General review
16a-[
18F]-fluoro-17ß-oestradiol ([
18F]FES): A biomarker for imaging oestrogen receptor expression with positron emission tomography (PET)
16a-[
18F]-fluoro-17ß-œstradiol ([
18F]FES) : un biomarqueur de l’expression des récepteurs aux œstrogènes pour l’imagerie par émission de positons (TEP)
C. Lefebvre-Lacœuille
a,b, F. Lacœuille
a,d, C. Rousseau
c, F. Courbon
e, F. Benard
f, O.-F. Couturier
a,d,*
aLUNAMUniversité,InsermUMR-S1066,Micro-etnanomédecinebiomimétiques,4,rueLarrey,49933AngersCedex09,France
bGynecologyandObstetricalDepartment,UniversityHospital–Angers,4,rueLarrey,49933AngersCedex09,France
cNuclearMedicineDepartment,ICOSaint-Herblain,France
dNuclearMedicineDepartment,UniversityHospital–Angers,4,rueLarrey,49933AngersCedex09,France
eNuclearMedicineDepartment,InstitutUniversitaireduCancer,Oncopole,Toulouse,France
fNuclearMedicineDepartment,Vancouver,Canada
Received8January2015;accepted20January2015 Availableonline6March2015
Abstract
Oestrogensplayamajorroleinthedevelopmentofgynaecologicaloestrogen-dependentdiseasesthatoverexpressoestrogenreceptors(ER+).
TheERstatusisassessedusingimmunohistochemistryanalysisoftissuessamples.Itisbelievedthatanon-invasivemethodsuchaspositron emissiontomography(PET)thatwouldaccuratelyevaluateandquantifyinvivothepresenceofERcouldplayanimportantroleinmanagingsuch diseases.PETusingfluorinatedoestrogenanaloguesmaybehelpfulinselectingpatientswhowillbenefitfromendocrinetherapyorcouldbeused toidentifyhigh-gradecancerwithpoorerprognosis.Amongmorethan20fluorinatedoestrogensanaloguesthathavebeenproposedasPETtracer candidates,16a-[18F]fluoro-17b-oestradiol([18F]FES)hasbeenthemostactivelyinvestigatedinpreclinicalandclinicalstudies.
#2015ElsevierMassonSAS.Allrightsreserved.
Keywords:Fluoroestradiol;FES;PET
Résumé
Les œstrogènes jouentun rôlemajeurdansledéveloppementdesmaladies gynécologiqueshormono-dépendantesquisur-expriment des récepteursauxœstrogènes(RE+).LestatutenREestévaluéàpartirdel’analyseimmuno-histologiqued’échantillonsdetissus.Cependant,une méthodenoninvasive,tellequelatomographieparémissiondepositons,capabled’évalueretdequantifierlaprésenceinvivodeRE,pourraitjouer unrôleimportantdanslapriseenchargedecesmaladies.Latomographieparémissiondepositonsavecunanaloguefluoréd’unœstrogène pourraitainsiaideràlasélectiondespatientesquitireraientunbénéficed’untraitementhormonaloupourraitidentifierdestumeursdehautgrade deplusmauvaispronostique.Parmiplusde20analoguesfluorésdesœstrogènesquiontétéproposéscommecandidatsTEPtraceurs,la16a- [18F]fluoro-17b-œstradiol([18F]FES)aétélaplusactivementétudiéeenprécliniquecommechezl’homme.
#2015ElsevierMassonSAS.Tousdroitsréservés.
Motsclés: Fluoroestradiol;FES;TEP
Availableonlineat
ScienceDirect
www.sciencedirect.com
MédecineNucléaire39(2015)64–70
*Correspondingauthorat:NuclearMedicineDepartment,UniversityHospital–Angers,4,rueLarrey,49933AngersCedex09,France.
E-mailaddress:[email protected](O.F.Couturier).
http://dx.doi.org/10.1016/j.mednuc.2015.02.005
0928-1258/#2015ElsevierMassonSAS.Allrightsreserved.
1. Endogenousoestrogens
Oestrogensactonsexualfunctionsanddeterminethefemale secondarysexual characteristics. Oestrogens are produced in tissues containing aromatase, the enzyme that catalyses the conversionofC19steroidstooestrogens.Inovulatorywomen, oestradiol (E2)is mainly secreted by the ovaries in a cyclic mannerandcontrolledbythehypothalamic–hypophysealaxis (aromatase expression in ovarian granulosa cells is FSH- dependent).Inthepostmenopausalperiod,themajorsourceof oestrogensisperipheraltissue(adiposetissueandskin)where aromatase activity converts adrenal androstenedione to oestrone (E1) that in turn is converted into oestradiol (E2) by17ß-hydroxysteroid-dehydrogenaseinextra-ovariantissues [1].Ovariesarenotonlytheprincipalsourceofoestrogensin premenopausal women but are also the key target tissue of oestrogenactivity.Itmustbenotedthatthereisnoaromatase activity in healthy uterine tissue, whereas an inappropriate aromataseactivityhasbeenobservedinuterinediseasessuchas endometriosis,leiomyomaandendometrialcancer[2–5].
