© Springer 2005
`Breast Cancer Research and Treatment (2005) 92: 169-174
`
`DOT 10.1007/s10549-004-4776-0
`
`Report
`
`Sensitivity to further endocrine therapy is retained following progression onfirst-line
`fulvestrant
`
`J.F.R. Robertson!, A. Howell’, V.A. Gorbunova?, T. Watanabe*, T. Pienkowski°, and
`M.R.Lichinitser?
`City Hospital, Nottingham, UK; >Christie Hospital, Manchester, UK; 3Cancer Research Center of Russian Academy
`of Medical Sciences, Moscow, Russia; *International University of Health and Welfare, Tochigi, Japan; °Centrum
`Onkologii, im M Sklodowskiej-Curie, Warsaw, Poland
`
`Key words: advanced breast cancer, endocrine sequencing,
`tamoxifen
`
`fulvestrant, sensitivity to subsequent
`
`treatment,
`
`Summary
`
`There is a need for new endocrine agents that lack cross-resistance with currently available treatments to extend the
`endocrine treatment window and delay the need for cytotoxic chemotherapy. This retrospective analysis evaluated
`the response of postmenopausal patients with previously untreated metastatic/locally advanced breast cancer to
`further endocrine treatment following progression on first-line fulvestrant or tamoxifen. Patients received fulve-
`strant 250 mg (intramuscular injection every 28 days) plus matching tamoxifen placebo (once daily), or tamoxifen
`20 mg (orally once daily) plus matching fulvestrant placebo (every 28 days) in a double-blind, randomized, phase
`III trial. Treatment continued until disease progression or withdrawal, when further endocrine therapy wasinitiated
`(at the treating physician’s discretion). Information regarding subsequent therapies and responses was obtained by
`follow-up questionnaire. Two-hundred-and-forty-five questionnaires were returned (from 587 patients), 149 of
`which yielded follow-up data on patients receiving second-line endocrine therapy following fulvestrant (1 =83) and
`tamoxifen (7 = 66). Second-line therapy produced objective responses (OR) in 6/44 (13.6%) and clinical benefit (CB)
`in 25/44 (56.8%) patients who had CB with fulvestrant and produced OR in 5/41 (12.2%) patients and CB in 27/41
`(65.8%) patients who had CB with first-line tamoxifen. For patients deriving no CB from trial therapy, second-line
`therapy produced OR in 3/39 (7.7%) and CB in 15/39 (38.5%) patients in the fulvestrant group and OR in 4/25
`(16.0%) and CB in 12/25 (48.0%) patients in the tamoxifen group. Results from this questionnaire-based study
`suggest that postmenopausal women with advanced breast cancer who respondtofirst-line fulvestrant or tamoxifen
`retain sensitivity to subsequent endocrine therapy.
`
`Introduction
`
`Tamoxifen, a selective estrogen receptor modulator
`(SERM), is widely used for the first-line treatment of
`advanced breast cancer in both postmenopausal and
`premenopausal women andis well established as adju-
`vant therapy for early breast cancer [1]. Despite an ini-
`tial response to tamoxifen, many patients eventually
`undergo disease progression, necessitating the use of
`different therapies. Many tumors remain hormonesen-
`sitive after progression and may respond to subsequent
`endocrine treatments providing these agents are not
`cross-resistant. This ability to respond to multiple lines
`of endocrine therapy may delay the need for the intro-
`duction of cytotoxic chemotherapy in somepatients.
`Fulvestrant is a new type of estrogen receptor (ER)
`antagonist that has no agonist effects. It binds, blocks
`and accelerates degradation of the ER leading to reduced
`cellular levels and subsequent attenuation of estrogen-
`dependent gene expression [2,3].
`In postmenopausal
`
`women with advanced breast cancer who have pro-
`gressed on prior antiestrogen therapy, fulvestrant was
`found to beat least as effective as the third-generation,
`highly selective aromatase inhibitor (AI) anastrozole in
`terms of time to progression (TTP) and objective
`response (OR; complete response [CR] + partial re-
`sponse [PR]) [4,5]. In a morerecent analysis, fulvestrant
`was shownto be similar to anastrozole with respect to
`overall survival in this setting [6].
