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`review
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`Annals of Oncology 17: 200-204, 2006
`doi:10.1093/annonce/mdj047
`Published online 26 October 2005
`
`Fulvestrant, a new treatment option for advanced
`breast cancer: tolerability versus existing agents
`|. Vergote'* & P. Abram?
`*University Hospitals, Leuven, Belgium; “Belvoir Park Hospital, Belfast, UK
`
`Received 17 April 2005; revised 10 September 2005; accepted 12 September 2005
`
`Owingto its favourable tolerability profile versus cytotoxic chemotherapy, endocrine therapy is the treatment of
`
`choice for postmenopausal women with hormone receptor-positive advanced breast cancer (ABC). However,
`tolerability concerns associated with some endocrine treatments and the potential for cross-resistance has
`helped to drive the need for new, effective and better-tolerated agents. Fulvestrant is a new type of oestrogen
`receptor antagonist with no agonisteffects. In phaseIll trials, fulvestrant has been shownto be atleast as effective
`as the third-generation aromataseinhibitor (Al) anastrozole in the treatment of postmenopausal women with ABC
`progressing on prior tamoxifen therapy. Fulvestrant is administered as a once-monthly 250 mg intramuscular
`injection into the gluteus muscle. Here we review the tolerability of fulvestrant in the treatment of postmenopausal
`
`women with hormone-sensitive ABC and compare it with that of the four mostfrequently prescribed endocrine
`treatments for advanced disease (tamoxifen, anastrozole, letrozole and exemestane). Compared with these
`agents, fulvestrant is well tolerated and is associated with a lowerincidenceofjoint disorders compared with the
`non-steroidal Als and none of the potential androgenic side-effects that are sometimes seen with steroidalAls.
`Itis also associated with hot flushes compared with tamoxifen. Fulvestrant therefore providesclinicians and
`
`patients with a useful, well-tolerated option for the treatment of hormone-sensitive ABC. Integration of such
`agents into the endocrine treatment sequence may extend the opportunity for using well-tolerated therapies
`
`before chemotherapy needs to be considered and thus may improve quality oflife for patients with ABC. The
`overall safety profiles of newer agents such as fulvestrant will become increasingly clear with their ongoing use.
`Key words:breast, breast cancer, fulvestrant, hormone, neoplasms, therapy
`
`
`
`introduction
`
`For patients with advanced breast cancer (ABC) in whom
`palliation of symptoms and maintenance of quality of life are
`the primary objectives, it is important that any treatmentis
`well tolerated to aid compliance and treatment success. Owing
`to its favourable tolerability profile, endocrine therapy is the
`treatment of choice for postmenopausal women with hormone
`receptor-positive ABC (i.e. about 73% ofthe total
`postmenopausal ABC population). Currently available
`endocrine treatments for advanced disease include the
`selective oestrogen receptor (ER) modulator tamoxifen, the
`third-generation, non-steroidal aromatase inhibitors (AIs)
`anastrozole and letrozole, and the steroidal AI exemestane.
`The most recent addition to the armamentarium of endocrine
`agents is fulvestrant, a novel ER antagonist with no agonist
`effects [1]. It binds, blocks and degrades the ER, thereby
`downregulating cellular ER levels, which in turn leads to
`reduced expression of the progesterone receptor.
`
`“Correspondence to: Dr |. Vergote, University Hospitals Leuven, Department of
`Gynecologic Oncology, Gasthuisberg, Herestraat 49, B-8000 Leuven, Belgium.
`Tel: +32-16-34-46-85; Fax: +32-16-34-46-29;
`E-mail: Ignace.Vergote@uz.kuleuven.ac,be
`
`Here wereview thetolerability profile of fulvestrant [250 mg
`once monthly, intramuscular (i.m.) injection], and compareit
`with tolerability data from the four most frequently prescribed
`endocrine treatments for ABC: tamoxifen (20 mg oncedaily,
`orally), anastrozole (1 mg once daily,orally), letrozole (2.5 mg
`once daily, orally) and exemestane (25 mg oncedaily, orally).
