tamoxifen versus the newer serms: what is the evidence?

Tamoxifen versus the newer SERMs: what is the evidence?

Anthony Howell

CRC Department of Medical Oncology, University of Manchester, Christie Hospital, Manchester, UK

Introduction

Breast cancer remains the most common cancerand the second leading cause of cancer death inwomen in the US and Europe [1]. A substantialbody of experimental, clinical and epidemiologicalevidence indicates that steroid hormones play a majorrole in the aetiology of breast cancer. Endogenousoestrogens support the development and growth ofthe breast and breast tumour cells, they also haveprofound beneficial and carefully regulated effectson other tissues such as the endometrium, vagina,bone, liver and vessels of the cardiovascular systemas summarised in Table 1.

The clinical responsiveness of the breast to oe-strogen deprivation was first demonstrated over 100years ago [2]. Pharmacological inhibition of thetumour stimulatory effects of physiological oestro-gen concentrations was first reported using highdose stilboestrol, triphenylchloroethylene and triph-enylbromoethylene [3]. Anti-oestrogen therapy sincethe 1940s, and tamoxifen in particular, has rev-olutionised the treatment of breast cancer. Today,tamoxifen (Nolvadex, ICI 147,741) is the anti-oestro-gen of choice for adjuvant therapy after surgery and

for recurrent breast cancer. Coupled to this, how-ever, are the general issues surrounding the healthof perimenopausal and postmenopausal women inwhom reduced oestrogens levels are associated withskeletal problems resulting from reduced bone den-sity (osteoporosis) and increased cardiovascular risk.Many of the modulators of oestrogen action, such astamoxifen, have a beneficial effect on bone densityand serum lipids, but have adverse effects on theuterus. Thus, an anti-oestrogen breast cancer therapywhich safely eliminates the negative effects of themenopause on women's health in the absence oftoxicity is the challenge for the new millennium.

The term 'anti-oestrogen' refers to agents whichblock the effects of physiological concentrations ofoestrogen at the oestrogen receptor (ER). Selec-tive Oestrogen Receptor Modulator (SERM) was aterm coined to describe the phenomenon of apparentblocking of the ER at one site (e.g., the tumour)and stimulatory activity at another site (e.g., bone).Thus, a single drug could have both agonist and an-tagonist activity depending on the cell type. SERMswere then divided into SERM 1 (tamoxifen), SERM2 (raloxifene) and SERM 3 (a compound with noother common name closely related structurally to

Table 1Summary of the effects of oestrogen (E2, 17(i-oestradiol) on target tissues

Target organ/tissue Pharmacological and physiological effects of oestrogen

Breast

Endometrium andvagina

Cardiovascularsystem

Bone

CNS (Brain)

Liver .

Promotes breast epithelial cell proliferation, development and growth of the breast together with other growthstimulating factors e.g. progesterone, corticosteroids, prolactin, insulin. Associated with poor clinical outcome inER+ breast cancer patients

Stimulates proliferation of epithelial cells and regulates cyclical changes. Unopposed is associated with malignancy

Reduces risk factors associated with CVD, predominantly serum lipid and lipoprotein composition

ER found on both osteoclasts and osteoblasts. Regulates expression of bone cytokines

Feedback actions on the hypothalamus and limbic system. Controls mood swings and cognitive function possiblyreducing the onset and progression of Alzheimer's diseaseInfluence on liver-derived coagulation factors and plasma proteins and regulation of lipids (see also CVD)

ER = oestrogen receptor, CVD = cardiovascular disease.

255

Downloaded from https://academic.oup.com/annonc/article-abstract/11/suppl_3/255/272205by gueston 13 April 2018

256 A. Howell

raloxifene). However nearly all oestrogens may haveagonist or antagonist activity depending upon drugdose and target cell type. For example, the highdoses of oestrogens used to inhibit breast tumourshave agonist activity in normal tissues. They mayalso become agonists to the tumour with the passageof time as demonstrated by the phenomenon of with-drawal responses [4]. An exception to the combinedagonist/antagonist activity of most oestrogens andanti-oestrogens may be the so-called steroidal 'pure'anti-oestrogens which are apparently devoid of ag-onist activity. The lack of agonist activity may berelated to the fact that they appear to have a differentmechanism of action with respect to their effect onER. Levels of ERs in tumours decline markedly ontreatment so that this group of compounds have beencalled selective oestrogen receptor downregulators.The acronym SERM may have some uses but wehave used the term anti-oestrogen throughout thisarticle for the sake of clarity.

Tamoxifen: advantages and disadvantages

Tamoxifen, a non-steroidal, triphenylethylene-basedanti-oestrogen (Fig. 1), with tissue specific oestro-genic (agonist) and anti-oestrogenic (antagonist) ac-tivity, has been the anti-oestrogen of choice in theclinic for over 25 years [5]. Its biological effects

are mediated primarily by inhibiting the actions ofoestrogen through its binding to the ER. The dif-ferential actions of tamoxifen occur by selectiveoestrogen receptor modulation according to the celland gene promoter type.

The anti-oestrogenic activity of tamoxifen in thebreast has established it as the 'gold standard' for thetreatment of all stages of breast cancer. Tamoxifengiven for different durations in an adjuvant settinghas been associated with a reduction in the risk ofboth contralateral breast cancer and metastatic cancer[6]. These data supported the prospective evaluationof tamoxifen in the prevention of cancer in womenat high risk from the disease [7]. As a result, the USFood and Drug Administration (FDA) has approvedtamoxifen for breast cancer prevention [8].

The oestrogenic activity of long-term tamoxifentreatment is associated with at least two other clini-cal benefits normally associated with premenopausalphysiological oestrogen concentrations (Table 1). Ta-moxifen therapy helps to maintain bone density [9]and lowers circulating low density lipoprotein choles-terol [10], effects of importance to perimenopausaland postmenopausal women.

The most frequent side effect associated with ta-moxifen therapy is the occurrence of 'hot flushes'which is thought to be related to the antagonistic ac-tion of tamoxifen on the hypothalamic pituitary axis.However, side effect that causes the most concern is

Tamoxifen 4-Hydroxytamoxifen Toremifene

Idoxifene

HO,

CO2H

TAT-59 DroloxifeneFig. 1. Triphenylethylene anti-oestrogens.

