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`Breast Cancer Research and Treatment
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`Marc E. Lippman, MD.l (Editor‘in—Chief), Gary C. Chamness, Ph.D.2/Robert L. Dickson, PhD.1 (Editors),
`C. Kent Osborne, M.D.2/Gary M. Clark, Ph.D.2 (Associate Editors)
`‘Vz‘ncent I Lombardi Cancer Research Center Georgetown University, Washington DC, USA
`2 University of Texas Health Science Center at San Antonio, San Antonio TX, USA
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`Breast Cancer Research and Treatment
`
`Marc E. Lippman, MD. | (Editor-in~Chiei), Gary C. Chamness, PhD. 2 / Robert L. Dickson, PhD. | (Editors),
`C. Kent Osborne, MD. 2 / Gary M. Clark, PhD. 2 (Associate Editors)
`1 Vincent T. Lombardi Cancer Research Center, Georgetown University. Washington DC, USA
`2 University of Texas Health Science Center at San Antonio. San Antonio. TX, USA
`
`Editorial ofi‘ice address:
`lOl Philip Drive. Assinippi Park,
`Karen S. Cullen, BREA Editorial Office. Kluwer Academic Publishers,
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`Breast Cancer Research and Treatment 25: l~9, 1993.
`© 1993 Kluwer Academic Publishers. Printed in the Netherlands.
`
`15th San Antonio Breast Cancer Symposium —— Plenary lecture
`
`The future of new pure antiestrogens in clinical breast cancer
`
`Alan E. Wakeling
`Bioscience I, ICI Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
`
`Key words: breast cancer, antiestrogens, tamoxifen, resistance
`
`Summary
`
`The rationale for seeking to identify new pure antiestrogens was based on the recognition that existing
`antiestrogens, exemplified by tamoxifen, all possess partial agonist (estrogenic) activity. Conceptually,
`pure antiestrogens should be more effective than tamoxifen in ablating the mitogenic action of estrogens
`on breast tumor growth. The discovery and properties of the pure antiestrogens ICI 164,384 and ICI
`182,780 are described and contrasted with those of tamoxifen. Key characteristics of these compounds
`which may be of particular relevance to their therapeutic application in the treatment of breast cancer are
`described. These include experimental data which predict efficacy in patients whose disease recurs during
`tamoxifen treatment, and the potential for pure antiestrogens to demonstrate greater efficacy than tamoxifen
`In first-line treatment of advanced breast cancer. The data imply that gains in efficacy could emerge as
`more rapid, more complete, or longer—lasting tumor remissions. Clinical trials with ICI 182,780 will reveal
`whether one or more of these predictions is correct.
`
`Introduction
`
`The nonsteroidal antiestrogen tamoxifen, (‘Nolva—
`dex’l, ICI 46,474), is established as the treatment
`of choice for the endocrine therapy of advanced
`breast cancer [1]. Its ease of use and the absence
`0f Serious side effects in patients stimulated trials
`l0 assess the value of tamoxifen in adjuvant treat-
`ment of primary breast cancer [2,3] and, more re-
`cently, the initiation of trials to test its potential
`3.8 a chemo-preventive agent in women at high
`nsk of developing breast cancer [4,5]. The pro—
`P‘mion of patients with advanced breast cancer
`
`who respond to Nolvadex, and the average dura-
`tion'of response, are not significantly greater than
`those obtained with other endocrine treatments.
`
`Nolvadex treatment is palliative, and the majority
`of women who respond to treatment
`,will
`experience relapse.
`In adjuvant therapy, Nolvad—
`ex extends the disease-free interval and overall
`survival compared with no treatment [3]. Current
`clinical practice in the adjuvant use of Nolvadex
`shows an increasing trend towards continuation of
`drug treatment until disease recurrence. These
`clinical observations pose
`several
`important
`questions about future directions for treatment,
`
`Addressfor oflprmts and correspoyndence; Alan E, wakeling, Bioscience I, lCI Pharmaceuticals, Alderley Park, Macclesfield,
`fitteshire SKIO 4TG, United Kingdom
`I
`Nolvadex’ is a Trade Mark, the property of Imperial Chemical Industries plc
`
`0W
`ten
`
`ting
`
`Box
`
`{Elli
`
`ilh
`
`Mewmy."
