the upper limit of normal [ULN]; alanine aminotransferase or aspartate aminotransferase > 2.5 times or > 5 times the ULN in the absence and presence of hepatic metastasis, respectively). Patients receiving long-term anticoagulant therapy, having a platelet count of < 100 × 109/L or an international normalized ratio > 1.6 were excluded. Previous treatment with fulvestrant or exemestane, or recent exposure to extensive radiotherapy, nonapproved drug treatments (within 4 weeks) or a luteinizing hormone-releasing hormone analogue (within 4 months) were also reasons for exclusion. Initiation of corticosteroids, adrenocortical suppressants, low-dose progestins, or ketoconazole was not permitted during the study, but continuation of existing treatment with these agents was allowed at the investigator’s discretion.
348 • Clinical Breast Cancer
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This study was approved by the relevant local ethics committees and was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization/World Health Organization Good Clinical Practice requirements. Written informed consent was obtained from each patient before study entry. Efficacy and tolerability findings from this study are reported elsewhere.14
Trial Design EFECT is a randomized, double-blind, double-dummy, parallel-group, multinational, multicenter phase III study conducted across several countries, comparing the efficacy and tolerability of fulvestrant versus exemestane. Fulvestrant IM was administered at a dose of 500 mg on day 0, 250 mg on days 14 and 28, and 250 mg every 28 days thereafter (Figure 1). The pharmacokinetic profile of fulvestrant following this LD regimen (target of 30 patients) was investigated in this substudy.
Assay Methods Serial blood samples (10 mL) for pharmacokinetic analyses were collected pre-dose and at 1 hour post-dose on day 1, and at any time on days 2, 8, 14, 17, 28, 56, 84, 112, 140, and 168 after the first dose of fulvestrant. Samples were collected in lithium-heparin tubes, centrifuged at 1000 g for 10 minutes within 10-15 minutes of sampling. The plasma was immediately separated, frozen, protected from light, and stored at –20oC until required for analysis. All samples were analyzed at a central laboratory (Analytico Medinet; Breda, The Netherlands). Plasma concentrations of fulvestrant were assessed using a validated, highly sensitive and specific, high-performance liquid chromatography–mass spectrometry assay after liquid-liquid extraction with deuterated fulvestrant used as an internal standard. A detailed description of this assay method has been reported previously.10 Fulvestrant concentrations were calculated from peak area ratios (fulvestrant:internal standard) by reference to a calibration series constructed by adding known amounts of fulvestrant to control plasma and extracting these standards in parallel with the test samples. Quantification was performed by reference to a least-squares linear regression line generated from standard samples.
Pharmacokinetic Assessments Individual and population-predicted pharmacokinetic parameters were estimated with pharmacokinetic models run within the software program NONlinear Mixed Effects Modeling (University of California, San Francisco). The pharmacokinetic model used in this analysis was a 2-compartment system with first-order absorption and first-order elimination. The parameters assessed included clearance, volume of distribution at steady state (initial volume + peripheral volume), and distributional clearance. The maximum observed plasma concentration (Cmax) and the minimum observed plasma concentration (Cmin) at month 1 and at steady state, along with the time to reach the maximum plasma concentration (Tmax), were determined as secondary pharmacokinetic parameters. The area under the curve (AUC) of plasma concentration versus time between 0 days and 28 days after the first dose (AUC0-28day), which reflected overall exposure of the drug, was also calculated at month 1 and at a steady state. Data were summarized as mean (± standard deviation [SD]).
Peter McCormack, Francisco Sapunar
Characteristic Median Age, Years (Range)
Fulvestrant (n = 37) 66 (48-85)
Previous Treatments, n (%) Adjuvant endocrine therapy
7 (18.9)
Endocrine therapy for advanced disease
30 (81.1)
1 Previous endocrine therapy
18 (48.6)
> 1 Previous endocrine therapy
19 (51.4)
Adjuvant chemotherapy
14 (37.8)
Chemotherapy for advanced disease
9 (24.3)
Adjuvant radiation therapy
20 (54.1)
Radiation therapy for advanced disease
15 (40.5)
Other breast cancer treatment
4 (10.8)
AI-Sensitive Disease, n (%)
19 (51.4)
AI-Resistant Disease, n (%)
18 (48.6)
Disease Stage, n (%) Locally advanced Metastatic
50
40
30
20
10
0
10
20 30 40 Observed Concentration (ng/mL)
50
Loading-Dose Fulvestrant Pharmacokinetics 2 (5.4) 35 (94.6)
Sites of Metastases, n (%) Bone
26 (70.3)
Lung
13 (35.1)
Liver
10 (27)
Lymph nodes
9 (24.3)
Skin/soft tissue
6 (16.2)
Visceral Involvement, n (%) Yes
20 (54.1)
No
17 (45.9)
Hormone Receptor Status, n (%) ER-positive and/or PgR-positive
13 (35.1)
ER-positive and PgR-positive
24 (64.9)
WHO Performance Status, n (%) 0 (normal activity)
21 (56.8)
1 (restricted activity)
14 (37.8)
2 (in bed q 50% of the time)
Figure 2 Observed and Population-Predicted Individual Plasma Concentrations Individual Predicted Concentration (ng/mL)
Table 1 Patient Demographics and Clinical Characteristics
2 (5.4)
Measurable Disease Yes
29 (78.4)
No
8 (21.6)
Abbreviations: AI = aromatase inhibitor; ER = estrogen PgR = progesterone receptor; WHO = World Health Organization
receptor;
Results Patient Demographics In total, 37 patients receiving fulvestrant were enrolled into this EFECT substudy, and 269 fulvestrant plasma concentrations were recorded. The baseline demographics and clinical characteristics of this study population are summarized in Table 1. In brief, the patient population of this pharmacokinetic substudy reflected the overall population enrolled in EFECT.14 All of the patients enrolled had HR-positive breast cancer, with the majority of patients (94.6%) having metastatic disease and visceral involvement (54.1%).