Gonadal synthetic pathways start with cholesterol being deliveredtothecellsbytheplasmalipoproteins(Fig.1).Active oestrogens are formed from circulating oestrone sulphate or oestradiol sulphate, as the result of deconjugation by sulphatase. Oestradiol and its derivatives are transported in thebloodstream boundeithertosexbindingprotein (SBGor sexhormone-bindingproteinSHBGinhumans)ortoalbumin.
SBG binding protects steroids against liver metabolism, ensurestheirtransporttothe targettissuesandcontributesto theircelluptake,throughmembrane receptorsfor SBG [6,7]
(Fig.2).The hormonesare glucurono-conjugatedintheliver andfurthereliminatedbythekidneys.
2. Oestrogenreceptors
Oestrogenreceptors(ERs)arelocatedincellnucleiintarget tissues.ERscaptureandretaincirculatingsteroidsandinitiate biologicaleventssuchastissueproliferationandanti-apoptosis
actionthatisthemechanisticlinkbetweentheoestrogenaction and the growth of oestrogen-dependent cancer. Immunohis- tochemistry (IHC) is currently the standard for ER status determinationintissuecollections.Inthebreastcancerpatient, ERstatusishighlypredictiveofresponsetoendocrinetherapy [8].Inhumanendometrialtissue,quantitationofERishighest during the first 2weeks of the menstrual cycle, during the proliferative phase under oestrogen action. Endometrial cancers contain ERs and display an inverse relationship betweenERstatus andtumour grade[9].
Biological effects of oestrogens are mediated by two receptors,ERa andERb.ERa is expressedinendometrium, breast, ovarian stromal cells and the hypothalamus [10], whereasERbiswidelyfoundindifferent tissuetypessuchas ovarian granulosacells,kidney,brain,bone,heart,lungs,gut, prostate and endothelium [11]. However, ERb may explain tissue responses to oestrogen in whichERa is undetectable.
Both ER subtypes share a conserved structure with six functionaldomains(AtoF)thatcontributetotheirtranscrip- tional activity(Fig.2).Amongdifferent regionsofER,AF-1 (amino-terminal region) andAF-2 (carboxy-terminal region) can activate gene expression through binding to oestrogen responseelements (EREs)inresponsivegenes[12].ERaand ERb undergo a conformational change and form functional heterodimers on DNAwhen the functional E region of the receptor bindstooestrogen. Akeyfeatureof thisoestrogen–
receptorcomplexistheavailabilityofthehelix-12portionof ER tolockthe steroidinthe hydrophobicpocket.Thisisthe baseoftheconceptofselectiveoestrogenreceptormodulators (SERM), i.e. anti-oestrogens prevent helix-12 from closing, explaining their competitive modulation by determining interactions with co-activators and co-repressors of ER. A possible explanation for the agonist or antagonist effect of tamoxifen is the fact that the ratio between co-activators (agonist effects) and co-repressors (antagonist effects) may vary indifferent tissues.Thusinbreasttissue,tamoxifenisa competitive inhibitor of ER activity, and therefore inhibits growth of oestrogen receptor positive breast cancers. In the uterus,ithaspartialagonisteffectsandthereforeisassociated withatwofoldtofourfoldincreaseintheincidenceofuterine cancer, whichis not the casewith raloxifen, another SERM withnoagonistactivity.Anotherexplanationisthattamoxifen silences onlyAF-2whereasAF-1remainsactivated,resulting inapartialagonistactionoftamoxifencomparedtoraloxifen.
3. ERadeterminationandexpressionin cancers
ERa is the predominant subtype expressed by more than 70%ofhumanbreastcancerswhereasERbisprimarilypresent inadenocarcinomasoflungorigin.HumanERaandERbare highly homologous, sothat antibodiesused inIHC todetect ERa in breast carcinomas may detect ERb in pulmonary adenocarcinomas. Both regulate transcription of responsive genesincludingtheprogesteronereceptor(PgR)thusoftenco- expressedandcommonlytestedwithERatoassesshormone receptorstatusofabreasttumour.AccordingtotheAmerican Society of Clinical Oncology (ASCO) and the College of
Fig.1.Endogenousoestrogens:amongthesexualsteroids,oestrogensderive fromtheoestranenucleus,progestinsfromthepregnaneskeletonandandrogens fromtheandrostaneskeleton.
¨strogènesendogènes:parmilesstéroïdessexuels,lesœstrogènesdériventdu noyauœstrane,lesprogestéronesdusquelettepregnaneetlesandrogènesdu squeletteandrostane.
American Pathologists (CAP), for optimal IHC ER/PgR in breast cancer, it is recommended that ER and PgR assays shouldbeconsideredpositiveifthereareatleast1%positive tumour nuclei in the sample [13]. However, some breast tumours that are identified asERa positive by IHC and/or mRNAtesting,havenoERa proteinexpressionorexpressa dysfunctionalERaprotein(mRNAsplicingvariants,inwhich oneormoreexonsareabsent).Thesevariantshavetheability to suppress the E2-dependent transcriptional activation by bothwild-typeERaandERb,i.e.caninhibitthefunctionof the wild-type ERa protein when co-expressed in the same cell[14].
