`Anthony Howell, Mitchell Dowsett
`
`Clinical review
`
`Regression of advanced breast cancer as a result of
`endocrine therapy was first described over 100 years
`ago.' Interest in this form of treatmentincreased when
`treatment with the antioestrogen tamoxifen after
`surgery for breast cancer was shown to improve
`patients’
`survival.’* Treatment also reduced the
`incidence of new cancers in the contralateral breast,
`which has led to a number of trials of tamoxifen as a
`preventive measure in women athigh risk.‘ New, poten-
`tially more active endocrine agents are now being
`introduced into clinical practice. In this review we
`outline the mechanism of action of these treatments
`and summarise recent results of clinical trials assessing
`their efficacy in comparison with older drugs; we also
`speculate about future trends in endocrine therapy and
`summarise clinical trials in progress.
`
`Methods
`
`This article is based, in part, on our own collaborative
`experimental work andclose association with pharma-
`ceutical companies developing new endocrine agents.
`Additional reviews andoriginal articles were obtained
`from searches of oncological 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 ofoestrogen to its receptor in
`the nucleus of responsive cells or reduce serum and
`tumour concentrations of oestradiol. In postmenopau-
`sal women androgens (mainly from the adrenal
`glands) are converted into oestrogens by the enzyme
`aromatase, which is presentin a range oftissues andis
`foundin 60-70% of breast carcinomas.”
`The trend for endocrine therapies over the past
`100 years has been towards simpler and more widely
`applicable treatments. Originally pharmacological
`doses ofoestrogens were used to block theproliferative
`effect of oestrogen, but now this is achieved with
`tamoxifen.’ Oestrogen concentrations were reduced by
`surgery (oophorectomy, adrenalectomy, and hypophy-
`sectomy), but now analogues of luteinising hormone
`releasing hormone, which effectively ablate ovarian
`steroidogenesis, may be used in premenopausal
`women; aromatase inhibitors are used in postmeno-
`pausal women.
`
`BMJ VOLUME 315 4 OCTOBER 1997
`
`
`
`Tamoxifen is an antioestrogen but has a complex
`pharmacology, partly due to its metabolism to numer-
`ous biologically active compounds. It is an oestrogen
`agonist-antagonist
`that depends on its competitive
`binding to oestrogen receptors. Several other bio-
`chemical pathways are affected by tamoxifen, but their
`clinical
`importance is doubtful;
`the predominant
`importance of the oestrogen receptor dependent
`pathway is
`supported by clinical
`responses
`to
`tamoxifen being largely confined to tumours positive
`for oestrogen.
`In an oestrogenic environment tamoxifen stops the
`proliferation ofbreast cancer cells that bind to oestro-
`gen receptors, Butif oestrogen concentrations are low,
`tamoxifen mayact as an oestrogen agonist andlead to
`the proliferation of these cells, at least
`in model
`systems. Reducing this agonistactivity has become the
`major target of new drugs andhas led to the develop-
`ment of non-steroidal drugs that act like tamoxifen, as
`well as steroidal compounds that are derivatives of
`oestradiol.’ These two groups differ in their interaction
`with oestrogen receptors. The non-steroidal com-
`
`BMJ 1997;315:863-6
`
`863
`
`This content downloaded from 128.220.8.15 on Sun, 17 Jan 2016 03:10:36 UTC
`All use subject to JSTOR Terms and Conditions
`
`AstraZeneca Exhibit 2040 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00904
`
`
`
`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 coactivators and corepressors 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 III developmentinclude toremifene,
`droloxifene, TAT-59, and idoxifene. Other
`than
`toremifene, each of these has improved antagonist-
`agonist balance in standard model systems such as the
`immature rat uterine weighttest." °
`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
`oestrogen receptor
`is effectively inactive. There is
`debate as to whether this is due to lack ofdimerisation
`in the oestrogen receptoror a lack of bindingto oestro-
`gen response elements, but it seems clear that the acti-
`vating functions are blocked andthatthestability of the
`oestrogen receptor is reduced such that the oestrogen
`receptor content of the tumouris greatly reduced.