`A recent double-blind, randomized, parallel-group
`study has comparedtheefficacy and tolerability of ful-
`vestrant and tamoxifen as
`first-line treatments for
`postmenopausal women with advanced breast cancer
`[7]. In patients treated with fulvestrant versus tamoxifen,
`the OR rate was found to be 31.6 and 33.9% and the
`median duration of response was 13.8 and 13.9 months,
`respectively. Median TTP was 6.8 months in the fulve-
`strant group and 8.3 months in the tamoxifen group
`(AR = 1.18; 95% CI = 0.98-1.44; p = 0.0876),
`a
`non-significant difference. The clinical benefit (CB, CR +
`
`AstraZeneca Exhibit 2064 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00900
`
`

`

`170
`
`JFR Robertson et al.
`
`PR + stable disease [SD] =24 weeks) rate was 54.3%
`with fulvestrant and 62.0% with tamoxifen.
`Among patients with ER-positive and/or progester-
`one
`receptor
`(PgR)-positive
`tumors, prospectively
`planned statistical analyses revealed a small, non-sig-
`nificant estimated treatment difference in OR in favor of
`fulvestrant (33.2 versus 31.1%; estimated treatmentdif-
`ference 2.1%; odds ratio = 1.10; 95% CI = 0.74-1.63;
`p=0.64) [7].
`In this known receptor-positive group,
`which comprised ~78% of all patients in the trial, CB
`rates were 57.1 and 62.7% for fulvestrant and tamoxifen,
`respectively [7].
`Here we report the findings of a retrospective eval-
`uation of the sensitivity of tumors to further endocrine
`treatment following progression onfirst-line fulvestrant
`or tamoxifen within a phase III clinicaltrial.
`
`Treatment
`
`Patients were randomized to receive either fulvestrant
`250 mg via a 5 ml intramuscular (i.m.) injection once
`
`every 28 + 3 days plus placebo to match tamoxifen
`20 mg orally once daily, or tamoxifen 20 mg orally once
`daily plus placebo to match fulvestrant 250 mg i.m.
`
`(5 ml), once every 28 + 3 days. Treatment continued
`until disease progression (PD) or withdrawal, after
`which point further therapy was initiated at the discre-
`tion of the treating physician. Unless consent was
`withdrawn, patients were followed up for progression
`and survival until death.
`
`Assessment of response to treatment
`
`Methods
`
`Objective
`
`The best responses to treatment with fulvestrant or
`tamoxifen during the trial and to subsequent treatment
`were assessed according to Union Internationale Contre
`le Cancer (UICC) criteria. Responses were classified as
`either: CR (defined as disappearance of all known dis-
`ease), PR (no evidence of PD and a >50% decrease in
`
`
`To obtain data on the ability of patients with advanced and_objectivethe size of all measurable lesions
`
`
`Improvement in all evaluable, non-measurable lesions),
`breast cancer, who have been treated with first-line ful-
`vestrant or tamoxifen, to respond to subsequent endo-
`SD (no evidence of PD without evidence for CR or PR)
`crine therapy. Responses to subsequent therapies were
`or PD (>25% increase in size of any measurablelesion,
`compared between patients who did and did not show
`worsening of any existing, non-measurable lesion, or the
`CB therapy.
`appearance of a new lesion). The OR rate was defined as
`the proportion of patients with a CR or PR. CB was
`defined as the proportion of patients with an OR or SD
`lasting >24 weeks.
`Information regarding the subsequent therapy and
`responses were obtained by follow-up questionnaire,
`sent
`to all
`treating physicians. Figure 1 presents the
`overall treatment scheme for the study and summarizes
`the outcomes for patients receiving first-line fulvestrant
`or tamoxifen treatment.
`
`Patients
`
`Patients were postmenopausal women with metastatic
`or locally advanced breast cancer that was ER and/or
`PgR-positive or ER/PgR status unknown. Patients had
`received no prior therapy for advanced disease, although
`some patients (~23%) had received endocrine therapy in
`the adjuvant setting (tamoxifen treatment
`that had
`ceased >12 months prior to trial entry in all cases).
`Women were considered postmenopausal if they met
`any
`of
`the
`following
`criteria:
`aged
`260 years;
`aged <45 years with amenorrhea for
`longer
`than
`12 months and with an intact uterus; follicle-stimulating
`hormone level within postmenopausal range; having
`undergone a bilateral oophorectomy. Additional inclu-
`sion criteria were: histological or cytological proof of
`breast cancer; the presence of at least one measurable
`lesion; objective evidence of disease recurrence or pro-
`gression not considered amenable to curative treatment;
`World Health Organization (WHO) performancestatus
`of 0, 1 or 2; life expectancy >3 months.
