Endocrine therapy in post-menopausal women with metastatic breast cancer: From literature and guidelines to clinical practice

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ContentslistsavailableatScienceDirect

Critical

Reviews

in

Oncology/Hematology

j ou rn a l h o m e pa g e :w w w . e l s e v i e r . c o m / l o c a t e / c r i t r e v o n c

Endocrine

therapy

in

post-menopausal

women

with

metastatic

breast

cancer:

From

literature

and

guidelines

to

clinical

practice

Valentina

Sini

a,b

_,

_Saverio

_Cinieri

c

_,

_Pierfranco

_Conte

d,e

_,

_Michelino

_De

_Laurentiis

f

_,

Angelo

Di

Leo

g

_,

_Carlo

_Tondini

h

_,

_Paolo

_Marchetti

i,j,∗

a_Surgical_and_Medical_Department_of_Clinical_Sciences,_Biomedical_Technologies_and_{Translational}_Medicine,_{“Sapienza”}_University_of_Rome,_Italy b_Oncology_Department,_Santo_Spirito_Hospital,_Rome,_Italy

c_Medical_Oncology_Department_&_Breast_{Unit—Hospital}_of_Brindisi_and_Medical_Oncology_{Department—European}_Institute_of_Oncology,_Milan,_Italy d_Medical_Oncology_2,_Venetian_Oncological_Institute,_Padova,_Italy

e_Department_of_Surgical,_Oncological_and_{Gastroenterological}_Sciences,_University_of_Padova,_Padova,_Italy f_Department_of_Breast_Oncology,_National_Cancer_Institute_{“Fondazione}_Pascale”,_Naples,_Italy

g_Medical_Oncology_Department,_“Sandro_{Pitigliani”}_Hospital_of_Prato,_Istituto_Toscano_Tumori,_Prato,_Italy h_USC_Oncologia_Medica,_Azienda_Ospedaliera_Papa_Giovanni_XXIII,_Bergamo,_Italy

i_Department_of_Clinical_and_Molecular_Medicine,_Medical_Oncology_Division,_{Sant’Andrea}_Hospital,_{“Sapienza”}_University_of_Rome,_Rome,_Italy j_IDI-IRCCS,_Rome,_Italy

Contents

1. Introduction...58

2. Certaintiesandnewapproachesinthetreatmentofestrogenreceptorpositivemetastaticbreastcancer...58

2.1. Tamoxifenversusmegestrolacetate...58

2.2. TamoxifenversusotherSERMs...59

2.3. Tamoxifenversusﬁrst-andsecond-generationAIs...59

2.4. Third-generationAIs:anastrozoleandletrozole(competitive,non-steroidal)andexemestane(non-competitive,steroidal)versusmegestrol acetateinadvancedpretreatedbreastcancer...59

2.5. Third-generationAIS:anastrozoleandletrozole(competitive,non-steroidal)andexemestane(non-competitive,steroidal)versustamoxifen asﬁrst-lineendocrinetherapy ... 59

2.6. Fulvestrant ... 59

3. Firstlineendocrinetherapy:whichstudies? ... 59

3.1. MaincontemporarystudiesinﬁrstlinesettingforHR+Her2−metastaticbreastcancerpatients...59

4. Resistancetoendocrinetherapy:newapproaches...61

4.1. Enhancingbeneﬁtofendocrinetherapybytargetinggrowthfactorreceptors...61

4.2. TargetingangiogenesisandendocrineresistanceinHR+metastaticBC...62

4.3. CombinationsofdifferentendocrineagentsinHR+metastaticBC...62

4.4. CombinationsofmTORinhibitorsinER+metastaticbreastcancer...62

5. Algorithmformanagementofpost-menopausalHR+metastaticbreastcancer...63

6. Maintenanceendocrinetherapy:whichevidence?...65

7. Conclusions...65

Authors’disclosuresofpotentialconﬂictsofinterest...65

Authorcontributions ... 65 Funding...66 Acknowledgement...66 References...66 Biography...68

a

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i

c

l

e

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n

f

o

Articlehistory: Received17November2015 Accepted15February2016

a

b

s

t

r

a

c

t

Currentinternationalguidelinesrecommendendocrinetherapyastheinitialtreatmentofchoicein hor-monereceptorpositiveadvancedbreastcancer.Endocrinetherapyhasbeenamainstayofhormone responsivebreastcancertreatmentformorethanacentury.Todateitisbasedondifferent

∗ Correspondingauthorat:MedicalOncology,“Sapienza”UniversityofRome,ViadiGrottarossa,1035-39,00189Rome,Italy. E-mailaddress:paolo.marchetti@ospedalesantandrea.it(P.Marchetti).

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Keywords:

Advancedbreastcancer Endocrinetherapy Hormonereceptorpositive Postmenopausal Treatment Maintenance Endocrineresistance

approaches,such asblockingtheestrogenreceptorthroughselective receptorestrogenmodulators, depletingextragonadalperipheralestrogensynthesisbyaromataseinhibitorsorinducingestrogen recep-tordegradationusingselectivedown-regulators.Despiteestrogenand/orprogesteronereceptorpositive status,uptoaquarterofpatientscouldbeeitherprimarilyresistanttohormonetherapiesorwilldevelop hormoneresistanceduringthecourseoftheirdisease.Differentmechanisms,eitherintrinsicoracquired, couldbeimplicatedinendocrineresistance.

Inthepresentworkavailableendocrinetherapiesandtheirappropriatesequenceshavebeenreviewed, andthemostpromisingstrategiestoovercomeendocrineresistancehavebeenhighlighted.

1. Introduction

About70%ofbreastcancersexpressthehormonereceptor(HR). Hormonalmanipulationhasbeenamainstayofhormone respon-sivebreastcancertreatmentformorethanacentury,andoften representstheﬁrstofseverallinesoftreatmentinthemetastatic setting.

Todateendocrine therapy is basedondifferent approaches, suchasblockingtheestrogenreceptor(ER)throughselectiveER modulators(SERMs),reducingestrogenlevelsbydepleting extrag-onadalperipheralestrogensynthesisbyaromataseinhibitors(AIs) orinducing ER degradationusing selectiveER down-regulators (SERDs).

Asubstantialproportionofpatients,uptoone-quarter,despite ERand/orprogesteronereceptor(PgR)positive status,couldbe eitherprimarilyresistanttohormone therapies orwill develop hormoneresistanceduringthecourseoftheirdisease.

ER maintains active in tumor with acquired resistance to endocrinetherapy,andcontinuedendocrinetherapyin combina-tionwithotheragentsareeffectiveinsuchpatients.

Otheravailabletherapies,suchchemotherapyorcombinations ofendocrineandtargettherapies,asPI3K-mTORinhibitors,could haveakeyroleinprimaryorsecondaryresistantHR+metastatic breastcancer.

Also,a properviewof availableendocrine therapies, related studies,theirappropriatesequencesandrelativestrategiesto over-comeendocrineresistance,couldhelpourdailyclinicalpractice. 2. Certaintiesandnewapproachesinthetreatmentof estrogenreceptorpositivemetastaticbreastcancer

Sitesandextentofdisease,related symptoms,ERlevelsand humanepidermalgrowthfactor-2(HER2)status,disease-freeand treatment-freeintervals,andperformancestatusarekeyfactorsin thechoiceoftreatmentinmetastaticHR+breastcancer.

While hormone-unresponsive or life-threatening disease requireschemotherapy,HR+metastaticbreastcancerpatientsare usuallycandidatetoendocrinetherapy.Indeedwhileinitial treat-mentwithchemotherapyratherthanendocrinetherapymaybe associatedwithahigherresponserate,thetwoinitialtreatments hadasimilareffectonoverallsurvival(OS)(Wilckenetal.,2003). Nostudiesdirectlycomparedendocrineandchemotherapyinthis setting.

Maininternationalguidelinesrecommendendocrinetherapyas thetreatmentofchoiceinHR+advancedbreastcancer:

• NCCNGuidelines:Manywomenwithhormone-responsivebreast cancerbeneﬁtfromsequentialuseofendocrinetherapyat dis-ease progression. Therefore, women with breast cancer who respond to endocrine therapy with either tumor shrinkage or long-term disease stabilization should receive additional endocrinetherapyatdiseaseprogression(NCCN,2015).