GW 5638


Tamoxifen versus the newer SERMs: what is the evidence? 257

Table 2Pre-clinical and clinical assessment of new anti-oestrogens

Pre-clinical in vitro and in vivo assessmentsERa and ER0 receptor bindingERa and ERfJ transcriptional activationAnti-oestrogenic activity in breast and uterusTumour antagonism in animal modelsActivity in cell linesOestrogenic activity on bone and serum lipidsMechanism of ER activation (co-activators, co-repressors andligand-independent activity)

Clinical assessmentActivity as first-line therapyActivity in tamoxifen resistant tumoursActivity as neo-adjuvant and adjuvant therapyActivity in preventionSide-effect profileEffects on women's health

the increased risk of endometrial cancer related to theoestrogen agonist activity of tamoxifen on the uterus[7,11,12]. In addition, tamoxifen can have more fre-quent but less serious side effects on the uterus, in theform of endometrial polyps, and simple and complexhyperplasia. Anti-oestrogen therapy is also associatedwith an increased incidence of thromboembolic phe-nomena including deep vein thrombosis, pulmonaryembolism and possibly cerebrovascular events [7].Finally, tamoxifen therapy is associated with the ac-quisition by tumours of 'tamoxifen resistance', wheretamoxifen no longer inhibits tumour growth but mayactually promote it [4].

Despite these negative aspects of tamoxifen ther-apy, the benefits for the treatment and preventionof breast cancer are thought to substantially out-weigh the risks. The success of tamoxifen in thetreatment of breast cancer has proved invaluable inthe search for, and development of, new anti-oestro-gens that selectively retain the favourable estrogenicand anti-estrogenic properties of tamoxifen. It is thestandard against which all new therapies will bemeasured in well established pre-clinical and clinicalsettings (Table 2). Although tamoxifen has revolu-tionised the treatment of breast cancer, the searchcontinues for new agents which will confer increasedresponse rates and durations of response in patientswith advanced disease, increased cure rates and timesto relapse in the adjuvant setting, reduce tumour bur-den in the neo-adjuvant setting, play a clearly definedrole in disease prevention and improve the generalhealth of postmenopausal women [13].

New anti-oestrogens

Since the publication of our last review in 1996 [13],there has been a marked increase in the pre-clinicaland clinical information available on the new anti-oestrogens and in our understanding of their mecha-nisms of action via the oestrogen receptor (ER).

Three main avenues have been followed in anattempt to improve on tamoxifen [13]. One has beento produce analogues of tamoxifen by chemicallyaltering the triphenylethylene structure of tamoxifenin an attempt to block the metabolic hydroxylationat the 4-position and to reduce metabolic inactivationby altering the side chain. Second new non-steroidalfixed ring structures derived from the stilbene struc-ture of stilboestrol have been synthesised. The aimof these syntheses was to prevent the isomerisa-tion that occurs around the double bond in thetriphenylethylenes. These structures include benzoth-iophenes [14,15], naphthalenes [16] and benzopyrans[17]. The third approach has been to synthesisesteroidal analogues of oestrogen with growth in-hibitory activity [19-22].

These three classes of anti-oestrogens (triph-enylethylenes, cyclic and steroidal) (Table 3) areknown to differ in their affinities for the ER, theirmechanisms of action in relation to the ER, andin their effects on the key tissues as assessed ina whole range of in vitro and in vivo, pre-clinicalassay systems (Table 2). Clarification of the clinicalpotential of these and future agents will however

Table 3Anti-oestrogens with past or potential clinical value

Triphenylethylenes (tamoxifen derivatives)ToremifeneDroloxifeneIdoxifeneTAT-59GW 5638

'Cyclic compounds'Benzothiapbenes

Raloxifene (LY 156,758)SERM 3 (LY 353,381)

NonapthalenesLasofoxifene (CP-336,156)LY 326,315

BenzopyransEM800 (SCH 57050)EM600 (SCH 57068)

Steroidal compoundsICI 182,780RU 58608SR 16234


258 A. Howell

a. Benzothiophenes

Raloxifene (LY 156,758) SERM 3 (LY 353,381)

b. Napthalenes

Lasofoxifene (CP 336,156)

HO

LY 326,315

c. Benzopyrans

EM 800 (SCH 57050) EM 652 (SCH 57068)Fig. 2. 'Cyclic/fixed ring' anti-oestrogens.

depend on an improvement in our understanding ofthe various mechanisms and molecular determinantsof ER-mediated response in the breast but espe-cially at other sites of action such as bone and thecardiovascular system.

The newer triphenylethylenes include the tamox-ifen analogues toremifene [23], idoxifene [24], drolox-ifene (3-hydroxytamoxifen) [25], TAT-59 [26] andGW 5638 [27] (Fig. 1). The newer cyclic compoundsinclude benzothiophenes (raloxifene (LY 156,758)and SERM 3 (LY 353381) [14,15], napthalenes (la-sofoxifene [CP-336,156] andLY326,315) [16,17] andbenzopyrans (EM 800 [SCH 58050] and its metabolite

EM600 [SCH 58068]) [18] [Fig. 2]). All these agentscompetitively inhibit oestrogen binding to the ER andhave mixed agonist/antagonist activity mediated bytheER.

The newer steroidal anti-oestrogens (Table 2) in-clude ICI 164, 384 and ICI 182,780, in whichthe addition of a side-chain at the 7a position ofoestradiol, leads to the complete abrogation of thetrophic/agonist action of oestradiol on the uterus andalso blocks the uterotrophic action of tamoxifen [19].Another steroidal pure anti-oestrogen devoid of anypartial agonist activity is RU 58668 [22]. It differsfrom ICI 182,780 in that its bulky side chain extends



IC1164,384 IC1182,780

H3C0

RU 58,668 SR 16234Fig. 3. Steroidal anti-oestrogens.

from oestradiol's l i p carbon atom rather than fromthe 7a carbon. The orally active steroidal anti-oestro-gen SR 16234 has a methyl group at the 7a positionand a bulky side chain at the 170 position (Fig. 3).Although some of the agents outlined above havealready been withdrawn from clinical development(particularly many of the triphenylethylenes) for thetreatment of breast cancer because they offer no ad-vantage over tamoxifen, their pre-clinical and clinicalcharacteristics are briefly reviewed in the followingsection in an attempt to provide an insight into theproperties that might contribute to the developmentof optimally clinically effective anti-oestrogens.