`Patients were excluded from thetrial if they hadlife-
`threatening metastatic or visceral disease, a history of
`brain or leptomeningeal involvement or symptomatic
`pulmonary lymphangitic spread. Other exclusion crite-
`ria included the following: prior treatment with fulve-
`strant; previous endocrine therapy for advanced breast
`cancer;
`treatment with luteinizing hormone-releasing
`hormone analogs within the previous 3 months; sys-
`temic cytotoxic therapy within the previous 4 weeks.
`
`Results
`
`Patients
`
`In total, 313 patients received first-line fulvestrant and
`of these, 99 patients (31.6%) experienced an OR and 170
`(54.3%) derived CB. Two-hundred-and-seventy-four
`patients received first-line tamoxifen and, of these, 93
`(33.9%) experienced an OR and 170 (62.0%) derived CB.
`Two-hundred-and-forty-five questionnaires were
`re-
`turned by trial
`investigators, 149 of which yielded
`evaluable follow-up data on patients who had received
`second-line endocrine therapy (83 treated with first-line
`fulvestrant and 66 treated with first-line tamoxifen).
`Reasons for follow-up data being unavailable were as
`follows: patient did not receive second-line endocrine
`treatment; patient received more than one endocrine
`therapy as second-line treatment; patient received che-
`motherapy as second-line treatment; investigator unable
`to assess response; insufficient patient records; patients
`
`AstraZeneca Exhibit 2064 p. 2
`
`

`

`Endocrine sequencing after fulvestrant
`
`171
`
`Patients with metastatic
`or locally advanced
`breast cancer
`
`NOLLYZINOGNVY
`
`Fulvestrant 250 mg i.m.
`once every 28 + 3 days
`(n=313)
`
`Tamoxifen 20 mg
`orally once daily
`(n=274)
`
`Patients deriving a CB
`response onfulvestrant
`(n=170)
`Patients without a CB
`responseon fulvestrant
`(n=143)
`Patients deriving a CB
`response on tamoxifen
`(n=170)
`Patients without a CB
`response on tamoxifen
`(n=104)
`
`TWAMVHYCHLIAAYONOISSSH5O0Xd
`
`Further therapy
`[Table 1] (n=44)
`
`Further therapy
`[Table 3] (n=39)
`
`Further therapy
`[Table 2] (n=41)
`
`Further therapy
`[Table 4] (n=25)
`
`CB=clinical benefit
`
`Figure 1. Study treatment scheme and outcomes for patients receiving first-line fulvestrant or tamoxifen.
`
`were lost to follow-up; questionnaires were not returned;
`patient consent withdrawn in follow-up phase; and
`second-line endocrine treatment stopped before assess-
`ment of response dueto sideeffects.
`
`Response to subsequent endocrine therapy in patients
`deriving CB fromfirst-line endocrine treatment
`
`Overall, 85 of the 149 (57.0%) patients with available
`follow-up data derived CB from first-line treatment (44/
`83 [53.0%] treated with fulvestrant, 41/66 [62.1%] treated
`with tamoxifen).
`
`CB with first-line fulvestrant
`Of the 44 patients who derived CB from first-line ful-
`vestrant and had follow-up data available, second-line
`treatments included: Als (7=29; anastrozole [n=20],
`letrozole [1=7],
`fadrozole [n=1], aminoglutethimide
`[2=1]),
`tamoxifen (n= 12), medroxyprogesterone ace-
`tate (1=2), and megestrol acetate (n= 1). Second-line
`hormonal therapy produced an OR in 6/44 (13.6%) and
`CB in 25/44 (56.8%) patients (Table 1). Nineteen pa-
`tients (43.2%) did not respond to second-line endocrine
`therapy.
`
`CB with first-line tamoxifen
`Of the 41 patients who had CB with first-line tamoxifen
`and had follow-up data available, second-line treat-
`ments included Als (#=31; anastrozole [n= 21], letroz-
`ole
`[n=5],
`fadrozole
`[n=2],
`exemestane
`[n=3)]),
`
`megestrol acetate (1=5), fulvestrant (2=1), and med-
`roxyprogesterone acetate (2=1). In addition, three pa-
`tients were
`administered
`commercially
`available
`tamoxifen as
`their second-line therapy. Second-line
`hormonal
`therapy produced an OR in 5/41 (12.2%)
`patients and CB in 27/41 (65.8%) patients (Table 2).
