Clinical review
`
`Recent advances in endocrine therapy of breast cancer
`Anthony Howell. Mitchell Dowsett
`
`Regression of advanced breast tanner as a reSult of
`endocrine diempy was first desm’bed over 100 years
`ago.‘ Interest in this form of munem mutated when
`treatment with the antioestmgen tamwdfen after
`surgery for breast meet was shown to improve
`patients mnrival' ’ Treatment also reduced the
`incidence of new cancers in the contralateral breast.
`whichhasledtoanumberofuialsoftamoxifenasa
`
`prevmfive measwe in women at high risk.‘ New, pottin-
`tially were active endocrine agents are now being
`introduced into clinical practice. In this review we
`outline the mechanism of action of these treatments
`
`mdsmnmariserecmtremfltsofclirficaloialsasaessing
`their efficacy in comparison with older drugs; we also
`speculate about fiimre trends in endocrine diempy and
`summarise clinical trials in progress.
`
`Methods
`
`This article is based. in part, on our own collaborative
`experimental work and close association with pharma-
`companies developing new endocrine agents.
`Additional review. and
`articles were obtained
`from searches of ontological journals. Recent data
`were obtained from presentations at the May meeting
`of the American Society for Clinical Oncology.
`
`Mechanism of action of newer endocrine
`
`therapies
`
`Breast cancer cells that are endocrine dependent need
`oestrogen to proliferate." Most endocrine therapies
`either block the binding of cesnogen to its receptor in
`the nucleus of responsive cells or reduce serum and
`armour concenuations of oesoadiol. In postmenopau-
`5a] women andmgena (mainly from the adrenal
`glands) are converted into oesuogens by the enzyme
`ammatascwhichiepmsentin arrange offissues andis
`found in 60-70% of breast carcinomas.6
`The trend for endocrine therapies over the past
`100 years has been towards simpler and more widely
`applicable treatments. Originally pharmacological
`doses ofoestmgenswereusedtoblock the
`efimofoesmmbutnowthisisachievedwlth
`tamoxifen.“ Oestr'ogen concentrations were reduced by
`surgery (ocphorectcmy, adrenalectomy, and hypophy~
`Sectomy), but now analogues of luteinising hormone
`releasing hormone, which eifectively ablate ovarian
`steroidogenesis, may he used in premenopansal
`women; ammataae inhibitors are used in postmeno-
`pausal women.
`
`BM] VOLUME 315 4 OCTOBER 1997
`
`
`
`'Ihmosdfen is an antiooctrogen but has a complex
`phmnacology, partly due to its metabolism to numer-
`ous biologimlly active compounds. It is an oestrogen
`moist-antagonist that depends on its competitive
`binding to oestrogen receptors. Several other bio-
`chemical pathways are afmd by tamoxifen, but their
`clinical
`importance is doubtful;
`the predominant
`importance of the oestrogen receptor dependent
`padnvayissnpportedhyclinicalmponeeeto
`tamordfen being largely confined to tumours positive
`for oestrogen.
`In an oestrogenic environment tamoxifen stops the
`proliferation of breast cancer cells that bind to oestro-
`gen receptors. But if oestrogen concentrations are low.
