Clinical review
`
`Recent advances in endocrine therapy of breast cancer
`Anthony Howell, Mitchell Dowsett
`
`Regression of advanced breast cancer as a result of
`endocrine therapy was first described over 100 years
`ago‘ Interest in this form of ueaunent increased when
`treatment with the antioestrogen tamoxifen after
`surgery for breast cancer was shown to improve
`patients‘
`survival.’ 3 Treatment also reduced the
`incidence of new cancers in the contralateral breast,
`whichhasledtoamunberoftrialsoftamoxifenasa
`
`preventive measure in women at high risk.‘ New, poten-
`tially more active endocrine agents are now being
`introducedintoclinic.alpractice.Inthisreviewwe
`outline the mechanism of action of these Iratments
`and summarise recent results ofclinical trials assessing
`their eflicacy in comparison with older drugs; we also
`speculate about fiitnre trends in endocrine therapy and
`summarise clinical trials i:n progress.
`
`Methods
`
`This article is based, in part, on our own collaborative
`experimental work and close as.-sociaxion with pharma-
`ceutical companies developing new endocrine agents.
`Addict"'onal reviews and original articles were obtained
`Eom 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 of oestrogen to its receptor in
`the nucleus of responsive cells or reduce serum and
`tumour concentrations of oestracliol. In postmenopau-
`sal women androgens (mainly from the adrenal
`glands) are converted into oestrogens by the enzyme
`aromatase, whidi is present in a range oftissues and is
`found in 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
`dosesofoestrogenswereusedtoblocktheproliferative
`efEectofoestrogen,butnowthisi.5achieved with
`tamoxifen." Oestrogen concentrations were reduced by
`surgery (oophorectorny, adrenaloctomy, and hypophy~
`sectomy), but now analogues of luteinising hormone
`releasing hormone, which eflecfively ablate ovarian
`steroidogenesis, may be used in premenopausal
`women; aromatase inhibitors are used in postmeno-
`pausal women.
`
`Bhfl VOLUME. 315 4 OCTIDBER 199'?
`
`CRC Depamnent
`
`Bllfl’ 1997;315:365-6
`
`‘Tamoxifen is an antzioestrogen 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-
`chemittal pathways are aifected by mmoxifen, but their
`clinical
`importance is doubtful;
`the predominant
`importance of the oestrogen receptor dependent
`patlrway is
`supported by clinical
`responses
`to
`tamoxifen being iargely confined to tumours
`for oestrogen.
`In an oestrogenic envirorunent tamoxifen stops the
`proliferation of breast cancer cells thatbind to oestro-
`gen receptors. But if oestrogen concentrations are low.
`tamoxifenmay actasan oestrogen agonistandlead 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 tamoxifen. as
`well as steroidal compounds that are derivatives of
`oestradiol.’ These two groups di.fl‘er in their interaction
`with oestrogen receptors. The non-steroidal com-
`
`863
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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 transtzription 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 development include 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 weight test.” 5'
`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 receptor or a lack ofbinding to oest:ro-
`gen response elements, but it seems clear that die acti-
`vating functions are blocked and that the stability of the
`oestrogen receptor is reduced such that the oestrogen
`receptor content of the tumour is greatly reduced.
`Bodi Faslodex and idoxifene are more effective
`
`antitumour agents than tamoxifen in animal model
`systems, and both show activity in cells and tumours
`that have become resistant to tamoxifen.’
`
`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,” "
`Tamoxifenb oestrogen agonist activity is advanta=
`geous on some tissues other than breast cancer.
`including bone and liver. but not enclometrium.
`Experimental evidence indicates that chemical modifi-
`cations can enhance the therapeutic eificacy and toler-
`ability of rton-steroidal compounds and lead to a
`group of compounds called SERMS (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 cndome-
`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 reported phase ill and randomised pnase II trials at new non-steroirtat
`antiuestrogens
`
`Itrun [I'll]
`Tarntmten versus turemitens"
`
`; — ‘ A T
`
`Data
`Illllfilll
`20
`
`‘ ml
`200
`
`_ _' _
`
`J:ITnln:§teie“‘
`T
`
`'rAr's9‘°
`
`“2ti'_7
`59
`10°
`1a
`TT TT ’2n
`__'7i*4'i§"
`
`'GtirnplerlJe raspunsa plus partial rasnonse.