Fig.1. Endocrinetherapyinvolvesmanyagents.

• ABC1Guidelines:Endocrinetherapyisthepreferredoptionfor HR+disease,eveninthepresenceofvisceraldisease,unlessthere isconcernor proofofendocrine resistanceorthereisdisease needingafastresponse(Cardosoetal.,2012a).

• ESMO Guidelines: Endocrine therapy is the preferred option except if clinically aggressive disease mandates a quicker responseoriftherearedoubtsregardingendocrine responsive-nessofthetumor(Cardosoetal.,2012b).

Todateendocrinetherapyinvolvesmanyagents(Fig.1).For many years tamoxifen, a selectiveERmodulator (SERM) which antagonises estrogen signaling in HR+ breast cancer,has been themainstayinthetreatmentofHR+breast cancer.Tamoxifen becamethestandardtherapyforadvancedbreastcancerafter hav-ingdemonstrated first-lineefficacyandmore favorable toxicity profilewhencompared witha rangeof otherendocrine agents inthis setting (Fossati etal.,1998).Asystematic review,on35 randomizedcontrolledtrials(RCTs),comparingtamoxifenwitha rangeofotherendocrinetherapies,includingovarectomy, mege-strol acetate, aromatase inhibitors (AIs), medroxyprogesterone acetate,SERMs,goserelinandfluoxymesterone,reportedan over-allresponserate(ORR)of30%withtamoxifenversus29%withthe otheragentsandanOShazardratioof1.02[confidenceinterval (CI)0.94–1.10],withoutgrossstatisticalheterogeneitybetween tri-als(p=0.48)ordifferenceshormonalcategories(p=0.60)(Fossati etal.,1998).

2.1. Tamoxifenversusmegestrolacetate

InatleastfiveRCTs(Allegraetal.,1985;Gilletal.,1993;Ingle etal.,1982;Morgan,1985;Mussetal.,1988;Patersonetal.,1990) tamoxifendemonstratedtohavecomparableefficacywith mege-strolacetate,that actsbyinhibitingpituitaryfunctionand thus suppressingluteinizinghormoneandthesubsequentproductionof estrogen,intermsofORRandOS,withabetterside-effectprofile.

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2.2. TamoxifenversusotherSERMs

Tamoxifenhasalsobeentested againstseveralotherSERMs, and,overall,itwasthereforedeemedtobeasgoodas,orbetter than,allalternativeSERMs.Inparticulartamoxifenresulted com-parabletotoremifene(n=1421)(Pyrhonenetal.,1999)oridoxifene (n=220)(Johnston,2001)andwassuperiortodroloxifene[ORR (P=0.02)andtimetoprogression(TTP)(P<0.001)](Buzdaretal., 2002)andtoarzoxifene[progression-freesurvival(PFS;P=0.01)] (Deshmaneetal.,2007).

Thestudyofapproachesforpatientswithtumorsresistantto tamoxifenledtothedevelopmentofnewstrategies:

2.3. Tamoxifenversusﬁrst-andsecond-generationAIs

Thefirst generationAI aminoglutethimide wasshown tobe comparablewithtamoxifenalone(Liptonetal.,1982;Smithetal., 1981)orwithaminoglutethimideplustamoxifen(Ingleetal.,1986; Rose et al., 1986). AIswork by inhibiting aromatase signaling, whichultimatelyblockstheestrogenreceptor.Butfirstgeneration compoundswereunspecificwithsubsequenttoxicityandneedof adrenalhormonalsupplementation.

2.4. Third-generationAIs:anastrozoleandletrozole(competitive, non-steroidal)andexemestane(non-competitive,steroidal) versusmegestrolacetateinadvancedpretreatedbreastcancer

WiththirdgenerationAIs,letrozole,anatrozoleandexemestane, problemsaboutadrenaltoxicityofpreviouscompoundswere over-come.Theywereevaluatedincomparisonwithhormonalagents usedin“tamoxifen-resistant”disease,ofwhichmegestrolacetate wasthedrugofchoicebeforethecomingofAIsandfulvestrant.

AnastrozoleshowednosignificantdifferenceinTTPfrom mege-strolacetateonaninitialanalysis(Buzdaretal.,1997;Jonatetal., 1996).However,a plannedsubsequentanalysis found anastro-zole1mgtobeassociatedwithsignificantlyincreasedOSversus megestrolacetate(median26.7versus22.5months,respectively; P<0.025) (Buzdar et al.,1998).Twostudies ofletrozole 2.5mg versusmegestrolacetateshowednosignificantdifferenceinTTP orOS(Buzdaretal.,2001;Dombernowskyetal.,1998). Exemes-taneresultedinanincreasedTTP(4.7versus3.8months;P=0.037) andasignificantlylongerOS(medianOSnotreachedfor exemes-tane at time of publication versus 28.5 months for megestrol acetate;P=0.039) compared with megestrol acetate (Kaufmann etal.,2000).AIswereinitiallyintroducedbasedonbetterside-effect profilebutsimilarTTPversusmegestrolacetate.Subsequently,this decisionwassupportedbytheOSdatawithanastrozoleandthe increasedefficacyseenwithexemestane.

2.5. Third-generationAIS:anastrozoleandletrozole(competitive, non-steroidal)andexemestane(non-competitive,steroidal) versustamoxifenasﬁrst-lineendocrinetherapy

Similarlytotheadjuvantsetting, wherethird-generation AIs resultedsuperiortotamoxifeninlargetrials(Forbesetal.,2008; Jonat et al., 2006; Coates et al., 2007; van de Velde et al., 2011;Coombesetal.,2004),intheadvanceddisease,overall,the third-generationAIsweredeemedmoreeffectiveintermsof dis-easecontrolthantamoxifen,inpotentially“tamoxifen-sensitive” disease.Theywerewelltolerated.Thereforetheybecamethe pre-ferredﬁrst-lineendocrinetherapy.

Inparticular,anastrozolewasshowntobesuperiorto tamox-ifenintermsofTTPinaNorthAmerican-basedtrial(Nabholtzetal., 2000).On the other hand nosigniﬁcant differencein TTPwas reportedintheTARGETtrial(Bonneterreetal.,2000).

However,only45%ofpatientsintheTARGETtrialwereknown tohaveanHR+tumor;whilealmost90%ofpatientsintheNorth American-basedtrialwereknowntobeHR+,andinapooled ret-rospectiveanalysisofthetwotrialsincludingpatientswithknown HR+tumors,anastrozoleresultedsuperiortotamoxifenintermsof TTP,withoutdifferencesinOS(Nabholtzetal.,2003).

LetrozolesigniﬁcantlyprolongedTTPcomparedwithtamoxifen withoutasigniﬁcantdifferenceinOS(Mouridsenetal.,2003).Also exemestaneshowedlongerPFS(assessedusingtheWilcoxontest) thantamoxifen(Paridaensetal.,2008).

2.6. Fulvestrant

Fulvestrant is a selective estrogen receptor down regulator (SERD). Unlike the selective ER modulator tamoxifen, fulves-trant isdevoidofanyknownagonistactivity.Fulvestranthasa steroidal structure that competitively binds to the ER withan afﬁnitymuch greater thanthatof tamoxifen. Fulvestrant, bind-ingtotheER,down-regulates,blocks,andcausesdegradationof theER,culminatingincompleteabrogationofestrogen-sensitive genetranscription(Wakeling,2000).Preclinicalstudiesconﬁrmed thepotentialof fulvestranttoinhibitthegrowthof tamoxifen-resistant,aswellastamoxifen-sensitive,humanbreastcancercell lines (Wakelinget al., 1991;Hu etal., 1993; Lykkesfeldt etal., 1994).Thisuniquemechanismof actionmayresultinalackof cross-resistancewithotherendocrineagents.

Afterstudieshadshowedthatitwasaseffectiveasanastrozole 1mg/dayinthetreatmentofHR+advancedbreastcancerinthe second-linesettingpre-treatedwithtamoxifen(Robertsonetal., 2003,2004),itwasinitiallyapprovedatadoseof250mg/month.