`
`fulvestrant
`
`oestrogen agonist activity
`In a phase I trial involving 30 healthy postmenopausal women,
`volunteers received a single dose of 125 or 250 mgfulvestrant or
`placebo im. followed 2 weekslater by 20 mg/day
`ethinyloestradiol for 2 weeks. No evidence of agonist activity in
`the endometrium was observed with fulvestrant [2]. In addition,
`when compared with placebo, after 21 days of treatment the
`mean change in oestrogen-stimulated endometrial thickening
`was prevented using 250 mg fulvestrant (1.5 versus 8.1 mm;
`P< 0.001). Therefore, in contrast to tamoxifen, which has
`well-knownagonist effects in the endometrium,fulvestrant
`lacks oestrogen agonist effects and so is unlikely to be associated
`with an increased risk of endometrial cancer with long-term use.
`
`© 2005 European Society for Medical Oncology
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`Ooa
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`AstraZeneca Exhibit 2075 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLC v. AstraZeneca AB IPR2017-01910
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`Annals of Oncology
`
`comparative tolerability: fulvestrant versus
`anastrozole
`
`Two phase III studies have shown that fulvestrantis at least
`as effective as anastrozole in the treatment of postmenopausal
`woinen (7 = 851) with ABC whohaveprogressed or relapsed
`on prior tamoxifen treatment [3, 4]. This was also borne out in
`the subgroup of patients with visceral metastases [5].
`Study 0020 (1 = 451) was an open-label, randomised, parallel-
`group, multicentre study conducted in Europe, South Africa
`and Australia, in which fulvestrant was delivered in a single 5 ml
`im. injection. The median duration of follow-up in this study
`was 14.4 months[4]. Study 0021 (m = 400) was a double-blind,
`randomised, multicentre, parallel-group study conducted in
`North America in which fulvestrant was delivered in two
`x 2.5 ml im. injections. The median duration of follow-up in
`this study was 16.8 months [3]. Overall, the median duration
`of treatment for both studies was 5.5 months (range 0.9-36.8)
`in the fulvestrant group and 5.5 months (range 0.6—31.4) in the
`anastrozole group.
`Both studies were prospectively designed to allow combined
`analysis of data [6]. Combined analysis of the safety data showed
`that both treatments were well tolerated and there was a low
`incidence of withdrawals due to adverse events (AEs) overall
`(fulvestrant, 2.8%; anastrozole, 1.9%) and those AEs considered
`to be drugrelated (fulvestrant, 0.9%; anastrozole, 1.2%). The
`most common AEs in these trials were nausea (26% versus
`25.3%), asthenia (22.7% versus 27.0%), pain (18.9% versus
`20.3%), vasodilatation (dizziness, light-headedness,
`symptomatic hypotension) (17.7% versus 17.3%) and headache
`(15.4% versus 16.8%) in the fulvestrant and anastrozole groups,
`respectively [6]. In these studies, seven AEs considered relevant
`to endocrine therapy were pre-defined for statistical analysis. In
`bothtrials, there was nostatistically significant difference
`between treatment groups in the incidence of weight gain,
`thromboembolic disease, gastrointestinal disturbance, hot
`flushes or urinary tract infections (Figure 1). However, there
`wasa significantly lower incidence of joint disorders (including
`arthralgia, arthrosis and arthritis) with fulvestrant (5.4%)
`compared with anastrozole (10.6%) (P = 0.0036) (Figure 1).
`The effect of fulvestrant on lipid variables was also monitored
`as part of laboratory investigations in thesetrials; no major
`changesin lipid variables occurred with either treatment
`(AstraZeneca, data onfile). In an extended follow-up for
`time to death, conducted when 75% of patients had died,
`no long-term safety concerns were apparent[7].