`Fourteen patients (34.1%) did not respond to second-
`line endocrine therapy. In the three patients who re-
`ceived second-line tamoxifen, a best response of SD was
`reported in each case.
`
`Response to subsequent endocrine therapy in patients who
`derived no CB from first-line endocrine treatment
`
`Sixty-four of the 149 (43.0%) patients with available
`follow-up data did not derive CB from trial therapy (39/
`83 (47.0%) treated with fulvestrant, 25/66 (37.9%) trea-
`ted with tamoxifen).
`
`No CB with first-line fulvestrant
`Of the 39 patients who did not derive CB from first-line
`fulvestrant and had follow-up data available, second-line
`treatments included Als (#=22; anastrozole [n= 12], le-
`trozole [n=6], fadrozole [7=3], exemestane [n=1]),
`tamoxifen (1=12), megestrol acetate (n=1), and med-
`roxyprogesterone acetate (#=4). Second-line therapy
`produced
`an OR in
`3/39
`(7.7%)
`and CB in
`15/39 (38.5%) patients (Table 3). Twenty-four (61.5%)
`patients did not respond to second-line endocrine therapy.
`
`Table I. Response to subsequent therapy in patients who derived clinical benefit from fulvestrant as trial therapy
`
`Number of patients
`
`
`
`
`
`
` Total CR PR SD CB PD
`
`
`
`
`
`Endocrine therapy
`Aromatase inhibitors
`Anastrozole
`Letrozole
`Fadrozole
`
`Aminoglutethimide
`Tamoxifen
`
`44
`29
`20
`7
`
`1
`12
`
`3
`1
`1
`0
`0
`
`0
`2
`
`5
`2
`0
`2
`0
`
`0
`1
`
`19
`11
`10
`0
`1
`
`0
`7
`
`25
`14
`ll
`2
`1
`
`0
`10
`
`19
`15
`9
`as
`0
`
`1
`2
`
`0
`1
`1
`0
`0
`1
`Megestrol acetate
`
`Medroxyprogesterone acetate 2 me 0 0 0 0
`
`
`
`
`
`
`Abbreviations: CR = complete response; PR = partial response; SD = stable disease; CB = clinical benefit; PD = disease progression.
`
`AstraZeneca Exhibit 2064 p. 3
`
`

`

`172
`
`JFR Robertson et al.
`
`Table 2. Response to subsequent therapy in patients who derived clinical benefit from tamoxifen astrial therapy
`
`Total
`CR
`PR
`SD
`CB
`PD
`
`
`Number of patients
`
`Endocrine therapy
`Aromatase inhibitors
`Anastrozole
`Letrozole
`Fadrozole
`Exemestane
`
`41
`31
`21
`5
`2
`3
`
`2
`2
`2
`0
`0
`0
`
`3
`3
`2
`1
`0
`0
`
`22
`16
`10
`3
`0
`3
`
`27
`21
`14
`4
`0
`3
`
`14
`10
`7
`1
`2
`0
`
`3
`2
`2
`0
`0
`5
`Megestrol acetate
`0
`3
`3
`0
`0
`3
`Tamoxifen
`Fulvestrant
`1
`0
`0
`0
`0
`1
`
`Medroxyprogesterone acetate
`1
`0
`0
`1
`1
`0
`
`Abbreviations: CR = complete response; PR = partial response; SD = stable disease; CB = clinical benefit; PD = disease progression.
`
`No CB with first-line tamoxifen
`Of the 25 patients who did not derive CB from first-line
`tamoxifen and had follow-up data available, second-line
`treatments included Als (1=17; anastrozole [n=10],
`letrozole [1 =6], exemestane [7=1]), megestrol acetate
`(n=4) and medroxyprogesterone acetate (7=2). Sec-
`ond-line therapy produced an OR in 4/25 (16.0%) and
`CB in 12/25 (48.0%) patients (Table 4). Thirteen pa-
`tients (52.0%) did not respond to second-line endocrine
`therapy. Two patients who progressed on tamoxifen
`were given commercial tamoxifen as subsequent ther-
`apy.
