Aromatase inhibitors in breast cancer

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The development of aromatase inhibitors for breast cancer therapy is a result of successful translational research exploring the biochemical effects of different compounds in vivo. Studies assessing plasma oestrogen levels as well as in vivo
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  REVIEW Aromatase inhibitors in breast cancer P E Lønning  Section of Oncology, Institute of Medicine, Haukeland University Hospital, University of Bergen, 5021 Bergen,Norway(Requests for offprints should be addressed to P E Lønning; Email: per.lonning@helse-bergen.no) Abstract The development of aromatase inhibitors for breast cancer therapy is a result of successfultranslational research exploring the biochemical effects of different compounds  in vivo  . Studiesassessing plasma oestrogen levels as well as  in vivo   aromatase inhibition have revealed a consistentdifference with respect to biochemical efficacy between the third generation compounds (anastrozole,letrozole and exemestane) and the previous, first and second generation drugs, corresponding to theimproved clinical effects of these compounds as outlined in large phase III studies. Thus, endocrineevaluation has been found to be a valid surrogate parameter for clinical efficacy. Moreover, the resultsfrom these studies have added important biological information to our understanding of endocrineregulation of breast cancer. Based on the clinical results so far, aromatase inhibitors are believed toplay a key role in future adjuvant therapy of postmenopausal breast cancer patients and potentiallyalso for breast cancer prevention. Interesting findings such as the lack of cross-resistance betweensteroidal and non-steroidal compounds should be further explored, as this may add additionalinformation to our understanding of breast cancer biology. Endocrine-Related Cancer   (2004)  11  179–189 Introduction The last decade has been a most successful era in thedevelopment of endocrine therapy of breast cancer.Improvements include the introduction of novel com-pounds like the selective oestrogen receptor downregula-tors (SERDS) (Howell  et al.  2002), and furtherdevelopment of medical ovarian suppression in themetastatic as well as in the adjuvant setting (Klijn  et al. 2001, Jakesz  et al.  2002, Jonat  et al.  2002).However, the most important improvement has beenthe successful development of third generation aromataseinhibitors in metastatic disease and, more recently, in theadjuvant setting. The successful development of thesecompounds was based on careful preclinical development(Furet  et al.  1993, Njar & Brodie 1999) but, not least,careful evaluation of their  in vivo  endocrine effects intranslational research studies assessing their ability tosuppress plasma oestrogen levels, and direct assessment of their effects on  in vivo  aromatisation, using sensitivemethods developed for such purposes (Dowsett  et al. 1987, Jacobs  et al.  1991, Lønning & Ekse 1995). Studiesutilising these assays confirmed the superior biochemicalefficacy of the third generation compounds compared withthe first and second generation inhibitors (Lønning 1996,Geisler  et al.  1998, 2002).While several contemporary reviews considering theclinical effects of these compounds have been published(Goss & Strasser 2001, Smith & Dowsett 2003), the aim of this paper was to discuss the endocrine and clinicalachievements, together with particular emphasis on theimportance of translational research in the developmentof these compounds. Endocrine rationale for aromataseinhibition Following the menopause, oestrogens are synthesised indifferent non-glandular tissues, including liver, bonemarrow, muscle, skin, fat and connective tissue (Schwei-kert  et al.  1976, Smuk & Schwers 1977, Perel & Killinger1978,Frisch etal. 1980,Matsumine etal. 1984)aswellasinbenign and malignant breast tissue (Perel  et al.  1982, Reed etal. 1989,Miller etal. 1990,Bulun etal. 1993).Whileithasbeen recognised for many years that the main contributorofthe substrateandrostenedioneistheadrenalgland, therehas been some controversy considering the contribution of androgensfromthepostmenopausalovary.Basedonmore Endocrine-Related Cancer   (2004)  11  179–189 Endocrine-Related Cancer   (2004)  11  179–189 Online version via http://www.endocrinology.org1351-0088/04/011–179 # 2004 Society for Endocrinology  