Triphenylethylenes

These are the most extensively studied of all the ERmodulators and include the early anti-oestrogenstriphenylchloro and bromoethylenes, chlomipheneand tamoxifen. It was the concern over the effectsof tamoxifen on the uterus and the desire for moreactive compounds that lead to the development of thetamoxifen analogues described below.

Toremifene

Toremifene is a chlorinated analogue of tamoxifen(Fig. 1), with similar site-specific oestrogenic andanti-oestrogenic activity [23]. It has been shown

in pre-clinical studies to have similar ER bindingand anti-tumour activity to tamoxifen [19], but lessDNA adduct formation in the endometrium [28].Toremifene has similar stimulatory effects to tamox-ifen on the endometrium in athymic mice [23] and inpostmenopausal patients receiving toremifene ther-apy for twelve months [29], which suggests thattoremifene, like tamoxifen, might be associated withan increased risk of endometrial cancer. Phase HItrials [30-32] have demonstrated that toremifene isas effective as tamoxifen in the first-line treatmentof metastatic breast cancer (MBC), with a simi-lar side-effect profile. As a result toremifene hasbeen approved for the first-line treatment of MBCin patients with ER positive and ER unknown dis-ease. Use of toremifene in an adjuvant setting alsoshows no difference in recurrence rates between itand tamoxifen [33] again with a similar side effectprofile. Low response rates in phase II studies inpatients previously treated with tamoxifen suggestcross-resistance with tamoxifen [13,34]. Meta-analy-sis of all clinical trial data comparing toremifene andtamoxifen showed both agents to be equally effectivein the treatment of advanced breast cancer in post-menopausal women [35]. Thus, to date, toremifeneshows no advantages over tamoxifen.


260 A. Howell

Idoxifene, dwloxifene and TAT-59

Unlike toremifene, all three agents bind to the ERmore effectively than tamoxifen [13,24,26]. Idoxifenehas an iodine atom at the 4 position of tamoxifen(Fig. 1) which is associated with reduced carcinogenicpotential [36]. Pre-clinical [37] and phase I—II stud-ies [24] were moderately encouraging although idox-ifene showed little activity when used after tamoxifenfailure [38]. However, idoxifene has been withdrawnfrom development as a breast cancer therapy and forthe treatment of osteoporosis because of uterine ef-fects similar to those seen with tamoxifen.

The pre-clinical [25] and phase n data [40-43]for droloxifene (3-hydroxy tamoxifen) (Fig. 1), werealso encouraging. However, droloxifene did not ap-pear to offer any advantages over tamoxifen forthe treatment of breast cancer patients. As a resultdroloxifene too, has been taken off the market forthe treatment of breast cancer and is currently beingdeveloped for the prevention of osteoporosis.

TAT-59 is a prodrug developed in Japan thatrequires dephosphorylation to become the ac-tive metabolite of tamoxifen, 4-hydroxytamoxifen(Fig. 1). This agent has a high affinity for the ER[26,44]. A phase m trial comparing TAT-59 with ta-moxifen in the first-line treatment of MBC has beenreported [45]. The overall response rate was 30% inthe TAT-59 arm and 26.5% in the tamoxifen arm. Theside effect profile was mild, and again was similar tothat of tamoxifen. There are no details of the effectsof TAT-59 on bone density or serum lipid profile.TAT-59 it is no longer in development.

GW 5638 is an acidic triphenylethylene in whichthe amino side chain has been replaced by a car-boxylic acid moiety (Fig. 1). When assayed in vitro,it functions as an ER antagonist in a manner thatis distinct from that of other known ER modulators[27]. However, quite unexpectedly it has the proper-ties of a bone selective anti-oestrogen and exhibitsdecreased uterotrophic activity relative to tamoxifenin pre-clinical studies [27]. GW 5638 is currently inclinical development but no data with respect to itseffectiveness are available.

Cyclic/fixed ring compounds

Benzothiophenes

These were developed in an attempt to avoid the ago-nist problems associated with the triphenylethylenesand to be more selective in their action on spe-cific target tissues, namely breast and bone. Detailed

structure activity studies [46] identified raloxifene(Fig. 2a) as having a unique profile of biological ac-tivity. Currently raloxifene and its derivative SERM 3are undergoing clinical trials. Raloxifene is effectivefor the treatment of osteoporosis and prevents breastcancer. SERM 3 is being developed for the treatmentof early and advanced breast cancer.

Raloxifene

Raloxifene (formerly called keoxifene) is a non-steroidal benzothiophene derivative that binds tothe ER with high affinity. It has been shown inpre-clinical studies to have anti-oestrogenic effectson both the breast and the uterus and oestrogeniceffects on the bone, cholesterol levels and vascu-lar smooth muscle cells [14,47-49]. In fact ralox-ifene was developed for, and most of its clinicalevaluation has been for, the treatment of osteo-porosis in postmenopausal women [50-52]. Pre-liminary clinical studies showed raloxifene to de-crease bone turnover and lower serum cholesterollevels without increasing serum triglyceride concen-trations or causing endometrial proliferation [50]These observations were confirmed by Delmas etal. [52], in a 2 year osteoporosis prevention trial,and raloxifene has been approved in the US forthe prevention of osteoporosis in postmenopausalwomen.

Evidence of the potential of raloxifene as a breastcancer therapy came from the Multiple Outcomesof Raloxifene Evaluation (MORE) trial [53] whichshowed that the incidence of ER positive breastcancer was 74% lower in the raloxifene group than inthe placebo group. As in the tamoxifen breast cancerprevention trial [7], the effect was seen exclusively inpatients who developed ER positive breast cancers.Significantly the incidence of endometrial cancer wasnot increased, and was in fact slightly lower, in theraloxifene treatment groups when compared withplacebo.

