Clinical review
`
`Recent advances in endocrine therapy of breast cancer
`Anthony Howell, Mitchell Dowsett
`
`
`Tare
`
`Regression of advanced breast cancer as a result of
`
`endocrine therapy was first described over 100 years
`ago.' Interest in this form of treatmentincreased when
`treatment with the antioestrogen tamoxifen after
`:
`surgery for breast cancer was shown to improve
`patients’
`survival** Treatment
`also reduced the
`incidence of new cancers in the contralateral breast,
`which has led to a number oftrials of tamoxifen as a
`preventivemeasureinwomenathigh riskNew,poten-
`Phase
`aime
`patients
`tially more active endocrine agents are now being —newnalmarsh
`
`os 7) GRC Department
`i
`University of
`Manchester,
`Christie Hospital
`NHSTrust,
`Manchester
`|
`eaten
`|
`| ees,
`;
`eenof
`
`
`
`introduced into clinical practice. In this review we
`outline the mechanism of action of these treatments
`‘
`ae
`3
`5
`and summarise recent results of clinical trials assessing
`their efficacy in comparison with older drugs; we also
`si
`e aboutfuture trends in endocrinetherapy and
`summarise clinical trials in progress.
`
`Methods
`This article is based, in part, on our own collaborative
`experimental work andclose association with pharma-
`ceutical companies developing new endocrine agents.
`Additional reviews and original articles were obtained
`from searches of oncological journals. Recent data
`were obtained from presentations at the May meeting
`of the American Society for Clinical Oncology.
`
`Mechanism of action of newer endocrine
`therapies
`Breast cancer cells that are endocrine dependent need
`oestrogen to proliferate.” Most endocrine therapies
`either block the bindingof oestrogen toits receptor in
`the nucleus of responsive cells or reduce serumand
`tumour concentrationsofoestradiol. In postmenopau-
`sal women androgens (mainly from the adrenal
`glands) are converted into oestrogens by the enzyme
`aromatase, which is present in a range oftissues and is
`foundin 60-70% of breast carcinomas.”
`The trend for endocrine therapies over the past
`100 years has been towards simpler and more widely
`applicable
`treatments. Originally pharmacological
`doses ofoestrogens were used to block the proliferative
`effect of oestrogen, but now this is achieved with
`tamoxifen.’ Oestrogen concentrations were reduced by
`surgery (oophorectomy, adrenalectomy, and hypophy-
`sectomy), but now analogues of luteinising hormone
`releasing hormone, which effectively ablate ovarian
`steroidogenesis, may be used in premenopausal
`women; aromatase inhibitors are used in postmeno-
`pausal women.
`
`BMJ VOLUME 315 4 OCTOBER 1997
`
`
`
`Biochemistry, Royal
`|
`ate ae ean Oe| omer
`t,London
`SW36]
`Mitchell Dowsett
`professor
`Correspondence to:
`Professor Howell
`
`;
`
`ns have less
`peesasifthiswilleae
`toimportantclinical gains
`Trialsinvolvingrmanythousands ofbreast cancer
`patients areunderwayto comparetheseexciting
`new agentswith tamoxifenasfirstline therapy,
`bothasadjuvanttreatmentand for advanced
`disease
`
`
`BMJ 1997:315:868-6
`
`863
`
`Antioestrogens!
`Pharmacology
`Tamoxifen is an antioestrogen but has a complex
`pharmacology, partly due to its metabolism to numer-
`ous biologically active compounds. It is an oestrogen
`agonist-antagonist
`that depends on its competitive
`binding to oestrogen receptors, Several other bio-
`chemical pathwaysare affected by tamoxifen, but their
`clinical
`importance is doubtful;
`the predominant
`importance of the oestrogen receptor dependent
`pathway is
`supported by clinical
`responses
`to
`tamoxifen being largely confined to tumours positive
`for oestrogen.
`In an oestrogenic environment tamoxifen stops the
`proliferation of breast cancer cells that bind to oestro-
`gen receptors, Butif oestrogen concentrations are low,
`tamoxifen may act as an oestrogen agonist and lead to
`the proliferation of these cells, at
`least
`in model
`systems. Reducing this agonistactivity has become the
`majortarget of new drugs and has led to the develop-
`mentof non-steroidal drugs that act like tamoxifen, as
`well as steroidal compounds that are derivatives of
`oestradiol.’ These two groups differ in their interaction
`with oestrogen receptors. The non-steroidal com-
`
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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 transcription of oestrogen responsive genes. A
`complex series of coactivators and corepressors can
`also substantially modify the agonist or antagonist
`response to the complex of drug and oestrogen recep-
`tor. Drugs of this type which are in or have recently
`completed phase III 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." ”
`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 whetherthis is due to lack of dimerisation
`in the oestrogen receptoror a lack ofbinding tooestro-
`gen response elements, butit seems clear that the acti-
`vating functions are blocked andthatthe stability of the
`oestrogen receptoris reduced such that the oestrogen
`receptor contentof the tumouris greatly reduced.
