Clinical review
`
`Recent advances in endocrine therapy of breast cancer
`Anthony Howell. Mitchell Dowsett
`
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`Regression of advanced breast tanner as a result of
`2:11:33
`endocrine therapy was first described over 100 years
`omen; at
`ago“ Interest in this form of treatment increased when
`M39633” ,
`treatment with the antioestmgen tamoxifen after
`Christie Hospital
`.
`NHS Trust.
`surgery for breast cancer was shown to unprove
`"Manchester
`patients'
`survival.2 3 Treatment:
`also reduced the
`;
`M20 43)::
`incidence of new cancers in the contralateral breast
`i'
`A“!“‘5any “MIL
`which has led to a number of trials of tarnordfen as a
`. Agm
`preventive measure in women at high risk.‘ New, poten- MII!NEWM}30%W53“
`daily more active endocrine agents are now being
`hawahmflmmWWMW 1 pm“ (if
`introduced into clinical practice. In this review we
`.
`Biochemistry. nay-.11
`outline the mechanism of action of these treatments
`wgmimfi‘nfln
`and summarise recent results of clinical trials assessing
`sws 51]
`their efficacy in comparison with older drugs; we rdso
`Mitchell Dawson
`3
`e about future trends in endocrine therapy and
`WW
`summarise climcal trialsin progress.
`Corresptmtleuce to:
`Professor Howell
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`Methods
`
`This article is based, in part. on our own collaborative mmmW 017mgm
`experimental work and close association with pharma— PM areundtrmyto 90mmmuniting
`
`l . flWilli: 31131391
`ceutical companies developing new endocrine agents.
`new agmmfi‘fillh
`Additional reviews and original articles were obtained m l”-adjmurm mmmm
`from searches of oncologioal journals. Recent data m
`were obtained from presentations at the May meeting
`of the American Society for Clinical Oncology.
`
`
`
`3w newness-s
`
`Mechanism of action of newer endocrine
`
`therapies
`Breast cancer cells that are endocrine dependent need
`oestrogen to prolilerate.5 Most endocrine therapies
`either block the binding of oestrogen to its receptor in
`the nucleus of responsive cells or reduce sentm and
`tumour concentrations of oesn'adiol. 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
`found in 60—70% of breast carcinornas6
`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
`eEect of oestrogen, but now this is achieved with
`tamoxifen.” Oestrogen concentrations were reduced by
`surgery (oophorectomy, adrenalectomy, and hypophy—
`sectorny), but now analogues of luteinising hormone
`releasing hormone, which elfectively ablate ovarian
`steroidogenesis, may be used in premenopausal
`women; aromatase inhibitors are used in postmeno—
`pausal women.
`
`BM] VOLUME 315 4 OCTOBER 1997
`
`Aurtlioestrogens1
`
`Pharmacology
`Tamoxifen is an antioesu’ogen 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 pathways are alfected 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. But if 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 agonist activity has become the
`major target of new drugs and has led to the develop-
`ment of non-steroidal drugs that act like tamoxifen, as
`well as steroidal compounds that are derivatives of
`oestradiol,’ These two groups dili'er in their interaction
`with oestrogen receptors» The non-steroidal com-
`
`363
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`

