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`Contents lists available at ScienceDirect
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`The Breast
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`ELSEVIER
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`journal homepage: www.elsevier.com/brst
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`; Gt aaa es
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`Original article
`
`Bone turnover markers in postmenopausal breast cancer treated with
`fulvestrant -— A pilot study
`
`A. Agrawal®*, R.A. Hannon”, K.L. Cheung?, R. Eastell>, J.RR. Robertson?
`“University of Nottingham, Professorial Unit of Surgery, City Hospital Campus, Nottingham University Hospitals, Hucknall Road, Nottingham NG5 1PB, UK
`5 University of Sheffield, Academic Unit of Bone Metabolism, Metabolic Bone Centre, Sorby Wing, Northern General Hospital, Sheffield S5 7AU, UK
`
`ABSTRACT
`ARTICLE INFO
`
`
`Background: Tamoxifen has a protective effect on bone metabolism in breast cancer; aromatase inhib-
`itors deleterious and that of fulvestrant is unknown.
`
`Article history:
`Received 21 January 2009
`Received in revised form
`2 April 2009
`Accepted 16 April 2009
`
`
`Keywords:
`Bone markers
`Breast cancer
`Locally advanced
`Fulvestrant
`Sea
`
`
`
`
`
`Methods: Fourteen locally advanced breast cancers with clinical benefit on fulvestrant (250 mg/month)
`as first-line primary endocrine therapy had sequential serum bone-specific alkaline phosphatase (BAP),
`N-terminal propeptide of procollagen type 1 (PINP) and C-terminal telopeptide (CTX) at0, 1, 6,12, and 18
`months. Mean percentage changes (95% CI) were calculated.
`Results: Changes from baseline at 1, 6, 12, and 18 months with BAP (3.9-46.8 ng/ml) were +1.5 (—9.8 to
`412.9), +2.2 (22.1 to +26.6), +17.6 (—12.4 to +47.6), +10.8 (—29.9 to +51.7); with PINP (20.6-82.1 ng/
`ml) were +3.4 (12.0 to 19.0), +18.8 (—36.7 to +74.2), +47.5 (—21.4 to 116.3), +33.3 (—49.5 to +116.1)
`and with CTX (0,14-1,35 ng/ml) were +30.8 (0.1 to +61.6), +13.9 (—22.3 to +50,2), +42,9 (—12.7 to
`498.5), +45.2 (—28,3 to +118,8).
`Conclusions: Long-term (18 months) stability of bone markers may be exploited by using fulvestrant
`earlier in sequence of endocrine therapies particularly in adjuvant setting in those with pre-existing
`decreased bone mass,
`
`
` © 2009 Elsevier Ltd. All rights reserved.
`
`Background
`
`that accompanies declining
`The increased bone turnover
`estrogen levels at the onset of menopause in women leads to
`decreased bone mass and increased risk of fracture.
`In post-
`menopausal womenwith breast cancer this may be further aggra-
`vated by treatment with antiestrogen. Aromatase inhibitors such as
`anastrozole (Arimidex™, AstraZeneca), letrozole (Femara™, Novar-
`tis) or exemestane (Aromasin™,Pfizer) do not have any estrogenic
`agonistic activity and cause increased bone turnover resulting in
`significant loss in bone mass.' Tamoxifen, however, affords some
`protection by virtue ofits partial agonistic activity.?~+
`
`Abbreviations: LAPC, locally advanced primary breast cancer; BAP, bone-specific
`alkaline phosphatase; PINP, N-terminal propeptide of procollagen type 1; CTX, C
`terminal
`telopeptide; ER, estrogen receptor; TIP,
`time to progression: PgR,
`progesterone receptor; CB, clinical benefit; OR, objective response; MBC, metastatic
`breast cancer; SD, stable disease; CV, coefficient of variation; Cls, confidence
`intervals.
`* Corresponding author. Tel.: +44 115 82 31878/76; fax: +44 115 82 31877.
`E-mail addresses: amit.agrawal@nottingham.ac.uk (A. Agrawal), rahannon@
`sheffield.ac.uk (R.A. Hannon), kl.cheung@nottingham.ac.uk (KL. Cheung), reastell@
`sheffield.ac.uk (R. Eastell), john.robertson@nottingham.ac.uk (J.ER. Robertson).