Preclinicalmodelsandpharmacokineticstudiessuggestedthe possibilitytoobtain,throughaloadingdose,plasmaconcentrations offulvestranttwicehigherthanthoseobtainedwiththe conven-tionalmonthlyadministration.Besides,higherdosesoffulvestrant (500mg)allowedtoobtainthesteadystateinfewweeksfromthe beginningoftreatment(Robertsonetal.,2007).

Basedontheseinformation,randomizedstudiesevaluated efﬁ-cacyofaschedulewithloadingdose,followedbystandarddose offulvestrant(250mg)(Chiaetal.,2008)ortheuseofhighdose fulvestrant(500mg)(Wakelingetal.,1991).

Fulvestrant500mgwascomparedtofulvestrant250mgina phase IIIrandomized controlledtrial in women withadvanced breastcancer(CONFIRMtrial)(DiLeoetal.,2010,2012)andto anas-trozole1mg/dieinﬁrstlinesetting(FIRSTtrial)(Robertsonetal., 2009,2010;Robertson,2014)and,ashereinaftermoreextensively reported,Fulvestrant500resultedsuperiorbothtoFulvestrant250 andtoanastrozole.

Furthermore,thisﬁndingisfullyconsistentwiththeprevious reportedincreasedbiologicaleffects seenwiththe500mgdose comparedwith250mg(Kuteretal.,2007).

In summary, fulvestrant 500mg has a biologically greater effectandprovidesaclinicallymeaningfulbeneﬁtoverfulvestrant 250mg.Thestandarddosingscheduleoffulvestrantshouldbe5 00mgand,basedonitsincreasedefﬁcacy,shouldbeconsidered earlyinthetreatmentofadvanceddisease(Cardosoetal.,2012b). 3. Firstlineendocrinetherapy:whichstudies?

3.1. MaincontemporarystudiesinﬁrstlinesettingforHR+ Her2−metastaticbreastcancerpatients

• FIRST trial is a randomized phase II randomized, open-label, multicenter studyon205patientsrandomized toreceive ful-vestranthigh-dose (HD) regimen(500mg/monthplus 500mg on day 14 of month 1) versus anastrozole (1mg/d) in the

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first-linesetting. Allpatientsenrolledin this trialwere post-menopausalwomenwithER+and/orPgR+locallyadvancedor metastaticbreastcancernevertreatedwithendocrinetherapy foradvanceddisease,butcouldhavereceivedadjuvantendocrine therapyforearlydisease,provideditwascompletedmorethan 12 months beforerandom assignment. This study showed a significantadvantage for fulvestrant 500mg in terms of TTP (hazardratio=0.626; P=0.0496) (Robertson et al., 2009).The significant difference in TTP persisted with longer follow-up (23.4monthswithfulvestrantversus13.1monthswith anas-trozole;hazard ratio=0.66; P=0.01) (Robertson et al., 2010). Moreover,asreportedatSanAntonioBreastCancer Symposium 2014,FulvestrantshowedabenefitinOSversusanastrozole:54.1 monthsforfulvestrantversus48.4monthsforthosewhoreceived anastrozole(Robertson,2014).Adverseeventswerecomparable betweenthetwotreatmentarms(Robertsonetal.,2009). • CONFIRM trial is a double-blind, parallel-group, multicenter,

phaseIIIstudy.Patientswererandomlyassignedtofulvestrant 500mg(500mgintramuscularlyonday1,then500mgondays14 and28andevery28daysthereafter,n=362patients)or250mg every28days(n=374).PrimaryendpointwasPFS.Secondary endpointsincludedobjectiveresponserate(ORR),clinical bene-fitrate(CBR),durationofclinicalbenefit(DoCB),OS,andquality oflife(QOL).PFSwassignificantlylongerforfulvestrant500mg than250mg(hazardratio=0.80;95%CI,0.68–0.94;P=.006).ORR wassimilarinbotharms(9.1%v10.2%,respectively).CBRwas 45.6%forfulvestrant500mgand39.6%forfulvestrant250mg. DoCBandOSwere16.6and25.1months,respectively,forthe 500-mggroup,whereasDoCBandOSwere13.9and22.8months, respectively,inthe250-mggroup.Fulvestrant500mgwaswell toleratedwithnodose-dependentadverseevents.QOLwas sim-ilarforbotharms(DiLeoetal.,2010).ThefinalOSanalysisat 75%maturity,presentedatSanAntonioBreastCancer Sympo-sium2012,showedthatfulvestrant500mgisassociatedwith 4.1-monthincreaseinmedianOSanda19%reductionintherisk ofdeathcomparedwithfulvestrant250mg(DiLeoetal.,2012). Thestudyincludedbothfirstandsubsequentlinespatients.Itis worthnotingthatthemostrepresentedsubgroupswerepatients whoexperiencedrelapseonadjuvantendocrinetherapy(48.3% infulvestrant500mgarmand45.2%infulvestrant250mgarm) andpatientswhopresentedwithdenovoadvanceddiseaseand experiencedprogressiononfirst-lineendocrinetherapy(35.9% and33.4%respectively).Overall,thelastendocrinetherapybefore fulvestrantwasanaromataseinhibitorfor42.5%ofpatientsand anantiestrogenfortheremaining57.5%ofpatients

• SWOG0226studyevaluatedcombinedendocrinetherapyagents withtheantiestrogenfulvestrantplustheAIanastrozole,aimed atseekingtoleverageERdegradationbyfulvestrantin endocrine-resistant disease. This study included a population of 694 post-menopausal patients, randomized to receive anastrozole 1mgdaily(n=345patients)orthecombinationofanastrozole andfulvestrant500mgloadingdosefollowedbyamonthly injec-tionoffulvestrant250mg(n=349).Allpatientswerepreviously untreatedformetastaticdisease,Prioradjuvanttamoxifenwas allowed,and40%ofpatientsreceivedthisadjuvant endocrine therapy.Thestudydemonstrateda6-monthimprovementinOS forthecombinationfulvestrantplusanastrozole(medianOS47.7 versus41.3months,hazardratio=0.81;p=0.049).Thisbeneﬁt likewiseappeared tobemainlyrestricted tothosewho were entirelyendocrinetherapy-naive,even intheadjuvant setting (47.7versus39.7months,hazardratio=0.74)(Mehtaetal.,2012). • FACTstudyisaphaseIIIrandomizedtrialthatrandomlyassigned 514 patients to receive fulvestrant plus anastrazole (experi-mental arm; n=258 patients) or anastrozole (standard arm; n=256),atthesamescheduleofSWOG0226trial.Theywere post-menopausalorpre-menopausalwomenreceivingGn-RH,

previouslyuntreatedformetastaticdisease.Thistrialallowedthe enrollmentofpatientswhoreceivedadjuvantendocrine ther-apy,andalsoAI,ifcompleted>12monthsbeforetheenrolment. Endocrine-pretreatedpatientsshowednobenefitfromthe com-bination (Bergh et al., 2012).Median TTP was 10.8 and 10.2 monthsinexperimentalversusstandardarm,respectively (haz-ardratio0.99;95%CI0.81–1.20,p=0.91).MedianOSresulted37.8 and38.2monthsforexperimentalandstandardarm,respectively (hazardratio1.0;95%CI0.76–1.32,p=1.00)(Berghetal.,2012). • HORIZONtrialisa largemulticenter internationalrandomized placebo-controlled phase III trialthat tested theefficacy and safetyoffirst-lineoralletrozole2.5mgdaily/temsirolimus30mg daily(5daysevery2 weeks)versusletrozole/placebo in1112 patientswithAI-naive,HR+advanceddisease.Patientshadtobe nevertreatedformetastaticdisease.40%hadreceivedadjuvant endocrinetherapy.Thestudydidnotshowoverallimprovement intheprimaryend pointPFS(medianPFS=9months;hazard ratio=0.90;95% CI, 0.76–1.07;P=.25)norin the 40%patient subsetwithprioradjuvant endocrinetherapy.Thoseon letro-zole/temsirolimusexperienced moregrade 3–4events(37%v 24%)thanletrozolealone.Addingtemsirolimustoletrozoledid notimprovePFSasfirst-linetherapyinpatientswithAI-naive advancedbreastcancer.Indeed,thetrialwasstoppedfor futil-itybytheindependentdatamonitoringcommittee.ORRandOS werealsosimilarbetweengroups.Thepatientpopulationinthe HORIZONstudywaslargelyAI-naiveandtemsirolimus/letrozole wasthefirstendocrinetreatmentformetastaticdisease(Wolff etal.,2013).