Results of the individual predicted plasma concentrations suggested a reasonable fit to the observed data and suggested an accurate representation of the pharmacokinetics for the LD regimen (Figure 2). The mean (± SD) population estimate clearance was 32.3 ± 5.2 L/h (range, 15.2-41.6 L/h), and for the volume of distribution was 71,353 ± 37,088 L (range, 8,370-184,465 L]. The maximum drug concentration (Cmax) was observed within the first month at an average of 12.2 ± 7.1 days after dose, and had a mean population value of 19.7 ng/mL (median, 14.1 ng/mL; Figure 3); this decreased slightly on subsequent months, and it was maintained at approximately 1215 ng/mL for the remainder of the dosing period. Analysis of the individual and population-predicted profiles (Table 2) of the LD regimen indicated that exposure (AUC0-28 days) was slightly higher during the first month compared with steady state. However, Cmax and Cmin were similar throughout the dosing period, with no evidence of accumulation over time. In addition, predicted ratio values of 1.0 for Cmax steady-state: Cmax month 1 and 0.8 for Cmin steady-state: Cmin month 1 support similar plasma concentrations throughout the dosing period. Steady-state fulvestrant plasma levels were attained by month 1 with the LD regimen.
Discussion The fulvestrant AD regimen (250 mg per month) has proven efficacy; it is at least as effective as anastrozole in the treatment of postmenopausal women with HR-positive advanced breast cancer who have recurred or progressed while on a prior antiestrogen therapy.8,9 However, previous pharmacokinetic analysis of the fulvestrant AD regimen10 has revealed that steady-state levels can take up to 3-6 months to be reached. The time taken to achieve fulvestrant steady-state levels might potentially be an important issue in terms of the risk of early progression and time to response (TTR) for some patients on treatment. For example, a higher rate of early progression/relapse within the first 3 months of fulvestrant treatment was noted in a phase III first-line trial of fulvestrant (250 mg per month) versus tamoxifen (20 mg per day) in postmenopausal women with advanced breast cancer,11 and it has been speculated that this observation might be related to a
Clinical Breast Cancer August 2008 • 349
Pharmacokinetic Profile of the Fulvestrant Loading Dose Regimen Table 2 Mean Observed Individual and Population-Predicted Pharmacokinetic Parameter Estimates
Figure 3 Observed and Population-Predicted Profile of the Fulvestrant Loading Dose Regimen Predicted Concentration (ng/mL)
40 Populated-Predicted Observed
30
Parameter Estimates
Cmin, ng/mL
19.7 ± 18.5
16.7 ± 8.7
9.6 ± 2.9
7.7 ± 1.6
9131.4 ± 5752.7
8010.7 ± 1847.2
Cmax, ng/mL
15
14.7
Cmin, ng/mL
9.8
7.9
8220
7530
AUC0-28 days, ngñh/mL Population-Predicted Parameter Estimates (Mean)
10
0
Steady State
Observed Individual Parameter Estimates (Mean ± SD) Cmax, ng/mL
20
Month 1
28
56
84
112 140 Time (Days)
168
196
224
delay in the time taken for this drug to reach steady-state plasma concentrations. Interestingly, despite the time taken to achieve steady-state levels, the TTR with fulvestrant has been shown to be consistent with oral endocrine therapies such as tamoxifen and anastrozole.15 It is also interesting that efficacy was similar between fulvestrant and anastrozole in the second-line treatment of postmenopausal women with advanced breast cancer, suggesting that factors other than the time to reach steady-state fulvestrant levels might have influenced the earlier progressions observed in the first-line trial of fulvestrant versus tamoxifen. However, it is possible that this effect was masked by the inclusion of a more hormone-resistant population versus the first-line setting. This present pharmacokinetic study conducted within the confines of the phase III EFECT trial has shown that steady-state levels of fulvestrant can be achieved earlier (within 1 month) with an LD regimen compared with standard 250-mg monthly administrations used in the AD regimen and confirms previous model calculations (Figure 4). The fulvestrant LD regimen in this pharmacokinetic analysis resulted in Cmin values within the first month (19.7 ± 18.5) that are similar to those attained at steady state (ie, 3-6 months) when using the AD regimen (6.2-6.5 ng/mL).10 Analysis of the population-predicted profile of the LD schedule indicates that, although the exposure (AUC028days) is slightly higher during the first month, the Cmax and Cmin values were similar throughout the dosing period. Pharmacokinetic analysis of the individual Cmax and Cmin values during month 1 and at steady state indicate a predicted ratio of 1.0 for Cmax steady-state: Cmax month 1 and 0.8 for Cmin steady-state: Cmin month 1, further suggesting similar plasma concentrations throughout the study. Plasma concentrations were on average in the region of 12-15 ng/mL throughout the dosing period, which are in line with those expected to be achieved at steady state with the AD regimen (Figure 4).10 Clearance remained unaffected by the LD regimen and, although a 2-3–fold accumulation over the first 6 months of treatment with the AD regimen has been reported previously,10 no evidence of accumulation over time was observed in this pharmacokinetic study of the LD regimen. This finding confirms that, with the LD regimen, fulvestrant plasma levels achieve pharmacokinetic steady state earlier. Overall, data from EFECT have shown that a fulvestrant LD regimen is effective and well tolerated in patients with HR-positive