`tamoxifen may an as an oestrogen agonist and lead to
`the proliferation of these cells, at least
`in model
`systems. Reducing this agonist activity has become the
`major target of new drugs and has led to the develop-
`ment of non-steroidal drugs that act like tamosdfcn. as
`well as steroidal compounds that are detiVatives of
`oestmdiol.’ These two groups differ in their interaction
`with oestrogen receptors. The non-steroidal com-
`
`CRC Depexunem
`
`w 1997;815:863-6
`
`853
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`Clinical review
`
`
`
`pounds bind to oestrogen receptors, leading to their
`activation and dimerisation and their binding to
`specific oestrogen response elements on DNA which
`causes transcription of oestrogen responsive genes. A
`complex series of coacdvators and compressors can
`also substantially modify the agonist or antagonist
`responSe to the complex of drug and oestrogen recep
`tor. Drugs of this type which are in or have recently
`completed phase In development include toremifeneI
`dmloxifene. TAT-59, and idoxifene. Other
`than
`toremil‘ene, each of these has improved antagonist-
`agonist balance in standard model systems such as the
`immature mt uterine weight test“ ”
`in contrast the steroidal antagonists (exemplified by
`ICI 182780, Faslodex} have been characterised as pure
`antagonists, as in their case the complex of drug and
`cestrogen receptor
`is effectively inactive. There is
`debate as to whether this is due to lack of dimer-nation
`
`in the oestrogen receptor or a lack of binding to oestro—
`gen response elements, but it seems clear that the acti-
`vating functions are blodted and that the stability of the
`oestrogen receptor is reduced such that the oestrogen
`receptor content of the tumour is greatly reduced
`Both Faslodex and idoxifene are more effective
`
`antitumour agents than tamoxifen in animal model
`systems. and both show activity in cells and rumours
`that have become resistant to tamoxifen.7
`
`Conventional clinical pharmacology of the new
`antioestrogens has not been instructive for
`their
`clinical development because there are no good surro—
`gate markers of their activity against cancer. Their
`clinical development
`is being helped by a novel
`approach, in which pathological markers of prolifera-
`tion and. apoptosis are measured in primary breast
`carcinomas after short
`term, presurgical
`treatment
`with the drugs before surgery "' "
`Tamoxifcn's oestrogen agonist activity is advanta—
`geous on some tissues other than breast cancer.
`including bone and liver, but not endometrium.
`Experimental evidence indicates that chemical modifi-
`cations can enhance the therapeutic elficacy and toler-
`ability of non—steroidal compounds and lead to a
`group of compounds called SEEMS (selective oestro—
`gen receptor modifiers). An example is raloxifene,
`which is
`in its late stages of development as an
`antiosteoporotic agent; it lacks the breast and endome-
`trial stimulation of oestrogen. New compounds of this
`type will soon enter clinical development for breast
`cancer treatment and are candidates for breast cancer
`
`prevention strategies."
`
`Table 1 Recently repaired phase ill and randomised phase iI trials at new non-steroidal
`antiuestrogens
`
`now [I'll]
`Tamoxifen versus turemttene”
`
`Dost
`In at
`Romania
`
`[ow]
`pltlunlr
`I'll)"
`77777270
`171757
`19
`
`7— ! ‘ 7 7
`
`7 607
`200
`
`21
`221
`212
`22
`
`7 347
`30
`handmised phase it trial
`handling?
`7 7
`7
`7
`
`7 r 7
`‘ _
`740 7
`as
`ii
`—
`77 — 7
`x44
`m‘ 59"
`’ Randomised phase ll trial
`is
`15
`1t:
`7 7
`‘7“;
`55
`11
`' 20'
`
`7137(7—7 ’77 77407 31
`
`
`'Cnmpleta response plus ital-ital rasponse.
`
`Gunman!
`PM trial as first line
`treatment in advanced disease
`7
`
`7
`
`Clinical results
`
`Tamoxifen is the "gold standard," but its agonist effect
`may stimulate tumour growth and cause treatment to
`fail.” The newer non-steroidal antioestrogens have
`been developed bemuse [with the exception of
`toremifene) they have reduced agonist activity.
`Table 1 shows some recent studies of new amines—
`
`crogens A phase 1]] trial found that toremifene was not
`superior to tamoxifen. ” The analogue droloxifene
`seemed active in phase II trials when used at doses of
`20-100 mg/clay, as did the japanese drug TAT—59.” “i
`We need more information from phase II trials about
`idoxifene and data from phase 1]]
`trials comparing
`tamoxifen with droloxifene, TAT-59, and idoxifene.