• TheBreastCancerTrials ofOralEverolimus-2(BOLERO-2)is a randomizedphaseIIIstudyin724patientswithHR+advanced breastcancerwhohadrecurrenceorprogressionwhile receiv-ingprevious therapy witha nonsteroidal aromataseinhibitor intheadjuvant settingortotreatadvanceddisease(orboth), thatcomparedeverolimusandexemestaneversusexemestane andplacebo(randomlyassignedina2:1ratio).Theprimaryend pointwasPFS.SecondaryendpointsincludedOS,ORR,andsafety. CombinationtherapywithexemestaneandthemTORinhibitor everolimusresulted in a signiﬁcantly longerPFS (6.9months witheverolimusplusexemestaneand2.8monthswithplacebo plusexemestane,accordingtoassessmentsbylocal investiga-tors(hazardratio=0.43;95%CI0.35–0.54;P<0.001).MedianPFS was10.6monthsand4.1months,respectively,accordingto cen-tralassessment(hazardratio,0.36;95%CI,0.27–0.47;P<0.001) andhigherresponseratethanthesingleagentexemestane.The mostcommongrade3or4adverseeventswerestomatitis(8%in theeverolimus-plus-exemestanegroupversus1%inthe placebo-plus-exemestanegroup),anemia(6%versus<1%),dyspnea(4% versus1%),hyperglycemia(4%versus<1%),fatigue(4%versus 1%),andpneumonitis(3%versus0%).Everolimuscombinedwith anAIimprovedPFSinpatientswithHR+advancedbreast can-cerpreviously treatedwithnonsteroidal aromataseinhibitors. Thistrialonlyincludedpretreatedpopulation.Previoustherapy includedletrozoleoranastrozole(100%), tamoxifen(48%), ful-vestrant(16%), andchemotherapy(68%) (Baselga etal.,2012; Piccart-Gebhartetal.,2012).

• IntheTamoxifenandRAD001(TAMRAD)study,asmaller ran-domizedphaseIItrialinasimilarpatientpopulation,patients receiving the combination of tamoxifen and everolimus had higherclinicalbeneﬁtrate(61%)andlongerTTP(8.6months) thanthegroupreceivingtamoxifenalone(42%and4.5months). Inthatstudy,patientswithsecondaryresistancetoAIseemedto beneﬁtmorefromthecombinationthanpatientswithprimary resistance,supportingtheconceptthatcross-talkbetween path-waysandthesequentialupregulationofthePI3K/mTORsignaling isamechanismofresistance(Bachelotetal.,2012).

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• Itisworthofnotethatthesebeneﬁtswerenotwithouttoxicity.In thisstudy,astheprevious(Bolero-2)(Baselgaetal.,2012; Piccart-Gebhart et al., 2012)combined everolimus/endocrine therapy hadsubstantiallyhigherstomatitis,rash,fatigue,diarrhea,and anorexiathansingle-agentendocrinetherapy.

• IntheSanAntonioBreastCancerSymposium2012resultsfroma randomized phase II study comparing letrozole alone (L) to letrozoleplusPD0332991(L+P)werepresented.PD0332991 isa selective inhibitorof CDK 4/6thatprevents cellularDNA synthesis by blocking cell cycleprogression. Preclinical stud-iesinbreastcancercelllinepanelidentifiedintheluminalER subtype,elevatedexpressionofcyclinD1andRbprotein,and reducedp16expressionasbeingassociatedwithsensitivityto PD0332991(Finnetal.,2009).It wasdesigned asatwo-part study,inwhichpart1enrolledpost-menopausalwomenwith ER+/HER2–advancedBC;part2inadditiontoER+/HER2–as eli-gibility criteria,screened for CCND1amplification and/orloss of p16, evaluated by FISH. The primary endpoint was PFS; secondary endpoints include ORR, OS, safety, and correlative biomarkerstudies.Inbothparts,post-menopausalwomenwith ER+/HER2–advancedBCwererandomized1:1toreceive letro-zoleeitherwithorwithoutPD0332991.66ptswererandomized inPart1and99ptsinPart2.PreliminaryresultsfromPart1of thisstudyhavebeenpreviouslyreported(Finn,2012) demon-strating a significantimprovementin median PFSin theL+P versusLarm(HR=0.35;95%CI,0.17–0.72;p=0.006).Withthe additional99ptsrandomizedinPart2(N=165),thestatistically significantimprovementinmedianPFS(26.2versus7.5months, respectively)continuestobeobserved(hazardratio=0.32;95% CI,0.19–0.56;p<0.001).TheORRfortheL+Parm(n=84)was 31% versus 26% for the L arm (n=81) and the clinical bene-fitratewas68%versus44%,respectively.Themostcommonly reportedtreatment-relatedadverse eventsinthecombination armwereneutropenia,leukopenia,anemia,andfatigue.The com-binationofPD0332991andletrozoleiswelltoleratedandshows encouragingclinicalbenefit, confirmingthesensitivity of ER+ breastcancertoPD0332991observedinpreclinicalmodels(Finn etal.,2012).Aphase3trialinthissettingisnowongoing. • Very recently, during the last ASCO Meeting, results from

PALOMA 3 (Nicholas et al., 2015) study were presented. It assessedtheefﬁcacyofpalbociclibandfulvestrantin endocrine-resistant advanced breast cancer. Palbociclib combined with fulvestrantimprovedprogressionfreesurvivalinHRadvanced breastcancerthathadprogressedonprior endocrinetherapy. MedianPFSwas9.2monthsforPalbociclib+Fulvestrantand3.8 monthsforPlacebo+Fulvetratnt(HR0.422,95%CI0.318–0.560, P<0.000001)anditresultedwelltolerated.

4. Resistancetoendocrinetherapy:newapproaches

Unfortunatelyboth de novo and acquired resistance to endocrine therapy are important clinical problems. Different mechanismshavebeenimplicatedinendocrineresistance,either intrinsic, occurringde novo attheinitial exposureto endocrine therapiesoracquired,occurringafteraninitialresponsetotherapy (Bedardetal.,2008;DawoodandCristofanilli,2007),andrecent effortshavecenteredaroundstrategies tocombatthis resistance (MoyandGoss,2006).

ERexpressionis currentlythemain biomarkerofresponse to endocrine therapy and the lack of ER hasto beconsideredthe principalmechanismofprimaryendocrineresistance(Zillietal., 2009;MusgroveandSutherland,2009).LossofERalfaorERbeta mutationsarewidelyacceptedaspotentialmechanismsofacquired resistance.OfnoteisthatlossofERoccursin15–20%ofendocrine

resistantbreastcancers andless than1%of HR+tumorshaveER mutations(Gutierrezetal.,2005;HerynkandFuqua,2004).

Furthermore ER activity is a part of a more complexsys-tem of intracellular signaling pathway, and the bidirectional crosstalkbetweenERandgrowthfactorssignalingisimplicated inbothdenovoandacquiredresistance.Preclinical studiesimpli-catecross-talkbetweenERandcritical signalingpathways,such as the epidermal growth factor receptor/human epidermal-growth factor receptor-2 (EGFR/HER2) and IGFR or activation of their downstream signaling pathway through extracellular signal-regulatingkinase1/2/mitogenactivatedproteinkinase cas-cade and the phosphoinositide3-kinase (PI3K)/proteinkinase B (AKT)/mammaliantargetofrapamycin (mTOR)pathway,askey mediatorsofendocrineresistance(Johnstonetal.,2005;Johnston, 2010).

4.1. Enhancingbeneﬁtofendocrinetherapybytargetinggrowth factorreceptors

TargetingEGFR“up-front”,asshowninxenograftmodels,might delayresistancetotamoxifen(Thoennissenetal.,2010).ForHER2+ tumors, combined targeted therapy at the onset of “acquired endocrineresistance”isbetterthandelayingresistanceup-front (Wangetal.,2005).