`
`0960-9776/$ - see front matter © 2009 Elsevier Ltd. All rights reserved.
`doi:10.1016/j.breast.2009.04.002
`
`Fulvestrant (Faslodex™, AstraZeneca) is a new estrogen receptor
`(ER) antagonist with no estrogen agonist effects’ and has a novel
`mode of action;
`it binds, blocks and increases degradation of ER
`protein, leading to an inhibition of estrogen signaling through the
`ER.°” In a prospectively planned combined analysis of the data from
`two randomizedtrials of similar design (Trials 20 and 21) fulvestrant
`wasreported to be at least as effective as anastrozole in termsof time
`to progression (TIP; 5.5 months vs, 41 months, respectively)? A
`subsequent prospectively planned, combined analysis of survival data
`reported that the median overall survival was not significantly
`different between the two treatments.? In a further double-blind,
`randomized phase III trial (Trial 0025) fulvestrant (250 mg/month)
`was compared with tamoxifen (20 mg/day)in thefirst-line treatment
`of postmenopausal women with advanced breast cancer.'° Prospec-
`tive planned analysis of patients with ER and/or progesterone receptor
`(PgR) positive tumours {~80% of the population) showed median TIP
`of 8.2 months for fulvestrant and 8.3 months for tamoxifen with
`similar clinical benefit (CB) and objective response (OR) rates and
`overall survival between groups. However, to date there has been no
`data of the effect of fulvestrant on bone metabolism in humans,
`Boneis constantly renewed by the process of bone remodelling,
`in which old bone is resorbed by osteoclasts and replaced by new
`bone, whichis laid down by osteoblasts. Markers of bone resorption
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`and formation, measured in serumor urine, reflect the activity of
`osteoclasts and osteoblasts, respectively. This study is the first to
`report the effect of fulvestrant on markers of bone turnover when
`used in postmenopausal women with locally advanced primary
`breast cancer (LAPC)
`in whom there was no evidence of overt
`metastatic disease.
`
`Materials and methods
`
`Patients
`
`Postmenopausal women with LAPC or metastatic breast cancer
`(MBC) received fulvestrant (250 mg) as their first-line primary
`endocrine therapy (so patients were endocrine naive) as part of an
`open-label prospective clinical trial that had received approval of
`the institutional Ethics Committee. Patients underwent staging
`investigations as per study protocol and included blood tests (full
`blood count, liver function tests, calcium, phosphate, CA15.3 and
`CEA), chest X-ray and pelvic X-ray for potential skeletal metastases.
`Bonescintigram was usedif plain radiography was not definitive in
`diagnosing or
`ruling out metastases. Patients gave written
`informed consentforthe trial including sequential serum samples
`andtissue biopsies. Twenty-five of 30 patients with LAPC/MBC who
`were recruited in this study had clinical benefit (CB). The remaining
`5 patients progressed within 6 months and were not included in
`the study. Of the 25 patients with CB, 2 males and 4 MBC patients
`were not
`included in the analysis. Thus, a series of 19 post-
`menopausal women with endocrine-naive LAPC (primary breast
`cancer > 5cm and/or skin involvement) who had CB during ful-
`vestrant therapy were included. Patients with CB were selected so
`that any bone marker changes would reflect likely the activity of
`fulvestrant on bony tissue and not disease progression including
`bone metastasis (and so the MBC patients were excluded).
`Patients with LAPC had tumours of TNM stageIIb, IIa orIIIb
`(Table 1). Fulvestrant (250 mg) was administered as a once-monthly
`intramuscular injection into the gluteus muscle, Patients had
`regular 3 monthly clinical examinations along with CA15.3 and CEA
`assessments. CB was defined as objective response (complete or
`partial response) or stable disease [SD] for >6 months’ duration.!!2
`
`Bone marker assessments
`
`Sequential blood samples were taken at baseline and after 1, 6,
`12 and 18 monthsof fulvestrant treatment with majority of patients
`still being on treatment at 18 months. Patients were notstrictly
`fasting thoughthe large majority of samples were taken at the same
`time of the day (late mornings).