`The pure antioestrogen ICI 182780 (Fasiodex)
`showed little agonist activity in preclinical Less and in
`the only clinical
`trial
`in advanced breast cancer
`performed to date." Notably. it is active when given
`after failure of tamoxifen and produces remissions of
`two years whereas standard second line endocrine
`therapy usually gives a one year median duration of
`response. Again. randomised data are required to con—
`firm these promising preliminary dam.
`
`Aromatase inhibitors
`
`Pharmacology
`Using aromatase inhibition to suppress oestrogen syn—
`thesis was developed as a treatment for breast cancer
`over 20 years ago.” During the intervening period
`many inhibitors have been developed. Plasma oestro-
`gen concentrations have been widely used to assess
`pharmacological cflecfiveness,but such assays have not
`been sulficently sensitive to provide reliable compari-
`sons between inhibitors. Isotopic methods that directly
`measure the. inhibition of enzyme activity throughout
`the body have provided more useful comparative data.
`There is no evidence that any of the inhibitors
`differentially inhibit aromatase in different tissues. The
`inhibitors may be considered as two families, steroidal
`and non—steroidal.
`
`Mai—steroidal
`
`All of the non—steroidal agents are active orally. Until
`I992 the only widely available inhibitor was aminoglu-
`tethimide. This drug inhibits several cytochrome P450
`enzymes, including some involved in steroidogenesis,
`and has been widely used in breast cancer in combina-
`tion with replacement doses of glucowrticoid as a
`"medical adrenalectoniy." When aminoglutethimide’s
`clinical effectiveness was shown to be due to its inhibir
`tion of aromatase, this enzyme became a therapeutic
`target The side effects of aminoglutethimide (mainly
`skin rashes and neurological symptoms),
`its lack of
`specificity (requiring replacement glucocorticoid), and
`its
`relatively low potency have been targets
`for
`pharmaceutical improvement and have been well met
`by the most recent drugs.
`anastrozole
`derivatives,
`A series of u-iazole
`(Arimidex),"’ 2”
`letrozole (Femaralf' 2" and vorozole
`(Rivizor)” 2‘ have all been shown to have excellent
`selectivity for aromatase in preclinical models, and this
`has been confirmed in dinical studies. Their intrinsic
`
`potency is considerably greater than that of amino—
`glutethimicle, In patients. aminoglutethimide inhibits
`total body aromatisatjon by about 91%, while anastro—
`
`BM] VOLUME. 31!?)
`
`4 OCTOBER 1997
`
`864
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`
`
`Clinical review
`
`Table 2 Recently reported phase lll trials which compare standard second line endocrine therapy with the new triazole inhibitors
`Elm
`Nil Ill
`Pmpultlen [5%] Bl
`Halli“ survival
`
`Elma
`imminent
`patterns
`pattern: resynmllnn‘
`(mantis)
`comment
`
`.
`A
`Anasnozure‘m
`1
`263
`42.2 (+750)
`25.?
`‘
`_
`V
`gamma];
`1d
`248
`73733 _ 7
`25.57
`33:53:31”? “Vamp” m“
`Megestrel acetate
`150
`253
`40.3
`22.5
`’
`_
`7
`Latrozele’l
`as
`tea
`1727.3 (7730)
`272767
`7
`item's-
`2‘51
`.13:
`at
`’ '_26_J__’ 3.223032%? “m” “'““
`Meyestrul acetate
`160
`189
`NH
`23.5
`
`7
`
`i
`
`7
`
`7
`
`7
`
`,
`
`7
`
`
`
`
`
`
`
`throne? 7
`mm”
`Aminnglutethirnide plus hyfimmrtisone
`new}?
`77
`7
`7
`Mnrnnglutelhlmlde plus hydrocorltsnne
`
`7
`7 7.
`
`7 its
`2-5
`5::
`755
`5m
`7.7
`30
`
`not; 5557
`
`7
`
`r
`
`in
`279
`279
`
`7-
`
`r
`r
`7 _
`
`7
`7
`77
`No date
`_ _ Trend for survival advantage lor both
`“was or lemme
`7"
`7 _
`Trend lur survival advantage wlth
`7
`7 vornzole
`
`7— 7
`m
`2015 (750:
`7 7 190
`7 2.5
`7
`inmate" 7
`
`Megestml acetate 7 11750 7 185 7 775.7677 7 7 287.7?