`Fulvestrant im. injection was well tolerated locally; in most
`cases injection-site reactions were non-serious, mild and
`transient: only 4.6% and 1.1% offulvestrant im. injections in
`trials 0021 and 0020,respectively resulted in injection-site
`events. Across the two studies, only two patients (0.5%) in the
`fulvestrant group withdrew becauseofinjection-site events. In
`a comparison of fulvestrant and placebo injections in trial 0021,
`there was no difference in the incidence of injection-site
`reactions, demonstrating that the fulvestrant im. injection is
`well tolerated in contrast to some other injectable anticancer
`agents such as the steroidal AI formestane. For example, in
`a phase II dose-finding study, formestane treatment (500-1000
`mg monthly) resulted in injection-site events (abscesses, painful
`
`60 5
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`Gastrointestinal
`Hot
`Urinarytract
`Joint Thromboembolic Vaginitis
`Weight
`disturbances
`flushes
`infection
`disorders
`disease
`gain
`
`Figure 1. The incidence of predefined adverse events in a combined analysis
`of two phaseII] trials comparing fulvestrant with anastrozole as second-line
`treatments in patients with advanced breast cancer [6]. Reprinted by
`permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.
`
`lumpsandallergic-type reactions) in 19% ofpatients [8].
`To date, there have been no head-to-head clinical studies
`comparing fulvestrant with either letrozole or exemestane.
`
`comparativetolerability: fulvestrant versus
`tamoxifen
`
`A double-blind, double-dummy randomised phaseIII trial has
`shown that fulvestrant has similar efficacy to tamoxifen in the
`first-line treatment of postmenopausal women (n = 587) with
`hormonereceptor-positive ABC [9]. The median duration of
`treatment in this study was 8.3 months (range 0.9-26.5) in the
`fulvestrant group and 9.3 months (range 0.9-25.1) in the
`tamoxifen group.
`At a median follow-up of 14.5 months, the most frequent
`AEs in both groups were nausea (20.3% fulvestrant versus
`22.5% tamoxifen), asthenia (19.4% versus 20.3%),
`vasodilatation (14.8% versus 21.4%), pain (13.9% versus
`19.2%) and bone pain (13.9% versus 17%) [9]. Most AEs
`were mild or moderate in severity. A total of 129 (41.6%)
`patients in the fulvestrant group and 139 (51.3%) patients in
`the tamoxifen group experienced drug-related AEs. The most
`frequent drug-related AEs in both treatment groups were
`vasodilatation, injection-site pain and nausea.
`Of the AEs prospectively detined for statistical comparison,
`there were no significant differences between the two treatment
`groups for vaginitis and thromboembolic disease. There was
`a trend for fewer gastrointestinal disturbances (nausea,
`vomiting, diarrhoea and constipation) with fulvestrant (37.1%
`versus 43.2%; P = 0.16) and the incidence of hot flushes was
`lower in the fulvestrant group than in the tamoxifen group
`(17.7% versus 24.7%; P = 0.05) (Figure 2). Thelatter
`observation may berelated to the fact that fulvestrant does
`not cross the blood-brain barrier (AstraZeneca, data on file).
`
`tamoxifen
`
`Tamoxifen is generally well tolerated, although with long-term
`use its partial oestrogen agonist properties increase the risk of
`endometrial cancer. In an overview of the randomisedtrials
`of adjuvant tamoxifen including data for 37 000 women,the
`
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`PLOT‘TEAlngvoApsssatuAsurydoysuyor/AreiqryJomoyuasty“gUO},Ie/S10'syeuMolpsoyxo'ououuR//:dyywospeperopuMmoc]
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`Volume 17 | No. 2 | February 2006
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`doi:10.1093/annone/mdj047 | 201
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`AstraZeneca Exhibit 2075 p. 2
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`50 +
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`20 +
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`W Fulvestrant
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`Tamoxifen
`
`Annals of Oncology
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`P=0.16
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`117
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`Ey
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`P=0.0501
`67
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`Figure 2. The incidence of predefined adverse events in a phase III trial
`comparing fulvestrant with tamoxifen as first-line treatments in patients
`with advanced breast cancer [9]. Reprinted with permission from the
`American Society of Clinical Oncology.