`The clotted blood samples were centrifuged (1000 g for 15 min),
`and the serum suitably aliquoted and stored at —20 °C. All samples
`taken from the same patient were analyzed in the samebatchat the
`
`Table 1
`Patient and disease baseline characteristics.
`
`Median age, years (range)
`
`Tumour grade, n (%)
`
`2
`3
`
`Estrogen receptor (ER) status
`Median ER H-score
`% Cells staining positive
`
`LAPC (n= 19)
`73.6 (54.9-90.9)
`
`4 (211)
`13 (68.4)
`2 (10.5)
`
`220
`100
`
`end of the study. Serum wasanalyzed for the following markers of
`bone formation and resorption.
`The bone formation markers, bone alkaline phosphatase (BAP)
`and N-terminal propeptide of procollagen type 1 (PINP), and the
`bone resorption markers were measured. Bone ALP, an isoenzyme
`of alkaline phosphatase, was measured using an automated
`chemiluminescent
`immunoenzymatic assay (Beckman Access
`Ostase™ 37300). Intra-assay coefficient of variation (CV) was <2.6%
`and the normal reference range for postmenopausal women was
`3.9-46.8 ng/ml. PINP, a by-product of type I collagen synthesis, was
`measured by a quantitative radioimmunoassay (Orion Diagnostica
`UniQ™ PINP RIA). The intra-assay CV was 6.0% and the normal
`reference range for postmenopausal women was 20,6-82,1 ng/ml.
`Serum CIX,a degradation productof crosslinked type I collagen,
`was measured by an enzyme-linked immunoassay (Serum Cross-
`laps™, Nordic Bioscience Diagnostics). The intra-assay CV was 3.9%
`and the normal reference range for postmenopausal women was
`0.14-1.35 ng/ml.
`
`Statistical analysis
`
`Data were analyzed using Statgraphics Plus™ version 5 (Hern-
`don, VA)
`statistical
`software. Data are presented as mean
`percentage change (from baseline)
`in marker level with 95%
`confidence intervals (CIs),
`
`Results
`
`The patient and disease characteristics are shown in Table 1. The
`median duration of CB for patients receiving fulvestrant was 28,0-++
`months (range: 10.9-55.4 months;
`treatment ongoing in 15
`patients at 18 months and in 11 patients at the time of analysis).
`There were no ‘baseline’ data for 5 patients in whom a sample of
`blood at baseline was not available. Therefore, 14 patients had bone
`marker measurements at baseline, 1, 6, 12 and 18 months. Mean
`percentage change (from baseline) in serum PINP, bone ALP and
`CTX levels in these 14 patients is shownin Table 2. Wilcoxon signed
`rank test did not show anysignificant difference from baseline at
`any time-point for any of the 3 markers in these patients,
`Of the 5 patients who did not have baseline sample available,
`the marker assessment was over a 17-month period from 1 to 18
`months. Kruskal-Wallis analysis revealed no significant changes in
`bone markers between any of the time-points over this 17-month
`period in these patients. Similarly, in all 19 patients with LAPC, no
`significant changes were apparent over the 18-monthperiod.
`
`Discussion
`
`LAPC patients who had shown CB wereselected for this study so
`that bone turnover marker levels being estimated were not
`confounded by the presence of overt or occult progressive bony
`metastases. Furthermore since median time to progression of
`disease was about 24 months, only samples collected in the first 18
`monthsofthe trial were used for marker assessments. This was to
`
`avoid as far as possible confounding the results with any early
`biochemical evidence due to undiagnosed progression of occult
`bony metastases or the developmentof new overt bony metastases.
`The chosen bone formation and resorption markers are established
`markers of bone turnover which have been validated in several
`studies.!? Although bone markers havehighintra-individualvariability
`and diurnal variation (especially CTX)" they provide more dynamic
`and earlier measurement of the skeletal status when compared with
`bone mineral density measurement." Serum markers, however,
`exhibit less intra-individualvariation than urinary markers.”
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`Table 2
`Mean and CI (95% confidence interval) for LAPC (n = 14)patients.