Printed in Great Britain   recent evidence (Sluijmer  et al.  1995, Couzinet  et al.  2001),it now seems clear that the contribution of the postmeno-pausal ovaries to circulating androgens is, at best, minor,probably negligible. The main substrate for aromatisationis androstenedione, which is aromatised into oestrone(Fig. 1). While the aromatase enzyme may also aromatisetestosterone directly to oestradiol, the fact that androste-nedione levels are about fourfold higher compared withtestosterone levels in postmenopausal women, and thehigher affinity of the aromatase enzyme for the androste-nedionesubstrate,contributetomakingoestronethemajorcirculating unconjugated oestrogen in postmenopausalwomen (Lønning  et al.  1990). While oestrone sulphateexists in higher concentrations (Geisler  et al.  1997), this isan inactive conjugate that may act as a depot and(probably) a source of oestrogens to the tissue. Whenconsidering circulating oestradiol, it has been estimatedthat probably half the amount is converted from circulat-ing oestrone, while the residual is produced by directaromatisation of testosterone (Lønning  et al.  1990).An interesting subject relates to tissue versus plasmaoestrogen levels in postmenopausal women. It has beenrecognised for decades that tissue oestradiol concentrationis 10–20 higher compared with circulating oestradiol levelsin postmenopausal women (Edery  et al.  1980, vanLande-ghem  et al.  1985, Vermeulen  et al.  1985, Miller  et al.  1998,Geisler  et al.  2001) in contrast to the findings inpremenopausal women. The explanation is probably thatcirculating oestrogens are allsynthesised in the tissue; thus,thereisapassive‘gradient’fromtissuetowardplasma(Fig.1), although a study in rats suggested active uptake fromthe circulation (Masamura  et al.  1997). The fact thattumour oestradiol concentration is often higher than theconcentration seen in surrounding non-malignant tissue isconsistent with local synthesis but also high concentrationof the 17 b -hydroxysteroid reductase in the tumours(vanLandeghem  et al.  1985, Vermeulen  et al.  1985).While the aromatase enzyme expressed in different tissuesis the same, a number of different promoters have beenidentified as playing a different role in different compart-ments (Chen  et al.  2001, Bulun  et al.  2003), suggestingpotentiallocalregulationbyhormones,growthfactorsandinterleukins (Reed  et al.  1993, Zhao  et al.  1995, 1996,Agarwal  et al.  1996, Simpson  et al.  1999, Singh  et al.  1999).Notably,whiletissueconcentrations ofoestradiolare high,we and others have found the concentration of oestronesulphate to be somewhat lower in tissue compared with thecirculation (Vermeulen  et al.  1985, Geisler  et al.  2001).While this may refute the hypothesis that plasma oestronesulphatemaybetakenupbythetissue(Santner etal. 1986),the possibility exists that it may be rapidly metabolised tounconjugated steroids; interestingly, there is evidence thatoestrone sulphate may be actively transported across thecell membrane (Pizzagalli  et al.  2003). Studies evaluatingthequantitativecontributionoflocaloestrogenproductionin the tumours versus systemic uptake have revealed asubstantial inter-individual variation (James  et al.  1989,Miller 1994), suggesting that local production plays animportant role in some, but not all, tumours. Compounds Aromatase inhibitors may be divided into two majorclasses, the so-called non-steroidal (previously oftentermed ‘type 2 inhibitors’) and the steroidal compounds(previously termed ‘type-1 inhibitors’) (Fig. 2). The non-steroidal inhibitors belong to two different chemicalclasses, the so-called aminoglutethimide-like compounds,including aminoglutethimide itself and rogletimide, andtriazole derivatives, including anastrazole, letrozole andvorozole. The steroidal compounds are all derivatives of androstenedione, the main substrate for the aromataseenzyme.The two classes of compounds differ with respect totheir biochemical action on the aromatase enzyme. While CirculationTissue E 1 SA E 1 E 2 Taromatase aromatase Adrenals A TE 1 E 2 E 1 S? ? Figure 1  Pathways of oestrogen synthesis in postmenopausalwomen. E 2 , oestradiol; E 1 , oestrone; E 1 S, oestrone sulphate; A,androstenedione, T, testosterone. ONH 2 HC 2 H 5 ONAminoglutethimideCH 3 CH 3 CH 3 CH 3 NC CNAnastrozoleLetrozoleNC CN      N     N FormestaneOOHONNNNOCH2OExemestane Figure 2  Chemical structure of different aromatase