`~.,.._me.___...._we....,__,,
`
`InnoPharma Exhibit 1058.0004
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`

`

`
`
`2
`
`aAE Wakelt'ng
`
`twokof which are considered here. Firstly, what
`treatment(s) should be applied in patients re—vlv
`Vlapsing during or after Nolvadex treatment?
`Secondly, will pure antiestrogens provide more :-
`effective treatment of advanced breast cancer than
`
`Nolvadex or other currently available drug
`treatments?
`It will be argued that pure anti-‘
`estrogens have particular properties which Willl"'('~";.
`provide answers to these important questions.
`
`Rationale for pure antiestrogens
`
`_In early animal studies it was shown that tamoxl‘”" "
`‘ ifen antagonises the tropic actions of endogenous»,
`or exogenous estrogens but also, when adminis— ,,
`tered alone to immature (or ovariectomised) rats...
`
`
`
`
`
`
`
`
`
`
`
`Estrogens stimulate tumor growth by binding to
`estrogen receptors‘(ER) in the cell nucleus. The
`estrogen—ER complex then dimerizes and binds to
`
`“specific DNA-.sequences(estrogen response ele-
`ments, ERE),
`to activate the transcription of
`
`estrogen responsive genes which ultimately trigger
`cell proliferation. Tamoxifen disrupts this process
`by binding to ER-Jand interfering with normal
`transcriptional responses to estrogens [11]. The
`estrogenic effects of tamoxifen strongly imply that
`.the tamoxifen-receptor “complex in the cell
`nucleus is not inert — it retains some capacity to
`transduce signals similar to those induced by the
`estrogen—ER‘complex [11].
`In contrast it might
`be anticipated that pure antiestrogens should bind
`tojER to form an ER-complex which either does
`not bind to ERE’s or, if DNA binding does occur,
`
`.
`
`is, unable to promote transcription.
`
`Discovery of novel antiestrogens
`
`itself has tropic (estrogenic) effects .
`and mice,
`[6,7]. Thus, tamoxifen has the characteristics/Of
`an antiestrogen With partial agonist activity. In,
`animals and in man the balance between stimula-fl,
`tory and inhibitory activities of tamoxifen varies.
`The two key elements of the search for pure anti-
`widely depending on the organ, cell, or specific
`estrogens were, firstly, ,a medicinal chemistry
`protein measured as an indicator of estrogenic.
`activity [8,9]. Tamoxifen shares this property
`strategy to . identify novel ER ligands
`and,
`with chemically similar, triphenylethylene-derived
`secondly,
`robust and reliable biological
`test
`agents, described earlier and more recently [10].
`systems. The strategy chosen for initial chemistry
`A consequence of this partial agonist activity is
`is described elseWhere [12] and'involved synthesis
`,
`that complete blockade of the action of estrogens,
`_ oft, estradiol‘analogues ,- bearing C7-substiwems
`which retain a high affinity 'forER, an essential
`cannot be achieved with tamoxifen. Although it a
`is not known whether the partial agonist activity-7’
`""7feature recognized in our drug‘target Prom8 [13]“
`
`of tamoxifen in any way limits its clinical effi--~
`Facile and reproducible testing-for both estrogen
`
`cacy, complete ablation of the estrogenemediated‘
`,, .agonist and antagOnist activityjn vivo was provld‘
`
`tumor growth is a desirable objective since it?
`_ ed by measurement of uterotropic and annuterOf
`might be anticipated to provide more rapid, mere ’7
`‘
`
`“’“tropic effects in immature rats [14]. In this assaya
`complete, or
`longer~lasting tumor
`responses.