350 • Clinical Breast Cancer
August 2008
AUC0-28 days, ngñh/mL
Abbreviations: AUC0-28 days = area under the curve of plasma concentration versus time between 0 and 28 days; Cmax = maximum drug concentration; Cmin = minimum drug concentration
advanced breast cancer who have progressed or recurred after treatment with a nonsteroidal AI.14 However, as this trial did not compare the LD regimen with the AD schedule, conclusions regarding any differences in efficacy with these 2 regimens cannot be drawn at present. As suggested by the pharmacodynamic data, higher doses of fulvestrant might potentially lead to greater biologic activity.13 The ER downregulation observed with fulvestrant is a dose-dependent process,16 with increasing steady-state plasma concentrations resulting in further ER downregulation. In addition to downregulation of ER, a dose-dependent suppression in the levels of the cell proliferation marker Ki-67 has been noted during fulvestrant treatment.6 It is therefore possible that higher fulvestrant doses might lead to further ER downregulation, reduced proliferation, and improved efficacy.13 Additional pharmacokinetic simulations suggest that a high-dose (HD) regimen (500 mg per month plus 500 mg on day 14 of month 1) should increase fulvestrant plasma levels while maintaining the earlier attainment of steady state (within month 1) observed with the LD regimen in this study. The ongoing international phase III CONFIRM (COmparisoN of Faslodex® In Recurrent or Metastatic breast cancer) trial will compare the fulvestrant AD and HD regimens in 720 postmenopausal women with HR-positive advanced breast cancer after failure of 1 previous endocrine therapy. The NEWEST (Neoadjuvant Endocrine therapy for Women with Endocrine Sensitive Tumors) trial, a smaller phase II study (160 postmenopausal women), is also comparing these 2 fulvestrant dosing regimens and assessing the correlation between changes in Ki-67 labeling index (LI), ER downregulation, and clinical response after 16 weeks of fulvestrant treatment.17 Preliminary results from this trial showed that the fulvestrant HD regimen reduced mean Ki-67 LI to a significantly greater extent compared with fulvestrant AD18 and provided us with the first clinical indication that HD fulvestrant might result in improved activity. The fulvestrant LD regimen used in the present study is also currently being explored in combination with the AI anastrozole in phase III trials in patients who have progressed or recurred while on AI treatment (SOFEA [Study Of Faslodex® versus Exemestane with/ without Arimidex®]) and in those receiving first-line treatment for
Peter McCormack, Francisco Sapunar
Conclusion This pharmacokinetic study demonstrated that the fulvestrant LD regimen displayed a similar pharmacokinetic profile to that predicted in the pharmacokinetic model, with steady-state levels being attained within 1 month rather than up to 3-6 months as observed with the AD regimen. Ongoing studies will compare the efficacy of the fulvestrant LD regimen in combination with anastrozole versus AI treatment alone, while other trials will confirm whether the activity of fulvestrant can be further improved with an increased dose.
Acknowledgements We are indebted to all the women who participated in the study, and we would like to thank the trial investigators (detailed below), nurses, data managers, pharmacists, and other support staff. The authors would like to thank Robert Liversage, PhD, from Complete Medical Communications, who provided medical writing support, funded by AstraZeneca. The following investigators participated in the pharmacokinetic substudy of EFECT. Argentina: LE Fein, Centro Oncológico de Rosario, Rosario City; Belgium: L Dirix, AZ, sint Augustinus Oncologish centrum, Oosterveldlaan; M Piccart, Institut Bordet, Bruxelles; Canada: J Robert, CHAUQ Hopital du St-Sacrement, Quebec, PQ; S Dent, Ottawa Hospital, Ottawa, ON; JA Roy, Hopital de Sacre-Coeur, Montreal, QC; P Ganguly and HB Murphy, Cancer Centre, St John’s, NL; Spain: M Martin, Hospital Clinico S Carlos, Madrid; M Munoz, Servicio de Oncología, Barcelona; United Kingdom: J Robertson, City Hospital, Nottingham; United States: N Abranson, Baptist Cancer Institute, Jacksonville, FL; A Brufsky, Magee Womens Hospital, Pittsburg, PA; A Buzdar, M. D. Anderson Cancer Center, Houston, TX; JT Cole, Ochsher Clinic Foundation, New Orleans, LA; K Tkaczuk, Greenebaum Cancer Center, Baltimore, MD; L Bosserman, Wilshire Oncology Medical Group Inc, La Verne, CA; R Lambert, South Carolina Oncology Associates, Columbia, SC; EP Lester, Oncology Care Associates P. L. L. C., St Joseph, MI; T Siddiqui (replaced Dr Shea), University of Florida Davis Cancer Center, Gainesville, FL; W Keiser, Redwood Regional Medical Group, Santa Rosa, CA; D Weckstein, New Hampshire Oncology Hematology, Hooksett, NH; LM Lewkow, Virginia Cancer Institute, Richmond, VA; JT Carpenter Jr, University of Alabama, Birmingham, AL; H Jhangiani, Compassionate Cancer Care Medical Group, Fountain Valley, CA; CL Vogel, Comprehensive Cancer Care Specialists, Baca Raton, FL.