4. RationalefortargetingER
The role of ERb in endocrine cancer treatment remains unclearandtodate,thetherapeuticactionofendocrinetherapy isstillbasedandmediatedbyERa.Cancer therapytargeting ER include ER blockade strategy using selective oestrogen receptor modulator(SERM) witha tissue-specificagonist or antagonisteffectssuchastamoxifenorraloxifen,oraselective oestrogen receptor demodulator (SERD) such as fulvestrant, whichhave beenclaimedtobecompletely devoidof agonist effects[15].Anotherstrategyistoremovetheagonisteffectof oestrogen using aromatase inhibitors (AI), which prevent
peripheralandtumourconversionofandrogenstooestrogens.
Inallcases,thepresenceofERorPgRisrequiredfortheuseof endocrine therapy, which is often preferred to systemic treatment for two major reasons. Firstly, endocrine therapy has fewer side effects than systemic therapy and secondly tumours that are likely to respond to endocrine therapy, i.e.
thosethatareER-positive and/orPgR-positiveare associated withimprovedsurvival[16].
IHC of ER is used for making clinical therapy decisions, despiteseriouslimitationsontheassessmentofthetruenumber of receptorsexpressed,duetolaboratory variability,intrinsic heterogeneityofERwithinthesamelesionandvariationsinER statusamongtheprimaryandmetastaticsites[17].Moreover,a part of ER-positive tumours does not respond to endocrine therapy due to dysfunctional ER. These limitations of IHC determination may justify the use of another method of selectionofpatientswhomaybenefitfromendocrinetherapy, suchasmolecularimaging,i.e.anon-invasivemethodableto identifyboththepresenceandthe functionalityofERbefore therapy. This role could be attributed to positron emission tomography (PET)with fluorinatedoestrogen analogues ina combined theranosticapproach searchingfor the presenceof molecular targetsbefore endocrinetherapy andevaluationof ERfunctionalitythroughtheassessmentoftheresponsetothis therapy.
Fig.2. ModelforE2pathwaysandactionintargettissue.SHBGmustbindtothemembranereceptor(SHBG-R)beforeoestradiol(E2)interactswithSHBGboundto themembrane(SHBG-Rpathway).Ifnot,i.e.ifE2bindsfirsttoSHBG,itisblockedfrominteractingwiththecellmembrane.E2canalsopassdirectlythroughthe cellmembrane(classicpathway).Inthecellnucleus,E2-oestrogenreceptor(ER)complexundergoesadimerizationbeforebindingtoanoestrogenresponseelement (ERE)inthepromoterregionofanoestrogen-responsivegene.Recruitmentoftranscriptionalco-regulators(p160familyofco-activators,namely,SRC-1,SRC-2, andSRC-3)resultsintheformationofatranscriptionunitthatinitiatesandmodulatesRNAsynthesis.TheERisdividedintosixregions(A–F).TheDNA-binding domain(C)isessentialfortheinteractionoftheE2-ERcomplexwiththeERE.TheE2-bindingdomain(E)isthesiteofcompetitivebindingbyanti-oestrogens.
PassagetransmembranaireetactiondeE2danslestissuscibles:SHBGdoitêtreliéeàsonrécepteurmembranaire(SHBG-R)avantqueE2puisseinteragiravecla SHBGliée(voieSHBG-R).Danslecascontraire,c’est-à-diresiE2selied’abordàlaSHBG,ilestbloquédanssoninteractionaveclamembranecellulaire.E2peut aussitraverserdirectementlamembranecellulaire(voieclassique).Danslenoyaucellulaire,lecomplexeE2-recépteurauxœstrogènes(RE)subitunedimérisation avantsaliaisonavecunélémentderéponseauxœstrogènes(ERE)danslarégionpromotriced’ungènesensibleauxœstrogènes.Lerecrutementdeco-régulateursde latranscription(famillep160deco-activateurs,àsavoir,SRC-1,SRC-2,etSRC-3)conduitàlaformationd’uneunitédetranscriptionquidéclencheetmodulela synthèsedel’ARN.LeREestdiviséen6régions(A–F).ledomainedeliaisonàl’ADN(C)estessentielpourl’interactionducomplexeE2-ERavecERE.Ledomaine (E)deliaisonavecE2estdeliaisoncompétitiveaveclesanti-œstrogènes.
5. Pharmacology of16a-[18F]-fluoro-17ß-oestradiol
16a-[18F]-fluoro-17ß-oestradiol ([18F]FES) is a radiola- belledoestrogenthatnon-invasivelymeasuresregionalERbio- distributionandwhose tissueuptakeis correlatedwithtissue ERexpression[18,19].Analoguesofoestradiolmustdisplaya goodaffinity for SHBGandalbumin.In ratsandinhumans, about 95% of [18F]FES are bound toplasmaproteins (either SBG or albumin) [20,21]. Even though most of [18F]FES initiallybindstoalbuminrightafterintravenousadministration, veryquicklythereafterthetraceristransferredtoSBG[22].At equilibrium,45%ofthenon-metabolised[18F]FESisboundto plasmaSBG,andthisfractionremainsstableovertime,which theoretically would allow delivering a sufficient amount of tracertoimageER+tissues.
Like the other sexual steroids, [18F]FES is glucurono- conjugatedintheliverandfurthereliminatedbythekidneys.