`tamoxifen alone maximally’i’increases the uterine
`
`Conceptually, this objective could be achieved by
`weight 2—fold, compared with‘S—fold for estralel'
`
`treatment with a pure antiestrogen.
`_
`Correspondingly, coadministration of tamoxifen
`f The profile of activity of a pure antiestrogen is
`and estradiol demonstrates a maximum 60% inm—
`‘ easily understood in the pharmacological sense;
`bition of the tropic action of estradiol.
`1“
`
`developments in understanding the molecular
`addition to this bioassay, the intrinsic POtenCy 0f
`
`mode of action of estrogens and how this is
`new compounds could be monitored accurately m
`affected by tamoxifen, also facilitated; a bio-
`‘i
`'vitro by receptor binding measurements [15] and
`
`‘ chemical concept of how such agents might work.
`cell growth inhibition assays with _ estrogen'
`
`
`
`InnoPharma Exhibit 1058.0005
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`

`

`Clinical potential of pure antiestrbgens‘
`
`3
`
`action of ICI 164,384ihave shownrthatkit binds
`ER with fa substantially higher“? affinity than
`tamoxifen (~10lfold), but, unlike tamoxifen,‘fails
`' to activate transcription of estrogemresponsive
`genes (see. [18] for review).
`It is not yet clear
`‘whether the [blockade of IERASi’gnaling by ICI
`164,384 is due "to axfailure’fof«thergreceptor
`complex to dimerize‘arid bindito ERE‘ [19] or to
`
`an inactivation p, of j the transcriptional activation
`function of the DNA-bound ireceptor‘complex
`[20]. Both mechanisms. mayfctontribute to the
`expression of “pure:antagonistfiactivitysfi ‘, ICI
`164,384 treatment leads ’itorarrapid reduction of
`cell and tissue ER concentration - [21,22],“ an effect
`which is likelytoqseverely, attenuate thegcapacity
`of estrogen-responsivefijcells
`reSpdnd tog" the
`natural hormone;
`Complete ablation bf- estfég’é‘h mas-by, Icr‘
`164,384 in vivarequiredlhighf‘dosesiof drug_{23]
`, and, for this reason, ICI:‘164,384“did,notmerit
`serious consideration as ajdrugcandidate: "More
`,8 potent compounds were‘sought which retained the
`8, advantageous“ pharinacological:;profile Oyf‘fICI
`, 164,384, compared Withflthe tamoXifenLlike partial
`‘_ agonists. A new compound,,ICIV»182,78Q,7EX+[9-
`(4,4,5,5,5¥pentaifluoropentylsuifinyl)nonyl]é
`estra—1,3,5(10)—triene:3,17[3§diol (Figured-1),,lwa‘s
`selected for intensive study [24],],;:__;1C1f182,780.
`differs from ICI 164,384 tufted/gay? features or»
`the 70¢ side—chainij the; ripymoiety‘ "of ICI
`164,384 was replaCed bywasuplfinyl group and the “
`terminal alkyl functiOn was fluorinated to reduce
`the potential
`for metabolic attack [12].
`ICI
`182,780 has a four to five-fold greater affinity for
`ER than ICI 164,384 and similarly is 5—fold more
`potent in inhibiting the growth ofLMCF-7 cells
`[24].
`In the ratuterotropic/antiutemtropic test,
`ICI 182,780 is 10-fold more potent
`than ICI
`
`164,384 [24].
`
`
`
`,
`
`sensitive human breast cancer (MCF—7) cells [:16].
`
`’
`
`’
`
`Synthesis of novel 70t-alkylamide analogues of ,
`estradiol provided the first examples of com—
`pounds devoid of estrogenic activity but capable,
`when administered together with estradiol, rrof
`blockingvcompletely the uterotropic effect of the
`natural hormone in rodents [12,17]. Structure;
`
`activity analysis reVealed the importance of the
`position,‘-length, and flexibility of the C7 side-
`chain in determining pure antagonist activity [12].