References 1. 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.
Figure 4 Population-Predicted Profiles for the Fulvestrant Loading Dose and Approved Dose Regimens Predicted Plasma Concentration (ng/mL)
metastatic breast cancer (SWOG Study 0226 and FACT [Faslodex® and Arimidex® in Combination Trial]). Together, the results from these trials should determine whether increased fulvestrant dosing, either with loading alone or increased monthly dose, might correlate with improved clinical activity.
30 Loading Dose Approved Dose
25 20 15 10 5
0
28
56
84
112 140
168
196
224
252 280
Time (Days) Reproduced with permission from AlphaMed Press, Inc. Robertson JF. Oncologist 2007; 12:774-84.
2. Wakeling AE. Similarities and distinctions in the mode of action of different classes of antioestrogens. Endocr Relat Cancer 2000; 7:17-28. 3. Curran M, Wiseman L. Fulvestrant. Drugs 2001; 61:807-13. 4. Howell A, Osborne CK, Morris C, et al. ICI 182,780 (Faslodex): development of a novel, "pure" antiestrogen [published erratum appears in: Cancer 2001; 91:455]. Cancer 2000; 89:817-25. 5. Nicholson RI, Hutcheson IR, Harper ME, et al. Modulation of epidermal growth factor receptor in endocrine-resistant, oestrogen receptor-positive breast cancer. Endocr Relat Cancer 2001; 8:175-82. 6. 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 primary breast cancer. Cancer Res 2001; 61:6739-46. 7. Schiff R, Massarweh SA, Shou J, et al. Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance. Clin Cancer Res 2004; 10:331S-6S. 8. 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. 9. Howell A, Pippen J, Elledge RM, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: a prospectively planned combined survival analysis of two multicenter trials. Cancer 2005; 104:236-9. 10. Robertson JF, Erikstein B, Osborne KC, et al. Pharmacokinetic profile of intramuscular fulvestrant in advanced breast cancer. Clin Pharmacokinet 2004; 43:529-38. 11. 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; 22:1605-13. 12. Nabholtz JM, Bonneterre J, Buzdar A, et al. Anastrozole (Arimidex™) versus tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: survival analysis and updated safety results. Eur J Cancer 2003; 39:1684-9. 13. Robertson JF. Fulvestrant (Faslodex) -- how to make a good drug better. Oncologist 2007; 12:774-84. 14. 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 EFECT. J Clin Oncol 2008; 26:1664-70. 15. Dodwell D, Pippen J. Time to response: comparison of fulvestrant and oral endocrine agents. Clin Breast Cancer 2006; 7:244-7. 16. DeFriend DJ, Howell A, Nicholson RI, et al. Investigation of a new pure antiestrogen (ICI 182780) in women with primary breast cancer. Cancer Res 1994; 54:408-14. 17. Kuter I, Hegg R, Singer CF, et al, on behalf of the NEWEST investigators. Fulvestrant 500 mg vs 250 mg: first results from NEWEST, a randomized, phase II neoadjuvant trial in postmenopausal women with locally advanced, estrogen receptor-positive breast cancer. San Antonio Breast Cancer Symposium Newsletter. December 13, 2007; 1:13.
Clinical Breast Cancer August 2008 • 351
Introduction Fulvestrant is an estrogen receptor (ER) antagonist licensed for the treatment of postmenopausal women with hormone receptor (HR)– positive advanced breast cancer whose disease has progressed or recurred during previous antiestrogen therapy. Unlike the selective ER modulator tamoxifen, which displays mixed antagonist/agonist properties, fulvestrant has no agonist effects.1,2 Fulvestrant has a different mechanism of action compared with tamoxifen; it binds, blocks, and increases degradation of the ER, leading to an inhibition of estrogen signaling.3 This AstraZeneca Pharmaceuticals, Macclesfield, Cheshire, UK Submitted: Nov 21, 2007; Revised: Mar 26, 2008; Accepted: Apr 10, 2008 Address for correspondence: Peter McCormack, PhD, Department of Clinical Pharmacology, AstraZeneca R&D Alderley Park, Parklands, Macclesfield, Cheshire, SK10 4TG, U Fax: 44-0-1625-517428; e-mail: [email protected]
distinctive mode of action offers the potential to overcome tumor resistance to previous endocrine agents.4 In addition, increased degradation of the ER by fulvestrant might limit cross-talk between growth factor receptor– and ER-mediated signaling pathways and thus increase the duration of response observed with fulvestrant treatment.5-7 In 2 similarly designed phase III studies, both with time to progression (TTP) as the primary efficacy endpoint, fulvestrant (250 mg per month, intramuscular [IM] injection) was shown to be at least as effective and well tolerated as the aromatase inhibitor (AI) anastrozole (1 mg per day, orally) in the treatment of postmenopausal women with advanced, tamoxifen-resistant breast cancer (Trial 0020 conducted in Europe, South Africa, and Australia; Trial 0021 in North America).8,9 Pharmacokinetic data, conducted within the context of these phase III clinical trials, showed that fulvestrant took approximately 3-6 months to reach steady-state levels with this approved dosing (AD) regimen.10 In a phase III trial for the first-line treatment of postmenopausal women with advanced breast cancer (Trial 0025 conducted in 26 coun-
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1526-8209, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Clinical Breast Cancer August 2008 • 347
Pharmacokinetic Profile of the Fulvestrant Loading Dose Regimen Figure 1 Fulvestrant Loading Dose and Approved Dose Regimens 500 mg (Via 2 x Fulvestrant 250 mg) LD
Fulvestrant AD
250 mg
250 mg
Day 0
Day 14 Month 1
250 mg
250 mg
250 mg
250 mg
Day 28 Day 56 Month 2 Onward
Abbreviations: AD = approved dose; LD = loading dose
tries), fulvestrant (250 mg per month) was not shown to be superior to tamoxifen (20 mg per day) for the primary endpoint of TTP.11 This was unexpected because fulvestrant is comparable with anastrozole in the second-line setting,8 and anastrozole is superior to tamoxifen in the first-line setting.12 It was hypothesized that earlier progressions observed in some patients during fulvestrant treatment in Trial 002511 might have been a result of the delay in achieving steady-state and potentially therapeutic fulvestrant levels with the AD regimen. As a result of this hypothesis, pharmacokinetic simulations of the time to reach steady state with different fulvestrant dosing regimens were developed13 using the data derived from previous fulvestrant trials.10 These modeling data predicted that steady-state fulvestrant levels should be attained sooner (within 1 month) by using a loading dose (LD) regimen of 500 mg on day 0, 250 mg on days 14 and 28, and 250 mg monthly thereafter. The aim of the present study, conducted within the context of the phase III EFECT (Evaluation of Fulvestrant versus Exemestane Clinical Trial; 9238IL/0048), was to characterize the pharmacokinetic profile of a fulvestrant LD regimen and assess the time taken to achieve steady-state plasma levels.