Bio-distributionstudiesof [18F]FESshowed a rapidmetabo- lisationof[18F]FESfollowinginjection.After2hours,mostof the circulating radioactivityand non-targettissues activityis dueto [18F]FES metabolites [20],which didnot bind toER targettissues.Thisrapidformationofradiolabelledmetabolites (only 20% of [18F]FES remains non-metabolised after 20minutes)thatarenottakenupbyER+tumoursmayfurther complicate quantitative analysis and will contribute to the background activity seen on the images [21]. This suggests startingimageacquisition20to30minutespostinjection,due tothefastclearanceofthetracer,whilethe activityresulting fromradiolabelledmetabolitesremainsfairlyconstantoverthat periodoftime.Underlyingthisfindingisthepatternofentero- hepaticcirculation,wheremetabolitesexcretedintothebileare efficiently reabsorbed in the small intestine, with little radioactivityreachingthe largeintestine(Fig.3).
6. Specificityandaffinityof[18F]FESfortissues expressingER
The bindingaffinity of [18F]FES for ERwas evaluated in testscarriedoutinbindingaffinitycompetitionstudiesof[3H]
oestradiol on mammary tumour cell lines Michigan Cancer Foundation-7(MCF-7).Thebindingaffinityof[18F]FESwith MCF-7cellsislower(57%)thanthatof oestradiolused as a reference (100%) [23]. The selectivity of [18F]FES binding with ERa and ERb subtypes has been studied with purified humanERaandERbreceptorsaccordingtocompetitive[3H]
oestradioltests[24].Theresultsexpressedasapercentageof relativeaffinity([3H]oestradiolaffinitydefinedas100%)found a relative affinity of 54.9% and 22% for ERa and ERb respectively. Therefore, [18F]FES possesses an affinity 2.5 timeshigher forERa thanforERb.
Inadultrats,tissuedistributionstudiesbyKiesewetteretal.
showedhighbindingaffinityof[18F]FEStoER+tissuessuchas theuterusandovaries.Ahighlevelof[18F]FESwasalsofound inliver(metabolisation)andinkidneys(elimination)compared toothertissuessuch asblood,muscles,lungandbones[25].
Inhumanstudies,anhighagreementbetweenthe[18F]FES uptakeandER statusoftumourshasbeenreported[26].The
uptakevalueof[18F]FESwithPETisavalidatedmeasureofthe expression of ER in breastcancer. In aseries of 13 patients treated forbreastcancer,Mintun etal.observedan excellent correlation between the intensity of tracer uptake and quantificationof ER expressionmeasuredbyIHCperformed after surgery [18]. This correlation was demonstrated for primitivemammarytumoursbutalsofortheirmetastases[27], andinmostofthe followingclinicalstudies.
7. Clinicalstudies
[18F]FES-PETisanon-invasivemethodforassessinginvivo regional ER expression that has emerging potential for diagnosising and monitoring treatment of breast cancer and othergynaecologicalcancers.Themajoradvantagesofinvivo assessment of ER expression are to avoid sampling error
Fig.3. Liketheothersexualsteroids,[18F]FESisglucurono-conjugatedinthe liverandfurthereliminatedbythekidneys.[18F]FESmetabolitesexcretedinto thebileareefficientlyreabsorbedinthesmallintestine,withlittleradioactivity reachingthelargeintestine.
Commelesautresstéroïdessexuels,la[18F]FESestglucurono-conjuguéedans lefoieetéliminéeparlasuiteparlesreins.Lesmétabolitesdela[18F]FESsont excrétésdanslabileetsontefficacementréabsorbésdanslepetitintestin,avec peuderadioactivitégagnantlegrosintestin.
(addressingtheheterogeneityofERexpression),andtoassess the biological activity of the receptor at diagnosis and in response to treatment. However, in oestrogen-dependent diseases other than breast cancer, the use of [18F]FES-PET imaging has only been the subject of preliminary studies targetingendometrialtissues.
7.1. Femalegenitaltract
Tsuchida et al. studied a group of 16 healthy female volunteersandreportedaselectivebindingof[18F]FESinthe uterus.Theseauthorsalsofoundthat[18F]FESuterineuptake becamegreaterduringthe proliferativephasethanduringthe secretory phase (relative to menstrual cycle RE expression) [28].Inapreliminaryclinicalstudy,Tsujikawaetal.validated themeasurementofERexpressionby[18F]FES-PETimaging inbenignuterinedisease(endometrialhyperplasiaandfibroma) and in malignant endometrial disease and fibromyosarcoma [29].
Acombinedapproachusing[18F]FESand[18F]FDGcould be usefulfor non-invasive evaluation of ERa distribution as wellas ERa function, related tothe differentiationgrade of endometrial carcinoma [30] and of mesenchymal uterine tumours[31].Tumour[18F]FESuptakewassignificantlylower (P<0.001)whereastumour[18F]FDGuptakeand[18F]FDG/
[18F]FESratio(P<0.005andP<0.001, respectively) were significantlyhigherinuterinesarcomasthaninleiomyomas.
