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OfficialreprintfromUpToDate www.uptodate.com2015UpToDate

AuthorsAlphonseTaghian,MD,PhDMoatazNElGhamry,MDSofiaDMerajver,MD,PhD

SectionEditorDanielFHayes,MD

DeputyEditorDonSDizon,MD,FACP

Overviewofthetreatmentofnewlydiagnosed,nonmetastaticbreastcancer

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.Literaturereviewcurrentthrough:Apr2015.|Thistopiclastupdated:Aug25,2014.

INTRODUCTIONGlobally,breastcanceristhemostfrequentlydiagnosedcancerandtheleadingcauseofcancerdeathinwomen.IntheUnitedStates,breastcanceristhemostcommonlydiagnosedcancerandthesecondmostcommoncauseofcancerdeathinwomen.Inaddition,breastcanceristheleadingcauseofdeathinwomenages40to49years.

Breastcanceristreatedwithamultidisciplinaryapproachinvolvingsurgicaloncology,radiationoncology,andmedicaloncology,whichhasbeenassociatedwithareductioninbreastcancermortality[1].

Thistopicwillprovideanoverviewoftheinitialtreatmentofbreastcancerandposttreatmentsurveillance.Theepidemiology,clinicalmanifestations,diagnosis,stagingofbreastcancer,andspecificdiscussionsofthemultimodalitytreatmentsforearlybreastcancerandtheapproachtometastaticdiseasearediscussedelsewhere.(See"Clinicalfeatures,diagnosis,andstagingofnewlydiagnosedbreastcancer"and"Systemictreatmentformetastaticbreastcancer:Generalprinciples"and"Metastaticbreastcancer:Localtreatment".)

Becauseductalcarcinomainsitu(DCIS)andinvasivebreastcanceraremanageddifferently,wewillrestrictdiscussioninthistopictoinvasivebreastcancer.AdiscussiononDCISiscoveredseparately.(See"Breastductalcarcinomainsitu:Epidemiology,clinicalmanifestations,anddiagnosis"and"Ductalcarcinomainsitu:Treatmentandprognosis".)

PATIENTSTRATIFICATIONThevastmajorityofpatientswithnewlydiagnosedbreastcancerintheUnitedStatesanddevelopedcountrieshavenoevidenceofmetastaticdisease.Forthesepatients,thetreatmentapproachdependsonthestageatpresentation.Fortreatmentpurposes,breastcancerischaracterizedusingtheTumor,Node,Metastasessystem(TNM)(table1):

Approximately5percentofpatientswillhavesimultaneousmetastaticdiseaseidentifiedattheinitialpresentation(denovostageIVbreastcancer).Thetreatmentapproachtothesepatientsisdiscussedseparately.(See"RoleofbreastsurgeryforstageIVbreastcancer"and"Systemictreatmentformetastaticbreastcancer:Generalprinciples".)

EARLYSTAGEBREASTCANCERIngeneral,patientswithearlystagebreastcancerundergoprimarysurgery(lumpectomyormastectomy)tothebreastandregionalnodeswithorwithoutradiationtherapy(RT).Followingdefinitivelocaltreatment,adjuvantsystemictherapymaybeofferedbasedonprimarytumorcharacteristics,suchastumorsize,grade,numberofinvolvedlymphnodes,thestatusofestrogen(ER)andprogesterone(PR)receptors,andexpressionofthehumanepidermalgrowthfactor2(HER2)receptor.

BreastconservingtherapyBreastconservingtherapy(BCT)iscomprisedofbreastconservingsurgery(BCS,ie,lumpectomy)plusradiationtherapy(RT).ThegoalsofBCTaretoprovidethesurvivalequivalentofmastectomy,acosmeticallyacceptablebreast,andalowrateofrecurrenceinthetreatedbreast.BCTallows

EarlystageThisincludespatientswithclinicalstageI,IIA,orasubsetofstageIIBdisease(T2N1).

LocallyadvancedThisincludesasubsetofpatientswithclinicalstageIIBdisease(T3N0)andpatientswithstageIIIAtoIIICdisease.

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patientswithinvasivebreastcancertopreservetheirbreastwithoutsacrificingoncologicoutcome.SuccessfulBCTrequirescompletesurgicalremovalofthetumor(withnegativesurgicalmargins)followedbymoderatedoseRTtoeradicateanyresidualdisease.(See"Breastconservingtherapy".)

CriteriathatprecludeBCTinclude(see"Breastconservingtherapy",sectionon'PatientselectionforBCT'):

ForpatientswhodesireBCTbutarenotcandidatesatthetimeofpresentation,analternativeapproachistheuseofneoadjuvanttherapy,whichmayallowforBCSwithoutcompromisingsurvivaloutcomes.(See'Neoadjuvantsystemictherapy'below.)