`
`
`
`
`‘Gornplate response plus partial response: SiJ=stable disease (28 months).
`
`16.? (7:30)
`12-3
`71112
`«tr use) 7
`—
`
`3?
`
`7
`
`7725.1
`
`21.7
`
`7
`
`logical since stable disease gives equivalent palliation
`and survival.“9 The durations of response of the new
`agents have tended to be longer than the old, but even
`more important are the survival advantages shown by
`new agents The trial with the longest follow up shows
`that anastrazolc l mg has significant survival advan—
`tage over megestrol acetate 150 mg,” and the other
`trials show trends towards survival advantages.'lhe uni-
`formity of this diflcrence suggests that these trends are
`likely to become significant with further follow up.
`
`Trials in progress
`The introduction of new agents and the results of trials
`generate new questions and the need for new clinical
`trials. Table 3 outlines trials in progress or which are
`due to start shortly.
`We need to know whether the new non-steroidal
`andoestrogens [idmdfene, droloxifene, TAT-59)
`that
`show better preclinical characteristics than tamoxifen
`are better clinically. Large trials comparing all three
`new agents with tamoxifen are ongoing. The pure
`antioestrogen Faslodex looks highly pronfising in vino.
`in animal studies, and in early phase I] tests. However,
`phase
`II
`studies
`are notoriously unreliable in
`
`Table 3 Clinical trials using endocrine therapy protected or in progress in early
`ladluvant) anti advanced breast cancer (phase Ill)
`Treatment
`Mltmnl breast cancer
`Receptor blockade:
`Martian; —
`—-
`720 inq vfinfifinr
`
`7
`7
`tampxlfen
`7
`_ 7
`—
`20 mo v 20 n1 tamoxifen
`Bmiciritjne
`
`7
`7zn7ni§ '9 itififiaficixfif
`TAT-59
`125 mg r250 mu v20 mu
`Fesludex uni 7132732))
`tamnxtten 7
`Oeslmpen receptor.
`77nnaslrozule
`
`
`
`Munroe! breast lancer
`
`7
`
`7
`
`Tamoxifen
`Mancini;
`Anastrozote
`Tamoxifen
`
`7
`Both 7 7
`77 77
`7
`7
`77777
`Tamoxiian 2 years
`Tamoxilen 3 years
`Anastmzale
`
`
`Anestrotnle it years
`Feslutlear
`Letrozele
`Tamoxifen
`Letrazale
`
`Letmzule
`7
`7 7
`Tamoxifen
`Tammtifen 5 years
`Placebo 5 years
`Vurozule
`7
`fl_
`_ 7 7
`7
`7
`Verozole 5 years
`Emmestane
`Exemeetane
`Tamoxifen 2—3 years
`Tamoxifen 2-3 years
`Externestene 2-3 years Megestrol acetate
`
`
`7
`
`their recommended doses of
`zole and letmzole, at
`l rug/day and 2.5 rug/day, inhibit by about 97% and
`>99%. respottively.25 in many patients this results in
`plasma oestrogen concentrations which even the most
`sensitive immunoassays cannot detect.15
`
`Stefoidoi
`
`Two of the steroidal agents, formestane and excmes-
`tane, have undergone considerable clinical develop—
`ment. Formestane (4-hydroxynndrostenedione; Len-
`tamn) was the first selective inhibitor to be licensed.“ It
`is given by intramuscular
`injection because it
`is
`metabolised too quickly if taken orally.