7.2. Humanbreastcancer
In human breast cancer, [18F]FES has been used for detectingandstaging the disease [26,32,33].Desdashti etal.
found an 82% agreement between [18F]FES uptake and ER status of primary breast cancers [positive agreement in six tumours [18F]FES+/ER+ (standardised uptake value (SUV) 1.91.6],negativeagreementin13tumours[18F]FES /ER (SUV 0.50.2), and disagreement in four tumours [18F]FES /ER+).Eight otherbenign lesionsdid nottake up [18F]FES (SUV 0.60.2) [32]. In the same study but in a differentseriesofpatientswithpathology-provendisseminated disease (17 lesions), the concordance was 94% (16 con- cordances,9positiveand7negative).Inbothseries,[18F]FDG- PET was also performed, with 88% sensitivity and 100%
specificity,butwithoutanyrelationshipbetweentraceruptake andtumourERstatus.Inanotherstudy,53/57metastasesfrom breastcancerwereidentifiedusing[18F]FES(sensitivity93%), andtheuptakesignificantlydecreasedwhenmeasured17days on average after initiating the anti-oestrogen treatment (tamoxifen or toremifen) [33]. In 48 patients with primary and operable breast cancer, Gemignani et al. reported a correlation between tumour [18F]FES uptake and ER immu- nohistochemistry expression but not with oestrogen-related geneexpression[34].[18F]FESalsohelpedintheidentification ofmetastatic sitesinapreoperativesetting.Inthe metastatic setting, [18F]FES can demonstrate the heterogeneity of ER expression in the same patient, namely ER status of bone metastases[35].
8. [18F]FESformonitoringantihormonaltreatment
[18F]FES-PETuterineaccumulationisaffectedbyendocrine therapy, as it has been shown in two tamoxifen-treated postmenopausal patients in whom endometrial hyperplasia lesions were [18F]FES-negative, while they should be [18F]FES-avid lesions [36]. Likewise in another study, histologically proven endometriosis lesions were [18F]FES- negative in three patients with oestrogen-progestin therapy, whereas for afourth untreatedpatient inthe first part of the menstrual cycle, an histologically proven lesion of endome- triosiswas[18F]FES-positive[37].Thisinfluenceon[18F]FES uptake can also be used for assessing tumour response to endocrine therapy. In a case report relating the initial management of hormone therapy in endometrial well- differentiatedadenocarcinomaina30-year-oldwomanwishing to preserve fertility, [18F]FES was superior to MRI and [18F]FDG in assessing therapeutic response [38]. In another case of endometrialstromal sarcoma,high tumouruptake of [18F]FES before fulvestrant therapy provided a rationale for using thisER antagonist[39], andfulvestrant efficiencywas demonstrated 6months later by a strong decrease intumour [18F]FES uptake, and a 15% reduction in tumour diameters according to Response EvaluationCriteria in SolidTumours (RECIST).
Incontrasttouterinetissues,humanbreastcancer[18F]FES uptakedoes notseemtobe affectedbyexogenousoestradiol administration or other hormonalstatus variables [40,41].In humanbreastcancers,[18F]FES hasbeenused for predicting theresponsetotreatment[42]andfor demonstratingtheanti- oestrogenic effect of tamoxifen [26]. A metabolic flare resulting in a transient increase in tumour [18F]FDG uptake was sometimes reported in the early days after the onset of endocrine therapy and was usually followed by clinical remission [43]. Such metabolic changes, assumed to be associatedwithanagonisteffectofendocrinetherapy,should not be confused with progressivedisease, andthus could be evidencedusingacombinationof[18F]FDGand[18F]FES-PET imagingasproposedbyDehdashtietal.[26].Indeed,inasmall series (11 postmenopausal patients with biopsy-proven ER+
metastaticbreastcancer), theauthorsreported that[18F]FES- PETand[18F]FDG-PETperformedbeforeand7–10daysafter initiating tamoxifen treatment showed an increased in [18F]FDG uptake (the so-called ‘‘metabolic flare’’) and a decreasedin[18F]FESuptakeinthe7respondingpatients.In non-respondingpatients,[18F]FDGuptakedidnotchangeafter treatment, [18F]FES uptake was lower on the baseline study thaninresponders,andtheposttreatmentdecreasein[18F]FES uptakewasalsomorelimited.
Mortimer et al. reported that the initial tumour [18F]FES uptake (at baseline before the onset of endocrine therapy) predicted response to tamoxifen in locally advanced and metastaticbreastcancer[43].Fortywomenwithbiopsy-proven ER+breastcancerhad[18F]FES-PET beforeand7to10days after initiation of tamoxifen therapy. A decrease in tumour [18F]FES uptake was predictive of response to tamoxifen.
Interestingly,nopatientwithanSUVlessthanapproximately
1.5respondedtotamoxifen.Furtherstudieshavecorroborated these initial results, also showing that the level of tumour [18F]FESuptakebeforetherapywascorrelatedwithsubsequent tumour response to hormonal therapy [27,41,44]. Low [18F]FESuptake predicted alack of responseto ER-directed therapyandnobenefitofthistherapywasobservedwheninitial [18F]FES SUVmean was1.5. Likewise, in multimetastatic breastcancer patients,thosewith atleastone metastaticsite qualitatively [18F]FES-negative or with a low [18F]FES/
[18F]FDGratiowereunlikelytorespondtoendorcinetherapy.
Apparent conflicting results were obtainedin a recent study evaluatingthepredictivecombinedvalueofbaseline[18F]FES and[18F]FDGuptakeinneoadjuvantchemotherapy(NAC)in 18newlydiagnosedbreastcancer patients[45].In thisstudy, [18F]FESSUVwaslowerinrespondersvs.non-responders,but itshouldbenotedthatthehormonalstatusofthepatientswas notnotifiedandthatnoendocrinetherapywasassociatedwith theNAC(paclitaxelandcarboplatin).