MastectomyAmastectomyisindicatedforpatientswhoarenotcandidatesforBCTandthosewhoprefermastectomy.(See"Mastectomy:Indications,types,andconcurrentaxillarylymphnodemanagement",sectionon'Selectioncriteriaformastectomy'.)

RoleofRTPostmastectomyRTisindicatedforpatientsathighriskforlocalrecurrence,suchasthosewithcancerinvolvingthedeepmarginsandpathologicallyinvolvedaxillarylymphnodes.IfthelikelihoodofpostmastectomyRTishighpreoperatively,thismayaffectthechoiceofmastectomytype,thechoiceofthereconstructiveapproach,andoptimaltimingofthebreastreconstruction(immediateversusdelayed).BasedupontheEarlyBreastCancerTrialistsCollaborativeGroupmetaanalysisof3786womenwithinvasivebreastcancerundergoinganaxillarydissectionandmastectomy,therewasareductioninrecurrencesfornodepositivewomen([n=1314,onetothreenodespositive]and[n=1772,fourormorenodespositive])undergoingpostmastectomyradiation,butnotfornodenegativewomen[2].

Thus,preoperativecoordinationofcareassuresthebestoutcome.Inmanycenters,thisisaccomplishedbymultidisciplinarybreastclinics.(See"Adjuvantradiationtherapyforwomenwithnewlydiagnosed,nonmetastaticbreastcancer",sectionon'Patientstreatedwithmastectomy'.)

EvaluationoftheaxillarynodesTheriskformetastasestotheaxillarynodesisrelatedtotumorsizeandlocation,histologicgrade,andthepresenceoflymphaticinvasionwithintheprimarytumor.Althoughinternalmammaryorsupraclavicularnodesmaybeinvolvedattheinitialpresentation,theyrarelyoccurintheabsenceofaxillarynodeinvolvement.(See"Managementoftheregionallymphnodesinbreastcancer",sectionon'Internalmammarylymphnodes'and"Managementoftheregionallymphnodesinbreastcancer",sectionon'Supraclavicularlymphnodes'.)

Theevaluationoftheregionalnodesdependsonwhetheraxillaryinvolvementissuspectedpriortosurgery:

Forpatientspresentingwithclinicallysuspiciousaxillarylymphnodes,apreoperativeworkupincludingultrasoundplusfineneedleaspiration(FNA)orcorebiopsycanhelptodeterminethebestsurgicalapproach.

MulticentricdiseaseLargetumorsizeinrelationtobreastPresenceofdiffusemalignantappearingcalcificationsonimaging(ie,mammogramormagneticresonanceimaging[MRI])

PriorhistoryofchestRT(eg,mantleradiationforHodgkindisease)PregnancyPersistentlypositivemarginsdespiteattemptsatreexcision

Forpatientswithapositivebiopsy,anaxillarynodedissectionshouldbeperformedatthetimeofbreastsurgery.(See"Techniqueofaxillarylymphnodedissection".)

Forpatientspresentingwithanegativebiopsy,nofurtherworkupisrequiredpriortosurgery.Thesepatientsshouldundergoasentinellymphnodebiopsy(SLNB)atthetimeofsurgery.(See"Diagnosis,stagingandtheroleofsentinellymphnodebiopsyinthenodalevaluationofbreastcancer"and"Sentinellymphnodebiopsyinbreastcancer:Techniques".)

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AdjuvanttherapySystemictherapyreferstothemedicaltreatmentofbreastcancerusingendocrinetherapy,chemotherapy,and/orbiologictherapy.(See"Adjuvantchemotherapyforhormonereceptorpositiveornegative,HER2negativebreastcancer"and"AdjuvantmedicaltherapyforHER2positivebreastcancer"and"Adjuvantendocrinetherapyfornonmetastatic,hormonereceptorpositivebreastcancer".)

Tumorcharacteristicspredictwhichpatientsarelikelytobenefitfromspecifictypesoftherapy.Forexample,hormonereceptorpositivepatientsbenefitfromtheuseofendocrinetherapy.Inaddition,patientswithhumanepidermalgrowthfactorreceptor2(HER2)positivecancersbenefitfromtreatmentusingHER2directedtreatment.(See"Prognosticandpredictivefactorsinearly,nonmetastaticbreastcancer".)

Forpatientswithearlystagebreastcancer,treatmentisbasedontumorcharacteristics,patientstatus,andpatientpreferences:

LOCALLYADVANCEDBREASTCANCERLocallyadvancedbreastcancerisbestmanagedwithmultimodalitytherapyemployingsystemicandlocoregionaltherapy.(See'Patientstratification'above.)

NeoadjuvantsystemictherapyMostpatientswithlocallyadvancedbreastcancershouldreceiveneoadjuvantsystemictherapy.Thegoaloftreatmentistoinduceatumorresponsebeforesurgeryandenablebreast

PatientswithaclinicallynegativeaxillaryexaminationshouldundergoaSLNBatthetimeofsurgery.FurtherevaluationoftheregionalnodesdependsonthefindingsatSLNB.