`For example; itiwas shown that receptor binding
`and biological activity residesalmost exclusively
`in the 705 rather thanfthe 7B isomers. Pure ranti—
`estrogens‘ were found amongst compounds with an
`overall chain length of 16-18 ~at0ms,.tancl tertiary -
`rather than secondary amides are preferreds
`most potent pure antagonist amongst the alkylj
`amides was N-n-butyl—N-methyl~] 1 -(3,-'1.7B-di'—
`hydroxyestra— 1 ,3,5(10)-trien-70t—yl)undecanamide,
`ICI 164,384 (Figure 1). Studies of the modebf
`
`
`
`'_
`
`i
`
`,
`
`*
`
`*
`
`OH
`
`
`
`
`//’/<CH“2>5$¢P“[{(.
`
`
`9H_‘2“Z§CH3: 3
`
`
`r
`
`
`
`/5//(CH 2)980(CH2)3QF2CF3
`lCl 182,780
`I Figure 1. Structures of pure antiestrogens f
`
`L
`
`InnoPharma Exhibit 1058.0006
`
`

`

`4
`
`AE Wakeling
`
`Comparative pharmacology of tamoxifen and
`pure antiestrogens
`
`Animal studies
`
`The most graphic distinction between pure and
`partial-agonist antiestrogens is provided by rodent
`tissue response assays where tamoxifen is a full
`
`or partial agonist. Thus, when tamoxifen rather
`than estradiol is used to stimulate the uterus, both
`ICI 164,384 and ICI 182,780 can block complete-
`ly its trophic action [17,24]. A similar bioassay
`in which full, normal mammary ductal elongation
`in ovariectomised pubertal rats is induced by
`either estrogen or tamoxifen treatment, showed
`that ICI 164,384 alone had no stimulatory effect
`but could completely block the tropic action of
`estrogen or tamoxifen [25]. These pharmaco—
`logical observations strongly support a common
`biochemical mode of action for estradiol, tamoxi—
`fen, and the pure antiestrogens through the ER.
`It is also implicit in these observations that the
`pure antiestrogen-receptor complex, in contrast to
`the tamoxifen-receptor complex, is devoid of the
`capacity to induce the transcription of estrogen-
`responsive genes in viva.
`Comparisons of the effects of ICI 164,384 and
`ICI 182,780 vs.
`those of tamoxifen in intact
`female rats [23,24] showed that tamoxifen reduces
`uterine weight, but maximally is much less
`effective than ovariectomy, whereas the pure
`antiestrogens are almost as effective as ovari—
`ectomy. The fact that pure antiestrogens were
`slightly less effective than ovariectomy could be
`evidence that the size of the uterus is influenced
`by non—estrogenic hormones rather than any lack
`of antiestrogenic potency in these compounds.
`Some evidence of this emerged from studies
`where rats were treated with a combination of an
`LHRH analog (chemical hypophysectomy) and
`ICI 164,384. .Uterine weight was reduced below
`that achieved by the LHRH analog alone [26].
`Further interesting observations which may be
`relevant to clinical efficacy emerged from the
`
`_
`
`studies of antiestrogen effects in intact
`
`rats.
`
`Firstly, pure antiestrogen treatment did not affect
`
`gonadotropin concentrations or the body weight of
`the animals (Table 1), whereas tamoxifen ex-
`
`hibited estrogenic effects by reducing both body
`weight and circulating gonadotropin concentra-
`tions [23]. Since ovariectomy causes increased
`body weight gain and gonadotropin secretion by
`removal of the negative feedback of estrogens on
`the brain,
`it can be argued that the pure anti-
`estrogens, unlike tamoxifen, do not block ER in
`the brain at doses which have profound effects on
`the uterus. This peripheral versus central selec-
`tivity of action could haVe highly beneficial
`effects in premenopausal patients where anti-
`uterotropic effects and breast
`tumor growth
`inhibition might be achieved without disturbing
`the hypothalamic—pituitary-ovarian axis. More
`recent studies in intact or ovariectomized/estro—
`
`gen-treated monkeys using magnetic resonance
`imaging of the uterus, have confirmed that ICI
`182,780 is a pure antagonist and produces
`profound antiuterotropic effects achieved without
`concurrent "castration—like" increases of plasma
`gonadotropin concentration [27 and unpubliShed
`studies].