Anumberofclinicaltrialshavebeendesignedinorderto deter-mine whether theaddiction of signaltransduction inhibitors to endocrinetherapymayovercomeendocrineresistance,including combinationsofendocrinetherapieswithanti-HERtargeteddrugs, completeblockadeofERsignalingandcombinationswithdrugs thattargetthedownstreamsignalingpathways.

To date, several trials have explored the efﬁcacy of endocrinetherapyincombinationwithanti-HER2monoclonal anti-bodytrastuzumaborwithEGFR/HER2tyrosinekinaseinhibitors aslapatinib,erlotinibandgeﬁtinib(Johnston,2009a).

Cristofanillietal.,2010reportedprolongedPFSwith anastro-zoleplusgefitinib(n=43patients)versusanastrozoleplusplacebo (n=50;hazardratio=0.55;95%CI0.32–0.94)inpostmenopausal womenwithHR+metastaticbreastcancer.Theseresults,however, didnotagreewiththosecomingfromtheneoadjuvant random-izedcontrolledtrialofanastrozoleversusanastrozoleplusgefitinib (Smithetal.,2007).Moreoverthecombinationoftamoxifenwith orwithoutgefitinibdidnotresultinaPFSbenefitwiththeaddition ofgefitinibtotamoxifen(Osborneetal.,2007).

Rationaleforclinicaltrialsexploringthecombinationof hor-monaltherapiesandantiHer2agentsinmetastaticbreastcancer camefrompreclinicalstudieswhichdemonstratedthatthe addi-tion of trastuzumab to tamoxifen results in a strong growth inhibitionthroughacellcyclearrestinG0-G1(Thoennissenetal., 2010).

TAnDEMwastheﬁrstrandomizedphaseIIIstudytocombine ahormonalagentandtrastuzumabastreatmentforHER2+and HR+metastaticbreastcancer.Thattrial(on207patients)randomly assigned toreceiveanastrozole(n=104patients)oranastrozole plustrastuzumab(n=103)anddemonstratedthattheadditionof trastuzumabtoanastrozolesigniﬁcantlyimprovesPFS,TTP,andOS comparedwithanastrozolealone(Kaufmanetal.,2009).

Theefficacyoftheadditionoflapatinib,adualtyrosinekinase inhibitor, to letrozole has been investigated as first line treat-mentin1286womenwithhormonereceptorpositive(HER2+/−) metastaticbreastcancer.Theassociationoflapatinibandletrozole significantlyimprovedPFScomparedtoletrozolealoneinHER2+ population,witha29%reductionintheriskofdisease progres-sion(Johnstonetal.,2009).Nobenefitinthewholepopulationin whichthecombinationlapatinibandletrozoledidnotresultbetter thanletrozole(medianPFS14.7versus15months)(Kaufmanetal., 2009).

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In bothstudies, the addition of the growth factor inhibitor improvedclinicalbeneﬁtrate(CBR)andPFSbuttherewasno sig-niﬁcantdifferenceinOS(P=0.325fortrastuzumab(Osborneetal., 2007);notreportedforlapatinib)(Kaufmanetal.,2009).

AthirdtrialonHR+/Her2+metastaticbreastcancer,the eLEc-TRAtrial,comparedefficacyandsafetyofletrozolecombinedwith trastuzumabtoletrozolealone.Thestudyonlyincludedpatients withHER2andHR+metastaticbreastcancer,thatwere random-izedtoeitherletrozolealone(armA,n=31patients)orletrozole plus trastuzumab (arm B, n=26) as first-line treatment. Addi-tional35patientswithHER2-andHR+tumorsreceivedletrozole alone(armC).Median TTPin armA was3.3months compared to14.1months in armB (hazardratio 0.67;p=0.23)and 15.2 monthsinarmC(hazardratio0.71;p=0.03).Clinicalbenefitrate was39% forarmAcompared to65% inarmB(oddsratio2.99, 95% CI 1.01–8.84) and 77% in arm C (odds ratio 5.34, 95% CI 1.83–15.58).Thistrialconfirmedthatthecombinationofendocrine andantiHer2-therapyisaneffectivetreatmentoptionforpatients withHER2andHR+metastaticbreastcancer(Huoberetal.,2012). AphaseIIIstudyevaluatedFulvestrantwithorwithout lapa-tinibinpatientswithHR+advancedbreastcancer.Inthistrialboth patientsHER2+/₋ wereincluded.Atathirdinterimanalysis,no improvementswereobservedinPFSorOSwiththeadditionof lap-atinibtofulvestrant.However,inpatientswithHER2+tumors,a trendtowardsimprovedPFSwasobserved(5.9versus2.8months forfulvestrant+lapatinibversusfulvestrantalone;P=0.29). Treat-mentwasgenerallywelltolerated(Bursteinetal.,2010).

So,“up-front”co-targetingofHER2andHRcanimprove resis-tancetoAIs,andbeneﬁtfromthisstrategyisrestrictedtoknown ER+HER2+metastaticbreastcancerpatients.

4.2. TargetingangiogenesisandendocrineresistanceinHR+ metastaticBC

Preclinical(laHaba deet al.,2011)andretrospectiveclinical (Linderholmetal.,2011;Mandersetal.,2003;Rydénetal.,2005) datasuggestthathighvascularendothelialgrowthfactor(VEGF) levelsin tumor tissue from breast cancerare associated with a decreasedresponsetoendocrinetherapy.

Thecombinationof endocrinetherapy and bevacizumabhas showntobesafeandactiveinphaseIIclinicaltrials(Trainaetal., 2010;Forero-Torresetal.,2010).

The LEA trial, a phase IIIstudy presented in the San Anto-nioBreastCancerSymposim2012,addressedthehypothesisthat anti-VEGFtreatmentmightdelayresistancetoendocrinetherapy inpatientswithHR+advancedbreastcancer.Itwasabinational, multicentric, randomized, open label phase III study in which 380 patients with unresectable locally advanced or metastatic HR+/HER2- breast cancerpatients were randomized to receive endocrinetherapy(Letrozole2.5mgdorFulvestrant250mg1q 28)orthesameendocrinetherapywithBevacizumab15mg/kgq3 weeks.TheadditionofBevacizumabresultedinabetterPFS(18.4 versus13.8months),hazardratio0.83(CI0.65–1.06,p=0.1391) (Martinetal.,2012).

4.3. CombinationsofdifferentendocrineagentsinHR+ metastaticBC

Similarly,studiesevaluatedcombinedendocrinetherapyagents. Rationaleforthesestudies,thatevalutatedthecombinationofthe pureantiestrogenfulvestrantplusanAI,camefromthepossibility ofseekingtoleverageERdegradationbyfulvestrantin endocrine-resistantdisease.

Arecentstudy,theSWOG0226trial,(describedinmoredetail below)demonstrateda6-monthimprovementinOSforthe com-binationfulvestrantplusanastrozoleversusanastrozolealone.This

studyincludedapopulationofprimarilyendocrinetherapy–naive patientstreatedintheﬁrstlinesetting,andthepopulation ben-eﬁtingfromthecombinationappeared tobemainlythose who wereentirelyendocrinetherapy-naive,evenintheadjuvantsetting (Mehtaetal.,2012).

Bycontrast,theFACTstudy,anotherrandomizedtrialof anastra-zolewithorwithoutfulvestrantthatenrolledendocrine-pretreated patients,showednobeneﬁtfromthecombination(Berghetal., 2012).