Patients and Methods EFECT recruited postmenopausal women with HR-positive locally advanced or metastatic breast cancer whose disease had progressed while receiving treatment with a nonsteroidal AI or recurred while receiving (or within 6 months of discontinuation of) a nonsteroidal AI as adjuvant therapy. Patients who were currently receiving hormone replacement therapy or had received any intercurrent hormonal therapy after previous nonsteroidal AI therapy for advanced breast cancer were excluded from the study as were patients with severe/ uncontrolled systemic disease or hepatic impairment (total bilirubin > 1.5 times the upper limit of normal [ULN]; alanine aminotransferase or aspartate aminotransferase > 2.5 times or > 5 times the ULN in the absence and presence of hepatic metastasis, respectively). Patients receiving long-term anticoagulant therapy, having a platelet count of < 100 × 109/L or an international normalized ratio > 1.6 were excluded. Previous treatment with fulvestrant or exemestane, or recent exposure to extensive radiotherapy, nonapproved drug treatments (within 4 weeks) or a luteinizing hormone-releasing hormone analogue (within 4 months) were also reasons for exclusion. Initiation of corticosteroids, adrenocortical suppressants, low-dose progestins, or ketoconazole was not permitted during the study, but continuation of existing treatment with these agents was allowed at the investigator’s discretion.
348 • Clinical Breast Cancer
August 2008
This study was approved by the relevant local ethics committees and was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization/World Health Organization Good Clinical Practice requirements. Written informed consent was obtained from each patient before study entry. Efficacy and tolerability findings from this study are reported elsewhere.14
Trial Design EFECT is a randomized, double-blind, double-dummy, parallel-group, multinational, multicenter phase III study conducted across several countries, comparing the efficacy and tolerability of fulvestrant versus exemestane. Fulvestrant IM was administered at a dose of 500 mg on day 0, 250 mg on days 14 and 28, and 250 mg every 28 days thereafter (Figure 1). The pharmacokinetic profile of fulvestrant following this LD regimen (target of 30 patients) was investigated in this substudy.
Assay Methods Serial blood samples (10 mL) for pharmacokinetic analyses were collected pre-dose and at 1 hour post-dose on day 1, and at any time on days 2, 8, 14, 17, 28, 56, 84, 112, 140, and 168 after the first dose of fulvestrant. Samples were collected in lithium-heparin tubes, centrifuged at 1000 g for 10 minutes within 10-15 minutes of sampling. The plasma was immediately separated, frozen, protected from light, and stored at –20oC until required for analysis. All samples were analyzed at a central laboratory (Analytico Medinet; Breda, The Netherlands). Plasma concentrations of fulvestrant were assessed using a validated, highly sensitive and specific, high-performance liquid chromatography–mass spectrometry assay after liquid-liquid extraction with deuterated fulvestrant used as an internal standard. A detailed description of this assay method has been reported previously.10 Fulvestrant concentrations were calculated from peak area ratios (fulvestrant:internal standard) by reference to a calibration series constructed by adding known amounts of fulvestrant to control plasma and extracting these standards in parallel with the test samples. Quantification was performed by reference to a least-squares linear regression line generated from standard samples.
Pharmacokinetic Assessments Individual and population-predicted pharmacokinetic parameters were estimated with pharmacokinetic models run within the software program NONlinear Mixed Effects Modeling (University of California, San Francisco). The pharmacokinetic model used in this analysis was a 2-compartment system with first-order absorption and first-order elimination. The parameters assessed included clearance, volume of distribution at steady state (initial volume + peripheral volume), and distributional clearance. The maximum observed plasma concentration (Cmax) and the minimum observed plasma concentration (Cmin) at month 1 and at steady state, along with the time to reach the maximum plasma concentration (Tmax), were determined as secondary pharmacokinetic parameters. The area under the curve (AUC) of plasma concentration versus time between 0 days and 28 days after the first dose (AUC0-28day), which reflected overall exposure of the drug, was also calculated at month 1 and at a steady state. Data were summarized as mean (± standard deviation [SD]).