`
`864
`
`221
`212
`
`_s-3'
`{*1
`9'5
`15
`11
`'13
`
`In nt
`patI_|_n_t:
`215
`
`ltunnnsa
`[air
`19
`
`21
`22
`
`cummultt
`Phase III trial as first Iin
`ll'B3llI'l8l'Il lfl advanoed disease
`'
`
`> iranuurnised phasalltrial
`an
`, 4?. _
`- _ c
`_
`“F
`is
`55
`31
`
`randomised pnasa II trial
`
`_
`
`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 st'tId.ies of new amines-
`
`trogens. A phase 1]] trial found that torernifene was not
`superior to tamoxifen.“ The analogue dmloxifene
`seemed active in phase I] trials when used at doses of
`20-100 mg/day, as did the Japanese drug TAT-593'" "5
`We need more information from phase II trials about
`idoxifene and data from phase III trials comparing
`tamoxifen with droloxifene,TAT-59, and idoxifene.
`The pure antioestrogen ICI 182780 (Faslodezxl
`showed little agonist activity in predinical tests 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-
`firrn 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 eficctiveness, but such assays have not
`been suflicently sensitive to provide reliable compari-
`sons between inhibitors. Isotopic methods dial directly
`measure the inhibition of enzyme activity throughout
`the body have provided more useful coniparative data.
`There is no evidence that any of the inhibitors
`dilferentially inhibit aromatase in diflerent tissues. The
`inhibitors may be considered as two families, steroidal
`and nor1—steroida.l.
`
`Nrm—stera2'da!
`
`All of the rton—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 sreroidogenesis,
`and has been widely used in breast cancer in combina-
`tion with replacement doses of glucocorticoid as a
`“medical adrenalectomy." When arninoglutethimide’s
`clinical effectiveness was shown to be due to its inhibi-
`
`tion ol" aromatase, this enzyme became a therapeutic
`target. The side effects of aminoglutethimide (mainly
`skin rashes and neurological symptorns),
`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
`A series of
`triazole derivatives,
`(Arin1idex),"‘ "“
`letrozole (Femara).”' 2‘ and vorozole
`(Rivizor)’““ 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-
`glutethirnide. In patients. amirioglutethimide inhibits
`total body aromatisation by about 91%, while anastIo-
`
`BM] VOLUME 311:’) 4OCl'OBER I997
`
`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
`
`Astraleneca Ex. 2040 p. 2
`
`

`
`Tattle 2 Recently reported phase in trials which compare standard second line endocrine therapy with the new triazole inhibitors
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`Clinical review
`
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`logical since stable disease gives equivalent palliation
`and survival.” 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 anastrazole I mg has significant survival advan«
`large over rnegeslrol acetate 150 mg,“ and the other
`nials show trends towards survival advantages.The uni-
`formity of this dilference suggests that these trends are
`likely to become‘ significant with filrther 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
`
`that
`arrtioestzrogens (idoxifene, droloxifene, TAT-59)
`show better preclinical characteristics than tamoxifen
`are better clinically. Large trials comparing all three
`new agents with tamoxifen are ongoing. The pure
`antjoestrogen Faslodex looks highly promising in vim).
`in animal studies, and in early phase 1] tests. However,
`phase
`II
`studies
`are notoriously unreliable
`in
`
`Table 3 Clinical trials using endocrine therapy proiected or in progress in early
`tadjuvant] and advanced breast cancer (phase III)
`Treatment
`Atllrltnlrtl lrruart cancer
`
`lrlnnmd lrruut cancer
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`Feslotlex [It'll 132'r’80}
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`Anaslrozole
`
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`tarnoxlien
`V j
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`125 mg v 250 the v 2|) mg
`lamorlfert
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`Anastrrrzola
`Tamoxifen
`._
`Anastrozule
`Faelodex
`Letrnrole
`_ Ieneriteu
`
`_
`
`_
`_ _
`Tamoxifen 3 years
`Anastrorole 3 years
`
`_
`
`,
`Placebo 5 years
`_
`Vorozola 5 years W __
`Tamoxifen 2-3 years
`Exernestane
`Exemestane 2-3 years
`Megestrol acetate
`
`Tamoxifen
`Anastromte
`.
`- - “°1",,...