`
`Discussion
`
`These data represent the first evaluation of responses to
`treatment followingfirst-line fulvestrant in patients with
`advanced disease previously untreated with endocrine
`therapy. A total of 245 (42%) questionnaires were re-
`turned by trial investigators, which yielded usable fol-
`low-up data from 149
`(25.4%) of
`the patients
`randomized to treatment. Retrospective questionnaire-
`based analyses such as this may however be opento bias
`and in the absence of data collected from randomized
`
`these results should be considered informative
`trials,
`rather than definitive.
`Although derived from less than half the eligible
`patients, these data suggest that more than 50% of pa-
`tients with follow-up data available who previously de-
`rived CB from initial fulvestrant or tamoxifen treatment
`may retain sensitivity to subsequent endocrine therapy.
`Of those patients not responding to initial endocrine
`treatment, a slightly lower proportion (~38-48%) de-
`rived CB from subsequent therapy. This latter figure,
`which is slightly higher than expected for second-line
`endocrine therapy in patients with tumors that showed
`de novo progression to first-line endocrine therapy, was
`similar whether the initial therapy had been tamoxifen
`or fulvestrant.
`Second-line treatment with AIs such as anastrozole
`or letrozole produced similar response rates in patients
`whohad not responded to fulvestrant or tamoxifen.It is
`of interest to note that followingfirst-line fulvestrant, it
`appears that more patients received an AI as second-line
`treatment, compared with tamoxifen. This is consistent
`with the fact that AIs are now more frequently being
`prescribed as first-line treatment for postmenopausal
`patients with advanced breast cancer. However, whatis
`also clear is that after first-line fulvestrant, the CB rate
`
`Table 3. Response to subsequent therapy in patients who did not derive clinical benefit from fulvestrant as trial therapy
`
`Total
`CR
`PR
`SD
`CB
`PD
`
`
`Number of patients
`
`Endocrine therapy
`Aromatase inhibitors
`Anastrozole
`Letrozole
`Fadrozole
`Exemestane
`Tamoxifen
`
`39
`22
`12
`6
`3
`1
`12
`
`0
`0
`0
`0
`0
`0
`0
`
`3
`0
`0
`0
`0
`0
`3
`
`12
`9
`7
`2
`0
`0
`2
`
`15
`9
`7
`2
`0
`0
`5
`
`24
`13
`5
`4
`3
`1
`7
`
`Megestrol acetate
`0
`0
`1
`1
`0
`
`Medroxyprogesterone acetate
`4
`0
`0
`0
`0
`4
`
`Abbreviations: CR = complete response; PR = partial response; SD = stable disease; CB = clinical benefit; PD = disease progression.
`
`AstraZeneca Exhibit 2064 p. 4
`
`

`

`Endocrine sequencing after fulvestrant—173
`
`Table 4. Response to subsequent therapy in patients who did not derive clinical benefit from tamoxifen as trial therapy
`
`
`Total
`CR
`PR
`SD
`CB
`PD
`
`
`
`Number ofpatients
`
`Endocrine therapy
`Aromatase inhibitors
`Anastrozole
`Letrozole
`Exemestane
`Tamoxifen
`
`25
`17
`10
`6
`1
`2
`
`0
`0
`0
`0
`0
`0
`
`4
`3
`2
`1
`0
`0
`
`8
`7
`5
`2
`0
`0
`
`12
`10
`7
`3
`0
`0
`
`13
`7
`3
`3
`1
`2
`
`Megestrol acetate
`4
`0
`1
`1
`2
`2
`
`Medroxyprogesterone acetate
`2
`0
`0
`0
`0
`2
`
`Abbreviations: CR = complete response; PR = partial response; SD = stable disease; CB = clinical benefit; PD = disease progression.
`
`to second-line tamoxifen (10/12) is at least as good as to
`an AI (14/29). It should be noted that this is a retro-
`spective questionnaire-based study with data on just
`under half the patients who were randomized into the
`study. As such we should interpret these findings with
`some caution and should not makestatistical compari-
`sons between tamoxifen and Als based on this dataset.
`It should also be noted that although somepatients re-
`ceived tamoxifen as subsequent therapy in this study, no
`patients received fulvestrant other than the prospective
`study context of first-line endocrine therapy since, at
`that time, fulvestrant was notlicensed in the EU.