Finally,themodulationofERexpressionand/orERfunction byendocrinetherapy canalsobe demonstratedby[18F]FES- PET[27,33,46].Thedeclinein[18F]FESuptakewasgreaterfor antagonistsversusaromataseinhibitors(AIs),inrelationtoER blockagewithtamoxifenandfulvestrant,whereasAIslowerthe agonist concentration but donot block ER. Serial [18F]FES- PEThavebeenusedtomonitorthefulvestrantdoseneededto completelyabolish ER (i.e. atleast75% decrease inmedian tumour[18F]FESuptakeonscan2performed28daysafterthe onsetofendocrinetherapy).In6of16patients,anincomplete reduced tumour [18F]FES uptake was associated with early progression[47].
9. Safetyanddosimetry
Like all radiopharmaceuticals used in nuclear medicine including fluorinated PET tracers, [18F]FES is injected in minute amounts and thus no pharmacodynamic effect is expected. For diagnostic studies with [18F]FES, 200 to 400MBqaregenerallyused,whichcorrespondstoanamount upto10mgof [18F]FES.
Toxicitydatahavetobeinterpretedinthecontextofnatural exposure to more or less continuous physiological levels of oestrogenforwomen.Todate,notoxicityorsignificantadverse reactionshavebeenreportedfor [18F]FESinclinicalstudies.
The radiation dose delivered during [18F]FES-PETexam- ination is comparable to that delivered by [18F]FDG-PET examination,andremainsinthe sameorderof magnitude as that of other nuclear medicine examinations. Radiation dosimetrywasestimatedbyMankoffetal.usingdataobtained in 49 patients (52 studies) after intravenous injection of [18F]FES [48]. Absorbed doses were calculated using the procedures of the MIRD committee, taking into account the variationindosebasedonthedistributionofactivitiesobserved in the individual patients. Effective dose equivalent was calculated using International Commission on Radiological Protection Publication 60 (ICPR 60) weights for a standard woman. The effective dose equivalent was 0.022mSv/MBq.
The organ that received the highest dose was the liver
(0.13mGy/MBq), followed by the gallbladder (0.10mGy/
MBq) and the urinary bladder (0.05mGy/MBq). Thus, the organ doses were comparable tothose associatedwith other commonly performed nuclear medicine tests. The potential radiationrisksassociatedwith[18F]FES-PETstudyarewithin acceptedlimits.
Disclosure ofinterest
Theauthorshavenotsuppliedtheirdeclarationofconflictof interest.
References
[1] ZeitounK,TakayamaK,SasanoH,SuzukiT,MoghrabiN,AnderssonS, etal.Deficient17beta-hydroxysteroiddehydrogenasetype2expressionin endometriosis:failuretometabolize17beta-estradiol.JClinEndocrinol Metab1998;83:4474–80.
[2] Bulun SE, Economos K,Miller D,Simpson ER. CYP19 (aromatase cytochrome P450) gene expression in human malignant endometrial tumors.JClinEndocrinolMetab1994;79:1831–4.
[3] BulunSE,SimpsonER,WordRA.ExpressionoftheCYP19geneandits productaromatasecytochromeP450inhumanuterineleiomyomatissues andcellsinculture.JClinEndocrinolMetab1994;78:736–43.
[4] NobleLS,TakayamaK,ZeitounKM,PutmanJM,JohnsDA,Hinshel- woodMM,etal.ProstaglandinE2stimulatesaromataseexpressionin endometriosis-derived stromal cells. J Clin Endocrinol Metab 1997;82:600–6.
[5] NobleLS,SimpsonER,JohnsA,BulunSE.Aromataseexpressionin endometriosis.JClinEndocrinolMetab1996;81:174–9.
[6] BrandesSJ,KatzenellenbogenJA.Fluorinatedandrogensandprogestins:
molecularprobesforandrogenandprogesteronereceptorswithpotential useinpositronemissiontomography.MolPharmacol1987;32:391–403.
[7] NoéG,ChengYC,DabikéM,CroxattoHB.Tissueuptakeofhumansex hormone-bindingglobulinanditsinfluenceonligandkineticsintheadult femalerat.BiolReprod1992;47:970–6.
[8] Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351:1451–67.
[9] Hunter RE, Longcope C, Jordan VC. Steroid hormone receptors in adenocarcinomaoftheendometrium.GynecolOncol1980;10:152–61.
[10] YaghmaieF,SaeedO,GaranSA,FreitagW,TimirasPS,SternbergH.
Caloricrestrictionreducescelllossandmaintainsestrogenreceptor-alpha immunoreactivityinthepre-optichypothalamusoffemaleB6D2F1mice.
NeuroEndocrinolLett2005;26:197–203.
[11] BabikerFA,DeWindtLJ,vanEickelsM,GroheC,MeyerR,Doevendans PA. Estrogenic hormone action in the heart: regulatory network and function.CardiovascRes2002;53:709–19.
[12] Kraus WL,McInerney EM, KatzenellenbogenBS.Ligand-dependent, transcriptionallyproductiveassociationoftheamino-andcarboxyl-ter- minalregionsofasteroidhormonenuclearreceptor.ProcNatlAcadSciU SA1995;92:12314–8.