`Both Faslodex and idoxifene are more effective
`antitumour agents than tamoxifen in animal model
`systems, and both show activity in cells and tumours
`that have becomeresistant to tamoxifen.’
`Conyentional 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 andapoptosis are measured in primary breast
`carcinomas after short
`term, presurgical
`treatment
`with the drugs before surgery." "
`Tamoxifen’s oestrogen agonist activity is advanta-
`geous on some tissues other than breast cancer,
`including bone and liver, but not endometrium.
`Experimental evidenceindicates that chemical modifi-
`cations can enhancethe therapeutic efficacy and toler-
`ability of non-steroidal compounds and lead to a
`group of compoundscalled SERMS(selective cestro-
`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 compoundsofthis
`type will soon enter clinical development for breast
`cancer treatment and are candidates for breast cancer
`prevention strategies."
`
`Table 1 Recently reported phaseIII and randomised phase || trials of new non-steroidal
`antioestrogens
`
`Drug (ref)
`Tamoxifen versus toremifene'*
`
`Dose
`(mg/day)
`20
`
`No of
`patients
`215
`
`Response
`(%)*
`19
`
`Comment
`Phase III trial as first line
`treatment in advanced disease
`:
`
`21
`| 221
`200
`212
`22
`
`Droloxifene’® a BS 30
`Randomised phase|Itrial
`
`BC 40
`88
`47
`oO a
`100
`96
`a4
`Randomised phaseIl trial
`10
`15
`15
`TAT-59'5
`Se 20 1
`55
`gg 88 31
`
`“Complete response plus partial response,
`
`864
`
`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 because (with the exception of
`toremifene) they have reduced agonist activity.
`‘Table 1 shows some recent studies of new antioes-
`trogens. A phaseIII trial found that toremifene was not
`superior to tamoxifen.'' The analogue droloxifene
`seemedactive in phase II trials when used at doses of
`20-100 mg/day, as did the Japanese drug TAT-59."* '*
`We need more information from phaseII trials about
`idoxifene and data from phase II trials comparing
`tamoxifen with droloxifene, TAT-59, and idoxifene,
`The pure antioestrogen ICI 182780 (Faslodex)
`showed little agonist activity in preclinical tests and in
`the only clinical
`tial
`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 data.
`
`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 effectiveness, but such assays have not
`been sufficently sensitive to provide reliable compari-
`sons between inhibitors. Isotopic methodsthatdirectly
`measure the inhibition of enzymeactivity throughout
`the body have provided more useful comparative data.
`There is no evidence that any of the inhibitors
`differentially inhibit aromatasein different tissues. The
`inhibitors may be consideredas two families, steroidal
`and non-steroidal.
`
`Non-steroidal
`All of the non-steroidal agents are active orally. Until
`1992 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 glucocorticoid as a
`“medical adrenalectomy.” When aminoglutethimide’s
`clinical effectiveness was shown to be dueto its inhibi-
`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
`triazole
`(Arimidex),""* letrozole (Femara),'™ and vorozole
`(Rivizor)* * have all been shown to have excellent
`selectivity for aromatase in preclinical models, and this
`has been confirmedin clinical studies. Their intrinsic
`potency is considerably greater than that of amino-
`glutethimide. In patients, aminoglutethimide inhibits
`total body aromatisation by about 91%, while anastro-
`
`BMJ VOLUME 315 4 OCTOBER 1997
`
`This content downloaded from 128.220.8.15 on Sun, 17 Jan 2016 03:10:36 UTC
`All use subject to JSTOR Terms and Conditions
`
`AstraZeneca Exhibit 2040 p. 2
`
`
`
`
`
`Clinical review
`
`
`
`Table 2 Recently reported phaseIll trials which compare standard secondline endocrine therapy with the new triazole inhibitors
`Dose
`No of
`Proportion (%) of
`Median survival
`
`Drug
`(mg/day)
`patients
`patients responding
`(months)
`Comment
`
`Anastrozole"®
`1
`263
`42.2 (+80)
`26:7
`a
`;
`;
`
`Anastrozole
`:
`10
`248 ee eee
`
`22.5
`Megestrol acetate
`160
`253
`40.3
`a
`
`Letrozole?”