`If these observations are paralleled in
`patients, hot flashes or the psychosocial conse-
`quences of estrogen withdrawal should not occur
`in women treated with ICI 182,780. Tamoxifen
`does have central effects in patients, for example
`in inducing hot flashes [1], and concerns have
`also been expressed that its uterotropic action may
`increase the incidence of endometrial cancer [28];
`such concerns would be eliminated by treatment
`
`_
`with pure antiestrogens.
`One predicted undesirable action of pure antl-
`estrogens in therapeutic use may be a tendency to
`reduce bone density and hence to precipitate 0r
`_ exacerbate osteoporosis. Analysis of bone densrty
`in rats treated with ICI 182,780 failed to ref/ea1
`any effect whereas, in the same study, OVanec‘
`tomy significantly reduced bone density (Table 1)'
`This suggests that there are differentials in the
`sensitivity of peripheral estrogen target Organs to
`
`
`
`
`
`
`
`m,e,..._~w.~._._.._i,_‘,..~,Wwe--«w.W,"Mm,,W,M.,,M,M
`
`InnoPharma Exhibit 1058.000?
`
`

`

`
`
`Table I. Effects of ICI 182,780 infladult female rats
`
`Clinical potential of pure pantiestrogens
`
`5
`
`Plasma LH ;
`Treatment
`Uterine weight
`Body weight gain
`5’ Bone density i
`
`(mg)
`1
`. :
`(g)
`_
`V‘
`(mg/rill)
`_
`_'
`i
`‘ (g/ml)” .;
`302 i 3fo V
`60 :4
`.132 i 0.2:”;
`‘,‘
`£0,008;
`70 i 12.4
`114 i 6
`233.5 $7.12
`> 1.49m 0.006
`'
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`tiff
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`-
`
`.
`‘
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`L
`
`«
`
`i.
`
`.
`
`Intact control
`ovx control
`1C1182,780
`(mg/kg/d x 28)
`
`_
`
`»
`
`>
`
`0.1
`0.3
`1.0
`
`3.0
`
`208 :r 17
`174 i 162::
`94 i 9 :2
`
`';
`
`<21
`-.:-::;;:.;:
`
`68 i 4
`67 i 4
`70 i 4
`
`1.2 i 0.1 ‘
`_
`‘ 71.3 i 011"};
`‘
`. 2.8 :t 0.3?“
`
`“ 1528‘: 0.005 “
`1:528'1- 0.008
`“1.532 £0005
`
`‘
`
`,:
`
`103:2;444
`
`.,:--;;;~> 71i6
`
`‘
`
`° 2.4i0.6"1
`
`1.533: 0.005, x
`
`
`
`\new”,A,a1.hanks.,,
`
`antiestrogens as well as central versus'peripher’al
`differences, and cautions against premature judge‘-
`ment of likely pharmacological actions of 'these
`agents in man.
`
`Breast cancer cells
`
`_
`
`Functional disablement of the ER“ signalling
`CaPaCity by pure antiestrogens produces effects on
`human breast cancer cells which have‘kjprOfounwd
`therapeutic implications. A comparison “of the
`POtency and efficacy of tamoxifen, ICI 164384;
`and ICI 182,780 as inhibitors of the growth of
`estrogen-responsive MCF-7 human breaSttumorf
`derived cells, showed that the pure antieStrogens
`are up to two orders of magnitude more‘potentf
`reflecting in part
`their higher affinitykégfordliR},
`[23,24].