There have been two clinical reports involvinga total of 32 post-menopausal women. In the firststudy [54], no objective tumour response was ob-served in 14 patients with tamoxifen-resistant dis-ease. In the second more recent study, three objectiveresponses were reported in 18 patients with ER pos-itive breast cancer [55] (Table 4). The AmericanSociety for Clinical Oncology (ASCO) evidence-based technology assessment to determine whethertamoxifen and raloxifene were appropriate as breastcancer risk-reduction therapies in clinical practice,suggested that raloxifene use should currently bereserved for its approved indication, i.e. to prevent



Table 4Response to new anti-oestrogens as first or second line treatmentsfor MBC compared with tamoxifen (as first line)

SERM/SERD

TamoxifenRaloxifeneSERM3SCH 57068"ICI182780"(Faslodex)

No. ofpatients

500+18884319

CR + PR(%)

2719321437

SD(%)

2514192332

Total(%)

5233513769

" Previous treatment with tamoxifen for advanced disease.

bone loss in postmenopausal women [8]. A Study ofTamoxifen Against Raloxifene (STAR) is ongoing inpostmenopausal women at high risk of developingbreast cancer [56,57], and the results are awaitedwith interest.

SERM3

Modification of the carbonyl hinge which attachesthe side chain of raloxifene to the ER binding ben-zothiophene nucleus (Fig. 2) resulted in the produc-tion of LY353381 or SERM3, which is one of themost potent oral oestrogen antagonists produced todate when assayed in pre-clinical models of breastcancer [58]. Oestrogen antagonist effects were alsoobserved in the uterus. Oestrogen agonist effectswere observed in assays evaluating effects on bone,lipids and the central nervous system (CNS). Overall,SERM 3 is a more potent oestrogen antagonist thanraloxifene and has better bone preserving properties[15,59]. Results have been reported from a phaseI dose rinding study [60] and a phase II study inwhich SERM 3 was administered first-line to patientswith MBC [61] (Tables 4 and 5). From the phase Istudy two doses of SERM 3 for phase II evaluation

Table 5Phase I and phase n studies with SERM 3

Total Dose (mg)

10 20 50 100

Phase IPatients 32CR/PR/SD 0/0/6% Response" 19

8 8 8 80/0/3 0/0/0 0/0/1 0/0/238 0 13 25

Phase IIPatients 88CR/PR/SD 1/27/17 -% Response" 51

44 440/14/8 0/14/950 52

" Response denotes CR + PR + SD.

were chosen and patients randomised between 20mg and 50 mg. Only a small number (approximately9%) were previously treated with endocrine ther-apy (all tamoxifen). Thirty nine percent of patientshad locally advanced disease. The preliminary resultsof this study are shown in Table 5. The completeand partial remission rates were 32% and rose to51% when stable disease for more than 6 monthswas included. Thus, SERM 3 shows response ratesequivalent or possibly superior to tamoxifen. Moredata are required to be certain of the appropriatedose. There are several ongoing phase 2-3 studies ofSERM 3 in patients with tumours of the breast, ovaryand endometrium. In breast cancer there are ongoingphase HI studies verus tamoxifen for the first linetreatment of MBC and an adjuvant trial is planned.

Napthalenes

The napthalene nucleus has provided a structuraltemplate for several ER modulators including theanti-fertility agent, nafoxidene [62]. Nafoxidene wasshown to be equivalent to ethinyloestradiol for thetreatment of advanced breast cancer but was with-drawn because of severe skin phototoxicity. A re-duced nafoxidene derivative CP-336,156 (Fig. 2), hasbeen shown in pre-clinical evaluations to have potenttissue selective oestrogen action when administeredorally [16]. Recently a hydroxynapthalene ER mod-ulator, LY326.315, that exhibits fully differentiatedagonist/antagonist activity in reproductive and non-reproductive tissues in pre-clinical assays and alsohas good oral bioavailability has been reported [17].

Benzopyrans

Historically several oestrogen receptor modulatorshave been based upon a benzopyran framework in-cluding the contraceptive agent centchroman [63,64]and the osteoporosis/ HRT agent levormeloxifene[65].

EM-800 (SCH 58050)

EM-800 is a derivative of centchroman and wasoriginally developed as an orally active 'pure' anti-oestrogen. EM-800 is a prodrug that requires theremoval of two carboxylic acids to produce its activemetabolite EM-652 (SCH 58068) [18] (Fig. 2). Com-parison of the structure of EM-800 with centchro-man, shows that the anti-oestrogenic component ofthe centchroman molecule is moved to a positionin the non-steroidal skeleton equivalent to the 7aposition of the steroidal anti-oestrogen ICI 182 780


262 A. Howell

(Fig. 3). Both EM-800 and its active metabolite,EM-652, are potent antagonists of the ER subtypes aand p [66]. Pre-clinical, in vitro data showed EM-800and EM-652 to be the most potent anti-oestrogensknown to date when tested in breast cancer cell lines.They were also devoid of any of the oestrogen ago-nist activity for example stimulation of cell growth inZR 75-1 and MCF-7 cell lines in the absence of oe-strogens [67]. Mice treated with EM-800 developeduterine and vaginal atrophy that was greater than seenin ovariectomised animals. Also there was completeinhibition of mammary gland development [68,69].These studies confirmed the 'pure' anti-estrogeniceffect of EM-800 on the mammary gland, uterus,vagina and hypothalamo-pituitary-gonodal axis [69].Recent data concerning its activity on bone have ledto the reclassification of EM-800 as an anti-oestrogenwith both antagonist and agonist activity.

EM-800 was assessed in a phase II study inpatients who had failed tamoxifen treatment as anadjuvant or for advanced disease (Table 4). Of 43evaluable patients treated 14% had a complete orpartial remission and 23% had stable disease formore than 6 months. Encouraged by these results aphase III second line trial of EM-800 versus arimidexwas initiated but abandoned when the first interimanalysis showed inferiority of the anti-oestrogen toarimidex. EM-800 has been withdrawn from theclinic for the treatment of MBC. It continues to bedeveloped for breast cancer prevention.

Steroidal anti-oestrogens

These compounds include the 'pure' anti-oestrogensICI 164,384, ICI 182,780 and RU 58668 and theoral SERM SR 16234 [22,70]. The most advanced ofthese agents in terms of both pre-clinical and clinicalevaluation is ICI 182,780 [71,72].

ICI 182,780 and its predecessor ICI 164,383 weredeveloped as pure anti-estrogens [71]. ICI 164,383has been studied extensively in a pre-clinical setting,but it is the more potent ICI 182,780 that is beingactively studied in clinical trials in patients withadvanced breast cancer [20,21,73].