`05
`188
`12.8 (-SD)
`226
`-
`;
`Aerie 6 81 tore28mg
`
`Megestro! acetate
`160
`189
`16.4
`23.5
`
`-
`Letrozole=
`05
`“Total 555
`167 (-SD)
`No data
`_
`-
`Letrozole
`25
`7.8
`_
`_____ Trendfor survival advantage for both
`
`Aminoglutethimide plus hydrocortisone
`*
`=
`ile
`=
`testeG
`
`
`277
`47 (+80)
`~95.7
`Vorozole®
`25
`7
`oo
`
`:
`500. O79
`=
`;
`Trend for survival advantage with
`=
`——
`Aminoglutethimide plus hydrocortisone
`=e
`——— vorozole
`279
`37
`217
`30
`
`-
`Vorozole?
`28.0
`25
` ~—-190
`10.5 (-SD)
`Megestrol acetate - 160 485 CO 76 28.7
`
`
`
`
`
`“Complete response plus partial response; SO=stable disease (=6 months),
`
`their recommended doses of
`zole and letrozole, at
`1 mg/day and 2.5 mg/day, inhibit by about 97%and
`> 99%, respectively.” In many patients this results in
`plasma oestrogen concentrations which even the most
`sensitive immunoassays cannot detect.”
`
`Steroidal
`Two of the steroidal agents, formestane and exemes-
`tane, have undergone considerable clinical develop-
`ment. Formestane (4-hydroxyandrostenedione; Len-
`taron) was thefirst 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. Exemestane is orally
`active and seems to be selective at clinical doses.” No
`data have been published onits effects on whole body
`aromatisation. The only pharmacological data from a
`randomised comparison between any ofthe inhibitors
`showed the superiority of anastrozole over formestane
`in suppressing plasma oestradiol.”
`
`logical since stable disease gives equivalentpalliation
`and survival.” The durations of response of the new
`agents have tended to be longer than the old, but even
`more importantare the survival advantages shown by
`new agents. The trial with the longestfollow up shows
`that anastrazole | mg has significant survival advan-
`tage over megestrol acetate 160 mg,” and the other
`trials show trends towards survival advantages.The uni-
`formity of this difference suggests that these trends are
`likely to become significant with further follow up.
`
`Trials in progress
`Theintroduction of new agents andtheresults oftrials
`generate new questions and the need for newclinical
`trials. Table 3 outlines trials in progress or which are
`due to start shortly.
`We need to know whether the new non-steroidal
`antioestrogens (idoxifene, droloxifene, TAT-59)
`that
`showbetter preclinical characteristics than tamoxifen
`are better clinically. Large trials comparing all three
`new agents with tamoxifen are ongoing. The pure
`antioestrogen Faslodexlooks highly promisingin vitro,
`in animal studies, and in early phase II tests. However,
`phase I studies
`are notoriously unreliable in
`
`Clinical results
`Table 2 showsthe results of recent randomised clinical
`trials comparing aromatase inhibitors with standard
`second line endocrine therapy (after tamoxifen), The
`trials for letrozole and anastrozole had three arms: two
`doses of the new aromatase inhibitor compared with
`either the progestogen (megestrol acetate) or the old
`aromatase inhibitor (aminoglutethimide). Vorozole has
`been tested against these same comparators at a single
`dose in trials with two arms.” “
`triazole
`All
`three of
`the new non-steroidal
`derivatives (anastrozole, letrozole, and vorozole) and
`the steroidal derivative exemestane have shown
`minimal toxicity. In particular, they do not produce the
`troublesome weight gain of megestrol acetate nor the
`Tamoxifen
`Anastrozole
`Anastrozole
`Tamoxifen
`rash and neurological symptoms of aminoglutethim-
`
`ide. Since all four compounds are specific aromatase
`Both a
`— -
`—_
`Tamoxifen 2 years
`Tamoxifen 3 years
`Anastrozole
`
`inhibitors, glucocorticoid replacementis not required.