`it
`is more
`specific than aminoglutethimide but does not have
`more pharmacological activity. Excmestanc is orally
`active and seems to be selective at clinical doses.” No
`data have been published on its reflects on whole body
`aromatisation. The only pharmacological data from a
`randomised comparison between any ofthe inhibitors
`showed the superiority of anasn‘ozole over formestane
`in suppressing plasma or:st.radiol.""‘i
`
`Clinical results
`Table 2 shows the results of recent randomised
`
`trials comparing aromatase inhibitors with standard
`second line endocrine therapy (after tamoxifen). The
`trials for letrozole and anastmzole had three arms: two
`dimes of the new aromatase inhibitor compared with
`either the progestogen (megestrol acetate) or the old
`aromatase inhibi‘tor(aminoglutetl‘ti1nidc). Vorozole has
`been tested against these same comparators at a single
`dose in trials with two arms!5 2"
`triaeole
`All
`three of
`the new non—steroidal
`derivatives (anasmmole, letromle, and vorozole)‘ and
`the steroidal derivative exemestane have shown
`
`minimal toxicity. In particular, they do not produce the
`troublesome weight gain of megesu-ol acetate nor the
`rash and neurological symptoms of aminoglutethim—
`ide. Since all four compounds are specific aromatase
`inhibitors. glucocor’dcoid replacement is not required.
`In general, all the trial results point in the same
`direction. Overall response 1”de with the new and the
`old treatments are similar. Responses have been
`reported as either complete and partial remissions or
`as complete and partial remissions and stable disease
`for at least six months. The latter reports are more
`
`BM] VOLUMEEIEI
`
`4 OCTIU‘BER I997
`
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`Clinical review
`
`
`
`Table 4 Past, present. and potential future treatment of advanced breast cancer by
`blocking oestrogen receptor or reducing concentrations of oestrogenic steroids in
`postmenopausal patients
`Wan motor bluebe- ltetluotlnn at rostrum munitions
`
`Hypltonhyseotomy
`lilohdose oestrogen
`norm.“lectomy—
`Ainlnootutethlrnloe 1
`DoipttorectI-orny __
`t-OH androstenedione'
`Ariaslroiole
`7 f 77
`Lenozole
`r
`Eutsinisinu hon'none relishing humane agonists
`
`V N
`
`on-steroidal:
`Droloxltene
`
`Vorozole
`.
`narrow i. H _
`
`Sulphetaso inhibition
`Selective oestrogen receptor
`Lutetnler'no hormone roteeslno hormone antagonists
`moduhlors [39 {alumina}
`Staroldal:
`
`ICltBETEO (Fastener)
`
`8 Chandcr SK. Newton (1. McCague R. Dowsett M, Luqutann Y, Coombm
`RC. Pyrtulodine-‘l-iodntmmndfcn and 4-iodotamoxlfm new analogues
`of the amineslmgem tamoxifen for the treatment ofbreasl tanner. CW
`Rm [9915158518.
`9 Welding All. Dukes M. Bowler]. A potent spcdflc pm andestmgen with
`clinical potential Wiles 1991:5lz3ol3lfi7-73;
`10- De Friend [J]. Howell A. Nicholson RI. Antler’wn I”; Ween M. Manse]
`RE. at al. Int-emigration of a new purl: antioestmgm (1C1 182780) in
`women with primary breast. cancer. Camflri 1994;54:408-14.
`1 I Ellis PA, Saccani Jotti G. jcihnston 5RD. E Mtderson, A Howell. R
`A'Heme. et a]. induction of apoprosis by tamoxifen and ICI 182780 in
`primary breast cancer. Int} Saucer lElWflzfiUS—l I.
`12 Sam M. Glaseme AL. Bryant RU. Ralexifme: a selective estrogen
`receptor modulator.1Beam Miner Met 1994;12lsuppl ‘2):59-20.
`ls DeFr'tend D}. Anderson E Bell]. Wilks DP, We: CML, Manse] RE. el al.
`Enters of-t—hydmxylamrnttlen and a pure arttirxesmigen (ICI 182780) on
`the donogenic growth of human breast cancer cells in vitro. fir} Curran
`1994;70:2‘04- l 1,7
`l4 Hayes DF, Van ZyIJA. Hacking A. Goedlials L. Bezwodz WR. MailliaxthA.