The pre-clinical characteristics of ICI 182,780that define this compound as a 'pure' anti-oestrogendevoid of oestrogen-like activity have been exten-sively reviewed [71,74,75]. These include affinityfor the ER approximately a hundred times that oftamoxifen, the specific absence of oestrogen-like ac-tivity on the uterus and the capacity to completelyblock the stimulatory activities of oestrogens andanti-oestrogens with partial agonist activity like ta-moxifen. Moreover, ICI 182,780 has been shown

not to block the uptake of [3H]oestradiol in thebrain suggesting that ICI 182,780 does not crossthe blood-brain barrier [76] and therefore may notcause hot flushes. The pre-clinical animal data on theeffects of ICI 182, 780 on bone density are conflict-ing with reports of reduced cancellous bone volumein one study [77] and no effect on overall densityin another [78]. The absence of oestrogenic activ-ity has important consequences for the developmentof resistance, which is of major concern during ta-moxifen therapy. In vitro studies have demonstratedthat tamoxifen-resistant cell lines remain sensitive togrowth inhibition by ICI 182,780 [79,80], and thattamoxifen resistant tumours remain sensitive to ICI182,780 in vivo [81]. Pre-clinical studies in nudemice showed ICI 182, 780 to suppress the growth ofestablished MCF-7 xenografts for twice as long astamoxifen and to delay the onset of tumour growthfor longer than tamoxifen [81]. Pre-clinical animalstudies have also confirmed the complete absence ofuterine stimulatory activity and shown ICI 183,780to block the uterotrophic action of tamoxifen [71]. Inovariectomised, oestrogen-treated monkeys the ex-tent of involution of the endometrium was similarin animals treated with ICI 182,780 and in animalsin which oestrogen treatment was withdrawn [74].Overall these data indicate that the mode of actionand the pre-clinical effects of ICI 182,780 are distinctfrom those of tamoxifen and the newer non-steroidalanti-oestrogens cited above.

The limited data surrounding the clinical poten-tial of ICI 182,780 in patients with metastatic breastcancer are also encouraging. A phase I investigationof the effects of ICI 182,780, on primary ER-posi-tive and negative breast tumours in postmenopausalpatients and comparison with tamoxifen [20,82,83],showed ICI 182,780 administered for the short periodof time (7 days) between the first clinic appointmentand surgery, to cause a significant decrease in tu-mour proliferation as assessed by the Ki-67 labellingindex (LI). Tamoxifen caused a similar reduction inthe Ki-67 LI after a median 21 days treatment. InER positive tumours ICI 182,780 caused a profounddecrease in immunocytochemically detectable ER re-ceptor protein, whilst tamoxifen had no effect leadingto the suggeston that this type of drug be called a 'se-lective oestrogen receptor downregulator' (SERD).ICI 182,780 also significantly reduced the expressionof two oestrogen regulated genes, progesterone re-ceptor and pS2, whilst again tamoxifen had no effect.

One small phase II trial in 19 patients with ta-moxifen refractory disease demonstrated a partialresponse rate of 37% and a stable disease of 32%with a median duration of 25 months [21,73] (Ta-



ble 4), confirming the lack of cross resistance withtamoxifen predicted by the animal studies. This trialalso suggested that ICI 182, 780 might have fewerside effects in terms of menopausal symptoms thantamoxifen.

RU 58668 is another steroidal anti-oestrogen be-lieved to be devoid of any oestrogen agonist activity[22]. RU 58668 is active in cell culture and possessesall the properties of a 'pure' anti-oestrogen in ani-mal models [84,85]. Structural comparison with ICI182,780 (Fig. 3) shows the long hydrophobic sidechain to be attached at the l i p position. At present,there are no clinical data available for this anti-oestrogen, but the pre-clinical data suggest that RU58668 may be used for the treatment of ER positivepatients who are resistant to or have escaped from ta-moxifen treatment. Also its inhibition of tumour takesuggests a role in breast cancer prevention [84,85].

SR 16234

SRI6234 is an orally active steroidal anti-oestro-gen developed in Japan. It has a binding affinity forthe ER similar to that of oestradiol and in pre-clinicalstudies has been shown to have a potent anti-pro-liferative activity in vitro and potent anti-tumouractivity in vivo even against tumours generated froma tamoxifen resistant cell line. It showed potent ag-onist activity with regard to bone density and serumcholesterol but showed little uterotrophic activity.The evidence so far suggests that this compoundcould be effective in the treatment of patients whohave failed on tamoxifen therapy [86,87]. However,to date no clinical data are available although phase Istudies may begin in 2000.

There are therefore several anti-oestrogens in pre-clinical and clinical development. A major questionis which will be the most useful clinically? Clini-cal utility may be decided by a trade off betweenthe anti-tumour activity of the anti-oestrogen andits beneficial effects on normal tissues. In order todecide and also to determine how to develop evenmore selective agents it is important to understandthe mechanism(s) of interaction of anti-oestrogenswith the oestrogen receptor. We need to know if wecan group anti-oestrogens into particular classes andthe molecular determinants of their antagonist and/oragonist activity in specific tissues. The first step inthis process is to understand the interaction of thenatural ligand oestrogen with the ER and the factorsthat influence its site-specific activity.

References

1 Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics.CA Cancer J Clin 1998; 48: 6-29.

2 Beatson G. On the treatment of inoperable cases of carci-noma of the mamma: with suggestions for a new method oftreatment, with illustrative cases. Lancet 1896; 2: 104-107.

3 Haddow A, Watkinson JM, Patterson E. Influence of syntheticoestrogens upon advanced malignant disease. Br Med J 1944;2: 393-398.

4 Howell A, De Friend D, Anderson E. Clues to the mech-anisms of endocrine resistance from clinical studies in ad-vanced breast cancer. Endocrin-Rel Cancer 1995; 2: 131-139.

5 Cole MP, Jones CTA, Todd IDH. A new antioestrogenic agentin late breast cancer: an early clinical appraisal of ICI 146474.Br J Cancer 1971; 25: 271-275.

