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Giorgi Dzagnidze,1 Andrew R Green,2 Valerie Speirs,3 Henry Zhang,2 Abeer M Shaaban,4 Sally Garnett,5
Ian O Ellis,2 John FR Robertson,6 Justin Lindemann5
1National Oncology Center, Tbilisi, Georgia; 2Division of Pathology, School of Molecular Medical Sciences, University of Nottingham and
Nottingham University Hospitals NHS Trust, Nottingham, UK; 3Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK;

4St James’s Institute of Oncology, St James’s University Hospital, Leeds, UK; 5AstraZeneca Pharmaceuticals, Alderley Edge, UK;
6Division of Breast Surgery, Nottingham City Hospital, University of Nottingham, Nottingham, UK

● ER beta (14C8; 1:100; Abcam Ltd, Cambridge, UK) Table 1. ER beta H-score.
and ER beta 2 (57/3; 1:10 overnight at 4°C; Serotec, Fulvestrant Fulvestrant Fulvestrant Tamoxifen
Oxford, UK) were assessed on sections of the pre- ● Fulvestrant (Faslodex®) is an estrogen-receptor (ER) Patients
and post-treatment tissue specimens using antagonist with no known agonist effects, indicated for This randomized, multicenter, partially blinded study the treatment of postmenopausal women with advanced included 200 postmenopausal patients with previously breast cancer who have progressed or recurred on prior untreated breast tumors (stage T1–T3) that were ● ER alpha expression was assessed on sections of the endocrine therapy.1 It has a distinct mode of action either ER+ or ER unknown at entry to the trial. pre- and post-treatment tissue specimens using the different from other anti-estrogen therapies.2 *Calculated as mean change from baseline expressed as a percentage of the baseline mean value (mean used due to data being normally distributed) rat antihuman ER alpha antibody (Clone H222) Patients had to be fit for surgery within one month ● On binding to the ER, fulvestrant induces a rapid and supplied in the ER-ICA kit by Abbot Laboratories. and have a tumor large enough to provide sufficient dose-dependent degradation of ER alpha and concomitant PgR expression was assessed using the primary Table 2. ER beta 2 H-score.
decreases in progesterone receptor (PgR) levels and Ki67 anti-PgR antibody (Clone KD68) supplied by ● Patients were not eligible for the study if they had labeling index (LI) with doses up to 250 mg (Figure 1).3,4 Fulvestrant Fulvestrant
evidence of metastatic disease or had received any Effects on ER (alpha and beta) and PgR were prior treatment for their primary tumor.
Figure 1. Fulvestrant produces dose-dependent reductions
determined by immunohistochemistry using the in ER alpha expression, PgR expression, and Ki67 LI.4
Study design and treatments
H-score method of receptor analysis, which includes Post-treatment mean ER alpha H-scores
an assessment of both the intensity of staining and Patients with histologically proven primary breast cancer p=0.0001
the percentage of positively stained tumor nuclei.4 p=0.0006
were randomized to receive a single intramuscular dose Receptor levels were expressed as mean percentage *Calculated as mean change from baseline expressed as a percentage of the baseline mean value (mean used due to data being normally distributed) of fulvestrant (50 mg [n=39], 125 mg [n=38], or 250 mg [n=44]), continuous daily tamoxifen for 14–21 days (20 mg/day [n=36]), or matching tamoxifen placebo (n=43) ● As described previously, Ki67 expression was assessed ● Overall, no correlations were observed between either for 14–21 days prior to tumor resection surgery (Figure 2). using the MIB-1 anti-Ki67 antibody supplied by ER beta or ER beta 2 and ER alpha, PgR, or Ki67 LI Mean ± 1SEM
Coulter Electronics (Luton, United Kingdom).4 The Figure 2. Study design.
Ki67 LI (percentage of positively stained tumor nuclei) Tamoxifen
was determined and expressed as median percentage Figure 4. Scatter plot of absolute change in ER beta
Changes in ER beta or ER beta 2 did
First clinic
H-score versus a) absolute change in ER alpha H-score,
Days 15-22
Overall treatment effect p=0.0003; NS = not significant and b) absolute change in Ki67 LI.
not correlate with fulvestrant dose
Fulvestrant, 50 mg*
Post-treatment mean PgR H-scores
(50 mg, 125 mg, or 250 mg) or
Fulvestrant 50 mg
other variables that have previously
Fulvestrant 125 mg
Fulvestrant, 125 mg*
Fulvestrant 250 mg
been shown to be related to fulvestrant
Tamoxifen 20 mg
● There was no overall treatment effect following placebo Tru-cut/
200 patients
Fulvestrant, 250 mg*
activity (ER alpha expression, PgR
or anti-estrogen therapy on ER beta H-score (p=0.8537; specimen
Table 1) or ER beta 2 H-score (p=0.5494; Table 2). There expression, or Ki67 LI).
Mean ± 1SEM
Tamoxifen, 20 mg†
were no significant differences between the individual Tamoxifen
fulvestrant dose groups, tamoxifen and placebo groups fulvestrant
This study does not support the
for mean changes from baseline in either ER beta Tamoxifen placebo†

