Clinical review
`
`Recent advances in endocrine therapy of breast cancer
`Anthony Howell. Mitchell Dowsett
`
`Regression of advanced breast cancer as 3 result of
`endocrine therapy was first described over 100 years
`ago.‘ lntenestin this form of traunent increased when
`treatment with the antiotsttogen tamostifen afiaer
`surgery for breast cancer was shown to improve
`patients’
`sm-vival." Trmnnent also reduced the
`incidence ofnew rancem in the contralateral breast,
`whicl1has1edtoantnnberofn*ia]sofI:tmo)t'tfenasa
`
`preventive measureinwomen at high risk.‘New,pot1en-
`tiallymorearnivreeridoaineagenzsarenowbeirig
`introduced into clinical practice. In this review we
`outlinethemechanismofaetionoftheselreannents
`andsunnnarisereoentremltsofdirtirraluiaisassessing
`theireflicacyin::omparisonwitholderdnrgs;wealso
`spemlateahoutfirnireuendsinendocrinc therapy and
`sunnnafisedinimlnialsiripmgresx
`
`Methods
`
`This article is based. in parton our own collaborative
`expeftmental work and close association with pharma-
`oeutical colnpanies developing new endocrme agents.
`Additional reviews and original articles were obtained
`from searches of onoological journals. Recent data
`were obtained from presentations at the May meeting
`of the American Society for Clinical Oneologyt
`
`Mechanism of action of newer endocrine
`therapies
`Breast canoe-.r cells that are endocrine dependent need
`oestrogen to proliferate.’ Most endocrine therapies
`either block the binding of oestrogen to its receptor in
`the nucleus of responsive cells or reduce serum and
`lzumour concentrations ofoestradiol. In postmenopau-
`sal women androgens (mainly from the adrenal
`glands) are converted into oestrogens by the enzyme
`mumatasqwhichispresmtinaraitgeoffismes andis
`found in 60-70% of breast carcinomas.‘
`The trend for endocrine therapies over the past
`100 years has been tovrattis simpler and more widely
`appliaihle treatments. Originally pharmaeological
`doses ofoestrogens were used mbloclt the proliferative
`efi'ectofoestrogen,butnowthisisachievedwith
`tamoxifen.” Oestrogen concentrations were reduced by
`surgery (oopharecmmy, adrenalectomy, and liypophy~
`sectomy), but now analogues of lute-inising hormone
`releasing hormone, which efiectively ahlate ovarian
`stemiclogenesis, may be used in prernenopausal
`women; arnmatase inhibitors are used in postntu1o-
`pausal women.
`
`BM] VOLUMESIS 4 OCTOBER 1997
`
`
`
`Antioestrogensl
`Pharmacology
`Tamoxifen is an antiorstrogen but has a complex
`pharmacology. partly due to its metabolism to numer-
`ous biologically active compounds It is an oestrogen
`agonisbantagonist that depends on its competitive
`binding to oestrogen receptors. Several other bio-
`chemiral pathways are affected by tamoxifen, but their
`clinical
`importance is douhtfu};
`the predominant
`impormnee of the oestrogen receptor dependent
`pathway is
`supported by clinical
`response:
`to
`tamottifen being largely confined to tumours positive
`for oestrogen
`In an oestrogenic environment t:unox.ifen stops the
`pi-oli.fi:ra.tion ofbreast cancer cells thathind to oestro-
`gen receptors. But tfoestrogen concentrations are low.