[13] HammondMEH,HayesDF,DowsettM,AllredDC,HagertyKL,Badve S,etal.AmericanSocietyofClinicalOncology/CollegeofAmerican Pathologistsguidelinerecommendationsforimmunohistochemicaltest- ingofestrogenandprogesteronereceptorsinbreastcancer.JClinOncol 2010;28:2784–95.
[14] GarcíaPedreroJM,ZuazuaP,Martínez-CampaC,LazoPS,RamosS.The naturallyoccurringvariantofestrogenreceptor(ER) ERDeltaE7sup- pressesestrogen-dependenttranscriptionalactivationbybothwild-type ERalphaandERbeta.Endocrinology2003;144:2967–76.
[15] RobertsonJFR,ComeSE,JonesSE,BeexL,KaufmannM,MakrisA, etal.Endocrinetreatmentoptionsforadvancedbreastcancer–theroleof fulvestrant.EurJCancer2005;41:346–56.
[16]EarlyBreastCancerTrialists’CollaborativeGroup(EBCTCG),DaviesC, GodwinJ,GrayR,ClarkeM,CutterD,etal.Relevanceofbreastcancer hormonereceptorsandotherfactorstotheefficacyofadjuvanttamoxifen:
patient-levelmeta-analysisofrandomisedtrials.Lancet2011;378:771–84.
[17]CastagnettaL,TrainaA,DiCarloA,CarrubaG,CastoLoM,MesitiM, etal.Domultipleoestrogenreceptorassaysgivesignificantadditional information for the management of breast cancer? Br J Cancer 1989;59:636–8.
[18]MintunMA,WelchMJ,SiegelBA,MathiasCJ,BrodackJW,McGuire AH,etal.Breastcancer:PETimagingofestrogenreceptors.Radiology 1988;169:45–8.
[19]PetersonLM,MankoffDA,LawtonT,YagleK,SchubertEK,StekhovaS, etal.Quantitativeimagingofestrogenreceptorexpressioninbreastcancer withPETand18F-fluoroestradiol.JNuclMed2008;49:367–74.
[20]MathiasCJ,WelchMJ,KatzenellenbogenJA,BrodackJW,KilbournMR, Carlson KE, et al. Characterization of the uptake of 16 alpha- ([18F]fluoro)-17 beta-estradiol in DMBA-induced mammary tumors.
IntJRadApplInstrumB1987;14:15–25.
[21]MankoffDA,TewsonTJ,EaryJF.Analysisofbloodclearanceandlabeled metabolitesfortheestrogenreceptortracer[F-18]-16alpha-fluoroestra- diol(FES).NuclMedBiol1997;24:341–8.
[22]TewsonTJ,MankoffDA,PetersonLM,WooI,PetraP.Interactionsof 16alpha-[18F]-fluoroestradiol (FES) with sex steroid binding protein (SBP).NuclMedBiol1999;26:905–13.
[23]SeimbilleY,RousseauJ,BénardF,MorinC,AliH,AvvakumovG,etal.
18F-labeled difluoroestradiols: preparation and preclinical evaluation as estrogen receptor-binding radiopharmaceuticals. Steroids 2002;67:
765–75.
[24]YooJ,DenceCS,SharpTL,KatzenellenbogenJA,WelchMJ.Synthesisof an estrogenreceptorbeta-selectiveradioligand:5-[18F]fluoro-(2R,3S)- 2,3-bis(4-hydroxyphenyl)pentanenitrileandcomparisonofinvivodistri- bution with 16alpha-[18F]fluoro-17beta-estradiol. J Med Chem 2005;48:6366–78.
[25]KiesewetterDO,KilbournMR,LandvatterSW,HeimanDF,Katzenel- lenbogenJA,WelchMJ.Preparationoffourfluorine-18-labeledestrogens andtheirselectiveuptakesintargettissuesofimmaturerats.JNuclMed 1984;25:1212–21.
[26]DehdashtiF,FlanaganFL,MortimerJE,KatzenellenbogenJA,WelchMJ, Siegel BA. Positron emissiontomographic assessment of ‘‘metabolic flare’’ to predict response of metastaticbreast cancer to antiestrogen therapy.EurJNuclMed1999;26:51–6.
[27]LindenHM,StekhovaSA,LinkJM,GralowJR,LivingstonRB,EllisGK, etal.Quantitativefluoroestradiolpositronemissiontomographyimaging predictsresponsetoendocrinetreatmentinbreastcancer.JClinOncol 2006;24:2793–9.
[28]TsuchidaT,OkazawaH,MoriT,KobayashiM,YoshidaY,FujibayashiY, etal.Invivoimagingofestrogenreceptorconcentrationintheendome- triumandmyometriumusingFES-PET–influenceofmenstrualcycleand endogenousestrogenlevel.NuclMedBiol2007;34:205–10.
[29]TsujikawaT,YoshidaY,KudoT,KiyonoY,KurokawaT,KobayashiM, etal.Functionalimagesreflectaggressivenessofendometrialcarcinoma:
estrogenreceptorexpressioncombinedwith18F-FDG-PET.JNuclMed 2009;50:1598–604.
[30]TsujikawaT,YoshidaY,KiyonoY,KurokawaT,KudoT,FujibayashiY, etal.Functionaloestrogenreceptoraimaginginendometrialcarcinoma using16a-[18F]fluoro-17b-oestradiolPET.EurJNuclMedMolImaging 2011;38:37–45.