4.4. CombinationsofmTORinhibitorsinER+metastaticbreast cancer

The mammalian target of rapamycin (mTOR) is a signaling kinaseofthephosphatidylinositol3-kinase/proteinkinaseB(also known as Akt) signaling pathway that mediates cell growth and metabolism.It hastwo main downstream messengers:the ribosomalp70S6kinase(S6K1)andtheeukaryotictranslation ini-tiationfactor4E-bindingprotein(4E-BP1)(Margaritietal.,2011). Both proteins aretranslational activators critical for ribosome biogenesis and translation, including the synthesis of proteins necessary forcell cycle progression. In addition to its effect on proteintranslationmediatedbyS6K1and4E-BP1, mTORactivation-leadstothephosphorylationofseveraldownstreameffectorsand transcriptionfactors.DysregulationofthemTORpathwaycreates a favorable environment for the development and progression of many cancers, including breast cancer, and is associated with the development of resistance to endocrine therapy and tothe anti-HER2 monoclonalantibody trastuzumab.Interest on thePI3K/AKT/mTOR pathwayhasrecently intensiﬁed,not only because PI3K-activatingmutations are found in 36% of human breastcancers(CGANetwork,2012),butalsobasedondata com-ingfrompreclinical studies.Theydemonstratedthe association betweenactivationofthePI3K/AKT/mTORpathwayandendocrine resistance(Clarket al.,2002;Miller etal.,2009), butsensitivity mayberestoredbytreatmentwithmTORinhibitors(deGraffenried etal.,2004).

Inaddition, estrogendeprivationincreases apoptosis follow-ingPI3Kinhibitortreatment,providingarationaleforcombined therapyinHR+disease(Sanchezetal.,2011).

Moreover,inmodelsofestrogen-responsiveBC,subnanomolar everolimusconcentrationsreducedthegrowthofBCcellsinvitro, andenhancedantitumoractivitieswereobservedincombination withtheAI,letrozole(Boulayetal.,2005).

Clinical statement to the value of co-targeting ERand the PI3K/AKT/mTORpathwaycomesfromseveralkeytrials.

IntheBreastCancerTrialsofOralEverolimus-2(BOLERO-2),a randomizedphaseIIIstudyof 724postmenopausalwomen with HR+,HER2-negativemetastaticbreastcancer,progressedon ther-apywithanonsteroidalAI,combinationtherapywithexemestane andthemTORinhibitoreverolimusresultedinasigniﬁcantlylonger PFS(7.8versus3.2months)andhigherresponseratethanthe sin-gleagentexemestane(Baselgaetal.,2012;Piccart-Gebhartetal., 2012).

IntheTamoxifenandRAD001(TAMRAD)study,asmaller ran-domized phase IItrial in a similar patientpopulation, patients receivingthecombinationoftamoxifenandeverolimushadhigher clinicalbeneﬁtrate(61%)andlongerTTP(8.6months) thanthe group receiving tamoxifen alone (42% and 4.5months). In that study,patientswithsecondaryresistancetoAIseemedtobeneﬁt morefromthecombinationthanpatientswithprimaryresistance, supportingtheconceptthatcross-talkbetweenpathwaysandthe sequentialupregulationofthePI3K/mTORsignalingisa mecha-nismofresistance(Bachelotetal.,2012).

Itisworthofnotethatthesebeneﬁtswerenotwithout toxic-ity.Inbothstudiescombinedeverolimus/endocrinetherapyhad

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substantially higherstomatitis (56%),rash(36%to 44%),fatigue (33%to72%),diarrhea(30%to39%),andanorexia(29%to43%)than single-agentendocrinetherapy.

The third study evaluating the combination, the HORIZON trial,foundnobeneﬁtin PFSassociated withtheadditionofthe mTORinhibitor(temsirolimus)toAItherapy(letrozole).Indeed,the trialwasstoppedforfutilitybytheindependentdatamonitoring committee.ResponserateandOSwerealsosimilarbetweengroups (Wolffetal.,2013).

Onekeydifferencebetweenthesestudiesisthatthepatient populationintheHORIZONstudywaslargelyAI-naiveand tem-sirolimus/letrozolewasthefirstendocrinetreatmentformetastatic disease.Bycontrast,patientsinbothBOLERO-2andTAMRADhad AI-resistant disease.In BOLERO-2, 84% of patients had initially endocrine-sensitivediseaseandthenprogressedonanAI,sothis populationwasessentiallycharacterizedbythesamesecondary resistancepopulationthatshowedthegreatestbenefitinTAMRAD. Basedonthesedifferences,itseemsthatthemTORinhibitor benefitmayberestrictedtothosewithacquiredAIresistance.

However, it is worth of note that the combination therapy hasalsomarginallyoutperformedsingle-agentAIinthepreviously untreatedneoadjuvantsetting(Baselgaetal.,2009).

InthisphaseIIrandomizedtrialof270postmenopausalwomen, thosethatwhoreceived4monthsofpreoperativetherapy with letrozoleandeverolimushadaclinicalresponserateof68% com-paredwith59%inthosereceivingletrozolealone,suggestingthat cotargetingboth ER and mTORcircumventsde novo endocrine resistance,oratleastincreaseseffectivenessofinitialER-targeting, insomeuntreatedtumors.

Tumorbiologic differences couldalsoplay a role in the dif-ferentialbeneﬁtseen inthese trials.In this neoadjuvanttrialof everolimusplusAI,Boulayetal.,2005foundthatpatientswhose tumorshadactivatingmutationsinexon9ofPIK3CAshowedstrong antiproliferativeresponse(Ki67)tomTOR/AIcombinationtherapy butpoorresponsetoAIalone.

ThereisasubstantialvariabilityinPIK3CAmutationratesacross molecularsubtypes, with 45% in the luminal A compared with only29%intheluminalBsubsets(Margaritietal.,2011).Neither BOLERO-2northeHORIZONtrialincludedintrinsicsubtypingor othercorrelativebiomarkerdata,and,intheabsenceofbiomarker data,there couldbeunknowncross-trialdifferencesinthe pro-portionoftumors withPTENloss,PI3K activatingmutation,or otherpathwayaberrancy.Retrospectiveanalysisresultspresented byGabrielN. Hortobagyiinthe2013ASCOMeetingsuggest no predictivemarkerofeverolimusefficacy.Everolimusbenefit main-tainedinpatientsregardlessofgenealterationsinPI3KCAandPI3K pathwaygenes(Hortobagyietal.,2013).Thisanalysissuggeststhat PI3KpathwayitselforPI3KCAstatusaloneisnotabiomarkerofthe efficacyofeverolimus.Thisbenefitwasslightlylesspronouncedin patientswithFGFR1/2alterations.Theseobservationssuggestthat alargesubgroupofpatients(76%),definedbyminimalgenetic vari-ationsinthePI3KorFGFRpathways,orCCND1,derivesthemost benefitfromeverolimustherapy(HR=0.27versus0.40forthefull next-generationsequencingpopulation).

These observations appear inconclusive and predictive biomarkers for targeting the PI3K/mTOR pathway are still a workinprogress(JuricandBaselga,2012).

Itis unlikelythat wewillfindasingleapproach that incon-trovertibly reversesendocrine resistanceacrossallpopulations, anddifferentstrategies tocombatendocrine therapy resistance havefailedtoyieldconsistentresults. Forexample,among sev-eraltrialsofepidermalgrowthfactorreceptorinhibitioncombined withendocrinetherapy,somehavedemonstratedPFSbenefitfrom thecombinationinpatientswhohadnotreceivedpriorendocrine therapy(Johnston,2009b)whiletrialsinmoreheavilypretreated patientshavenotconfirmedthisbenefit(OsborneandSchiff,2011).

So, theadditionofmTORinhibitorsresultedpositive in pre-treated HR+ metastatic breast cancer, but no gain with the combinationintheﬁrstlinetreatment.

Aboveall“acquiredresistant”populationhasthemosttogain,as currentPFSwithfurtherendocrinetherapiesafterﬁrstlinesetting rangefrom3–4months,and,properlyinthissetting,combinations withagentsthatovercomeresistancecanimprovetheoutcomesof patients(Baselgaetal.,2012;Piccart-Gebhartetal.,2012).

5. Algorithmformanagementofpost-menopausalHR+ metastaticbreastcancer

While hormone-unresponsive or life-threatening disease requireschemotherapy,nolife-threateningdiseaseHR+metastatic BCpatientsarecandidatetoﬁrstlineendocrinetherapy.

Sitesand extentofdisease,relatedsymptoms,ERlevelsand HER2 status, disease-free and treatment-free intervals, perfor-mance status and patient wishes are key factors in ﬁrst line treatmentchoice(Fig.2).