`
`incidence of endometrial cancer was doubled intrials of 1 or
`2 years’ treatment and approximately quadrupledin trials of
`5 years’ tamoxifen [10]. Tamoxifen treatment may stimulate
`‘tumourflare’ subsequent to an initial response and is also
`associated with hot flushes and an increased risk of stroke
`and thromboembolic disease. In a trial comparing anastrozole
`with tamoxifen in the first-line treatment of ABC, tamoxifen
`was associated with a significantly higher incidence of
`thromboembolic events (6.5% versus 3.6%; P = 0.0434) and
`vaginal bleeding was also reported in fewer anastrozole-treated
`patients (2.2% versus 1%) [11]. The incidence of
`thromboembolic events in a trial comparing tamoxifen with
`letrozole was 2%and. 1%, respectively [12]. The agonist activity
`of tamoxifen may, however, have beneficial effects on bone
`mineral density, particularly with long-term treatment,
`e.g. in the adjuvant setting [13].
`
`aromatase inhibitors
`
`summary
`
`More than 1100 postmenopausal women havereceived
`fulvestrant during theclinical study programme. This new
`endocrine agent exhibits a predictable tolerability profile that
`may offer benefits compared with other agents including
`tamoxifen and the three currently available Als: anastrozole,
`letrozole and exemestane. In all the phaseIII trials in
`postmenopausal women, with locally advanced or metastatic
`
`202 | Vergote & Abram
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`Volume 17 | No. 2 | February 2006
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`AstraZeneca Exhibit 2075 p. 3
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`steroidal AI exemestaneis also associated with arthralgia. In
`a recent phase II study comparing the efficacy andtolerability
`of this steroidal AI with tamoxifen, 11% of exemestane-treated
`patients experienced arthralgia compared with 5% of those
`treated with tamoxifen [19].
`The most common AEs associated with anastrozole are
`transient gastrointestinal disturbances, generally mild-to-
`moderate in intensity, headache, asthenia, bone pain and hot
`flushes [20, 21]. The tolerability profile of letrozole appears to be
`broadly similar to that of anastrozole with the most commonly
`10
`P=0.26
`p=0.22
`17
`aS]
`encountered AEs also including nausea/vomiting, headache,
`
`
`o- am”|3
`asthenia, bone pain and hot flushes [16, 22]. In the only study
`Hotflushes
`Vaginitis
`Thromboembolic
`Gastrointestinal
`distubances
`disease
`to compare directly the efficacy and tolerability of anastrozole
`and letrozole, there were no significant differences in the
`incidence of any AEs [23].
`The most frequently reported drug-related AEs with
`exemestane treatmentare hot flushes, nausea and fatigue [24].
`Exemestane has weak androgenic properties and has been
`associated with androgenic side-effects such as weight gain,
`alopecia and acne, particularly when used at higher doses [25].
`In a phase III trial comparing the efficacy and tolerability of
`exemestane (25 mg/day) and megestrol acetate (160 mg/day),
`the incidence of grade 3 or 4 weight gain after a median of
`only 17 weeks’ treatment was 8% in the exemestane group
`and 17% in the megestrol acetate group (P = 0.001) [26].
`Androgenic side-effects such as hair loss, hypertrichosis,
`hoarseness and acne are more commonly reported with higher
`doses of exemestane, occurring in 10% of patients treated
`with a 200 mg daily dose [27]. In two short-term trials using
`25 mg/day exemestane, hypertrichosis and acne were reported
`in ~2% of patients [28] and grade 2/3 skin disorders were
`reported in 8% of patients (no reports in the tamoxifen group)
`[18]. In a recent phase III trial, alopecia was reported in 4% of
`patients receiving exemestane 25 mg/day compared with 1% of
`those receiving tamoxifen [19].
`Compared with tamoxifen, exemestane treatment was also
`associated with a higher incidence of increased gamma-glutamyl
`Third-generation Als are effective and generally well tolerated
`transferase (33% versus 26%), increased alkaline phosphatase
`in the treatment of postmenopausal women with ABC. The
`(26%versus 14%), increased bilirubin (11% versus 3%),
`selective non-steroidal Als anastrozole and letrozole have been
`dyspnoea (17% versus 11%) and AEs of the skin (19% versus
`shown to be at least as effective as tamoxifen in this setting and
`14%), whereas hot flushes (29% versus 24%), bone pain (22%
`versus 17%), nausea (21% versus 14%) and oedema (20%versus
`anastrozole was associated with significantly fewer
`10%) were all more common in tamoxifen-treated patients [18].