[31]ZhaoZ,YoshidaY,KurokawaT,KiyonoY,MoriT,OkazawaH.18F-FES and18F-FDG-PETfordifferentialdiagnosisandquantitativeevaluation ofmesenchymaluterinetumors:correlationwithimmunohistochemical analysis.JNuclMed2013;54:499–506.
[32]DehdashtiF,MortimerJE,SiegelBA,GriffethLK,BonaseraTJ,Fussel- manMJ,etal.Positrontomographicassessmentofestrogenreceptorsin
breastcancer:comparisonwithFDG-PETandinvitroreceptorassays.J NuclMed1995;36:1766–74.
[33] McGuireAH,DehdashtiF,SiegelBA,LyssAP,BrodackJW,MathiasCJ, etal.Positrontomographicassessmentof16alpha-[18F]fluoro-17beta- estradiol uptake in metastatic breast carcinoma. J Nucl Med 1991;32:1526–31.
[34] GemignaniML,PatilS,SeshanVE,SampsonM,HummJL,LewisJS, etal.Feasibilityandpredictability ofperioperativePETandestrogen receptor ligand in patients with invasive breast cancer. J Nucl Med 2013;54:1697–702.
[35] YangZ,SunY,ZhangY,XueJ,WangM,ShiW,etal.Canfluorine-18 fluoroestradiol positron emission tomography-computed tomography demonstratetheheterogeneityofbreastcancerinvivo?ClinBreastCancer 2013;13:359–63.
[36] TsujikawaT,OkazawaH,YoshidaY,MoriT,KobayashiM,TsuchidaT, etal.DistinctiveFDGandFESaccumulationpatternoftwotamoxifen- treatedpatientswithendometrialhyperplasia.AnnNuclMed2008;22:
73–7.
[37] GeorgeA,Lefebvre-LacoeuilleC,LacoeuilleF,FosseP,BouchetF,Croue A, et al. Ciblage des tissus endométriaux par la 16. Med Nucl 2014;38:439–48.
[38] Yoshida Y, Kurokawa T, Sawamura Y, Shinagawa A, Okazawa H, FujibayashiY,etal.ThepositronemissiontomographywithF1817be- ta-estradiolhasthepotentialtobenefitdiagnosisandtreatmentofendo- metrialcancer.GynecolOncol2007;104:764–6.
[39] vanKruchtenM,HospersGAP,GlaudemansAWJM,HollemaH,Arts HJG,ReynersAKL.Positronemissiontomographyimagingofoestrogen receptorexpressioninendometrialstromalsarcomasupportsoestrogen receptor-targetedtherapy:casereportandreviewoftheliterature.EurJ Cancer2013;49:3850–5.
[40] PetersonLM,KurlandBF,LinkJM,SchubertEK,StekhovaS,Linden HM,etal.Factorsinfluencingtheuptakeof18F-fluoroestradiolinpatients with estrogen receptor positive breast cancer. Nucl Med Biol 2011;38:969–78.
[41] PetersonLM,KurlandBF,SchubertEK,LinkJM,GadiVK,SpechtJM, etal.Aphase2studyof16a-[18F]-fluoro-17b-estradiolpositronemission tomography(FES-PET)asamarkerofhormonesensitivityinmetastatic breastcancer(MBC).MolImagingBiol2014;16:431–40.
[42] FlanaganFL,DehdashtiF,SiegelBA.PETinbreastcancer.SeminNucl Med1998;28:290–302.
[43] MortimerJE,DehdashtiF,SiegelBA,TrinkausK,KatzenellenbogenJA, Welch MJ. Metabolic flare: indicator of hormone responsiveness in advancedbreastcancer.JClinOncol2001;19:2797–803.
[44] KurlandBF,PetersonLM,LeeJH,LindenHM,SchubertEK,Dunnwald LK,etal.Between-patientandwithin-patient(site-to-site)variabilityin estrogenreceptor-binding,measuredinvivoby18F-fluoroestradiolPET.J NuclMed2011;52:1541–9.
[45] YangZ,SunY,XueJ,YaoZ,XuJ,ChengJ,etal.Canpositronemission tomography/computed tomography with the dual tracers fluorine-18 fluoroestradiolandfluorodeoxyglucosepredictneoadjuvantchemothera- pyresponseofbreastcancer?–Apilotstudy. PLoSOne2013;8:e78192.
[46] MortimerJE,DehdashtiF,SiegelBA,KatzenellenbogenJA,FracassoP, WelchMJ.Positronemissiontomographywith2-[18F]Fluoro-2-deoxy-D- glucoseand16alpha-[18F]fluoro-17beta-estradiolinbreastcancer:corre- lationwithestrogenreceptorstatusandresponsetosystemictherapy.Clin CancerRes1996;2:933–9.
[47] vanKruchtenM,deVriesEG,GlaudemansAW,vanLanschotMC,van FaassenM,KemaIP,etal.Measuringresidualestrogenreceptoravail- abilityduringfulvestranttherapyinpatientswithmetastaticbreastcancer.
CancerDiscov2014.
[48] MankoffDA,PetersonLM,TewsonTJ,LinkJM,GralowJR,Graham MM,etal.[18F]fluoroestradiolradiationdosimetryinhumanPETstudies.
JNuclMed2001;42:679–84.