Todate,anon-steroidalAIisthestandardchoiceforﬁrst-line treatmentin denovo metastaticHR+ breastcancer, in patients whodidnotreceiveprioradjuvant hormonaltherapy, inwhom thatprogressedonadjuvanttamoxifenor>1disease-freeinterval post-adjuvanttamoxifen.Selectedpreviouslyuntreatedmetastatic breastcancerpatientscouldbeneﬁtfromacombinedendocrine therapy withfulvestrantplus AI,aboveallifentirelyendocrine therapy-naive,evenintheadjuvantsetting(Mehtaetal.,2012).

It worth of note that primarily endocrine therapy-naive metastaticBCpatientsarenotatypicalcontemporarymetastatic population. Actually, the great majority of patients with HR+ metastaticBCreceivedendocrinetherapyintheadjuvantsetting. Tamoxifen is the mainstay in the treatmentof premenopausal women. On the other hand in post-menopausal women third-generationAIsresultedsuperior totamoxifen inlargeadjuvant trials.Mainstudiesevaluated5yearsofAIversustamoxifenfor5 years(up-frontstrategy)or2–3yearofAIsafter3–2yearsof tamox-ifen(earlyswitch)(Forbesetal.,2008;Jonatetal.,2006;Coates etal.,2007;vandeVeldeetal.,2011;Coombesetal.,2004).

Beingnon-steroidalAIswidelyusedintheadjuvantsetting,the choiceofdifferentendocrineagentsforﬁrst-lineadvanceddisease hastobeconsidered(Table1).

Sincetheresultsatalong-termfollow-up,fulvestranthastobe consideredavalidtherapeuticoptioninﬁrstlinesetting.

TheFIRSTtrialdemonstratedareductionintheriskof progres-sionanddeathwithfulvestrant500mgversusanastrozole1mg (hazardratio=0.626;P=0.0496)(Robertsonetal.,2010;Robertson, 2014).Again,intheCONFIRMtrialfulvestrant500mgwas demon-stratedtobesuperiortofulvestrant250mgintermsofTTPand OS(DiLeoetal.,2010,2012).Itisworthofnotethatallpatients hadreceivedapreviousendocrinetherapyandthestudyincluded patientsrelapsingduringadjuvanttreatment,witha<or>12month disease free interval post-adjuvant AI therapy, or progressing afterfirstlineendocrinetherapyfor“denovo”advanceddisease. ApproximatelyhalfofthepatientshadreceivedpriorAIandhalf prior tamoxifen. Therefore fulvestrant500mg would appear to haveconvincingdatainthepost-adjuvantAIsettinganditcouldbe recommendedinfirstlinesettingforpatientsthatrelapseon adju-vantendocrineAIeitherafteradisease-freeintervalpost-adjuvant AI.CONFIRMtrialalsosupportstheuseoffulvestrantassecondline treatmentformetastaticHR+patientswhoprogressduringfirstline AItherapy.

TheuseofmTORinhibitorsassociatedwithendocrinetherapy couldbeavalidoptionbutstudiesthatevaluatedthese combina-tionsreportedconﬂictingdata(Wolffetal.,2013;Baselgaetal., 2012; Piccart-Gebhart et al., 2012; Bachelot et al., 2012).These

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In favour of chemotherapy Uncertain In favour of endocrine therapy

Disease-free

interval

On treatment or <1yr 1-2 yrs >2 yrs

Visceral

Metastases

Massive burden (visceral crisis)

Moderate burden

Minimal burden

Symptoms Heavy Moderate Minimal or absent

Fig.2. CurrentCriteriausedtosupportFirstLinetreatmentchoicesinHR+MetastaticBreastCancer.

Table1

TreatmentalgorithmofendocrinetherapyinmetastaticbreastcancerbasedonphaseIIIdata,phaseIIdataortreatmentoptionbutnotsupportedbyrandomized,controlled, data.

Priortreatment Firstline Secondline Thirdline

Denovo/noprioradjuvant endocrinetherapy

AI(anastrozoleor

letrozole)(Nabholtzetal.,2000, 2003;Bonneterreetal.,2000; Mouridsenetal.,2003) or Anastrozole+fulvestranta (Mehtaetal.,2012) Fulvestrant500MG(DiLeo etal.,2010,2012;Robertson etal.,2009,2010;Robertson, 2014) orexemestane+everolimus (Baselgaetal.,2012; Piccart-Gebhartetal.,2012) or AI(anastrozoleor

letrozole)(Buzdaretal.,1997, 1998,2001;Jonatetal.,1996; Dombernowskyetal.,1998) Exemestane+everolimus (Baselgaetal.,2012; Piccart-Gebhartetal.,2012) or AI(AnastrozoleorLetrozole) (Buzdaretal.,1997,1998, 2001;Jonatetal.,1996; Dombernowskyetal.,1998) or Fulvestrant500mg(Robertson etal.,2003,2004) Recurrenceonadjuvant tamoxifenor>1disease-free intervalpost-adjuvant tamoxifen AI(anastrozoleor

letrozole)(Nabholtzetal.,2000, 2003;Bonneterreetal.,2000; Mouridsenetal.,2003) or Fulvestrant500MG(DiLeo etal.,2010,2012) Fulvestrant500MG(DiLeo etal.,2010,2012) orexemestane+everolimus (Baselgaetal.,2012) or AI(anastrozoleorletrozole) (Buzdaretal.,1997,1998, 2001;Jonatetal.,1996; Dombernowskyetal.,1998) AI(AnastrozoleorLetrozoleor Exemestane)(Buzdaretal., 1997,1998,2001;Jonatetal., 1996;Dombernowskyetal., 1998;Kaufmannetal.,2000) or Fulvestrant500mg(Robertson etal.,2003,2004)

Priornon-steroidalAItherapy with>1yeardisease-free intervalpost-adjuvantAI Fulvestrant500MG(DiLeo etal.,2010,2012;Robertson etal.,2010) or Exemestane+everolimus (Baselgaetal.,2012; Piccart-Gebhartetal.,2012) Exemestane+everolimus (Baselgaetal.,2012) or

Fulvestrant(Robertsonetal., 2003;DiLeoetal.,2010,2012)

Tamoxifen or DifferentAI

RecurrenceonadjuvantAI Exemestane+everolimus (Baselgaetal.,2012; Piccart-Gebhartetal.,2012) or Fulvestrant500MG(DiLeo etal.,2010,2012) Fulvestrant500MG(Robertson etal.,2003;DiLeoetal.,2010, 2012) or Exemestane+everolimus (Baselgaetal.,2012; Piccart-Gebhartetal.,2012) Tamoxifen or DifferentAI

Abbreviations:AI,aromataseinhibitor,CT:chemotherapy

a_It_may_be_that_patients_unexposed_to_prior_endocrine_therapy_with_highly_{endocrine-sensitive}_tumors_could_derive_the_largest_beneﬁt_from_the_combination_of_an_AI₊

Fulvestrant.HoweverconsideringthecontradictoryresultsoftheSWOG(50)_and_the_FACT(51)_trials,_it_seems_appropriate_to_wait_for_further_evidence_before_considering_this

combinationas“astandardofcare”.

studies, as previously reported, evaluated patientsin different treatmentsettings,andonekeydifferenceisthatthepatient popu-lationintheHORIZONstudywaslargelyAI-naiveandtheaddition ofthemTORinhibitor(temsirolimus)toAItherapy(letrozole),as ﬁrstlineendocrinetreatmentformetastaticdisease,determined nobeneﬁtinPFS.Indeed,thetrialwasstoppedforfutilitybythe independentdatamonitoringcommittee.Bycontrast,patientsin both BOLERO-2and TAMRADpresented AI-resistantdisease. In BOLERO-2,84%ofpatientshadinitiallyendocrine-sensitivedisease

andthenprogressedonanAI,sothispopulationwasessentially characterizedby thesamesecondary resistancepopulationthat showedthegreatestbeneﬁtinTAMRAD.Aboveall,inthe BOLERO-2trial16%ofpatientsinbotharmshadreceivedfulvestrantbefore exemestane±everolimusandthesepatientsbeneﬁttedfromthe combination. On the other hand no data support the reverse sequence.