`
`Marker: pre-treatment (n = 14)
`Bone ALP
`PINP
`CTX
`
`1 Month (n= 13)
`+15 (98 to +12.9)
`+3.4 (-12.0 to 19.0)
`430.8 (0.1 to +616)
`
`6 Months (n= 14)
`
`42.2 (22.1 to +26.6)
`
`
`
`18.8 (—36.7 to
`+74.2)
`
`13.9 (—22.3 to
`+50.2)
`
`12 Months (n = 11)
`+176 (—12A to +476)
`+475 (21.4 to +1163)
`+ 42.9 (-12.7 to +985)
`
`18 Months (n= 10)
`10.8 (—29.9 to +51.7)
`+33.3 (—49.5 to 116.1)
`445.2 (28.3 to +118.8)
`
`
`
`
`
`In these LAPC patients with no demonstrable bony metastases,
`the stability of bone turnover markers over 17-18 months period
`(Table 2} suggests the apparentlackof effect of fulvestrant on bone
`turnover. This was further supported by data in the further 5
`patients with unavailable baseline serum sample, in whom there
`wasnosignificantdifference between any of the time-points over 17
`monthsperiod.To the best of our knowledge, there is no known data
`in literature of long-term effect of fulvestrant on bone turnoverin
`humanstudies. Reportsofits effect in animals do exist but the data
`are conflicting, In an experimentby Gallagheretal.’” in adult female
`intact
`rats,
`fulvestrant
`reduced cancellous bone volume by
`increasing bone resorption and decreasing bone formation by
`abolishing protective effect of estrogen. The increase in bone
`formation indices was not seen in ovariectomised rats. However,it
`did not affect longitudinal or periosteal tibial growth in either
`ovary-intact or ovariectomised rats given estradiol or vehicle,
`Sibongaetal.® in a study of cancellous bonesin adult rats found that
`fulvestrant increased skeletal indices of bone turnover in ovary-
`intact rats with a reduction in cancellous bone area. However, in
`ovariectomised rats there was a reduction in bone turnoverthat was
`associated with an increase in bone area. Thusif the data from the
`
`above experiments in ovariectomised rats are extrapolated to
`postmenopausal womenas in our study then there is no clear
`evidence for negative influence of fulvestrant on bonetissue.
`In yet anotherstudy in rats, Lea etal.!° administered fulvestrant
`alone and in combination with the anti-androgen, bicalutamide
`(Casodex™, AstraZeneca, US) and compared the effects on the
`skeleton with those of ovariectomy. They reported that ovariec-
`tomised rats lost significantly greater cancellous bone volume
`compared with those treated with fulvestrant alone. The combi-
`nation of fulvestrant and bicalutamide, however, resulted in bone
`loss equivalent
`to that
`in ovariectomised animals. The study
`authors concluded that ovarian androgenspossibly protect against
`boneloss in rats made estrogen deficient otherwise by fulvestrant.
`This again if extrapolated to our postmenopausal women may
`mean that even if there wasboneloss induced by fulvestrant by
`virtue of it being a pure antiestrogen with no agonistic activity
`{unlike tamoxifen), ovarian androgens may alone have protected
`against significant bone loss, In contrast to fulvestrant, possible
`protective effect of androgens on bone is lost on treatment with
`aromatase inhibitors due to blockage of conversion of circulating
`androgens into estrogens (by aromatase inhibitors).
`In a multi-centre randomized study by Donnezetal.,7° 50 pre-
`menopausal women had short-term exposureto 3 dosesof fulves-
`trant (50 mg, 125 mg,or 250 mg) as an intramuscularinjection over
`12 weeks period and compared with goserelin and placebo in
`reduction of uterine fibroid growth before planned hysterectomy.