`
`Anastrozole 3 years
`Faslodex
`In general, all the trial results point in the same
`Letrozole
`Tamoxifen
`Letrozole
`
`direction. Overall response rates with the new and the
`Letrozole
`_
`_
`Tamoxifen
`Tamoxifen 5 years
`Placebo 5 years
`Vorozole
`old treatments are similar. Responses have been
`reported as either complete and partial remissions or
`a oe
`Vorozole 5 years a :
`Exemestane
`Tamoxifen2-3 years
`Tamoxifen 2-3 years
`Exemestane
`as complete and partial remissions and stable disease
`Exemestane 2-3 years|Megestrol acetate
`for at least six months. The latter reports are more
`
`Table 3 Clinical trials using endocrine therapy projected or in progress in early
`(adjuvant) and advanced breast cancer (phase II!)
`
`Treatment
`Adjuvant breast cancer
`Advanced breast cancer
`
`Receptor blockade:
`\doxifene
`=
`20mg v40mgv20m0
`
`7
`.
`tamoxifen
`:
`_
`Droloxifene
`—
`20mg v 20 mg tamoxifen
`
`7
`_TAT-59
`_
`~20mg v.20mg tamoxifen
`7
`20 mg v 20 mg tamoxifen
`125 mg v 250 mg v 20 mg
`Faslodex (IC 182780)
`tamoxiten
`
`Oestrogen receptor.
`Anastrozole
`
`:
`
`BMJ VOLUME 315 4 OCTOBER 1997
`
`865
`
`This content downloaded from 128.220.8.15 on Sun, 17 Jan 2016 03:10:36 UTC
`All use subject to JSTOR Terms and Conditions
`
`AstraZeneca Exhibit 2040 p. 3
`
`
`
`ee
`
`2s
`
`Chander SK, Newton C, McCague R, Dowsett M, Lugmano Y, Coombes
`RC. Pyrroledine-4-iodotamoxifen and 4-iodotamoxifen, new analogues
`of the antioestrogen tamoxifen for the treatment ofbreast cancer, Cancer
`Res 1991;51:585 1-8.
`9 Wakeling AE, Dukes M, BowlerJ. A potent specific pure antiestrogen with
`clinical potential. Cancer Res 1991;51:3867-73.
`10 De Friend DJ, Howell A, Nicholson RI, Anderson E, Dowsett M, Mansel
`RE, et al. Investigation of a new pure antioestrogen (ICI 182780) in
`women with primary breast cancer. Cancer Res 1994;54:408-14,
`11 Ellis PA, Saccani Joti G, Johnston SRD, E Anderson, A Howell, R
`A'Herne,et al. Induction of apoptosis by tamoxifen and ICI 182780 in
`primary breast cancer. /ntJ Cancer 1997;72:608-1 1,
`12 Sato M, Glasebrook AL, Bryant HU. Raloxifene: a selective estrogen
`receptor modulator,|Bone Miner Met 1994;12(suppl 2):S9-20.
`13 DeFriend DJ, Anderson E, Bell J, Wilks DP, West CML, Mansel RE,et al.
`Effects of4-hydroxytamoxifen and a pure antioestrogen (ICT 182780) on
`the clonogenic growth of humanbreast cancercells in vitro. Br Caneer
`1994;70:204-11.7
`Hayes DF, Van ZylJA, Hacking A, Goedhals L, Bezwoda WR, MailliardJA,
`et al. Randomised comparison of tamoxifen and two separate doses of
`toremifene in posunenopausal patients with metastatic breast cancer. |
`Clin Oncol 1995;13:2556-66,
`15 Rauschning W, Pritchard KL Droloxifene, a new antioestrogen:its role in
`metastatic breast cancer, Areast Cancer Res Treat 1994;31;83-94,
`16 Tominaga T. Early phase Tl clinical study ofTAT-59 (new antioestrogen) in
`patients with advanced breast cancer. 14th International Gongress of
`Chemotherapy, Montreal, Canada, 1995.