`Both Faslodex and idoxifene are more effective
`antitumour agents than tamoxifen in animal model
`systems, and both show activity in cells and tumours
`that have becomeresistant to tamoxifen.’
`Conyentional clinical pharmacology of the new
`antioestrogens has not been instructive for
`their
`clinical developmentbecause 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.""
`Tamoxifen’s oestrogen agonist activity is advanta-
`geous on some tissues other than breast cancer,
`including bone and liver, but not endometrium.
`Experimental evidenceindicates that chemical modifi-
`cations can enhancethe therapeutic efficacy and toler-
`ability of non-steroidal compounds and lead to a
`group of compoundscalled SERMS(selective cestro-
`gen receptor modifiers). An example is raloxifene,
`which is
`in its late stages of development as an
`antiosteoporotic agent;it lacks the breast and endome-
`trial stimulation of oestrogen. New compoundsofthis
`type will soon enterclinical development for breast
`cancer treatment and are candidates for breast cancer
`prevention strategies."
`
`Table 1 Recently reported phaseIII and randomised phaseII trials of new non-steroidal
`antioestrogens
`
`Dose
`No of
`
`Drug (ref)
`(mo/day)
`patients
`Tamoxifen versus toremifene® 20|
`215
`
`Response
`(%)*
`19
`
`Comment
`Phase Ill trial asfirst line
`treatmentin advanced disease
`:
`
`aa 60
`21
`221
`200
`212
`22
`
`Droloxifene® BD BG
`30
`Randomised phase |l trial
`88 a
`-
`oo
`—
`40
`| en:
`eo Oe
`15
`TAT-59"*
`10
`15
`Randomised phase II trial
`1
`—_
`20
`55
`ga 88 31
`
`“Complete responseplus partial response,
`
`864
`
`Clinical results
`Tamoxifen is the “gold standard,” but its agonist effect
`may stimulate tumour growth and cause treatment to
`fail.” The newer non-steroidal antioestrogens have
`been developed because (with the exception of
`toremifene) they have reduced agonist activity.
`‘Table | shows somerecent studies of new antioes-
`trogens. A phaseIII trial found that toremifene was not
`superior to tamoxifen.'* The analogue droloxifene
`seemed active in phase I trials when used at doses of
`20-100 mg/day, as did the Japanese drug TAT59."*
`We need more information from phase II trials about
`idoxifene and data from phase I trials comparing
`tamoxifen with droloxifene, TAT-59, and idoxifene.
`The pure antioestrogen ICI 182780 (Faslodex)
`showed little agonist activity in preclinical tests and in
`the only clinical
`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-
`firm these promising preliminary data.
`
`Aromatase inhibitors
`
`Pharmacology
`Using aromatase inhibition to suppress oestrogen syn-
`thesis was developed as a treatment for breast cancer
`over 20 years ago." During the intervening period
`many inhibitors have been developed. Plasma oestro-
`gen concentrations haye been widely used to assess
`pharmacological effectiveness, but such assays have not
`been sufficently sensitive to provide reliable compari-
`sons between inhibitors. Isotopic methods that directly
`measure the inhibition of enzymeactivity throughout
`the body have provided more useful comparative data.
`There is no evidence that any of the inhibitors
`differentially inhibit aromatase in differenttissues. The
`inhibitors may be consideredas two families, steroidal
`and non-steroidal.
`
`Non-steroidal
`All of the non-steroidal agents are active orally. Until
`1992 the only widely available inhibitor was aminoglu-
`tethimide. This drug inhibits several cytochrome P450
`enzymes, including some involved in steroidogenesis,
`and has been widely used in breast cancer in combina-
`tion with replacement doses of glucocorticoid as a
`“medical adrenalectomy.” When aminoglutethimide’s
`clinical effectiveness was shown to be due toits inhibi-
`tion of aromatase, this enzyme became a therapeutic
`target. The side effects of aminoglutethimide (mainly
`skin rashes and neurological symptoms),
`its lack of
`specificity (requiring replacement glucocorticoid), and
`its
`relatively low potency have been targets
`for
`pharmaceutical improvement and have been well met
`by the most recent drugs.