6 Early Breast Cancer Trialist's Collaborative Group. Tamox-ifen for early breast cancer: an overview of the randomisedtrials. Lancet 1998; 851: 1451-1467.

7 Fisher B, Constantino JP, Wickerham DL, et al. Tamoxifen forprevention of breast cancer report of the National SurgicalAdjuvant Breast and Bowel Project P-l Study. J Natl CancerInst 1998; 90: 1371-1388.

8 Chlebowski R, Collyar DE, Somerfield MR, et al. Ameri-can Society of Clinical Oncology Technology. Assessment ofbreast cancer risk reduction strategies: tamoxifen and ralox-ifene. J Clin Oncol 1999; 17: 1939-1955.

9 Love RR, Mazess RB, Barden HS, et al. Effects of tamoxifenon bone mineral density in postmenopausal women withbreast cancer. N Engl J Med 1992; 326: 852-856.

10 Love RR, Newcomb PA, Wiebe DA, et al. Effects of tamox-ifen therapy on lipid and lipoprotein levels in postmenopausalpatients with node-negative breast cancer. J Natl Cancer Inst1990; 82: 1327-1332.

11 Fisher B, Constantino JP, Redmond CK, et al. Endometrialcancer in tamoxifen treated breast cancer patients: findingsfrom the National Surgical Adjuvant Breast and Bowel Project(NASBP) B-14 Study. J Natl Cancer Inst 1994; 86: 527.

12 Assirikis VJ, Neven P, Jordan VC, et al. A realistic clinicalperspective of tamoxifen and endometrial carcinogenesis. EurJ Cancer 1996; 32A: 1464-1476.

13 Howell A, Downey S, Anderson E. New endocrine therapiesfor breast cancer. Eur J Cancer 1996; 32A: 576-588.

14 Clemens JA, Bennet DR, Black IJ, Jones CD. Effects of anew antiestrogen keoxifene (LY156758), on growth of car-cinogen-induced mammary tumours and on LH and prolactinlevels. Life Sci 1983; 32: 2869-2875.

15 Palkowitz AD, Glasebrook AL, Thresher KJ, et al. Discoveryand synthesis of [6-hydroxy-3[4-[2-(l-piperidinyl)ethoxy]phe-noxy]-2-(4-hydroxyphenyl)]benzo[P]thiophene: a novel high-ly potent selective estrogen receptor modulator. J Med Chem1997; 40: 1407-1416.

16 Ke HZ, Paralkar VM, Crasser WA, et al. Effects of CP-336,156, a new, non steroidal estrogen agonist/antagonist, onbone serum cholesterol, uterus and body composition in ratmodels. Endocrinology 1998; 139: 2068-2076.

17 Grese TA, Dodge JA. Selective estrogen receptor modulators(SERMS). Curr Pharmaceut Design 1998; 4: 71-92.

18 Gauthier S, Caron B, Cloutier J, et al. (SM+M-[7-(2,2-dimethyl-L-oxopropoxy)-4-methyI-2-[4-[2-(l-piperidinyl)-et-hoxy]phenyl]-2H-l-benzopyran-3-yI]-phenyl 2,2-dimethyl-pr-opanoate (EM-800): a highly potent, specific and orally activenonsteroidal antiestrogen. J Med Chem 1997; 40: 2117-2122.

19 Wakeling AE. Pharmacology of antiestrogens. In: M Oettle,


264 A. Howell

E Schillinger (eds), Estrogens and Anti-estrogens. H, Vol 135,Springer, Berlin, Heidelberg, New York, 1999, pp 179-194.

20 De Friend DJ, Howell A, Nicholson RT, et al. Investigation ofa new pure antiestrogen (ICI 182780) in women with primarybreast cancer. Cancer Res 1994; 54: 408-414.

21 Howell A, DeFriend DJ, Robertson JFR, et al. Pharmacoki-netics, pharmacological and antitumour effects of the specificanti-oestrogen ICI 182780 in women with advanced breastcancer. Br J Cancer 1996; 74: 300-308.

22 Van De Velde P, Nique F, Planchon P, et al. RU 58668:Further in vitro and in vivo pharmacological data related to itsantitumoural activity. J Steroid Biochem Mol Biol 1996; 59:449-457.

23 Kangas L, Nieminen A-L, Blanco G, et al. A new triph-enylethylene compound Fc-1157a II. Antitumour effects. Can-cer Chemother Pharmacol 1986; 17: 109-113.

24 Chander SK, McCague R, Luqmani Y, et al. Pyrrolidino-4-iodotamoxifen and 4-iodotamoxifen, new analogues of theanti-estrogen tamoxifen for the treatment of breast cancer.Cancer Res 1991; 51: 5851-5858-.

25 Loser R, Seibel K, Roos W, Eppenberger U. In vivo andin vitro antioestrogenic action of 3-OH-tamoxifen, tamoxifenand 4-OH-tamoxifen. Eur J Cancer Clin Oncol 1985; 21:985-990.

26 Toko T, Sugimoto Y, Matsuo E, et al. TAT-59, a new triph-enylethylene derivative with antitumour activity against hor-mone-dependent tumours. Eur J Cancer 1990; 26: 397-404.

27 Willson TM, Norris JD, Wagner BL, et al. Dissection ofthe molecular mechanism of action of GW 5638, a novelestrogen receptor ligand, provides an insight into the roleof the estrogen receptor in bone. Endocrinology 1997; 138:3901-3911.

28 Hemminki K, Rajaniemi H, Lindahl B, et al. Tamox-ifen-induced DNA adducts in endometrial samples frombreast cancer patients. Cancer Res 1996; 56: 4374-4377.

29 Tomas E, Kauppila A, Blanco, et al. Comparison betweeneffects of tamoxifen, toremifene and ICI 182780 on the uterusin postmenopausal breast cancer patients. Gynaecol Oncol1995; 59: 261-266.

30 Gershanovich M, Garin A, Baltina D, et al. A phase mcomparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer. Eastern Eu-ropean Study Group. Breast Cancer Res Treat 1997; 45: 251-262.

31 Pyrhonen S, Valavaara R, Modig H, et al. Comparison oftoremifene and tamoxifen in post-menopausal patients withadvanced breast cancer: a randomised double-blind trial, the'Nordic' phase m study. Br J Cancer 1997; 76: 270-277.