`

`Clinical review
`
`pounds bind to oestrogen receptors, leading to their
`activation and dimer-nation and their binding to
`specific oestrogen response elements on DNA which
`causes nansa'iption of oestrogen responsive genes. A
`complex series of coacrivators and compressors 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 1]] development include toremifene,
`droloxifene. TAT-59, and idoxilene. Other
`than
`toremil‘ene, 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 whether this is due to lack of dimerisation
`
`in the oestrogen receptor or a lack of binding to oestro-
`gen response elements, but it seems clear that the acti-
`vating functions are blocked and that the stability of the
`oestrogen receptor is reduced such that the oestrogen
`receptor content of the tumour is greatly reduced.
`Both Faslodex and idoxifene are more reflective
`
`antimmour agents than tamoxifen in animal model
`systems. and both show activity in cells and rumours
`that have become resistant to tamoxifen?
`
`Conventional clinical pharmacology of the new
`antioestrogens has not been instructive for
`their
`clinical development because there are no good surro-
`gate markers of their activity against cancer. Their
`clinical development
`is being helped by a novel
`approach, in which pathological markers of prolifera-
`tion and apoptosis are measured in primary breast
`carcinomas after short
`term, presurgical
`treatment
`with the drugs before surgery. "’ "
`Tamoxifen‘s oestrogen agonist activity is advanta-
`geous on some tissues other than breast cancer.
`including bone and liver, but not endometrium.
`Experimental evidence indicates that chemical modifi‘
`cations can enhance the therapeutic efficacy and toler—
`ability of non-steroidal compounds and lead to a
`group of compounds called SERMS (selective oestro—
`gen receptor modifiers). An example is raloxifene,
`which is
`in its late stages of development as an
`antiosteoporodc agent; it lacks the breast and endome-
`trial stimulation of oestrogen. New compounds of this
`type will soon enter clinical development for breast
`cancer treatment and are candidates for breast cancer
`
`prevention strategies."
`
`Table 1 Recently reported phase in and randomised phase II trials at new non-steroidal
`antiuestrugens
`
`‘
`
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`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 I shows some recent studies of new amines—
`
`trogens. A phase B] trial found that toremifene was not
`superior to tamoxifen.” The analogue dmloxifene
`seemed active in phase II trials when used at doses of
`20-100 tug/day, as did the japanese drug TAT59.""‘ ‘5
`We need more information From phase II trials about
`idoxifene and data from phase ll] trials comparing
`tamoxifen with droloxifene, TNT-59, and idoxiféne.
`The pure antioestmgen 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 cone
`firm these promising preliminary data.
`
`Aromatase inhibitors
`
`Pharmacology
`Using aromarase inhibition to suppress oestrogen syn—
`thesis was developed as a treatment for breast cancer
`over 20 years ago.” During the intervening period
`many inhibitors have been developed. Plasma oestro-
`gen concentrations have been widely used to assess
`pharmacological effectiveness. but such assays have not
`been sulficently sensitive to provide reliable compari-
`sons between inhibitors. Isotopic methods that directly
`measure the inhibition of enzyme activity throughout
`the body have provided more useful comparative data.
`There is no evidence that any of the inhibitors
`dilferentially inhibit aromatase in dilferent tissues. The
`inhibitors may be considered as two families, steroidal
`and non—steroidal.
`
`Non-imam
`
`All of the non—steroidal agents are active orally. Until
`I992 the only widely available inhibitor was aminoglu-
`tethimide. This drug inhibits several cytochrome P450
`enzymes, including some involved in steroidogenesis,
`and has been widely used in breast mncer in combina-
`tion with replacement doses of glucoeorticoid as a
`“medical adrenalectomy.“ When aminoglutethimide’s
`clinical effectiveness was shown to be due to its inhibi-
`
`tion of ammatase, this enzyme became a therapeutic
`target The side effects of amiooglutefltimide (mainly
`skin rashes and neurological symptoms),
`its lack of
`specificity (requiring replacement giucocorticoid), 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 u-iazole derivatives,
`(Arirnidex),"" 3“
`letrozole (Femara).2| L” and vorozole
`(Rivizorf’ 2‘ 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-
`glutelhirnide, In patients. aminoglutethlmide inhibits
`total body aromatisation by about Ella/t1, while anastm—
`
`BM] VOLUME 2115
`
`4 OCTOBER 1997
`
`21
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`This content downloaded from 128.22.08.15 on Sun, 17 Jan 2016 03:10:36 UTC
`All use. subject to ISTOR Terms and Conditions
`
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`
`