`The proportion of post
`fulvestrant
`responses
`reported here is similar to those previously described for
`second-line AI therapy in patients who failed on first-
`line tamoxifen treatment [8,9]. For example, in a study
`by Buzdar et al., CB was observed in 111/263 (42.3%)
`patients treated with second-line anastrozole [8] and in a
`study by Kvinnsland et al., CB was noted in 65/137
`(47.4%) patients receiving exemestane as second-line
`treatment [9]. The CB rate for those patients who were
`known not to have responded to prior tamoxifen was
`60% versus 47% for those who did respond [9]. In the
`present study, CB was observed in 11/20 (55.0%) pa-
`tients treated with second-line anastrozole after dem-
`onstrating CB with first-line fulvestrant treatment and in
`7/12 (58.3%) patients treated with second-line anas-
`trozole after not responding to first-line fulvestrant
`treatment.
`
`Ourresults are similar to those gained in a recentret-
`rospective analysis of response to subsequent endocrine
`treatment in 105 patients who had progressed on both
`initial endocrine therapy, usually tamoxifen, and on sec-
`ond-line fulvestrant. Of the 54 patients included in the
`analysis and who derived CB from fulvestrant treatment,
`25 (46.3%) derived CB from subsequent endocrinetreat-
`ment. In the group of patients who did not derive CB from
`fulvestrant treatment (n= 51), 18 patients (35.3%) derived
`CB from subsequent treatment. In this study, Als were
`used as subsequent endocrine therapy in >80% ofpatients
`[10]. Furthermore, preliminary results have been reported
`from an ongoing PhaseII trial determining the efficacy of
`fulvestrant in patients with advanced breast cancer who
`have progressed on prior endocrine therapy with tamox-
`
`ifen and Als. Here, CB was reported in 7/17 (41.2%) eli-
`gible patients after
`tamoxifen and AI
`failure [11].
`Additionally, in compassionate use programs, CB has
`been observed in patients receiving fulvestrant after pro-
`gression on multiple prior endocrine therapies, including
`both SERMsand Als [12-14].
`
`Conclusions
`
`The direct comparison between tamoxifen and fulve-
`strant as first-line endocrine therapy has been addressed
`in a previous publication [7]. This manuscript has fo-
`cused on sequencing and whetherthe use of one or other
`of these drugs asfirst-line therapy makes tumors more
`likely to become hormoneinsensitive.
`Postmenopausal women with advanced breast cancer
`who respond to first-line fulvestrant or tamoxifen ap-
`pear to retain sensitivity to subsequent endocrine ther-
`apy, Suggesting that subsequent progression after ER
`downregulation may not be due to loss of hormone
`sensitivity. In particular, CB rates to either tamoxifen or
`Als subsequentto first-line fulvestrant appear similar,
`although the number of patients in each sub-group is
`relatively small. When Als are used second-line, the re-
`sponse rates in patients who have progressed on fulve-
`strant or on tamoxifen are similar. These findings
`suggest that in terms of response to subsequent (..e.
`second-line) endocrine therapy, there does not appearto
`be a difference betweeninitial(i.e. first-line) antiestrogen
`therapy with tamoxifen or fulvestrant. In other words,
`fulvestrant is no more likely than tamoxifen in induce
`hormoneinsensitivity. Therefore, fulvestrant appears to
`offer an opportunity to prolong the time in which well-
`tolerated endocrine therapies are used before reliance
`upon cytotoxic chemotherapy is necessary.
`
`References
`
`1. Early Breast Cancer Trialists’ Collaborative Group, Tamoxifen
`for early breast cancer: an overview of the randomisedtrials.
`Lancet 351: 1451-1467, 1998
`2. Wakeling AE, Dukes M, Bowler J: A potent specific pure anties-
`trogen with clinical potential. Cancer Res 51: 3867-3873, 1991
`
`AstraZeneca Exhibit 2064 p. 5
`
`

`

`174
`
`JFR Robertson et al.
`
`10.
`
`11.
`
`mature phase IIItrials. Arimidex Study Group. Cancer 83: 1142-
`Robertson JF, Nicholson RI, Bundred NJ, Anderson E, Rayter
`1152, 1998
`Z, Dowsett M, Fox JN, Gee JM, Webster A, Wakeling AEF,
`Kvinnsland S, Anker G, Dirix LY, Bonneterre J, Prove AM,
`Morris C, Dixon M: Comparison of the short-term biologi-
`cal effects of 7alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-no-
`Wilking N, Lobelle JP, Mariani O, Salle Edi, Polli A, Massimini
`
`nyljestra-1,3,5,|(10)-triene-3,17beta-diol (Faslodex) versus G: High activity and tolerability demonstrated for exemestane in
`
`
`tamoxifen in postmenopausal women with primary breast cancer.