`uimoucitienmayactasanoesuogen agonistandleadto
`the proliferation of these cells, at least in model
`systems. Redudng this agonist activity has become the
`ma_jortargetofnewdrugsandhasledtotl1edevelop-
`ment of non-steroidal drugs that actlilte tamoxifen, as
`well as steroidal compounds that are derivatives of
`oesI:radiol.7 These two groups d.ifl'er in their interaction
`with oestrogen receptors The non-steroidal com-
`
`CRC l
`
`aw 199%!-}5:B53-6
`
`863
`
`This content downloadedfrom 128.220.8.15 on Sun, 17 Jan 2016 03:10:36 UTC
`All use subject to JSTOR Tcrms and Conditions
`
`Astrazeneca Ex. 2040 p. 1
`Mylan Pharms. Inc. V. AstraZeneca AB IPR2016-01324
`
`

`
`Clinical review
`
`pounds bind to oestrogen receptors, leading to their
`activation and dimcrisation and their binding to
`specific oesuogen 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 ofdmg and oestrogen recep-
`tor. Drugs of this type which are in or have recently
`completed phase III development include toremifene,
`clroloxifene, TAT-59, and idoxifcne. Other
`than
`toremifene, each of these has improved antagonist-
`agonist balance in standard model systems such as the
`immature rat uterine weight test." ”
`In contrast, the steroidal antagonists (exenrplified by
`ICI 182780. Faslodcx) have been chamcterised 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 receptor or a lack ofbinding to oestro-
`gen response elements, but it scans clear that die acti-
`vating functions arc blocked and that the stability of the
`oestrogen receptor is reduced such that the oestrogen
`receptor content of the tumour is greatly reduced.
`Bod-t Faslodex and idoxifene are more efl’ecn've
`
`antitttmour agents than tamoxifen in animal model
`systems, and both show activity in cells and rumours
`that have become resistant to tamoxifen.’
`Conventional clinical pharmacology of the new
`antioestrogcns has not been instnlctive for
`their
`cliriical development because there are no good surro-
`gate markers of their activity against cancer. Tl'teir
`clinical development
`is being helped by a novel
`approach, in whid: pathological markers of prolifeI'.1-
`tion and apoptosis an: measured in primary breast
`carcinomas alter short
`term, prc-surgical
`treatment
`with the drug before surgery."' "
`Tamox'tfen's oestrogen agonist activity is advanta-
`geous on some tissues other than breast cancer.
`including bone and liver, but not endntneuiutu.
`Experimental evidence indicates that chemical modifi-
`cations can enhance the therapeutic efiicacy and toler-
`ability of non-steroidal compounds and lead to a
`group of compounds called SI-ZRMS (selective oesn-as
`gen receptor modifiers). An example is raloxifene,
`which is
`in its late stages of" development as an
`antiosteoponotic agent; it lacks the breast and endorne»
`trial stimttlation of oestrogen. New compounds of this
`type will soon enter clinical development for breast
`cancer treatment and are candidates for breast catnccr
`prevention strategies."
`
`Tabla 1 Recently reported phase ill and randomised phase II trials at new non-steroidal
`antiuestmgens
`
`.
`.
`“'°“"'l
`Tarnuxllen versus turemifene“
`
`Dun
`l£L'_!‘.'|'1
`20
`
`III: at
`.|1!'£'_."'.'
`215
`
`Itupanta
`l"“,_l'___“"'“’_."""“'. _ .__ _._
`$9
`Phasa Ill trialas first lint
`lrezlmant in advanced disease
`
`V‘
`21
`221
`—!'-_*_6ll‘
`..
`.29
`2”,
`_ ._,- __ _ , _ _2°,°.. _
`Randomised pnasa n ma:
`39
`an
`llrnlnttltene”
`20
`_'_ i ___-_’:*97__ Lilli." '. vf _ V: : "Z : '_
`100
`96
`44
`
`la
`Thf-59“
`W‘ *7 “i ‘to
`— — 1 7 t 7
`'I'.'t:rnplato response plus partial tasnnnse.
`
`15
`11
`I3
`
`15
`55
`31
`
`nanuo_mssoa_pnasg n ma:
`
`B64
`
`Clinical results
`Tamoxifen is the “gold standard,” but its agonist elfect
`rnay stimulate tumour growth and cause ueaunent to
`fail." The newer non-steroidal amioestrogens have
`been developed berause (with the exception of
`toremifene) they have reduced agonisl activity.
`Table 1 shows some recent studies of new amines-
`trogens A phase 1]] trial found that toremifene was not
`superior to tamoxifen." The analogue droloxifene
`seemed active in phase I] trials when used at doses of
`20-100 mg/day, as did the japanese drug TA"l"—59.""‘ '5
`We need more information from phase II trials about
`idoxifene and data from phase III trials comparing
`tamoxifen with d1"0l0XlfC1'llE,TAT-59, and idoxifene.