32 Hayes DE, Van Zyl JA, Hacking A, et al. Randomised com-parison of tamoxifen and two separate doses of toremifene inpost-menopausal patients with metastatic breast cancer. J ClinOncol 1995; 13: 2556-2566.

33 Holli K, Joensun H, Valavaara R, et al. Interim results ofthe Finnish toremifene versus tamoxifen adjuvant trial. BreastCancer Res Treat 1998; 50: 283.

34 Pyrhonen S, Valavaara R, Vuorinen J, et al. High dosetoremifene in advanced breast cancer resistant to or relapsedduring tamoxifen treatment. Breast Cancer Res Treat 1994;29: 223-228.

35 Pyrohnen S, Ellmen J, Vuorinen M, et al. Meta-analysisof trials comparing toremifene with tamoxifen and factorspredicting outcome of antiestrogen therapy in postmenopausalwomen with breast cancer. Breast Cancer Res Treat 1999; 56:133-143.

36 McCague R, Parr IB, Haynes BP. Metabolism of the 4-iodo-derivative of tamoxifen by isolated rat hepatocytes. Demon-stration that the iodine atom reduces metabolic conversion andidentification of four metabolites. Biochem Pharmacol 1990;40: 2277-2283.

37 Nuttall ME, Bradbeer JN, Strorp GB, et al. Idoxifene a novelselective estrogen receptor modulator prevents bone loss andlowers cholesterol levels in ovariectomised rats and reducesuterine weight in intact rats. Endocrinology 1998; 139: 5224-5234.

38 Johnston SRD, Gumbrell L, Evans TRJ, et al. A phase Urandomised double blind study of idoxifene (40 mg/day)v tamoxifen (40 mg/day) in patients with locally advancedmetastatic breast cancer resistant to tamoxifen (920 mg/day).Proc Am Soc Clin Oncol 1999; 18A: 413.

39 Ke HZ, Simmons HA, Pirie CM, et al. Droloxifene a newoestrogen aritagonist/agonist prevents bone loss in ovariec-tomised rats. Endocrinology 1995; 136: 2435-2441.

40 Abe O. Japanese early phase JJ study of droloxifene in thetreatment of advanced breast cancer. Preliminary dose-findingstudy. Am J Clin Oncol 1991; 14: S40-S45.

41 Bellmunt J, Sole L. European early phase II dose-findingstudy of droloxifene in advanced breast cancer. Am J ClinOncol 1991; 14: S36-S39.

42 Haarstad H, Gundersen S, Wist, et al. Droloxifene a newantioestrogen phase II study in advanced breast cancer. ActaOncol 1992; 31: 425-428.

43 Rauschning W, Pritchard KI. Droloxifene a new antiestrogenits role in metastatic breast cancer. Breast Cancer Res Treat1994; 31: 83-94.

44 Koh JR, Kubota T, Asanuma F, et al. Antitumour effect oftriphenylethylene derivative (TAT-59) against human breastcarcinoma xenografts in nude mice. J Surg Oncol 1992; 51:254-258.

45 Noguchi S, Koyama H, Nomura Y, et al. Late phase IIstudy of TAT-59 (new antiestrogen) in advanced or recurrentbreast cancer patients: a double-blind comparative study withtamoxifen citrate. Breast Cancer Res Treat 1998; 50: 307.

46 Grese TA, Sluka JP, Bryant HU, et al. Molecular determinantsof tissue selectivity in estrogen receptor modulators. Proc NatlAcad SciUSA 1997; 94: 14105-14110.

47 Anzano MA, Peer CW, Smith JM, et al. Chemopreventionof mammary carcinogenesis in the rat: combined use ofraloxifene and 9-cis-retinoic acid. J Natl Cancer Inst 1996;88: 123-125.

48 Black U, Sato M, Rowley ER, et al. Raloxifene (LY 139481-HC1) prevents bone loss and reduces serum cholesterol with-out causing uterine hypertrophy in ovariectomised rats. J ClinInvest 1994; 93: 63-69.

49 Turner CH, Sato M, Rowley ER, et al. Raloxifene preservesbone strength and bone mass in ovariectomised rats. En-docrinology 1994; 135: 2001-2005.

50 Draper MW, Flowers DE, Huster WJ, et al. A controlledtrial of raloxifene (LY 39481) HC1: impact on bone turnoverand serum lipid profile in healthy post-menopausal women. JBone Miner Res 1996; 11: 835-842.

51 Walsh BW, Kuller LH, Wild RA, et al. Effects of ralox-ifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 1998; 279: 1445-1451.

52 Delmas PD, Bjamason NH, Mitlak BH, et al. Effects ofraloxifene on bone mineral density, serum cholesterol concen-trations and uterine endometrium in post menopausal women.N Engl J Med 1997; 337: 1641-1647.

53 Cummings SR, Norton L, Eckert S, et al. Raloxifene reducesthe risk of cancer and may decrease the risk of endometrial



cancer in post menopausal women: two year findings from theMultiple Outcomes of Raloxifene Evaluation (MORE) trial.Proc Am Soc Clin Oncol 1998; 17: 2a.

54 Buzdar AV, Marcus C, Holmes F, et al. Phase II evaluation ofLY 156758 in metastatic breast cancer. Oncology 1988; 45:344-345.

55 Gradishar WJ, Glusman JE, Vogel CH, et al. Raloxifene HC1a new endocrine agent is active in estrogen receptor positive(ER+) metastatic breast cancer. Breast Cancer Res Treat (SanAntonio Cancer Symposium Proc) 1997; 20: 53.

56 Jordon VC. Development of a new prevention maintenancetherapy for postmenopausal women. Recent Results CancerRes 1999; 151: 96-109.

57 Jordon VC, Morrow M, Raloxifene as a multifunctionalmedicine? Br Med J 1999; 319: 331-332.

58 Sato M, Turner CH, Wang T, et al. LY 353381 Bel: a novelraloxifene analog with improved SERM potency and efficacyin vivo. J Pharmacol Exp Ther 1998; 287: 1-7.

59 Sato M, Glasebrook AL, Bryant HU. Raloxifene: A selectiveestrogen receptor modulator. J Bone Miner Met 1994; 12:S9-S20.