`postmenopausal women with metastatic breast cancer who had
`Cancer Res 61: 6739-6746, 2001
`previously failed on tamoxifen treatment. Eur J Cancer 36: 976—
`982, 2000
`Howell A, Robertson JFR, Quaresma Albano J, Aschermannova
`A, Mauriac L, Kleeberg UR, Vergote I, Erikstein B, Webster A,
`Vergote I, Robertson JFR, Kleeberg U, Burton G, Osborne CK,
`Morris C: Fulvestrant, formerly ICI 182,780, is as effective as
`Mauriac L: Postmenopausal women whoprogress on fulvestrant
`anastrozole in postmenopausal women with advanced breast
`(‘Faslodex’) remain sensitive to further endocrine therapy. Breast
`Cancer Res Treat 79: 207-211, 2003
`cancer progressing after prior endocrine treatment. J Clin Oncol
`20: 3396-3403, 2002
`Perey L, Thiirlimann B, Hawle H, Bonnefoi H, Ahern J, Pagani
`Osborne CK, Pippen J, Jones SE, Parker LM, Ellis M, ComeS,
`O, Goldhirsch A, Dietrich D: Fulvestrant (Faslodex’) as hor-
`Gertler SZ, May JT, Burton G, Dimery I, Webster A, Morris C,
`monal
`treatment
`in postmenopausal patients with advanced
`Elledge R, Buzdar A: Double-blind, randomized trial comparing
`breast cancer progressing after treatment with tamoxifen and
`the efficacy and tolerability of fulvestrant versus anastrozole in
`aromatase inhibitors. Breast Cancer Res Treat 76 (Suppl 1): $72,
`postmenopausal women with advanced breast cancer progressing
`2002 (abstract 249)
`on prior endocrine therapy: results of a North American trial.
`Steger G, Bartsch R, Wenzel C, Pluschnig U, Hussain D, Mader
`J Clin Oncol 20: 3386-3395, 2002
`RM, Zielinski CC: Fulvestrant (Faslodex®) in metastatic breast
`Pippen J, Osborne CK, Howell A, Robertson JFR: Fulvestrant
`cancer. Breast Cancer Res Treat 82 (Suppl 1): S104, 2003 (abstract
`(Faslodex) versus anastrozole (Arimidex) for the treatment of
`437)
`advanced breast cancer: a prospective combined survival analysis
`Franco S, Perez A, Tan-Chiu E, Frankel C, Vogel CL: Fulve-
`of two multicenter trials. Breast Cancer Res Treat 82 (Suppl 1):
`strant (Faslodex®) demonstrates clinical benefit in heavily pre-
`$101, 2003 (abstract 426)
`treated postmenopausal women with advanced breast cancer: a
`Howell A, Robertson JFR, Abram P, Lichinitser MR, Elledge
`single-center experience. Breast Cancer Res Treat 82 (Suppl 1):
`R, Bajetta E, Watanabe T, Morris C, Webster A, Dimery I,
`$105, 2003 (abstract 429)
`Osborne CK: Comparison of fulvestrant v tamoxifen for the
`Petruzelka L, Zimovjanova M: Fulvestrant in postmenopausal
`treatment of advanced breast cancer in postmenopausal women
`women with metastatic breast cancer progressing on prior endo-
`previously untreated with endocrine therapy: a multinational,
`crine therapy — results from an expanded access programme. Eur J
`double-blind, randomized trial. J Clin Oncol 22: 1605-1613,
`Cancer (Suppl 2): 132, 2004 (abstract 264)
`2004
`Buzdar AU, Jonat W, Howell A, Jones SE, Blomqvist CP, Vogel
`CL, Eiermann W, Wolter JM, Steinberg M, Webster A, Lee D:
`Anastrozole versus megestrol acetate in the treatment of post-
`menopausal women with advanced breast carcinoma:results of a
`survival update based on a combined analysis of data from two
`
`Address for offprints and correspondence: JFR Robertson, Unit of
`Surgery, City Hospital, Hucknall Road, Nottingham NGS 1PB, UK;
`Tel.: + 44(0)115 969 1169, extn. 46859; Fax: +44(0) 115 840 2618;
`E-mail:John.Robertson@nottingham.ac.uk
`
`12.
`
`13.
`
`14.
`
`AstraZeneca Exhibit 2064 p. 6
`
`