`The pure anlioesuogen ICI 182780 (Faslodeid
`showed little agonist activity in preclinical tests and in
`the only
`trial
`in advanced breast cancer
`pcrfonned 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.
`
`Aromatasc inhibitors
`
`Pharmacology
`Using ammatase 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 concentmtiolls have been widely used to assess
`pharrnacological eflccliveness, but such assays have not
`been sulficcntly 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
`diifcrcntially inhibit aromatase in dilferent tissues. The
`inhibitors maybe considered as two families, steroidal
`and non-steroidal.
`
`N01:-steroidal
`All of the non—steroidal agents are active orally. Until
`i991.’ the only widely available inhibitor was aminog'lu-
`tclhimide. This drug inhibits several cytochrome P459
`enzymes, including some involved in stemidogenesis,
`and has been widely used in breast cancer in combina-
`lion with replacement doses of glucocorticoid as a
`“medical adrenalectomy.“ When an1inoglutetl1imide's
`clinical effectiveness was shown to be due to its inhibi-
`tion of aromatasc, this enzytne 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 dnlgs.
`anaslzrozole
`A series of
`Iriazole derivatives,
`(Ari111idex),"""" letrozole (Fema.ra),“' *2 and vorozole
`(Rivimr)”" have all been shown to have excellent
`selectivity for aromatase in preclinical models, and this
`has been conlirmorl in dinical studies. Their intrinsic
`
`potency is considerably greater than that of amino-
`glutethimidc. In patients. arninoglutcthimicle inhibits
`total body arornatisafion by about 91%, while masto-
`
`BM] VOLUME 315
`
`-l0C‘l'0Bl!‘.R 199?
`
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`All use subject to JSTOR Terms and Conditiom
`
`Astrazeneca Ex. 2040 p. 2
`
`

`
`Clinical review
`
`Tahla 2 Recently reported phase III trials which compare standard second line endrrcrine therapy with the new triazole inhibitors
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`7
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`vorazola
`
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`
`logical since stable disease gives equivalent palliation
`and survival.” The dtrrafions of response of the new
`agents have tended to be longer than the old, but even
`more irnportant are the survival advantages shown by
`new agents. The trial with the longest follow up shows
`that anastrazole 1 mg has sigrrilicanr survival advarr
`rage over megestrol acetate 150 mg,“ and the other
`trials show trends towards survival advant3ge'.s.'l"he uni-
`formity of this difference 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 nmrsteroidal
`anlioestzrogerrs (icloxifene, droloxifene, TAT-59)
`that
`show better preclinical charactefistics than tamoxifen
`are better clinically. Large trials comparing all three
`new agents with tamoxifen are ongoing. The pure
`antioestzrogen Fasiodex looks highly promising in vim).
`in animal studies, and in early phase 11 tests However,
`phase
`II
`studies
`are notoriously unreliable
`in
`
`zole and lelsrozole, at their recommended doses of
`1 mg/day and 2.5 mg/day, irthibit by about 97% and
`>9Q%, 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 memes-
`Iane, have undergone considerable clinical develop-
`ment. Fonnestane (4-hydroxyandrostenedione; Len-
`taron) was the first selective inhibitor to be licensed?‘ It
`is given by intmmtlscular injection because it
`is
`rnetabolised too quickly if taken orally.
`It
`is more
`Specific than aminoglutethimide but does not have
`more pharmacological activity. Excmestane is orally
`active and seems to be selective at clinical doses.” No
`data have been published on its eifects on whole body
`aromztisarion. The only pharmacological data from a
`randomised comparison between any of the inhibitors
`showed the superiority of anaslrozole over formestanc
`in suppressing plasma oeso'adioI."‘
`
`Clinical results
`Table ‘2 shows the results of recent randomised clinical
`
`trials comparing aromatase inhibitors with standard
`second line endocrine therapy (after tamoxifen). The
`trials for lerrozole and anastrozole had three anus: two
`
`doses of the new arnmatase inhibitor compared with
`either the progestogen lmegeslrol acetate} or the old
`aromatase inhibitor (a.minogluIed1imide).Vorozole has
`been tested against these same comparators at a single
`dose in trials with two anus.” "‘
`triazole
`All
`three of
`the new non-steroidal
`derivatives (anastrozole, letrozole. and voroaole) and
`the steroidal derivative exernestane have shown
`
`minimal toxicity. In particular, they do not produce the
`troublesome weight gain of rrregestrol acetate nor the
`rash and neurological symptoms of a.minoglut-ethim-
`ide. Since all four compounds are specific aromatase
`inhibitors, glucocorticoid replacement is not required.