investigation of ER beta or ER beta 2
Post-treatment mean Ki67 LI
Change in ER beta H-scor
*single intramuscular dose
● No correlation was observed between changes in ER beta as markers of the biological activity of
†continuous daily dose for 14-21 days
H-score and changes in ER beta 2 H-score (Figure 3). p=0.0002
high-dose fulvestrant (500 mg/month)
Figure 3. Scatter plot of absolute change in ER beta
in trials such as FIRST (Faslodex fIRst
H-score versus absolute change in ER beta 2 H-score.
● The administration of tamoxifen and tamoxifen placebo was double blind, and the administration Change in ER alpha H-score
line Study comparing endocrine
of fulvestrant (at one of the three doses) was open.
Fulvestrant 50 mg
Treatments) and CONFIRM (COmparisoN
Mean ± 1SEM
Fulvestrant 125 mg
● Patients were scheduled for tumor resection surgery Fulvestrant 250 mg
Fulvestrant 50 mg
of Fulvestrant In Recurrent or Metastatic
with curative intent between Day 15 and Day 22 after Tamoxifen 20 mg
Fulvestrant 125 mg
Fulvestrant 250 mg
breast cancer).
Tamoxifen 20 mg
● The Tru-cut/core biopsy taken at first clinic attendance for diagnostic purposes was used as the pre- randomization tumor sample. The post-treatment ER alpha is a well-established prognostic marker REFERENCES
specimen was obtained at definitive surgical resection.
in breast cancer. The clinical importance of ER beta 1. Howell A. Endocr Relat Cancer 2006; 13: 689-706.
in the management of breast cancer remains to be ● All of the tissue samples were fixed in 3.7% formalin defined. There are five known ER beta isoforms and immediately after removal, then embedded in paraffin 2. Wakeling AE. Endocr Relat Cancer 2000; 7: 17-28.
studies investigating the potential role of ER beta wax for sectioning and subsequent analysis of Change in ER beta 2 H-scor
3. DeFriend DJ et al. Cancer Res 1994; 54: 408-414.
in breast cancer have yielded conflicting results.5 Change in ER beta H-scor
● The action of fulvestrant on ER beta is currently Assessments
4. Robertson JF et al. Cancer Res 2001; 61: 6739-6746.
unknown and has been investigated in relation to ● The effects of anti-estrogen therapy on the levels of 5. Speirs V et al. J Clin Oncol 2008; Nov 10 [epub ahead of print].
other clinically important biomarkers (ER alpha, PgR, ER beta and ER beta 2 expression, and the relationship and Ki67 LI) in this study of postmenopausal women between these effects and changes in ER alpha, PgR, 6. Shaaban AM et al. Clin Cancer Res 2008; 14: 5228-5235.
Change in ER beta H-score
Change in Ki67 LI
7. Green AR et al. Histopathology 2008; In press.
Poster presented at the San Antonio Breast Cancer Symposium, San Antonio, TX, USA, December 10-14, 2008.


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