`anastrozole
`A series of
`triazole derivatives,
`(Arimidex),""* letrozole (Femara), and vorozcle
`(Rivizor)* * have all been shown to have excellent
`selectivity for aromatase in preclinical models, and this
`has been confirmed in clinical studies. Their intrinsic
`potency is considerably greater than that of amino-
`glutethimide. In patients, aminoglutethimide inhibits
`total body aromatisation by about 91%, while anastro-
`
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`
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`Clinical review
`
`Table 2 Recently reported phaseIII trials which compare standard second line endocrine therapy with the new triazole inhibitors
`Dose
`No of
`Proportion (%) of
`Median survival
`
`Drug
`(mg/day)
`patients
`patients responding*
`(months)
`Comment
`
`;
`;
`Anastrozole’® *
`1
`263
`42.2 (+S)
`267
`as
`anastrozole
`fo Ea
`
`Megestrol acetate
`160
`253
`40.3
`225
`5
`
`Letrozale”
`—
`05
`188
`12.8(-$D)
`26
`tageReMegestro! acetate
`
`160
`189
`16.4
`23.5
`
`-
`Letrozole™
`-
`05
`Total 555
`16.7 (-SD)
`No data
`Letrozole
`25
`7.8
`_
`_____ Trend for ‘survival advantage for both
`
`Aminoglutethimide plus hydrocortisone
`a
`atee =
`sceee
`
`
`277
`47 (480)
`“25.7
`Vorazole®
`25
`7
`——
`
`:
`279
`——
`-
`500
`Trend for survival advantage with
`sa
`J
`Aminoglutethimide plus hydrocortisone
`§=—_~_—
`— vorozole
`a7
`37
`30
`279
`ates
`si
`28.0 Oe
`10.5 (-SD)
`25
`190
`Vorozole®*
`Magestrol acetate 28.7 160 485 CO 76
`
`
`
`
`“Complete, response plus partial response; SD=stable disease (=6 months),
`
`
`
`their recommended doses of
`zole and letrozole, at
`1 mg/day and 2.5 mg/day, inhibit by about 97% and
`>99%, respectively.” In many patients this results in
`plasma oestrogen concentrations which even the most
`sensitive immunoassays cannot detect.”
`
`Steroidal
`Two of the steroidal agents, formestane and exemes-
`tane, have undergone considerable clinical develop-
`ment. Formestane (4-hydroxyandrostenedione; Len-
`taron) was the first selective inhibitor to be licensed.” It
`is given by intramuscular
`injection because it
`is
`metabolised too quickly if taken orally, It
`is more
`specific than aminoglutethimide but does not have
`more pharmacological activity. Exemestane is orally
`active and seemsto be selective at clinical doses.” No
`data have been published onits effects on whole body
`aromatisation. The only pharmacological data from a
`randomised comparison between any ofthe inhibitors
`showed the superiority of anastrozole over formestane
`in suppressing plasmaoestradiol.”
`
`logical since stable disease gives equivalentpalliation
`and survival.” The durations of response of the new
`agents have tended to be longer than the old, but even
`more important are the survival advantages shown by
`new agents. Thetrial with the longest follow up shows
`that anastrazole | mg has significant survival advan-
`tage over megestrol acetate 160 mg,” and the other
`trials show trends towards survival advantages.The uni-
`formity ofthis difference suggests thatthese trends are
`likely to become significant with further follow up.
`
`Trials in progress
`Theintroduction of new agents and theresults oftrials
`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
`antioestrogens (idoxifene, droloxifene, TAT-59)
`that
`show better preclinical characteristics than tamoxifen
`are better clinically. Large trials comparing all three
`new agents with tamoxifen are ongoing. The pure
`antioestrogen Faslodex looks highly promisingin vitro,
`in animal studies, and in early phase II tests. However,
`phase I studies
`are notoriously unreliable in
`
`Clinical results
`‘Table 2 showsthe results of recent randomised clinical
`tials comparing aromatase inhibitors with standard
`second line endocrine therapy (after tamoxifen). The
`trials for letrozole and anastrozole had three arms: two
`doses of the new aromatase inhibitor compared with
`either the progestogen (megestrol acetate) or the old
`aromatase inhibitor (aminoglutethimide). Vorozole has
`beentested against these same comparatorsat a single
`dose in trials with two arms.” “
`triazole
`All
`three of
`the new non-steroidal
`derivatives (anastrozole, letrozole, and yorozole) and
`the steroidal derivative exemestane have shown
`minimal toxicity. In particular, they do not produce the
`troublesome weight gain of megestrol acetate nor the
`Tamoxifen
`Anastrozole
`Anastrozole
`Tamoxifen
`rash and neurological symptoms of aminoglutethim-
`
`ide. Since all four compounds are specific aromatase
`Both
`— -
`_
`Tamoxifen 2 years
`Tamoxifen 3 years
`Anastrozole
`inhibitors, glucocorticoid replacement is not required.