inhibitors. Lønning: Aromatase inhibitors in breast cancer  180  www.endocrinology.org  the non-steroidal compounds bind to the p450 site of thearomatase complex, the steroidal compounds bind to thesubstrate-binding pocket (Miller 1989). In addition, thesteroidal inhibitors can bind irreversibly to the aromataseenzyme (Miller & Dixon 2000), for which reason they aretermed ‘suicide inhibitors’ or, more recently, aromataseinactivators. Whether the observed lack of completecross-resistance between the compounds is related totheir action on the aromatase enzyme or whether it couldbe due to some additional endocrine effects of thesteroidal compounds is discussed later in this paper. Endocrine studies The efficacy of the different compounds have beenassessed in  in vitro  studies using placental or ovariantissue with androstenedione as substrate for the enzyme.When compared with aminoglutethimide, the more recentsecond and third generation compounds were found to bemore potent (Batzl  et al.  1996). Notably, the differencesrecorded in  in vitro  systems may not be directly translatedinto what may happen  in vivo . For the  in vivo  efficacy of acompound, it should be emphasised that factors otherthan its direct inhibitory constant, such as total bodypharmacokinetics and local tissue penetration, may be of importance.The endocrine efficacy of different aromatase inhibi-tors may be assessed in two different ways. One possibilityis to determine plasma oestrogen levels; alternatively, wemay assess aromatisation directly by double-tracer injec-tions of   3 H-androstenedione and  14 C-oestrone withdetermination of the isotope ratio in the oestrogens.When considering plasma oestrogen measurements,the main limitation relates to the sensitivity of the assays.Based on a formal assessment of current methods andplasma oestrogen levels, we have concluded that it is notpossible to measure plasma oestrone and oestradiolsuppression below10–15%ofcontrol levelsinthe majorityof postmenopausal patients during treatment with thepotent third generation aromatase inhibitors and inactiva-tors, despite utilising the most sensitive radioimmunoas-says (Lønning 2001). In contrast, the oestrogen conjugate,oestronesulphate,existsinhigherconcentrations;here,itispossible to detect up to 99% suppression (Lønning & Ekse1995). The clinical relevance of this issue is illustrated in arecent paper comparing oestrogen suppression withanastrozole compared with letrozole in a cross-over study(Geisler  et al.  2002). For plasma oestradiol, we found nosignificant difference in suppression between the twocompounds due to the fact that most patients had theirplasma oestradiol suppressed down to the sensitivity limitof the assays during treatment with both compounds. Onthe contrary, we were able to detect a significant differencebetween the compounds with regard to their ability tosuppress plasma oestrone and, in particular, oestronesulphate. When considering oestrone sulphate, we foundmean plasma levels during treatment with letrozole to beone-third of the mean level recorded on treatment withanastrozole.A particular problem relates to oestrogen measure-ments in patients during treatment with steroidal com-pounds, such as exemestane. When considering the factthat the dose of drug administered (25mg/day) isprobably around 25000 times the amount of totalestrogens produced in a postmenopausal woman duringtherapy with such a compound (Lønning  et al.  1990), evenminor metabolites causing modest interactions in theradioimmunoassays could influence the results. Suchinteractions have been confirmed with respect to exemes-tane (Johannessen  et al.  1997), and sample purificationinvolving HPLC is always recommended for oestrogenassessment in patients during treatment with suchsteroidal compounds.Assessment of   in vivo  aromatisation may, in principle,be done with one of two methods. One possibility is toinfuse  3 H-labelled androstenedione and  14 C-labelledoestrone to achieve a steady-state concentration and todetermine the isotope ratio in the plasma oestrone fraction(Santen  et al.  1978). The second method is to administer abolus injection of   3 H-labelled androstenedione and  14 C-labelled oestrone followed by urine collection for 96h anddetermination of the isotope ratio in the oestrogenmetabolites. In a collaborative programme betweenProfessor Mitch Dowsett’s group in London and ourgroupinBergen,weusedsuchamethod(Jacobs