`

`
`
`
`
`Clinical review
`
`Tabla 2 Recentiy reported phase ill trials which compare standard second line endocrine therapy with the new triazole inhibitors
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`logical since stable disease gives equivalent palliation
`and survival? The durations of response of the new
`agents have tended to be longer than the old, but even
`more important are the survival advantages shown by
`new agents. The trial with the longest follow up shows
`that anastmzolc l mg has significant survival advam
`tagc over megestrol acetate 150 mg,” and the other
`trials show trends towards survival advantagesflhe uni-
`formity of this diflerettce suggests that. these trends are
`likely to become significant with further follow up.
`
`Trials in progress
`The introduction of new agents and the results of trials
`generate new questions and the need for new clinical
`trials. Table 3 outlines trials in progress or which are
`due to start shortly.
`We need to know whether the new non-steroidal
`antioestrogens (idoxifene, droloxifenc, T153159)
`that
`show better preclinical characteristics than tamoxifen
`are better clinically. Large trials comparing all. three
`new agents with tamoxifen are ongoing. The pure
`antiocstmgem Faslodcx looks highly promising in via-o.
`in animal studies, and in early phase I] tests. However,
`phase
`II
`studies
`are notoriously unreliable in
`
`Tabla 3 Clinical trials using endocrine therapy protected or in pro-gross in early
`(adjuvanti and advanced breast cancer (phase Ill}
`
`Trentmant
`Adlmnt breast cancer
`Annnud brunt mom
`Receptor blockade:
`‘20 inn 6iiirig—vim1?‘
`‘irficiie‘aie'
`i ‘
`—
`
`77 _
`tarnoxltsrl
`777
`7
`—
`20 the v 20 mo tamoxifen
`7Drgorflne
`
`-
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`TAT-59
`125 mg VZSO rnd v20 my
`Faslndsx um torso}
`tsrnoxitsn 7
`Onshooen remote:
`Anastrozolé
`
`7
`
`Tamoxifen
`Anastrozole ‘
`Anastrozole
`Tamoxiten
`
`7
`Both 7 7
`77
`7
`777
`Tamoxifen 2 years
`Tamotdlen 3 years
`Anastrozola
`
`
`Faslodo:
`7 _ 7 __
`Anastrotolflyesrs
`Lstrazole
`Tamoxifen
`Lstrozole
`
`7
`Latrozuia
`7
`7
`7
`77
`Tamoxiien
`Tamoxifen 5 years
`Placebo 5 years
`\torozola
`77777 _
`7
`_
`Vorozots 5 ysars
`Emmestane
`Tamoxifen 2—3 years
`Tamoxifen 2-3 years
`Exemestana 2-3 years
`
`7
`
`7
`
`7
`
`their recommended doses of
`zole and letmzole, at
`l rug/day and 2.5 rug/day. inhibit by about 97% and
`>990A1. respoctively.25 in many patients this results in
`plasma oestrogen concentrations which even the most
`sensitive immunoassays cannot detect?"
`
`Steroidnl
`
`Two of the steroidal. agents, formestane and enemas-
`tane, have undergone considerable clinical develop-
`ment. Formestanc (4-hydroxyandrostencdione; Len-
`tamn) 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. Excinestanc is orally
`active and seems to be selective at clinical doses.” No
`data have been published on its etfccts on whole body
`aromatisation. The only pharmacological data from a
`randomised comparison between any of the inhibitors
`showed the superiority ofanastrozolc over formestane
`in suppressing plasma oesuadiol.“
`
`Clinical results
`Table 2 shows the results of recent randomised clinical
`
`trials comparing arornatase inhibitors with standard
`second line endocrine therapy (after tamoxifen). The
`trials for letrozole and anastrozole had three arms: two
`doses of the new aromarase inhibitor compared with
`either the progestogen (mcgestrol acetate) or the old
`aromatasc inhibitor (aminoglutcthimidc). Vomzole has
`been tested against these same comparators at a single
`dose in trials with. two art-usQ 2‘
`triazolc
`All
`three of
`the new non—steroidal
`derivatives (anastmzole, letrozole, and vorozole)‘ and
`the steroidal derivative excmestane have shown
`
`minimal toxicity. In particular, they do not produce the
`troublesome weight gain of megestrol acetate nor the
`rash and neurological symptoms of aminoglutethim-
`ide. Since all four compounds are specific aromatase
`inhibitors. glucocorticoid replacement is not required.
`In general, all the trial results point in the same
`direction. Overall response rates with the new and the
`old treatments are similar. Responses have been
`reported as either complete and partial remissions or
`as complete and partial remissions and stable disease
`for at least six months. The latter reports are more
`
`BM] VOLUMEWFI
`
`4 OCTlUBl-LR l9!”
`
`This content downloaded from 128.22.08.15 on Sun, 17 Jan 2016 03:10:36 UTC
`All use. subject to ISTOR Terms and Conditions
`
`7_
`Exemeslnne
`Megastrol acetats
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`

`Clinical review
`
`
`
`TIM! ‘ Past. present. and potential future treatment of advanced breast cancer by
`trlooking oestrogen receptor or reducing concentrations at oestrogonic steroids in
`postmenopausal patients
`Oahu-n "motor limbo! Production at outwit munitions
`
`interwar
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`Selective oestrogen mentor
`Lutrtttstna hormone releasing hormone antagonists
`mortuhtors [no ralorritano}
`histoldal:
`“71182780 (Fasiodexi
`
`predicting superiority over old agents. Thus the
`recently started study comparing Faslodex with
`anestmzole as second line endocrine therapy for
`advanced disease and the comparison of Faslodex with
`tamoxifen as first line treatment that is to start late in
`1997 are highly important.
`The success of the new aromatase inhibitors as
`second line 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 opn'mal duration
`for tamoxifen as an adjuvant seems to be five years.
`Studies are in progress or shortly to start in which a
`dungcover to an aromatase inl'tibitor alter two or
`three years of tamoxifen is compared with continuous
`mordfen (table 3). Change to an aromatase inhibitor
`after
`five years of tomoxlfen in comparison with
`stopping all treatment is also being tested.
`
`Conclusions
`
`Although the principles of endocrine therapy have not
`changed over the past 100 years. new methods have
`resulted in less toxic and more widely applicable treat-
`ments {table 4). Also. for the first time, we have begun
`to see improvements in the 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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`cancer showing a dose—after mt! wpcriority of 25mg loo-molt- ora-
`megulml acetate. Eur] Cam-tr lgflfiflflAuuppl $249.
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`arirnideor (ammonia) and formestane in poalim
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`(AW 5 August .' 997i
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`Endpt'ece
`Misleading appearances
`A woman accompanied her husband to the doctor
`and waited for him during his checkup. After the
`examination the doctor came out and said. "I don't
`like the way your husband looks." "Neither do i,”
`said the woman. “but he‘s good with the kids."
`From The Best ofMedr‘cat Hunwrrr ‘(Howardj
`Bennett, ed. Philadelphia: Hartley and Belfits. 199 7)
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`BM] VOLUME 315 4 OCTOBER [99?
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`AstraZeneca Exhibit 2040 p. 4
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