`thromboembolic events than tamoxifen [11, 14]. The Als inhibit
`endogenous oestrogen synthesis via aromatase, which in
`In a subsequent phase III study, exemmestane was associated with
`a higher incidence of weight gain (19% versus 14%), arthralgia/
`postmenopausal womenresults in very low plasmalevels of
`myalgia (11% versus 5%) and diarrhoea (9% versus 3%)
`oestrogen, and these agents may therefore be associated with
`compared with tamoxifen. In this study, constipation
`some deleterious effects on bone [15].
`Joint disorders (e.g. arthralgia) have also been reported for
`(13% versus 8%) and vaginal discharge (7% versus 2%)
`
`all of the third-generation Als [6, 16-19]. For example,inatrial were more commonly seen in patients receiving tamoxifen [19].
`comparing the efficacy and tolerability of letrozole and
`megestrol acetate in patients with ABC,arthralgia was
`experienced by moreletrozole-treated patients (13.2%)
`compared with those receiving the comparator treatment
`(7.9%) [16]. However, in a phase III comparativetrial of
`letrozole and tamoxifen there was no difference in the incidence
`of arthralgia (16% versus 15%, respectively) [14]. As previously
`stated, significantly more anastrozole-treated patients
`experienced joint disorders compared with fulvestrant (10.6%
`versus 5.4%; P = 0.0036) in comparative phaseIIItrials [6]. The
`
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`8
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`Annals of Oncology
`
`breast cancer fulvestrant was well tolerated; AEs were generally
`mild or moderate in intensity. The higher incidence of joint
`disorders with the Als compared with fulvestrant illustrates
`the value of fulvestrant in a patient population who may be
`predisposed to musculoskeletal conditions.
`Fulvestrant has no proliferative effect on the endometrium
`[2] andis therefore unlikely to lead to an increased risk of
`endometrial cancer following long-term exposure such as that
`produced by tamoxifen [29]. There have been no reports of
`adverse events that may be attributable to androgenicactivity
`and fulvestrant is associated with a lower incidence of hot
`flushes compared with tamoxifen. In contrast to other
`endocrine agents used in the treatment of ABC, fulvestrant is
`administered as a once-monthly im. injection.
`In summary, fulvestrant 250 mg once-monthly i.m.injection
`is a well-tolerated and effective treatment for postmenopausal
`women with hormone-sensitive ABC. Thetolerability profile
`and route of administration of fulvestrant may also lead to
`improved patient compliance and thus better patient outcomes,
`although somepatients may prefer to receive their breast cancer
`treatmentorally [30]. The previously demonstrated lack of
`cross-resistance of fulvestrant with other endocrine treatments
`along with its favourable tolerability profile means that this
`agent providesclinicians and patients with a useful additional
`option for the treatment of hormone-sensitive ABC. Whilst the
`overall safety profiles of newer endocrine treatments will
`becomeincreasingly clear with their ongoing use, the
`integration of agents such as fulvestrant into the endocrine
`treatment sequence may extend the opportunity for using
`well-tolerated therapies before chemotherapy needs to be
`considered and thus any’ THPLOWE quality of life for paa
`with advanced disease. In addition, the good tolerability profile
`of fulvestrant may suggest possible benefits for this agent in the
`adjuvant setting where longer-term use would be anticipated.
`Although as yet unproven, clinical trials of fulvestrant in the
`adjuvant setting are being planned.
`
`acknowledgements
`
`Editorial assistance was provided by Dawn Batty PhD, with
`financial support from AstraZeneca.
`
`references
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`women with visceral and non-visceral metastases: combined results from two
`multicentre trials. Eur J Cancer 2003: 39: 1228-1233.
`6. 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 multicentertrials. Cancer 2003; 98:
`229-238.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`estrant v tamoxifen
`sal women
`double-blind,
`
`
`
`
`
`
`
`7. Pippen J, Osborne CK, Howell A, Robertson JFR. Fulvestrant (Faslodex) versus
`anastrozole (Arimidex) for the treatment of advanced breast cancer: a prospective
`combined survival analysis of two multicentertrials. Breast Cancer Res Treat
`2003; 82 (Suppl 1): S101 (Abstr 426).