Peter McCormack, Francisco Sapunar
Characteristic Median Age, Years (Range)
Fulvestrant (n = 37) 66 (48-85)
Previous Treatments, n (%) Adjuvant endocrine therapy
7 (18.9)
Endocrine therapy for advanced disease
30 (81.1)
1 Previous endocrine therapy
18 (48.6)
> 1 Previous endocrine therapy
19 (51.4)
Adjuvant chemotherapy
14 (37.8)
Chemotherapy for advanced disease
9 (24.3)
Adjuvant radiation therapy
20 (54.1)
Radiation therapy for advanced disease
15 (40.5)
Other breast cancer treatment
4 (10.8)
AI-Sensitive Disease, n (%)
19 (51.4)
AI-Resistant Disease, n (%)
18 (48.6)
Disease Stage, n (%) Locally advanced Metastatic
50
40
30
20
10
0
10
20 30 40 Observed Concentration (ng/mL)
50
Loading-Dose Fulvestrant Pharmacokinetics 2 (5.4) 35 (94.6)
Sites of Metastases, n (%) Bone
26 (70.3)
Lung
13 (35.1)
Liver
10 (27)
Lymph nodes
9 (24.3)
Skin/soft tissue
6 (16.2)
Visceral Involvement, n (%) Yes
20 (54.1)
No
17 (45.9)
Hormone Receptor Status, n (%) ER-positive and/or PgR-positive
13 (35.1)
ER-positive and PgR-positive
24 (64.9)
WHO Performance Status, n (%) 0 (normal activity)
21 (56.8)
1 (restricted activity)
14 (37.8)
2 (in bed q 50% of the time)
Figure 2 Observed and Population-Predicted Individual Plasma Concentrations Individual Predicted Concentration (ng/mL)
Table 1 Patient Demographics and Clinical Characteristics
2 (5.4)
Measurable Disease Yes
29 (78.4)
No
8 (21.6)
Abbreviations: AI = aromatase inhibitor; ER = estrogen PgR = progesterone receptor; WHO = World Health Organization
receptor;
Results Patient Demographics In total, 37 patients receiving fulvestrant were enrolled into this EFECT substudy, and 269 fulvestrant plasma concentrations were recorded. The baseline demographics and clinical characteristics of this study population are summarized in Table 1. In brief, the patient population of this pharmacokinetic substudy reflected the overall population enrolled in EFECT.14 All of the patients enrolled had HR-positive breast cancer, with the majority of patients (94.6%) having metastatic disease and visceral involvement (54.1%).
Results of the individual predicted plasma concentrations suggested a reasonable fit to the observed data and suggested an accurate representation of the pharmacokinetics for the LD regimen (Figure 2). The mean (± SD) population estimate clearance was 32.3 ± 5.2 L/h (range, 15.2-41.6 L/h), and for the volume of distribution was 71,353 ± 37,088 L (range, 8,370-184,465 L]. The maximum drug concentration (Cmax) was observed within the first month at an average of 12.2 ± 7.1 days after dose, and had a mean population value of 19.7 ng/mL (median, 14.1 ng/mL; Figure 3); this decreased slightly on subsequent months, and it was maintained at approximately 1215 ng/mL for the remainder of the dosing period. Analysis of the individual and population-predicted profiles (Table 2) of the LD regimen indicated that exposure (AUC0-28 days) was slightly higher during the first month compared with steady state. However, Cmax and Cmin were similar throughout the dosing period, with no evidence of accumulation over time. In addition, predicted ratio values of 1.0 for Cmax steady-state: Cmax month 1 and 0.8 for Cmin steady-state: Cmin month 1 support similar plasma concentrations throughout the dosing period. Steady-state fulvestrant plasma levels were attained by month 1 with the LD regimen.