etal. 1991)to determine  in vivo  aromatase inhibition during treatmentwith different first, second and third generation com-pounds. The results are shown in Table 1. A formalassessment of this method confirmed the possibility of detecting up to 99.1% aromatase inhibition in the majorityof patients (Dowsett  et al.  1995). The sensitivity of themethod is illustrated in the recent study comparinganastrozolewithletrozole,revealingasignificantdifferencein the degree of aromatisation between the compounds(Geisler  et al.  2002). Consideration of the clinicalimportance of a more complete aromatase inhibition isdiscussed later in this paper. Clinical efficacy of second generationaromatase inhibitors/inactivators inmetastatic breast cancer The second generation non-steroidal inhibitor fadrozoleand the steroidal inactivator formestane were comparedwith megestrol acetate as second-line therapy andtamoxifen as first-line therapy. While all these studies Endocrine-Related Cancer   (2004)  11  179–189 www.endocrinology.org  181  included a limited number of patients by today’sstandards, there was no evidence of improved responserate or time-to-progression for any of these compoundscompared with ‘standard’ therapy (Pe ´rez-Carrio ´n  et al. 1994, Buzdar  et al.  1996, Falkson & Falkson 1996,Thu ¨rlimann  et al.  1996, 1997 a ). Clinical efficacy of third generationaromatase inhibitors/inactivators inmetastatic breast cancer The results from clinical studies comparing anastrozole,letrozole and exemestane with megestrol acetate oraminoglutethimide in the second-line or tamoxifen inthe first-line setting have been reviewed in detail elsewhere(Lønning 2002), and only the conclusion is given here.While the results in the second-line setting are notunivocal, in general there is a trend for the superiorityof each compound compared with megestrol acetate andfor letrozole compared with aminoglutethimide (Buzdar et al.  1998, 2001, Dombernowsky  et al.  1998, Gershano-vich  et al.  1998, Kaufmann  et al.  2000).The results in the first-line setting seem moreconvincing. When considering anastrozole, there was asignificant improvement for anastrozole compared withtamoxifen regarding time-to-progression in one study,while the compounds were similar in a second (Bonneterre et al.  2000, Nabholtz  et al.  2000). Combining the resultsfrom the two studies, a significant superiority foranastrozole was revealed in patients harbouring oestrogenreceptor-positive tumours (Bonneterre  et al.  2001).Summarising the evidence, it may be concluded thatanastrozole is at least as good as tamoxifen, although itmay be questioned whether it could be claimed to besignificantly superior in statistical terms. When consider-ing letrozole, a large phase III study revealed superioritywith respect to time-to-progression as well as responserate for letrozole compared with tamoxifen. Importantly,in that study superiority was confirmed in subgroupsbased on oestrogen receptor analysis, metastatic locationand different parameters (Mouridsen  et al.  2001). Thus,for letrozole, a clear superiority compared with tamoxifenhas been confirmed.When considering exemestane, a phase II studyrevealed significant superiority compared with tamoxifen(Dirix  et al.  2001). However, the number of patients wassmall, and the results of the final phase III study in thenear future are awaited. Adjuvant therapy The results of the large ATAC study have recently beenreported (Baum  et al.  2002). This study revealed thesuperiority of anastrozole compared with tamoxifenregarding relapse-free survival when combining localand distant relapses in the statistical analysis (Table 2).So far, no superiority for survival has been recorded butthe follow-up time is short, and further analysis is Table 1  Aromatase inhibitors in current or previous use. The figures for the percentage aromatase inhibition are all obtained from a joint programme involving the Royal Marsden Hospital and our own institution, using the same experimental design Compound Type Generation DoseMean aromataseinhibition (%)  Reference Aminoglutethimide Inhibitor First 1000 mg/day 91 MacNeill  et al.  (1992)Fadrozole Inhibitor Second 2mg/day 82.4 Lønning  et al.  (1991)4mg/day 92.6Formestane (oral) Inactivator Second 125mg/day 72.3 MacNeill  et al.  (1995)125mg bid 70.0250mg od 57.3Formestane Inactivator Second 250mg/2wk 84.8 Jones  et al.  (1992)(intramuscular) 500mg/2wk 91.9500 mg/wk 92.5Anastrozole Inhibitor Third 1mg/day 96.7 Geisler  et al.  (1996 b  )10mg/day 98.1Anastrozole/letrozole a Anastrozole (1mg/day) 97.3 Geisler  et al.  (2002)Letrozole (2.5mg)  > 99.1Letrozole Inhibitor Third 0.5mg/day 98.4 Dowsett  et al.  (1995)2.5mg/day 98.9Exemestane Inactivator Third 25mg/day 97.9 Geisler  et al.  (1998) a Evaluated in the same 12 patients in a cross-over study.bid, twice daily; od, once daily; wk, weeks; 2wk, every second week. Lønning: Aromatase inhibitors in breast cancer  182  www.endocrinology.org  awaited. Interestingly, in that study, combined treatmentwith tamoxifen and anastrozole was found to be inferiorcompared with anastrozole monotherapy, suggesting anantagonistic effect of tamoxifen in patients on anastrozoletreatment. The reason for this will be discussed later.Of particular interest was the profound reduction of contralateral breast cancer seen in the anastrozole arm(Table 2). If this reduction is confirmed during long-termfollow-up and also in other studies evaluating aromataseinhibitors for adjuvant therapy, it may suggest aromataseinhibitors as effective agents for breast cancer preventionin postmenopausal high-risk women (see later section).Currently, several studies comparing letrozole as wellas exemestane with tamoxifen given as monotherapy orsequential administration using different time-intervalsare being conducted; the results of these studies areexpected in the near future. Lack of cross-resistance to aromataseinhibitors and inactivators An interesting observation in metastatic disease has beena lack of cross-resistance between aromatase inhibitorsand inactivators, now confirmed in several studies(Table 3).In general, these studies involved treatment with anaromatase inactivator following failure on an aromataseinhibitor; one small study reported the use of anastrozolein patients failing on formestane (HarperWynne &Coombes 1999). These studies have reported a lack of complete cross-resistance between the different com-pounds. While the largest study exploring exemestane inpatients failing aminoglutethimide, anastrozole or letro-zole revealed a small response rate (7%), the percentage of patients achieving stable disease >6 months was 17%,meaning that 24% of the patients benefited from havingthis therapy implemented following failure on the non-steroidal inhibitor (Lønning  et al.  2000). Notably, thatstudy (Lønning  et al.  2000) revealed little difference inresponse rates between patients who had previously failedon a third generation non-steroidal compound versusthose who had failed on aminoglutethimide (20 versus27%). While the findings in some studies that patientsfailing aminoglutethimide responded to exemestane(Thu ¨rlimann  et al.  1997 b , Lønning  et al.  2000) could beexplained by a more potent aromatase inhibition with thesecond compound, the findings that patients may respond Table 2  ATAC trial (Baum  et al.  2002): Results summary Treatment arm Hazard ratio 95.2% CI  P   value DFS in ITT populationAnastrozole vs tamoxifen 0.83 0.71–0.96 0.013>Ana + Tam vs tamoxifen 1.02 0.89–1.18 0.8DFS in ER+ populationAnastrozole vs tamoxifen 0.78 0.65–0.93 0.005Ana + Tam vs tamoxifen 1.02 0.87–1.21 0.8Incidence of new contralateralprimary breast tumoursAnastrozole vs tamoxifen 0.42 0.22–0.79 0.007Ana + Tam vs tamoxifen 0.84 0.51–1.40 0.5Ana, anastrozole; Tam, tamoxifen; ER+, oestrogen receptor positive; CI, confidence interval; ITT, intention-to-treat; DFS, disease-free interval. Table 3  Trials evaluating sequential treatment with aromatase inhibitors/inactivators in metastatic breast cancer Treatment and results First drug AG AG AG AG nAI For nAISecond drug For For Exe Exe Exe Ana ForNo. of patients 112 10 78 136 105 21 20RR second drug (%) 20.5 20.0 25.6 8.1 4.8 0 0RR + S.D.    6 mo (%) 42.9 50.0 60.3 27.2 20.0 62 55Reference I II III IV IV V VIAG, aminoglutethimide; Ana, anastrozole; Exe, exemestane; For, formestane; nAI, non-steroidal third generation aromataseinhibitors (anastrozole, letrozole and vorozole); RR, response rate; S.D.,    6 months (mo). References for these studies are(I) Murray & Pitt (1995); (II) Geisler  et al.  (1996 a  ); (III) Thu¨rlimann  et al.  (1997 b  ); (IV) Lønning  et al.  (2000); (V) HarperWynne &Coombes (1999); (VI) Carlini  et al.  (2001). Endocrine-Related Cancer   (2004)  11  179–189 www.endocrinology.org  183
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