`. Goss PE, Powles TJ, Dowsett M et al. Treatment of advanced postmenopausal
`breast cancer with an aromataseinhibitor, 4-hydroxyandrostenedione: phase I
`eport. Cancer Res 1986; 46: 4823-4826.
`, Howe
`al. Comparison of fulv
`A, Robertson JFR, Abram P e
`or the treatmen
`of advanced breast
`cancer in postmenopal
`previously untreated with endocrinet
`herapy: a multinational,
`andomized trial. J Clin Oncol 2004; 22: 1605-1613.
`10. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast
`cancer: an overview of the randomised trials. Lancet 1998; 351: 1451-1467.
`11. Bonneterre J, Buzdar A, Nabholtz JM et al. Anastrozole is superior
`to tamoxifen
`asfirst-line therapy in hormone receptor positive advanced breast carcinoma.
`Cancer 2001; 92: 2247-2258,
`12. Mouridsen H, Gershanovich M, Sun Y et al. Superiorefficacy of letrozole versus
`amoxifen asfirst-line therapy for postmenopausal women with advancedbreast
`cancer: results of a phaseIll study of the international letrozole breast cancer
`group. J Clin Oncol 2001; 19: 2596-2606.
`in tamoxifen-
`Endometrial cancer
`13. Fisher B, Costantino JP, Redmond CK et al.
`reated breast cancer patients: findings from the National Surgical Adjuvant
`Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 1994; 86: 527-537.
`14. Mouridsen H, Gershanovich M, Sun Y et al. Phase Ill study of Jetrozole versus
`amoxifen as first-line
`therapy of advanced breast cancer in postmenopausal
`women: analysis of survival and update of efficacy from the International
`Letrozole Breast Cancer Group. J Clin Oncol 2003; 21: 2101-2109.
`15, Buzdar A, Robertson JFR, Eiermann W, Nabholtz JM. An overview of the
`pharmacology and pharmacokinetics of the newer generation aromatase
`inhibitors anastrozole,letrozole and exemestane. Cancer 2002; 95: 2006-2016.
`16. Dombernowsky P, Smith |, Falkson G et al. Letrozole, a new oral aromatase
`inhibitor
`for advanced breast cancer: double-blind randomized trial showing
`a dose effect and improved efficacy and tolerability compared with megestrol
`acetate. J Clin Oncol 1998; 16: 453-461.
`17. Donnellan PP, Douglas SL, Cameron DA, Leonard RC. Aromataseinhibitors and
`arthralgia. J Clin Oncol 2001; 19: 2767.
`18. Paridaens R, Dirix L, Lohrisch C et al. Mature results of a randomized phase |I
`nulticenter study of exemestane versus tamoxifen asfirst-line hormone therapy
`‘or postmenopausal women with metastatic breast cancer. Ann Oncol 2003; 14:
`
`
`
`
`
`
` 1391-1398.
`
`
`
`
`
`22, Lamb HM, Adkins JC. Letrozole. A review of its use in postmenopausal women
`with advanced breast cancer. Drugs 1998; 56: 1125-1140.
`23. Rose C, Vtoraya O, Pluzanska A et al. An open randomised trial of second-line
`endocrine therapy in advanced breast cancer: comparison of the aromatase
`inhibitors letrozole and anastrozole. Eur J Cancer 2003; 39: 2318-2327.
`24, Buzdar A. Exemestane in advanced breast cancer. Anticancer Drugs 2000; 11:
`609-616.
`
`19, Pa idaens R, Therasse P, Dirix L a al. First line hormonal testinent (HT) for
`netastatic breast cancer (MBC) with exemestane (E) or tamoxifen (T} in
`postmenopausalpatients (pts) — A randomized phaseIll trial of the EORTC Breast
`1, Wakeling AE, Dukes M, Bowler J. A potent specific pure antiestrogen with clinical
`group. Proc Am Soc Clin Oncol 2004; 23: 6 (Abstr 515),
`potential. Cancer Res 1991; 51: 3867-3873.