`17 Howell A, DeFriend DJ, RobertsonJFR, Blamey RW, Anderson L, Ander-
`son E, et al. Pharmacokinetics, pharmacological and anti-tumour effects
`of the specific antioestrogen ICI 182780 in women with advanced breast
`cancer. Br{ Cancer 1996;74:300-8.
`18 Schwarzel WC, Kruggel WG, Brodie HJ. Studies on the mechanism of
`estrogen biosynthesis. VIII. The developmentof inhibitors of the enzyme
`system in human placenta. Endocrinology 1973;92:866-80.
`19 Buedar A, Jonat W, Howell A, Jones SE, Blomqvist C, Vogel CL, et al.
`Anastrozole, a potent andselective aromatase inhibitor, versus megestrol
`acetate in postmenopausal women with advanced breast cancer: results
`of overview analysis of two phase II trials./ Clin Oncol 1996;14:2000-11,
`20 Buzdar A,Jonat W, Howell A, Yin H, Lee D. Significant improved survival
`with Arimidex (anastrozole) versus megestrol acetate in postmenopausal
`advanced breast cancer: updated results of two randomized trials
`[abstract]. Proc Am Soe Clin Oncol 1997;16:156,
`Smith I, Dombernowsky P, Falkson G, Leonard, R, Panasci L, BellmuntJ,
`etal. Double-blind trial in postmenopausal women with advanced breast
`cancer showing a dose-effect and superiority of 2.5 mg letrozole over
`megestrol acetate. FurJ Cancer 1996;32A(supp! 2):49.
`22 Marty M, Gershanovich M, Campos B, Romien G, Lurie H, Bonaventura
`T, et al. Letrozole, a new potent, selective aromatase inhibitor superior to
`aminogiutethimide (AG)
`in postmenopausal women with advanced
`breast cancer previously treated with antioestrogens [abstract], Proc Am
`Soe Clin Oncol 1997;16:156,
`23 Bergh,J, Bonneterre J, Houston SJ, Uiger HJ, Murray R, NortierJ, et al.
`Vorozole (Rivizor) versus aminoglutethimide (AG) in the reanment of
`postmenopausal breast cancer relapsing after tamoxifen [abstract]. Proc
`Am Soe Clin Oncol 1997;16:156.
`24 Goss P, Winer E, Tannock 1, Schwartz LH, Kremer AB for the North
`American Vorozole Study Group. Vorozole vs megace in postmenopau-
`sal patients with metastatic breast carcinoma who had relapsed following
`tamoxifen [abstract]. Proe Am Soc Clin Oncol 1997;16:155.
`25 Dowsett M, Biological background to aromatase inhibition. The Breast
`1996;5:196-201,
`26 Coombes RC, Hughes SWM, Dowsett M, 4-Hydroxyandrostenedione:
`A new treatment for postmenopausal patients with breast cancer EurJ
`Cancer 1992;28.4:1941-5,
`27 Di Salle E, Ormati G, Paridaens R, Coombes RC, LobelleJP, Zurlo MG.
`Preclinical and clinical pharmacology of the aromatase inhibitor exemes-
`tane (FCE 24304),
`In: Motta M, Serio M, eds. Sex hormones and
`antihormones in endocrine
`¢ pathology: basic and clinical aspects.
`Amsterdam, Elsevier, 1994:303-9.
`28 Dowsett M, Vorobiof DA, Kleeberg UR, Carrion RP, Dodwell Dj, Robert-
`sonJFR, et al. A randomized study assessing oestrogen suppression with
`arimidex (anastrozole) and formestane in
`uisal advanced
`breast cancer patients. Hur| Cancer 1996;32A(suppl2):49,
`29 Howell A, Mackintosh J, Jones M, Redford J, WagstaffJ, Sellwoood RA.