`More significantly, analysisgijoff. the ;-
`growth dynamics of the cultured cells showed
`that, although both classes of agent share the
`abilitY,to block cell diVision in the G1 phase 0f
`the Cell cycle [29], both ICI 164,384 and ICI
`32,780 were much more effective than tamoxifen
`“1 reducing the proportion of cells-which remain
`able to synthesize DNA after prolonged exposure
`[24,30]. The proportion of cells which continued
`{0 Symhesize DNA in a two day period at the end
`of five days exposure to the antiestroge’ns,"was -
`reduced‘from 82% in control cultures to 37% by
`tamoxifen: but to only 7% by ICI 182,780 [24].
`
`This difference may be due to {the partial agonist
`activity-of tamoxifen Which amplified by inter?
`action With mitogenic Vsignals provided by growth
`factors,“an2effectawhiCh is absentkinlth‘e case of
`the pure antiestrogens [3013"?
`1“
`I If the greaterefficacy cf 'pure“"\Iersus-'partial
`agonist antiestrogens against human breast cancer
`cell growth" described if above translates to the
`clinical settingIOne-fmight anticipate significant
`benefits in the'rate and extent of tumor remission
`following" ‘ pure'iy-antiestrogen therapy compared
`with other fgg'antiestrogenic" therapies _
`It: is
`particularlywirnportant to recognize that if 1 the
`synergistic growth stimulatory interaction between
`eStradiol and insu1in-like growth factors demon~
`strated
`vitroi[16,30,31] occurs‘in patients there
`may be a massive difference inefficacy‘between
`treatments Which only reduce estrogen action“-
`(tamoxifen, aromatase inhibitors, LHRH analogs)
`compared with a treatment which can potentially
`sustain 100% blockade. Thus, there is a powerful
`rationale which argues the superiority of pure
`antagonists over other treatments. K
`‘ The major cause of death from breast cancer .
`is metastatic, disease rather than uncontrolled
`proliferation of the primary tumor.
`‘_ Metastatic
`spread depends on the capacity ofthe tumor cells
`to cross the basement membrane and invade into
`Surrounding tissue. _ Experimental studies with
`breast tumor-derived cell lines have _shown that-
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`invasive capacity and proliferative potential are
`independently variable [32].
`It
`is
`therefore
`important to know whether antiestrogens affect
`the phenotypic expression of invasive behavior by
`/ breast
`tumor cells.
`This question has been
`‘ examined in comparative studies of the effects of
`‘estradiol and several antiestrogens on the capacity
`of MCF-7 cells to cross a re—constituted basement
`
`_
`
`'
`
` 6
`
`‘ "membrane in vitro [33]. Both estradiol and 4’—
`
`hydroxytamoxifen, but not ICI 164,384, stimu-
`
`lated this activity; ICI 164,384 was also able to
`
`block estrogen and 4’—hydroxytamoxifen-stimu-
`lated invasion.
`ICI 164,384 also demonstrated
`
`anti-invasive activity against MCF-7 cells in an
`alternative bioassay [34]. These data argue that
`‘early treatment of breast cancer with a pure
`,_ antiestrogen might be particularly beneficial in
`'
`limiting tumor spread.
`
`‘ Tamoxifen resistance
`
`The mechanisms which might underlie the devel—
`- opment of resistance to tamoxifen among patients
`with advanced breast cancer who initially respond
`to treatment, has been studied using human breast
`3, cancer cells grown either in vitra or in vivo as
`xenografts in nude mice, and exposed continuous-
`ly to growth inhibitory concentrations of tam-
`oxifen.
`In vitro,
`long—term exposure of both
`MCF—7 and T47D cells to tamoxifen leads to a
`loss of sensitivity to the growth inhibitory activity
`‘of tamoxifen [35,36].
`In T47D cells it was sug-
`gested that the mechanism underlying the devel-
`opment of tamoxifen resistance in vitro is the
`selection of subpopulations of cells [which are
`growth stimulated by tamoxifen, rather than the
`selective outgrowthof cells which are unaffected
`bytamoxifen [36]. If these "tamoxifen-resistant"
`cells derive a growth advantage from tamoxifen
`exposure, one mechanism for such an effect could
`be the selective stimulation of a subpopulation of
`tumor cells in which the effect of tamoxifen is
`“interpreted” as predominantly estrogenic rather
`
`
`
`Is it likely that tumor cells
`than antiestrogenic.