`Buzdar A, Jonat W, Howell A et al. Anastrozole, a potent and selective aromatase
`
`inhibitor, versus megestrol acetate in postmenopausal women with advanced
`ew oestrogen receptor antagonist fulvestrant on the endometrium in healthy
`breast cancer: results of overview analysis of two phaseIll trials. Arimidex Study
`jostmehopausal volunteers. Br J Cancer 2002; 87: 1354-1359.
`Group. J Clin Oncol 1996; 14: 2000-2011.
`3. Osborne CK, Pippen J, Jones SE et al. Double-blind, randomizedtrial comparing
`21, Wiseman LR, Adkins JC. Anastrozole. A review of its use in the managementof
`he efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal
`postmenopausal women with advanced breast cancer. Drugs Aging 1998; 13:
`women with acvanced breast cancer progressing on prior endocrine therapy:
`321-3382.
`results of a North American trial. J Clin Oncol 2002; 20: 3386-3395.
`4. Howell A, Robertson JFR, Quaresma Albano J et al. Fulvestrant, formerly ICI
`182,780,is as effective as anastrozole in postmenopausal women with advanced
`reast cancer progressing after prior endocrine treatment. J Clin Oncol 2002; 20:
`3396-3403.
`5. Mauriac L, Pippen JE, Quaresma Albano J et al. Fulvestrant (Faslodex) versus
`anastrozole for the second-line treatment of subgroups of postmenopausal
`
`2. Addo S, Yates RA, Laight A. A phase|trial to assess the pharmacology of the 20.
`
`
`
`
`
`
`
`
`
`
`
`
`
`PLOT‘TEAlngvoApsssatuAsurydoysuyor/AreiqryJomoyuasty“gUO},Ie/S10'syeuMolpsoyxo'ououuR//:dyywospeperopuMmoc]
`
`Volume 17 | No. 2 | February 2006
`
`doi:10.1093/annone/mdj047 | 203
`
`AstraZeneca Exhibit 2075 p. 4
`
`

`

`Annals of Oncology
`
`20,
`
`26.
`
`27.
`
`Michaud LB, Buzdar AU. Risks and benefits of aromatase inhibitors in
`postmenopausal breast cancer. Drug Saf 1999; 21: 297-309.
`Kaufmann M, Bajetta E, Dirix LY et al. Exemestane is superior to megestrol
`acetate after tamoxifen failure in postmenopausal women with advanced breast
`cancer: results of a phaseIll randomized double-blind trial. The Exemestane
`Study Group. J Clin Oncol 2000; 18: 1399-1411,
`Thurlimann B, Paridaens R, Serin D et al. Third-line hormonal treatment with
`exemestane in postmenopausal patients with advanced breast cancer
`progressing on aminoglutethimide: a phase Il multicentre multinational stucly.
`Exemestane Study Group. Eur J Cancer 1997; 33: 1767-1773.
`
`28.
`
`29.
`
`30.
`
`Jones S, Vogel C, Arkhipoy A et al. Multicenter, phase I trial of exemestane as
`third-line hormonal therapy of postmenopausal women with metastatic breast
`cancer. Aromasin Study Group. J Clin Oncol 1999; 17: 3418-3425.
`Bergman L, Beslen ML, Gallee MP et al. Risk and prognosis of endometrial
`cancer after tamoxifen for breast cancer. Comprehensive Cancer Centres’ ALERT
`Group. Assessmentofliver and endometrial cancer risk following tamoxifen.
`Lancet 2000; 356: 881-887.
`Fallowfield L, Atkins L, Catt S et al. Patients’ preference for administration of
`endocrine treatments by injection or tablets: results from a study of women with
`breast cancer. Ann Oncol 2005; doi:10.1093/annone/mdj044.
`
`
`
`
`
`
`
`PLOT‘TEAlngvoApsssatuAsurydoysuyor/AreiqryJomoyuasty“gUO},Ie/S10'syeuMolpsoyxo'ououuR//:dyywospeperopuMmoc]
`
`
`
`
`
`
`
`204 | Vergote & Abram
`
`Volume 17 | No. 2 | February 2006
`
`AstraZeneca Exhibit 2075 p. 5
`
`