60 Hudis C, Buzdar A, Munster P, et al. Phase I study of a thirdgeneration selective estrogen receptor modulator (SERM 3,LY 353381.HC1) in refractory metastatic breast cancer. BreastCancer Res Treat 1998; 50: 306 (abstract 442).

61 Baselga J, Llombart-Cussac A, Bellet M, et al. Randomiseddouble blind phase II study of a selective oestrogen receptormodulator SERM (LY 353381) in patients with locally ad-vanced or metastatic breast cancer. Breast Cancer Res Treat1999; 57: 31 (abstract 35).

62 Tagnon HJ. Antioestrogens in treatment of breast cancer.Cancer 1977; 39: 2959-2964.

63 Ray S, Groves P, Kamboj VP, et al. Antifertility agent 12.Structure-activity relationship of 3,4-diphenyl-chromenes andchromans. J Med Chem 1976; 19: 276-279.

64 Kamboj VP, Ray S, Dhawan RB. Centchroman. Drugs Today1992; 227-232.

65 Holm P, Shalmi M, Korsgaard N, et al. Apartial oestrogen re-ceptor antagonist with strong and atherogenic properties with-out noticable effect on reproductive tissue in cholesterol-fedfemale and male rabbits. Arterioscler Thromb Vase Biol 1997;17: 2264-2272.

66 Mattel C, Provencher L Li X, et al. Binding characteristicsof novel nonsteroidal antiestrogens to the rat uterine estrogenreceptors. J Steroid Bjochem Mol Biol 1998; 64: 199-205.

67 Simard J, Labrie C, Beianger A, et al. Characterisation of theeffects of the novel non-steroidal antioestrogen EM-800 onbasal and estrogen-induced proliferation on T-47-D, 2R-75-1and MCF-7 human cancer cells in vitro. Int J Cancer 1997;73: 104-112.

68 Sourla A, Luo S, Labrie C, et al. Morphological changesinduced by six month treatment of intact and ovariectomisedmice with tamoxifen and the pure antioestrogen EM-800.Endocrinology 1997; 138: 5605-5617.

69 Luo S, Sourla A, Gauthier S, et al. Effect of 24 week treat-ment with the antioestrogen EM-800 on estrogen-sensitiveparameters in intact and ovariectomised mice. Endocrinology1998; 139: 2645-2656.

70 Tanabe M, Peters RH, Chao W-R, et al. SR 16234, anovel steroidal selective estrogen receptor modulator (SERM).Breast Cancer Res Treat 1999; 57: 52 (abstract 172).

71 Wakeling AE, Dukes M, Bowler J. A potent specific pureantioestrogen with clinical potential. Cancer Res 1991; 51:3867-3873.

72 Howell A, De Friend D, Robertson J, et al. Response to aspecific anti-oestrogen (ICI 182780) in tamoxifen resistantbreast cancer. Lancet 1995; 345: 29-30.

73 Howell A, Osbome CK, Morris C, Wakeling A. Faslodex(ICI 182,780). Development of a novel 'pure' antioestrogen.Cancer 2000; in press.

74 Dukes M, Miller D, Wakeling AE, Waterton JC. An-tiuterotrophic effects of a pure antioestrogen, ICI 182780;magnetic resonance imaging of the uterus in ovariectomisedmonkeys. J Endocrinol 1992; 135: 239-247.

75 Dukes M, Waterton JC, Wakeling AE. Antiuterotrophic ef-fects of the pure antioestrogen ICI 182780 in adult femalemonkeys (Macaca nemestrina): quantitative magnetic reso-nance imaging. J Endocrinol 1993; 138: 203-209.

76 Wade GN, Blaustein JD, Gray JM, Meredith JM. ICI 182780:a pure antiestrogen that affects behaviour and energy balancein rats without acting in the brain. Am J Physiol 1993; 34:R1392-R1398.

77 Gallagher A, Chambers TJ, Tobias JH. The estrogen antag-onist ICI 182780 reduces cancellous bone in female rats.Endocrinology 1993; 133: 2787-2791.

78 Wakeling AE. The future of pure antioestrogens in clinicalbreast cancer. Breast Cancer Res Treat 1993; 25: 1-9.

79 Coopman P, Garcia M, Brunner N, et al. Antiproliferativeand anti-estrogenic effects of ICI 164, 384 and ICI 182780in 4-OH-tamoxifen resistant human breast cancer cells. Int JCancer 1994; 56: 295-300.

80 Hu XF, Veroni M, De Luise M, et al. Circumvention oftamoxifen resistance by the pure anti-estrogen ICI 182780. IntJ Cancer 1993; 55: 873-876.

81 Osborne CK, Coronado-Heinsohn ER, Hilsenbeck SG, et al.Comparison of the effects of a pure steroidal antioestrogenwith those of tamoxifen in a model of human breast cancer. JNatl Cancer Inst 1995; 87: 746-750.

82 Anderson E, Nicholson R, Dowsett M, Howell A. Modelsof new antioestrogen action in vivo: primary tumours. Breast1996; 5: 186-191.

83 Robertson JFR, Dixon M, Bundred NJ, et al. A partially blindrandomised multicentre study comparing the antitumour ef-fects of single doses (50, 125, 250mg) of long acting (LA)faslodex (ICI 182780) with tamoxifen in postmenopausalwomen with primary breast cancer prior to surgery. BreastCancer Res Treat 1999; 57: 31 (abstract 28).

84 Van De Velde P, Nique F, Bremaud M-C, et al. Explorationof the therapeutic potential of the anti-oestrogen RU 58668in breast cancer treatment. Ann NY Acad Sci 1995; 761:164-175.

85 Van de Velde P, Nique F, Bouchoux J, et al. RU 58668, a newpure antioestrogen inducing a regression of human mammarycarcinoma implanted in nude mice. J Steroid Biochem MolBiol 1994; 48: 187-196.

86 Evans RM. The steroid and thyroid hormone receptor superfamily. Science 1988; 240: 889-895.

87 Hall JM, McDonnell DP. The estrogen receptor fj-isoform (ERP) of the human estrogen receptor modulates Era transcrip-tional activity and is a key regulator of the cellular response toestrogens and antiestrogens. Endocrinology 1999; 140: 5566-5578.


tamoxifen versus the newer serms: what is the evidence?

Documents