`In general, all the trial results point in the same
`direction. Overall response rates with the new and the
`old treatments are similar. Responses have been
`reported as either complete and partial remissions or
`as cornplete and partial remissions and stable disease
`for at least six rnonths. The latter reports are more
`
`EM] VOLUMIESI5 -I O(.'l‘()Bl£R I997
`
`Table 3 Clinical trials using endocrine therapy projected or in progress in early
`(adjuvant) and advanced breast cancer (phase Ill)
`‘treatment
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`
`This content downloaded from 128.220.23.15 on Sun, 17 Jan 2016 03:10:36 UTC
`All use subject to JSTOR Terms and Condition;
`
`Astrazeneca Ex. 2040 p. 3
`
`

`
`Clinical review
`
`Talill 4 Past. present. and potential ltrture treatment at advanced breast cancer by
`blocking oestrogen receptor or reducing concentrations of oestrogenic steroids in
`postrnonooausal patients
`tlutnun ncopu-r trluhu
`llluti dose rrsstroasns
`
`lhlrnrtton ll outrun unusnntultons
`
`F331
`
`i Antlndoltttstnlrrrlos
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`
`lion-steroidal
`
`Drolnxilana
`JP"'i‘°
`TAT-59
`Bslsctiw oestrogen racoptur
`modulators (en ralaidianel
`Sttrrolttat
`lCll82?8ll (fasiodsxl
`
`K
`V Vumiola
`E{°''''.'.‘''.°'f"''i .. _ _
`Sulphafiw lnltilrilion
`Lutatnising hormone releasing hormone antagonists
`
`- ,
`
`- _
`
`predicting superiority over old agents. Thus the
`recently started study comparing Faslodex with
`anaslmzole as second line endocrine therapy for
`advanced disease and the comparison ofFaslodex with
`tamoxifen as first line treatment that is to start late in
`1997 are highly important.
`The success of me new ammatase inhibitors as
`second line treatments for advanced disease has led to
`
`the initiation of trials using these drugs as lirst 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 arotnata.se inhibitor alter two or
`three years of tamoxifen is compared with continuous
`tamoxifen (table 3). Change to an aromatase inhibitor
`after litre years of tamoxifen in comparison with
`stopping all treatment is also being tested
`
`Conclusions
`
`Although the principles ofendocrine 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.
`
`Fr.md'mg: No additional Funding.
`Conflict of interest: We an involved and have been involved
`in the rlinial development of many of the compounds
`mentioned in this review.
`
`I
`
`fleatson GTZ On the neaunmt of inoperable case: of avcinoma of the
`mamma. Suggestions for a new metlmd of Irnmwttt with illl.lJfl'al:i|f£
`cases Lqvuzt l895:2:l0£-7.
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`bras! can-zer: an arty diriiml appraisal of ICI 146474. Sir] Carrion
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`creaunmt of only brunt cancer by hormonal. rytutmic, or immuno-
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`Li.p}:rn:ran M. Monaco ME,Bo1a.n G.EEects t‘J[DE5ItL’1l'£.¢!Cl'al‘l.l.()l 1nd oes-
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`Lima! l'395;3-}.'$'.29~50.
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`35$
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`clinitzl potem'J'ziL Cnrutrrflrs i991 5113867-73.
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`the clonogenic growth of human breast taxtcet cells in vitm Br} Gunner
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`
`Endpiece
`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 wornaii, “but he's good with the kids'’‘
`From Theflest qfMed€¢:aI Humour (I-Inward]
`
`Bennett, ed. Philadelpl1ia:Hanicy and Belfits, 1997)
`
`BM] VOLUME 315 4OC[UB'ER 1997
`
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`Astrazeneca Ex. 2040 p. 4