Discussion The fulvestrant AD regimen (250 mg per month) has proven efficacy; it is at least as effective as anastrozole in the treatment of postmenopausal women with HR-positive advanced breast cancer who have recurred or progressed while on a prior antiestrogen therapy.8,9 However, previous pharmacokinetic analysis of the fulvestrant AD regimen10 has revealed that steady-state levels can take up to 3-6 months to be reached. The time taken to achieve fulvestrant steady-state levels might potentially be an important issue in terms of the risk of early progression and time to response (TTR) for some patients on treatment. For example, a higher rate of early progression/relapse within the first 3 months of fulvestrant treatment was noted in a phase III first-line trial of fulvestrant (250 mg per month) versus tamoxifen (20 mg per day) in postmenopausal women with advanced breast cancer,11 and it has been speculated that this observation might be related to a
Clinical Breast Cancer August 2008 • 349
Pharmacokinetic Profile of the Fulvestrant Loading Dose Regimen Table 2 Mean Observed Individual and Population-Predicted Pharmacokinetic Parameter Estimates
Figure 3 Observed and Population-Predicted Profile of the Fulvestrant Loading Dose Regimen Predicted Concentration (ng/mL)
40 Populated-Predicted Observed
30
Parameter Estimates
Cmin, ng/mL
19.7 ± 18.5
16.7 ± 8.7
9.6 ± 2.9
7.7 ± 1.6
9131.4 ± 5752.7
8010.7 ± 1847.2
Cmax, ng/mL
15
14.7
Cmin, ng/mL
9.8
7.9
8220
7530
AUC0-28 days, ngñh/mL Population-Predicted Parameter Estimates (Mean)
10
0
Steady State
Observed Individual Parameter Estimates (Mean ± SD) Cmax, ng/mL
20
Month 1
28
56
84
112 140 Time (Days)
168
196
224
delay in the time taken for this drug to reach steady-state plasma concentrations. Interestingly, despite the time taken to achieve steady-state levels, the TTR with fulvestrant has been shown to be consistent with oral endocrine therapies such as tamoxifen and anastrozole.15 It is also interesting that efficacy was similar between fulvestrant and anastrozole in the second-line treatment of postmenopausal women with advanced breast cancer, suggesting that factors other than the time to reach steady-state fulvestrant levels might have influenced the earlier progressions observed in the first-line trial of fulvestrant versus tamoxifen. However, it is possible that this effect was masked by the inclusion of a more hormone-resistant population versus the first-line setting. This present pharmacokinetic study conducted within the confines of the phase III EFECT trial has shown that steady-state levels of fulvestrant can be achieved earlier (within 1 month) with an LD regimen compared with standard 250-mg monthly administrations used in the AD regimen and confirms previous model calculations (Figure 4). The fulvestrant LD regimen in this pharmacokinetic analysis resulted in Cmin values within the first month (19.7 ± 18.5) that are similar to those attained at steady state (ie, 3-6 months) when using the AD regimen (6.2-6.5 ng/mL).10 Analysis of the population-predicted profile of the LD schedule indicates that, although the exposure (AUC028days) is slightly higher during the first month, the Cmax and Cmin values were similar throughout the dosing period. Pharmacokinetic analysis of the individual Cmax and Cmin values during month 1 and at steady state indicate a predicted ratio of 1.0 for Cmax steady-state: Cmax month 1 and 0.8 for Cmin steady-state: Cmin month 1, further suggesting similar plasma concentrations throughout the study. Plasma concentrations were on average in the region of 12-15 ng/mL throughout the dosing period, which are in line with those expected to be achieved at steady state with the AD regimen (Figure 4).10 Clearance remained unaffected by the LD regimen and, although a 2-3–fold accumulation over the first 6 months of treatment with the AD regimen has been reported previously,10 no evidence of accumulation over time was observed in this pharmacokinetic study of the LD regimen. This finding confirms that, with the LD regimen, fulvestrant plasma levels achieve pharmacokinetic steady state earlier. Overall, data from EFECT have shown that a fulvestrant LD regimen is effective and well tolerated in patients with HR-positive
350 • Clinical Breast Cancer
August 2008
AUC0-28 days, ngñh/mL
Abbreviations: AUC0-28 days = area under the curve of plasma concentration versus time between 0 and 28 days; Cmax = maximum drug concentration; Cmin = minimum drug concentration
advanced breast cancer who have progressed or recurred after treatment with a nonsteroidal AI.14 However, as this trial did not compare the LD regimen with the AD schedule, conclusions regarding any differences in efficacy with these 2 regimens cannot be drawn at present. As suggested by the pharmacodynamic data, higher doses of fulvestrant might potentially lead to greater biologic activity.13 The ER downregulation observed with fulvestrant is a dose-dependent process,16 with increasing steady-state plasma concentrations resulting in further ER downregulation. In addition to downregulation of ER, a dose-dependent suppression in the levels of the cell proliferation marker Ki-67 has been noted during fulvestrant treatment.6 It is therefore possible that higher fulvestrant doses might lead to further ER downregulation, reduced proliferation, and improved efficacy.13 Additional pharmacokinetic simulations suggest that a high-dose (HD) regimen (500 mg per month plus 500 mg on day 14 of month 1) should increase fulvestrant plasma levels while maintaining the earlier attainment of steady state (within month 1) observed with the LD regimen in this study. The ongoing international phase III CONFIRM (COmparisoN of Faslodex® In Recurrent or Metastatic breast cancer) trial will compare the fulvestrant AD and HD regimens in 720 postmenopausal women with HR-positive advanced breast cancer after failure of 1 previous endocrine therapy. The NEWEST (Neoadjuvant Endocrine therapy for Women with Endocrine Sensitive Tumors) trial, a smaller phase II study (160 postmenopausal women), is also comparing these 2 fulvestrant dosing regimens and assessing the correlation between changes in Ki-67 labeling index (LI), ER downregulation, and clinical response after 16 weeks of fulvestrant treatment.17 Preliminary results from this trial showed that the fulvestrant HD regimen reduced mean Ki-67 LI to a significantly greater extent compared with fulvestrant AD18 and provided us with the first clinical indication that HD fulvestrant might result in improved activity. The fulvestrant LD regimen used in the present study is also currently being explored in combination with the AI anastrozole in phase III trials in patients who have progressed or recurred while on AI treatment (SOFEA [Study Of Faslodex® versus Exemestane with/ without Arimidex®]) and in those receiving first-line treatment for
Peter McCormack, Francisco Sapunar
Conclusion This pharmacokinetic study demonstrated that the fulvestrant LD regimen displayed a similar pharmacokinetic profile to that predicted in the pharmacokinetic model, with steady-state levels being attained within 1 month rather than up to 3-6 months as observed with the AD regimen. Ongoing studies will compare the efficacy of the fulvestrant LD regimen in combination with anastrozole versus AI treatment alone, while other trials will confirm whether the activity of fulvestrant can be further improved with an increased dose.