`et al. Randomised comparison of tamoxifen and two separate doses of
`toremilene in postmenopausal patience with metastatic breast writer. 1
`Chi! Onwl 1995;13:2556-56.
`if: Rattechning W. Fritch Kl. Dmloxifene. at new antioeetmgcn: its role in
`nrcmtan‘c breast (KNEW. River: (7mm Ru Tim: 1994;211:8384.
`) in
`lfi Tamil-135311 Early phase II clinical study ofTAT-S‘J [new anduesn
`patients with advanced breast cancer. l‘hh International Congress of
`Chemotherapy. Montreal. Canada. 1995.
`17 Howell A. DeFriend D}. RoloeranFR. Blarney RW, Anderson L Ander-
`son E. et a]. Phannacokinetios, pharmacological and anti-tumour clients
`ofthe specific antioemogen [Cl 182780 in women with advanced breast
`cancenBrj Cm 1996;74:30&&
`Studies on the niechaniun of
`I8 Sclrwaml WC. Krung WG. Brodie
`can-agar} biosynthes'fl. VII]. The development of inlu'birors of the enzyme
`system in human placenta Emboimzlag l973:9‘1:86fi‘8tl
`19 Border A.}onat W. Howell Alone-s SE. Blomqviet C. Vogel CL. at at.
`Anastrozolc. a potent and selective ammatase inhibitor. versus megeenol
`acetate in postmenopausal women with advanced breast cancer: vaults
`of overview analysis of two phase II] trials] Clr'n than! 1996;14:200041.
`20 Bands: Anion-at W. Howl] A. Yin H. I.“ 1). Significant improved survival
`with Arimidex (muosz mu: megesml acetate in pmun-enopausal
`advanced breast cancer: updated results of two randomized trials
`{abounctLPmc/tm Sat (2th Ono)! 1997;16:156.
`21 Smith 1. Darribernoweky P, Falkeon 0.1190an R. Pannsci L Bellmunt].
`or aLDouhle-blirtd trial in postmenopausal unmet: with admired breast
`cancer showing a dose—efi'cct and mperiority of 25mg lorrozole over
`megulml acetate. Eur] Cm 1995mm:qu 2):49.
`2% Marty M. Gershanovich M. Campos 8. Rainier! G. Lurle H, Bonaventure
`T. et at. [morale a new potent. selective aromatase inhibtlor superior to
`ominoglurerhimide [AG]
`in menopausal women with advanced
`breast cancer previously treated with mubcstrogens [abstract]. Procdm
`Sat Ch'n Dnml 1997;16:156.
`23 Bath. Bonneterrej. Houston S]. Uiger H]. Murray R. Nor-tier]. et a}.
`Vomzole (Rivizor) versus mninogiutcthirnide (AG) in the manna-til. of
`ptmennpausal breast cancer relapsing after tamoxifen [abstract]. Prior
`Am Soc Clr'n Oncol1997;16:156.
`24 Goes P. Wind E. Tanned l. Schwartz LH. Kramer All for the North
`American Vomzole Study Group. Vorozole vs megsne in postmenopau-
`sal patimts with metastatic breast carcinoma who had relapsed following
`mmoxifen [atom-act}. HotAm Soc CUM Owed 1997;161l55.
`25 Dawson M. Biological background to aromatase inhibition. The Smart
`1996;5;196-201.
`26 Coombes RC. Hughes SWM. Dowsett M. 4-Hydroxyandmstenedione:
`A new moment for postmenopausal patients with breast MET Eur]
`Cancer 1992;28Atl‘341-5.
`27 Di Selle E. Ornali G, Par-idem R. Coombes RC. [Abellejfl Zurlo MG.
`and clinical pharmacology of the amt-mine inhibitor enmes-
`tan: (FEE 24504).
`In: Mona M. Serial M. eds. Sex lime: and
`We}: mwrmmwmommmm
`Amsterdznl. Heavier. I994:303-9.