`which respond differentially to tamoxifen coexist
`
`within a phenotypically homogeneous population?
`Differentials between estrogenic and antiestrogen-
`ic responses to tamoxifen at the organ, cell, and
`
`gene level alluded to earlier, are well-established
`
`[10]. Also, the differential efficacy of pure and
`partial agonist antiestrogens on the proliferative
`potential of MCF-7 cells described earlier has
`been attributed to the estrogenic activity of
`tamoxifen [30];
`thus, the subpopulation of cells
`which continue to proliferate in the presence of
`tamoxifen, but not in the presence of pure anti-
`estrogens, may be that which eventually grows
`out as the dominant resistant line. An important
`prediction of this mechanism is that tumor cells
`growing because they "read" tamoxifen as an
`agonist, should remain sensitive to the growth—
`inhibitory effect of pure antiestrogens.
`In one
`case,
`that of
`the "tamoxifen-resistant" AL-l
`subline of MCF—7 cells, cell growth was still
`sensitive to inhibition by ICI 164,384 [37].
`Animal model studies have provided evidence
`that a similar positive selection pressure to
`generate "tamoxifen—resistant“ cells might operate
`in vivo. The growth of MCF-7 cells as solid
`tumors in nude mice is blocked initially by tam-
`oxifen but
`then resumes [38,39]. That
`those
`tumors which develop "resistance" to tamoxifen
`are not resistant in the sense generally understood
`in cancer therapeutics, was shown in two Ways.
`Firstly, re—transplantation studies showed that such
`tumors would grow only if the host was treated
`with either tamoxifen or estradiol and, secondlys
`that
`the growth of these tamoxifen "resistant"
`tumOrs is attenuated by the pure antiestrogen ICI
`164,384 [40]. Recent studies on the metabolism
`of tamoxifen in resistant tumors removed frOm
`nude mice indicate that responsive and resistant
`tumors differ in respect of concentrations of the
`parent drug and potentially estrogenic metabolites
`[41]. Tamoxifen-stimulated tumor growth may be -
`explained-by metabolic adaptation of the tumor.
`This mechanism, provides an alternatiVla will“
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`hypothesis examined above, that subpopulations
`of tumor cells with differential sensitivities to
`
`tamoxifen may coexist in the tumor. Preliminary
`data indicate that similar metabolic changes may
`occur in patients relapsing on Nolvadex treatment
`[42,43].
`It can be predicted that pure anti-
`
`estrogens would block the mitogenic effects of
`estrogenic tamoxifen metabolites as effectively as
`they do that of tamoxifen itself. Whether such
`metabolic adaptations could occur during long-
`term pure antiestrogen treatment is not known,
`but this seems unlikely to occur by the same
`mechanism(s) because the pure antiestrogens are
`quite different in structure from tamoxifen.
`
`These experimental data discussed above may
`have important clinical
`implications. Clearly,
`since pure antiestrogens are devoid of estrogenic
`activity, their therapeutic use would avoid at least
`one of the underlying reasons for the development
`of tamoxifen resistance, and implies that
`the
`average duration of response to treatment might
`be greater
`for a pure antiestrogen than for
`tamoxifen. Although it
`is not clear what pro-
`portion of breast tumors relapse during Nolvadex
`therapy because they become dependent
`for
`growth on tamoxifen rather
`than classically
`resistant, there is a sound pharmacological basis
`for evaluating pure antiestrogen treatment in such
`- patients.
`It could be argued that simple with-
`drawal of tamoxifen might also lead to tumor
`remission, and there is clinical evidence that
`
`Supports this assertion [44]. However, since
`tamoxifen can remain in tissues for very long
`Periods after drug withdrawal
`[45], additive
`treatment with a pure antiestrogen might further
`_ 1mpmve response rates.