`‘The definition of the “no change” category in patients treated with endo-
`crine therapy and chemotherapy for advanced carcinomaof the breast.
`EurJ Cancer Clin Oncol 1988;24:1567-72.
`(Accepted 5 August 1997)
`
`
`Bennett, ed. Philadelphia: Hanley and Belfus, 1997)
`
`Endpiece
`Misleading appearances
`A woman accompanied her husbandto the doctor
`and waited for him during his checkup. After the
`examination the doctor came out and said, “TI don't
`like the way your husband looks.” “Neither do I”
`said the woman,“but he’s good with the kids.”
`From The Best ofMedical Humour (Howard J
`
`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
`Oestrogen receptor blockade Reduction of oastrogen concentrations
`
`Past
`Hyphophysectomy
`Highdose oestrogens
`Adrenallectomy
`Aminogiutethimide
`Oophorectomy 7
`4-OH androstenedione= -
`Anastrozole
`Letrozole
`;
`Luteinising hormone releasing hormone agonists
`
`: F
`
`Non-steroidal:
`Droloxifene
`Vorozole
`Idoxifene
`a Bemestane
`
`TAT-59
`Sulphatase inhibition
`Selective oestrogen receptor
`Luteinising hormone releasing hormone antagonists
`modulators (eg raloxifene)
`Steroidal:
`
`\C1182780 (Fasiodex)
`
`uture
`
`predicting superiority over old agents. Thus the
`recently started study comparing Faslodex with
`anastrozole as second line endocrine therapy for
`advanced disease and the comparison of Faslodex with
`tamoxifen as first line treatmentthat is to start late in
`1997 are highly important.
`The success of the new aromatase inhibitors as
`secondline 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 therapies. The optimal duration
`for tamoxifen as an adjuvant seems to be five years.
`Studies are in progress or shortly to start in which a
`changeover to an aromatase inhibitor after 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 treatmentis also being tested.
`
`Conclusions
`
`Although theprinciples 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 terms of response duration and, most importantly,
`survival.
`
`Funding: No additional funding.
`Conflict of interest: We are involved and have been involved
`in the clinial development of many of the compounds
`mentioned in this review.
`
`1 Beatson GT. On the treatment of inoperable cases of carcinomaof the
`mamma. Suggestions for a new method of treatment with illustrative
`cases. Lancet 1895;2:104-7.
`2 Cole MP, Jones CTA, Todd [IDH. A new anti-oestrogenic agentin late
`breast cancer: an early clinical appraisal of ICI 146474. Br J Cancer
`1971;25:270-5.
`3 Early Breast Cancer Triallists Co-operative Group (EBCTCG), Systemic
`treatment of early breast cancer by hormonal, cytotoxic, or immuno-
`therapy, Lancet 1992;339;1-15,71-85.
`4 Cuzick J, Baum M. Tamoxifen and contralateral breast cancer. Lancet
`1985;i1:282.
`5 Lippman M, Monaco ME, Bolan G, Effects of oestrone, estradiol and oes-
`triol on hormone responsive human breast cancer in long term tissue
`culture.Cancer Res 1977; 37:1901-7,
`6 Miller WR. Endocrine treatment for breast cancers: biological rationale
`and current progress.| Steroid Biochem Mol Biol 1990;37:467-80.
`7 Howell A, DeFriend D, RobertsonJ, Blamey R, Walton P. Response to a
`specific antioestrogen (ICI 182780) in tamoxifer-resistant breast cancer,
`Lancet 1995;345:29-30,
`
`866
`
`BMJ VOLUME 315 4 OCTOBER 1997
`
`This content downloaded from 128.220.8.15 on Sun, 17 Jan 2016 03:10:36 UTC
`All use subject to JSTOR Terms and Conditions
`
`AstraZeneca Exhibit 2040 p. 4
`
`