Acknowledgements We are indebted to all the women who participated in the study, and we would like to thank the trial investigators (detailed below), nurses, data managers, pharmacists, and other support staff. The authors would like to thank Robert Liversage, PhD, from Complete Medical Communications, who provided medical writing support, funded by AstraZeneca. The following investigators participated in the pharmacokinetic substudy of EFECT. Argentina: LE Fein, Centro Oncológico de Rosario, Rosario City; Belgium: L Dirix, AZ, sint Augustinus Oncologish centrum, Oosterveldlaan; M Piccart, Institut Bordet, Bruxelles; Canada: J Robert, CHAUQ Hopital du St-Sacrement, Quebec, PQ; S Dent, Ottawa Hospital, Ottawa, ON; JA Roy, Hopital de Sacre-Coeur, Montreal, QC; P Ganguly and HB Murphy, Cancer Centre, St John’s, NL; Spain: M Martin, Hospital Clinico S Carlos, Madrid; M Munoz, Servicio de Oncología, Barcelona; United Kingdom: J Robertson, City Hospital, Nottingham; United States: N Abranson, Baptist Cancer Institute, Jacksonville, FL; A Brufsky, Magee Womens Hospital, Pittsburg, PA; A Buzdar, M. D. Anderson Cancer Center, Houston, TX; JT Cole, Ochsher Clinic Foundation, New Orleans, LA; K Tkaczuk, Greenebaum Cancer Center, Baltimore, MD; L Bosserman, Wilshire Oncology Medical Group Inc, La Verne, CA; R Lambert, South Carolina Oncology Associates, Columbia, SC; EP Lester, Oncology Care Associates P. L. L. C., St Joseph, MI; T Siddiqui (replaced Dr Shea), University of Florida Davis Cancer Center, Gainesville, FL; W Keiser, Redwood Regional Medical Group, Santa Rosa, CA; D Weckstein, New Hampshire Oncology Hematology, Hooksett, NH; LM Lewkow, Virginia Cancer Institute, Richmond, VA; JT Carpenter Jr, University of Alabama, Birmingham, AL; H Jhangiani, Compassionate Cancer Care Medical Group, Fountain Valley, CA; CL Vogel, Comprehensive Cancer Care Specialists, Baca Raton, FL.
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Figure 4 Population-Predicted Profiles for the Fulvestrant Loading Dose and Approved Dose Regimens Predicted Plasma Concentration (ng/mL)
metastatic breast cancer (SWOG Study 0226 and FACT [Faslodex® and Arimidex® in Combination Trial]). Together, the results from these trials should determine whether increased fulvestrant dosing, either with loading alone or increased monthly dose, might correlate with improved clinical activity.
30 Loading Dose Approved Dose
25 20 15 10 5
0
28
56
84
112 140
168
196
224
252 280
Time (Days) Reproduced with permission from AlphaMed Press, Inc. Robertson JF. Oncologist 2007; 12:774-84.
2. Wakeling AE. Similarities and distinctions in the mode of action of different classes of antioestrogens. Endocr Relat Cancer 2000; 7:17-28. 3. Curran M, Wiseman L. Fulvestrant. Drugs 2001; 61:807-13. 4. Howell A, Osborne CK, Morris C, et al. ICI 182,780 (Faslodex): development of a novel, "pure" antiestrogen [published erratum appears in: Cancer 2001; 91:455]. Cancer 2000; 89:817-25. 5. Nicholson RI, Hutcheson IR, Harper ME, et al. Modulation of epidermal growth factor receptor in endocrine-resistant, oestrogen receptor-positive breast cancer. Endocr Relat Cancer 2001; 8:175-82. 6. 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 primary breast cancer. Cancer Res 2001; 61:6739-46. 7. Schiff R, Massarweh SA, Shou J, et al. Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance. Clin Cancer Res 2004; 10:331S-6S. 8. 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. 9. Howell A, Pippen J, Elledge RM, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: a prospectively planned combined survival analysis of two multicenter trials. Cancer 2005; 104:236-9. 10. Robertson JF, Erikstein B, Osborne KC, et al. Pharmacokinetic profile of intramuscular fulvestrant in advanced breast cancer. Clin Pharmacokinet 2004; 43:529-38. 11. 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; 22:1605-13. 12. Nabholtz JM, Bonneterre J, Buzdar A, et al. Anastrozole (Arimidex™) versus tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: survival analysis and updated safety results. Eur J Cancer 2003; 39:1684-9. 13. Robertson JF. Fulvestrant (Faslodex) -- how to make a good drug better. Oncologist 2007; 12:774-84. 14. 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 EFECT. J Clin Oncol 2008; 26:1664-70. 15. Dodwell D, Pippen J. Time to response: comparison of fulvestrant and oral endocrine agents. Clin Breast Cancer 2006; 7:244-7. 16. DeFriend DJ, Howell A, Nicholson RI, et al. Investigation of a new pure antiestrogen (ICI 182780) in women with primary breast cancer. Cancer Res 1994; 54:408-14. 17. Kuter I, Hegg R, Singer CF, et al, on behalf of the NEWEST investigators. Fulvestrant 500 mg vs 250 mg: first results from NEWEST, a randomized, phase II neoadjuvant trial in postmenopausal women with locally advanced, estrogen receptor-positive breast cancer. San Antonio Breast Cancer Symposium Newsletter. December 13, 2007; 1:13.
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