`_
`Treatment choice for patients who relapse
`duflng. 0r at some time after, adjuvant Nolvadex
`therapy for primary breast cancer, is a subject of
`increasing importance. Based on the eXperimental _
`‘ Precedents discussed above,
`there is a sound
`_ raltionale for treating patients who relapse during
`adluVant Nolvadex therapy with pure antiestro- -
`gens. The number of patients in this category is
`
`Clinical potential of pure antiestrogens
`
`7
`
`likely to increase substantially in the future due to
`the trend to maintain adjuvant
`treatment until
`
`relapse. For patients who relapse at some time
`after completion of an adjuvant course of Nolvad-
`
`ex, there is no a priori reason to exclude a further
`trial of Nolvadex. However, based again on the
`arguments deployed above, that pure antiestrogens
`are the more effectiVe inhibitors of tumor cell
`
`growth and are less likely to induce treatment
`failure, it can be argued that a better option is
`
`treatment with a pure antiestrogen.
`
`Clinical application
`
`The relatively low oral bioavailability of ICI
`182,780 [24] necessitated development of altema-
`tive dosing regimens. Experimental studies in
`rats dosed parenterally with oil-based formulations
`of ICI 182,780, showed that antiestrogenic activ-
`ity could be sustained for long periods with a
`single injection. The potential therapeutic utility
`of such oil—depot formulations was demonstrated
`by a sustained antitumor action following single
`s.c.
`injections in nude mice transplanted with
`human breast tumors [24]. The likely dose and
`frequency of treatment in‘breast cancer patients
`was assessed by measuring the duration of anti-
`estrogenic action of oil depots of ICI 182,780 in
`monkeys (Macaca nemestrina) using magnetic
`resonance imaging (MRI) of the uterus [27].
`These studies showed that a single injection of
`4mg of ICI 182,780/kg at 4—weekly intervals
`provided increasingly effective blockade of
`estrogen-induced uterine proliferation, without
`significant accumulation of the drug monitored by
`analysis of plasma drug concentration [27].
`- Animal toxicology and human volunteer stud:
`ies have recently been successfully completed as
`a prelude to therapeutic studies with the oil depot
`fermulation of ICI 182,780 in patients. An initial
`therapeutic trialhas begun inpatients with ad-
`vanced breast cancer who have relapsed during
`Nol'vadex treatment.
`
`
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`Conclusions
`
`Extensive studies of the biological properties of a
`
`new class of steroidal antiestrogens, the 70t—sub~
`
`stituted estradiol analogs exemplified by ICI
`164,384 and ICI 182,780, have shown that these
`
`agents are pure antagonists. Mode of action
`
`studies are consistent with competitive inhibition
`of estrogen action through ER, leading to com-
`plete blockade of estrogen—induced transcription.
`By comparison with partial agonist antiestrogens
`like tamoxifen, pure antiestrogens achieve more
`complete regression of estrogen-dependent tissues
`in viva. Model studies with human breast cancer
`
`cells in vitro and in viva predict that these agents
`have the potential to be more effective therapeut—
`ically than currently available treatments for
`breast cancer. In particular, a proportion of breast
`tumors which recur during tamoxifen therapy,
`may remain sensitive to the antitumor action of a
`
`pure antiestrogen.
`
`References
`
`Antioestrogens in the
`Jackson M:
`l. Litherland S,
`management of hormone-dependent breast cancer.
`Cancer Treat Revs 15:183—194. 1987
`2. Smith I: Adjuvant tamoxifen for early breast cancer.
`BrJ Cancer 57:527-528, 1987 ]
`3. EBCTCG: Systemic treatment of early breast cancer by
`hormonal, cytotoxic, or immune therapy. Lancet 339:
`1-15, 1992
`
`4. Powles TJ, Tillyer CR, Jones AL, Ashley SE, Treleaven
`J, Davey JB, McKinna JA: Prevention of breast cancer
`with tamoxifen —— an update on the