`28 Dawson M. Vorobiof DA, Klee!)ng UR, Carrion RP. Dodwcll D}. Robe-rte
`SOnJFR. et a]. A randomized study assessing oestrogen suppression with
`arimidert (anasuoenlei and fonnestane in pmurmmpausal advanced
`breast tanner patients. Eur} Conn-(1996:32Atsuppl $149.
`99 Howell A. Mackintosh j,jones M, Redford]. Wagstafl']. Sellwoood M
`The definition of the “no change” category in patients malted with endo
`crinr: therapy and chemotherapy for animated carcinoma of the breast
`Eur} Conner Clio Damn! 1938;24:1567-72.
`{Amp-ml 5 Angie: I99”
`
`
`predicting superiority over old agents. Thus the
`recently started study comparing Faslodex with
`mastle as second line endocrine therapy for
`advanced disease and the comparison of Faslodex with
`tamoxifen as first line treatment that is to start late in
`1997 are highly imporan
`The success of the new aromatase inhibitors :15
`second line treatments for advanced disease has led to
`
`the initiation of trials using these drugs as first line
`agents for advanced disease and comparing them to
`tamoxifen as adjuvant drerapies The optimal duration
`for tamoxifen as an adjuvant seems to be five years.
`Smdies are in progress or shortly to start in which a
`changeover to an aromatase inhibitor alter two or
`three years of tamoxifen is compared with continuous
`tamoxifen {table 3). Change to an aromatase inhibitor
`after
`five years of tamoxifen in comparison with
`stopping all treatment is also being tested.
`
`Conclusions
`
`Although the principles of endocrine therapy have not
`changed over the past 100 years. new methods have
`resulted in less toxic and more widely applicable treat-
`ments {table 4). Also. for the first time, we have begun
`to see improvements in the effectiveness of treatment
`in tenns of response duration and, most importantly,
`survival.
`
`Ftuiding: No additional handing.
`Conflict of interest We are involved and have been involved
`in the clinial development of many of the compounds
`mentioned in this review.
`
`1 Beater-n GT. 0:: the moment of inoperable cases of carcinoma of the
`mamma. Su
`bus for a new method of treatment with illustrative
`m Lamar 1896:2flM-7.
`2 Cole MEJones CTA. Todd [DI-l. A new mdmflogenic agent in late
`breast cancer: an early clinical appraisal of 1C] 14-5474. Br} Cam”
`1971;25:2‘l0~5.
`3 My Breast Cancer Triallisrs Ctr-operative Group [EBCTCGl Systemic
`mm: of early breast cancer by hormonal. cytotoxic. or immunov
`therapy. Lanai l992:339:l-15.7l-85.
`4 Cuzick j. Baum M. Moxifen and contralateral breast cancer. Lancet
`1985;ii:2&2.
`5 Li
`M. MenacoME Baler-t (i. Efl'ccts of
`escradiol and tree-
`rriol on hormone responsive human breast cancer in long term tissue
`culmreCamRer 1977;37:1901-7.
`5 Miller W11. Bedouin: treatment for bro-at cancers: biologiml rationale
`and current progress.J. Smoidfliochem Mot Biol 1990;37:46?-30.
`7 Howell A. Mrlend I}. Robertson], Blarney R. Walton P. Response to a
`specific antioemrogen (ICI 182780) in LammLifm-milfilm breast mum.
`
`Lanai IQ95:34512930.
`
`Endpt'eoe
`Misleading appearances
`A woman accompanied her husband to the doctor
`and waited for him during his checkup After the
`examination the doctor came out and said, "I don't
`like the way your husband looks.” "Neither do 1,"
`said the woman, “but he‘s good with the kids"
`From Theflest ofMedical Hum (Howdj
`Bennett, ed. Philadelphia: Hartley and Belfus, 1997)
`
`Bfifi
`
`EM] VOLUME 315 4 OCI‘OB'ER [997
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`AstraZeneca Exhibit 2040 p. 4
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