`The primary safety end-point of bone resorption measured by
`urinary crosslinked N-telopeptide and free deoxypyridinolone were
`measured at baseline, 5, 9 and at 13 weeks (completion of study),
`There waslittle change in median bone resorption indices from
`baseline and in fact no statistical difference between various doses
`
`of fulvestrant and placebo. A recent phase II neoadjuvant trial
`(NEWEST)in 211 postmenopausal women with ER positive large
`primary breast cancers randomised patients into those receiving
`approved doseof fulvestrant (250 mg) versus loading dose (500 mg
`including additional 500 mg on day 14 offirst month) over a period
`of 16 weeks. This trial compared serum bone markers (BAP,
`
`PINP, CTX) besides the main tissue tumour indices. The study
`investigators reported no change in bone markers with either
`dose.?! This recent presentation of the NEWESTresults at the San
`Antonio Breast Cancer Conference supports the findings of this
`study. However, our study remains the only long-term data on the
`effect of fulvestrant on markers of bone metabolism,
`Journe et al.2? showed that ibandronate (a bisphosphonate)
`enhanced the growthinhibitory action of tamoxifen and fulvestrant
`in estrogen-sensitive MCF-7 breast cancer cells. The combination
`analysis identified additive interactions between ibandronate and ER
`antagonists. However, in the clinical setting it remains to be seen
`whether or not
`there is additive efficacy of fulvestrant plus
`a bisphosphonate in the treatment of bony metastases.2? On the
`other hand the apparently neutral effect of fulvestrant on bone
`metabolism makes either a higher dose of fulvestrant alone or ful-
`vestrant plus anastrozole combination, a potentially attractive
`option for future adjuvant endocrine therapy.
`
`Conclusions
`
`In this small patient series and within the limitations of inter-
`preting variability of response of bone markers, there was a lack of
`change in markers equating to long-term stability of bone turnover
`markers in postmenopausal women with LAPC treated with ful-
`vestrant for over a period of 18 months. This is in contrast to the
`increase in bone markers (serum BAP, PINP and CTX) at 12 months
`compared to the baseline seen in 58 patients who received anas-
`trozole in a sub-protocol study of patients in ATACtrial,
`Data from both animal and now human experiments portray
`a favourable profile of fulvestrant on bone tissue, While this is the
`first published report of the effects of fulvestrant on bone metab-
`olism in humans,
`the recent San Antonio presentation has
`confirmed that fulvestrant appears neutral in respect of bone
`metabolism. Furthermore the present study is the only one which
`has assessed the long-term effects of fulvestrant on bone metabo-
`lism. The possible lack of effect on bone turnover may be exploited
`clinically in the future especially in the adjuvant setting. However,
`larger randomized studies including head-to-head comparison of
`long-term bone turnovereffects of fulvestrant with tamoxifen and
`aromatase inhibitors are required to confirm these findings. The
`comparison could be more robust with inclusion of bone mineral
`density measurements along with serum samples as radiographs
`and tumour markers alone may not be sensitive enough.
`
`Conflict of interest statement
`
`Prof. Robertson and Dr. Cheung have received honoraria and
`funding from AstraZeneca. Prof. Eastell is a consultant to AstraZeneca.
`Prof, Eastell and Dr. Hannon have received honoraria and funding
`from AstraZeneca. Dr. Agrawal has been sponsored by AstraZeneca
`for Scientific Meetings in the past.
`
`Authors’ contributions
`
`Laboratory tests were arranged and provided by Dr. RA Hannon
`and Prof. R Eastell, Dr RA Hannon provided statistical help.
`Dr. A Agrawal drafted the manuscript which has been revised and
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`AstraZeneca Exhibit 2076 p. 3
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`A. Agrawalet al. / The Breast 18 (2009) 204-207
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`207
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`approved by Prof. JFR Robertson, Dr. RA Hannon, Prof. R Eastell
`and Dr. KL Cheung.
`
`Funding source
`
`The original clinical trial was funded by AstraZeneca, UK. This
`subset study (including laboratory tests for the bone markers),
`however, wasfunded by the Division of Breast Surgery, University
`of Nottingham, United Kingdom.
`
`Ethical approval
`
`The original clinical trial and subset studies were approved by
`the Local Research Ethics Committee, Nottingham, UK.
`
`Acknowledgements
`
`their gratitude to Nicola Linley
`The authors express
`(University of Nottingham, UK) for the preparation of serum
`samples and Fatima Gossiel (University of Sheffield, UK) and
`Julie Porter (University of Sheffield, UK) for running the bone
`marker assays.
`
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