`
`Faslodex
`: a a
`Anastrozole3.years
`In general, all the trial results point in the same
`Letrozole
`Tamoxifen
`Letrozole
`
`direction, Overall response rates with the new and the
`__Letrozole
`_
`=
`Tamoxifen
`Tamoxifen 5 years
`Placebo 5 years
`Vorozole
`old treatments are similar. Responses have been
`reported as either complete and partial remissions or
`_—
`a -
`/
`Vorozole 5 years
`Exemestane
`Exemestane
`Tamoxifen 2-3 years
`Tamoxifen 2-3 years
`as complete and partial remissions andstable disease
`Exemestane 2-3 years|Megestrol acetate
`for at least six months. The latter reports are more
`
`Table 3 Clinical trials using endocrine therapy projected or in progress in early
`(adjuvant) and advanced breast cancer (phaseII!)
`
`Treatment
`Adjuvant breast cancer
`Advanced breast cancer
`Receptor blockade:
`20mg v40mgv20mg
`“idoxifene
`=
`
`__
`tamoxifen —
`_
`—_
`20mg v 20 mg tamoxifen
`Droloxifene
`
`~
`20mg v.20mg tamoxifen
`-
`~TAT-59
`20 mgv 20mg tamoxifen
`Faslodex (IC 182780)
`125 mg v 250 mg v20 mg
`tamoxifen
`
`Oestrogen receptor:
`Anastrozole
`
`___
`
`|
`
`BMJ VOLUME 315 4 OCTOBER 1997
`
`865
`
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`

`
`
`
`
`
`
`Clinical review
`
`
`
`Present
`
`"Tamoxifen
`
`Table 4 Past, present, and potential future treatment of advanced breast cancer by
`blocking oestrogen receptor or reducing concentrations of oestrogenic steroids in
`postmenopausal patients
`Oestrogen receptor blockade Reduction of oestrogen concentrations
`
`Hyphophysectomy
`Highdoseoestrogens
`Past
`Adrenalectomy —
`Aminoglutethimide
`Oophorectomy
`4-OH androstenedione
`:
`_______Anastrozoe
`_
`a
`Letrienle a
`
`Luteinising hormone releasing hormone agonists
`Future
`Non-steroidal:
`Vorozole
`Droloxifene
`Idoxifene
`Exemestane
`
`TAT-59
`-Sulphatase inhibition
`Luteinising hormone releasing hormone antagonists
`Selective oestrogen receptor
`modulators (eg raloxifene)
`Steroidal:
`101182780(Fasiodex)
`
`-
`
`predicting superiority over old agents. Thus the
`recently started study comparing Faslodex with
`anastrozole as second line endocrine therapy for
`advanced disease and the comparisonof Faslodex with
`tamoxifen as first line treatmentthat is to start late in
`1997 are highly important.
`The success of the new aromatase inhibitors as
`secondline treatments for advanced disease has led to
`the initiation of trials using these drugs as first line
`agents for advanced disease and comparing them to
`tamoxifen as adjuvant therapies. The optimal duration
`for tamoxifen as an adjuvant seems to be five years.
`Studies are in progress or shortly to start in which a
`changeover to an aromatase inhibitor after two or
`three years of tamoxifen is compared with continuous
`tamoxifen (table 3). Change to an aromatase inhibitor
`after
`five years of tamoxifen in comparison with
`stoppingall treatmentis also being tested.
`
`Conclusions
`
`Although theprinciples of endocrine therapy have not
`changed over the past 100 years, new methods have
`resulted in less toxic and more widely applicable treat-
`ments (table 4). Also, for the first time, we have begun
`to see improvements in the effectiveness of treatment
`in terms of response duration and, most importantly,
`survival.
`
`Funding: No additional funding.
`Conflict of interest: We are involved and have been involved
`in the clinial development of many of the compounds
`mentioned in this review.
`
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`Endpiece
`Misleading appearances
`A woman accompanied her husbandto the doctor
`and waited for him during his checkup. After the
`examination the doctor came out andsaid, “I don’t
`like the way your husband looks.” “Neither do I”
`said the woman,“but he’s good with the kids.”
`From The Best ofMedical Humour (HowardJ
`Bennett, ed. Philadelphia: Hanley and Belfus, 1997)
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`BMJ VOLUME 315 4 OCTOBER1997
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`AstraZeneca Exhibit 2040 p. 4
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