`Tamoxifen 2 years
`Z
`Tamoxifen
`“*_‘°=°_‘*3
`Tammtifen 5 years
`Vnrozole
`______ _ g _
`W
`Eioemestane
`Tamoxifen 2-3 years
`
`_
`
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`
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`._.L-wIe_.
`Magastrol acetate
`
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`
`_ _
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`_
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`
`_
`
`terminus”
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`vB}b;6rE""'
`_
`_
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`
`7
`
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`2.5‘
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`
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`V
`
`7
`
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`27,9
`279
`
`r
`. _
`
`T ’ no
`T T 2.5
`vdrozo:e2‘'' ’
`’ we
`1'50
`Magestroracuara
`‘complete response plus partial response: 5D=stabIe disease [25 months}.
`
`T 7
`
`l
`
`zole and letrozole, at their recommended doses of
`] 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 imrnunoassays cannot detect?‘
`
`Steroids!
`
`Two of the steroidal agents, forrnestane and cxcrnes-
`tane, have undergone considerable clinical develop-
`ment Forrnestanr: (4-hydroxyandrostenedione; Len-
`tarori) was the first selective inhibitor to be licensed.“ It
`is given by intrarnuscular 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 closes.” No
`data have been published on its clfects on whole body
`aromatisarion. The only pharmacological data from a
`randomised comparison between any of the inhibitors
`showed the superiority of anastrozole over formestane
`in suppressing plasma oestiatliol.”
`
`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 letrozole and anastrozole had three arms: two
`
`doses of the new ammatase inhibitor compared with
`either the progestogcn (rnegestml acetate) or the old
`aromatase irtl1ibitor(an'u'noglutetl1imide). 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 vorozolel and
`the steroidal derivative exernestane have shown
`
`minimal toxicity. In particular, they do not produce the
`troublesome weight gain of megestrol acetate nor the
`rash and neurological symptoms of aminogluteth.im-
`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 trcatrrtents 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] VOLUMESIS -1 C|(.'l'0E-I-'.R I997
`
`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
`
`865
`
`Astraleneca Ex. 2040 p. 3
`
`

`
`Clinical review
`
`Fast
`
`Tattle 4 Past, present. and potential future treatment of advanced breast cancer by
`blocking oestrogen receptor or reducing concentrations of oestrogenic steroids in
`postmenopausal patients
`Guinean manta tumble
`_l-llntt_t.'tose o_estro-pe_ns
`
`ltetlvstlort at nitrogen tottclntrlttons
`
`Hvritthtsevtamt
`Adrejaleclnmy _ V
`Arnlnoqlttethlmide
`
`-‘_l8ll'EDltll-Ell
`
`Nun-steroidal:
`Dl‘D‘l|!J(ll!fi8
`
`Miami
`TAT-59
`Selective oestrogen receptor
`modulators (mp Ialnidiane}
`steroidal:
`IC|132i'8l} (Faslodexl
`
`tt~‘I2I—ll/end:o7s1sn;tth:Ite7
`ATstio§o1e T—"
`LEINZIIIE
`
`'
`
`‘ '
`
`Lut__einisin§1i1ort1tone releasing l'tontio_rie aucnists
`
`VDIDEDIE
`_A_>_ V_i
`Exeinsstarte
`Slilpllaiise i'n|tTiliiIiun V
`Lutainising horrnone releasing hormone antagonists
`
`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 treatment that is to start late in
`
`1997 are highly importa.nL
`The success of the new aromatase inhibitors as
`second line tireatzments 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 acljuvant therapies The optimal duration
`for tamoxifen as an adjuvant seems to be live 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 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 efiectiveness of treatment
`in
`terms of response duration and, most importantly.
`survival.
`
`Funding". No additional fianding.
`Conflict of interest: We are involved and have been involved
`in
`the clinlal development of many of the compounds
`mentioned in this review.
`
`1 Season 61'. On the treauncnt of inoperable cases of carcinoma of the
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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 I."
`said the woman. "but he's good with the kids.”
`From 'I7wBest qfil-iedical Httmtmr (Howa.rd_]
`
`Bennett, ed. Philadelphia: Hartley and Belfus, 1997)
`
`855
`
`BM] VOLUME 315 4 DCTOBIR 199?
`
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`Astraleneca Ex. 2040 p. 4