Basedonthesedifferences,itseemsthatthebeneﬁtfromthe addition of mTOR inhibitor may be restricted to patients with

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acquiredAIresistance.Moreoverthesebeneﬁtswerenotwithout toxicity.Inbothstudiescombinedeverolimus/endocrinetherapy hadsubstantiallyhigherstomatitis(56%),rash(36%to44%),fatigue (33%to72%),diarrhea(30%to39%),andanorexia(29%to43%)than single-agentendocrinetherapy.

Interestingdatainﬁrstlinesettingderivefromthecombination ofletrozoleplusPD0332991(Finnetal.,2012)(seepar.1.2),but thesedataneedtobeconﬁrmedbytheongoingphaseIIItrial.

Todate,duringﬁrstseverallinesoftreatmentinthemetastatic setting patientscoulddevelopacquired resistancetoendocrine therapy,anditconstitutesanimportantclinicalproblem.Inthis context,different strategiescouldovercometheacquired resis-tance.

It is unlikely that a single approach could incontrovertibly reverse endocrine resistanceacrossall population. So, properly planninganalgorithmthatincludesalltheavailableapproaches allowsthemostusefullong-termstrategy.

6. Maintenanceendocrinetherapy:whichevidence?

The use of endocrine therapy is wellestablished inpatients withhormone-dependent metastatic breast cancer. The role of maintenance endocrine therapy in controlling the regrowth of hormone-dependent clones after maximum cytoreduction with chemotherapyisaninterestingissue,eventhough,inliterature, datafocusedonthisstrategyarerare.Onlyoneprospective ran-domizedstudypublishedbyKlokeetal.in1999isavailable.In thisphase-III trial,90 patientswithadiseasecontrolledafter6 cyclesofanthracyclin- andifosfamide-containingregimenwere randomizedtoreceiveor notmaintenance therapyby medrox-yprogesteroneacetate.AlongermedianTTPwasreportedamong patientswhoweretreatedbymaintenancehormonetherapy(4.9 versus3.7months;p=0.02).Howeverthesmallsamplesize,the inclusionofreceptor-negativepatients,andtheuseofanolder gen-erationendocrinecompoundlimittheinterpretationofthistrial.

Tworetrospectivestudiesfoundhormonalmaintenance ther-apyasasignificantfactoramongseveralprognosticfactorsforPFS andOSafterfirstlinechemotherapy.In1997,Berrutietal., ana-lysedfactorsinfluencingORRandOSamong207patientstreated byepirubicin,followedornotbymaintenancehormonetherapy. Patientswho receivedmaintenanceendocrine therapy survived significantlylongerthanthosesubmittedtoobservation,inboth uni-andmultivariateanalysis.Theauthorconcludedthat“the pos-itiveimpactofmaintenancehormonaltherapyisimpressiveand deservesconfirmationinrandomizedstudies”.

Montemurroetal.,2002studied109consecutivepatientswith ERand/orPgR-positivemetastaticbreastcancer,receiving high-dosechemotherapywithhematopoieticprogenitorcelltransplant (HDCT),whowereprogressionfreeforatleast4monthsafterHDCT withcyclophosphamide,carmustineandthiotepa,andanalysedthe factorswhichimproveitsefﬁcacy.Ofthese,55werenon-randomly submittedtomaintenanceendocrine therapy.Thismaintenance hormonaltherapyappearedtobeasigniﬁcantfactorin multivari-ateanalysis,sincethattreatmentimprovedthePFSfrom19.2to 31.1months(p=0.022).Maintenanceendocrinetherapyretained independentprognosticvalueinthemultivariatemodel consider-ingotherimportantprognosticfactors,likecompleteresponse(CR) toHDCT,diseaseextentandpatternofmetastaticdisease.

Thelargestretrospectivestudy onthis subjectincluded 934 patientstreated formetastaticbreast cancerin4 Frenchcancer centres (Dufresne and Pivot et al., 2008). Hormonal treat-mentadministeredafterresponseorstabilizationwithﬁrst-line chemotherapyseemedrelatedtoabetteroutcomewith7.8–16.3 monthsforthedurationofPFS(p<0.0001)andfrom30to48.1 monthsfortheoveralldurationofmetastaticsurvival(p<0.0001).

Maintenancehormonaltherapywasgivenaloneafter chemother-apyin308patients.Hormonaltreatmentsincludedtamoxifen(94), aromataseinhibitors(153),fulvestrant(47)andmegesterolacetate (14). The median duration of first line chemotherapy was 4.4 months(ranges:3–9.7).Eventheinfluenceofthetypeofresponse achievedbyfirstlinechemotherapyiswellestablished(Greenberg etal.,1996),strikingly,thisstudydemonstratedthatthisbenefit wasobservedindependentlyofthetypeofresponseachievedby firstlinechemotherapy.Thechoiceofpatient/tumorcharacteristics forwhowouldorwouldnotreceivethemaintenancehormonal therapywasnotrandom,orcontrolledinanyway,andthismay haveledtoaselectionofbetterprognosispatients.

Neverthelessthemajorimpactobtainedbymaintenance hor-monaltreatmentaftertheﬁrstlinechemotherapymightindicate thatthisstrategyshouldberecommendedinpatientswithanER orPgRpositivetumors.

Based onthe amplitude of the beneﬁt observed, it may be ethically debatabletoconducta prospectiverandomized study. Moreover,randomizedtrials which assessthe beneﬁtof a new chemotherapyregimenshouldallowthepossibilitytogive main-tenancehormonaltreatment.

Inconclusionnocompellingevidenceexistsformaintenance endocrinetherapy.However,givenitslowtoxicity,maintenance endocrine therapy appears a reasonable option in endocrine responsivetumorsrespondingtochemotherapy.

7. Conclusions

Todate,endocrinetherapyisthemainstayofhormone respon-sivebreastcancertreatment.Itisbasedondifferentapproaches anditdoesnotappearthesequenceofhormonalagentsusedalters overallsurvival.Alsoitswidelyrecognizedroleincontrollingthe regrowthofhormone-sensitiveclonesaftermaximum cytoreduc-tionwithchemotherapyisaninterestingissue,eventhough,in literature,datafocusedonthisstrategyarerare.Itisworthofnote thatsomepatients,despiteHR+status,couldbeeitherprimarily resistanttohormonetherapiesorwilldevelophormoneresistance duringthecourseoftheirdisease.Therecentavailability ofthe combination ofeverolimus andexemestane isa signiﬁcantand importantadvanceinpatientswithacquiredendocrineresistance butweneedtobetterpredictandmanagetoxicities.

Authors’disclosuresofpotentialconﬂictsofinterest

Thefollowingauthor(s)indicatedafinancialorotherinterest thatisrelevanttothesubjectmatterunderconsiderationinthis article.EmploymentorLeadershipPosition:None.SaverioCinieri: partecipationinspeakers’bureauyes.AngeloDiLeo:GrantSupport fromAstraZeneca,Pfizer;HonorariafromAstraZeneca,Novartis, Roche,Pfizer,Eisai,GenomicHealth;AdvisoryboardsAstraZeneca, Novartis,Roche,Pfizer,Bayer,Lilly.MichelinoDeLaurentiis: Hon-orariafromAstraZeneca,Novartis,TakedaIpsen.PaoloMarchetti: Grant SupportfromAstraZeneca,Novartis,Roche,Bristol Myers Squibb,GlaxoSmithKline.OtherRemuneration:None.

Otherauthorsdeclarethatthereisnoconﬂictofinterestthat couldbeperceivedasprejudicingtheimpartialityoftheresearch reported.

Authorcontributions

Manuscriptwriting:Allauthors.

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Funding

Nofunds were requested fromany pharmaceuticalﬁrms or otherindustries/institutions.ValentinaSiniwasﬁnancedthrough the PhD University Grant program “Clinical and Experimental ResearchMethodologiesinOncology”providedbytheFacultyof MedicineandPsychology,“Sapienza”UniversityofRome. Acknowledgement

ValentinaSiniwasﬁnancedthroughthePhDUniversityGrant program “Clinicaland Experimental Research Methodologies in Oncology”providedbytheFacultyofMedicineand Psychology, “Sapienza”UniversityofRome.

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