Patientswhohavelessthanthreepathologicallyinvolvedsentinelnodesmaynotrequireacompleteaxillarynodedissection[3].However,whetherornotpatientswiththreeormorepathologicallyinvolvedsentinelnodesshouldundergoanaxillarynodedissectionisbestdeterminedonanindividualizedbasis,takingintoaccountallothertumorriskfactorsandthepatientsperformancestatusandcomorbidities.(See"Diagnosis,stagingandtheroleofsentinellymphnodebiopsyinthenodalevaluationofbreastcancer".)

Patientswithhormonereceptorpositivebreastcancershouldreceiveendocrinetherapy.Whethertheyalsoshouldreceiveadjuvantchemotherapydependsonpatientandtumorcharacteristics.(See"Adjuvantendocrinetherapyfornonmetastatic,hormonereceptorpositivebreastcancer"and"Adjuvantchemotherapyforhormonereceptorpositiveornegative,HER2negativebreastcancer",sectionon'Indicationsfortreatment'.)

Weofferchemotherapytopatientswithearlystagehormonereceptorpositivecancersthathavehighriskcharacteristics,suchashighgradetumor,largetumorsize(2cm),pathologicallyinvolvedlymphnodes,and/orhigh21generecurrencescore(31).

Intheabsenceofhighriskfeatures,weprefernottoadministerchemotherapy.

ForpatientswithER/PRandHER2negativedisease(triplenegativebreastcancer),weprefertoadministeradjuvantchemotherapyifthetumorsizeis0.5cm.BecausethesepatientsarenotcandidatesforendocrinetherapyortreatmentwithHER2directedagents,chemotherapyistheironlyoptionforadjuvanttreatment,followingorbeforeradiotherapy.Patientswithatriplenegativebreastcancer1cmshouldreceiveacombinationofchemotherapyplusHER2directedtherapy.Themanagementofsmall(1cm)HER2positivebreastcancersiscontroversial.(See"AdjuvantmedicaltherapyforHER2positivebreastcancer",sectionon'Patienteligibility'.)

Followingchemotherapy,patientswithERpositivediseaseshouldalsoreceiveadjuvantendocrinetherapy.(See"AdjuvantmedicaltherapyforHER2positivebreastcancer"and"Adjuvantendocrinetherapyfornonmetastatic,hormonereceptorpositivebreastcancer",sectionon'PatientswithHER2positivetumors'.)

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conservation.

Neoadjuvanttherapyresultsinlongtermdistantdiseasefreesurvivalandoverallsurvival(OS)comparabletothatachievedwithprimarysurgeryfollowedbyadjuvantsystemictherapy.(See"Neoadjuvanttherapyforbreastcancer:Rationale,pretreatmentevaluation,andtherapeuticoptions",sectionon'Patientselection'.)

Ourapproachtotheselectionoftreatmentintheneoadjuvantsettingisoutlinedbelow:

SurgicalapproachafterneoadjuvanttreatmentAllpatientsshouldundergosurgeryfollowingneoadjuvantsystemictherapy,eveniftheyhaveacompleteclinicaland/orradiologicalresponse.Inaddition,patientswhoexperienceprogressionwhileonneoadjuvantsystemictherapyshouldproceedwithsurgery,ratherthanswitchingthechemotherapyregimen.(See"Neoadjuvantsystemictherapyforbreastcancer:Response,subsequenttreatment,andprognosis",sectionon'Definitivesurgicaltreatment'.)

PrimarytumorThechoicebetweenbreastconservationandmastectomyafterneoadjuvanttreatmentisdependentonthetreatmentresponseandpatientcharacteristics(eg,breastsizeinrelationtoresidualtumorsize).Similarcriteriausedinthetreatmentofearlystagebreastcancerareapplied.However,patientswhopresentwithalarge(ie,T4)breastlesionshouldundergoamastectomyfollowingneoadjuvanttreatment.(See'Breastconservingtherapy'aboveand'Mastectomy'above.)

RegionalnodesAllpatientsrequireasurgicalevaluationoftheregionalnodesfollowingneoadjuvanttreatment.(See'Evaluationoftheaxillarynodes'aboveand"Neoadjuvantsystemictherapyforbreastcancer:Response,subsequenttreatment,andprognosis",sectionon'Nodalevaluation'.)

PrimarysurgeryAlthoughsomepatientsmaybecandidatesforprimarysurgeryatpresentation,patientswithlocallyadvanceddiseasehaveanextremelyhighriskoflocalrecurrenceanddistantmetastases[4].Asaresult,weprefertotreatpatientswithlocallyadvancedbreastcancerwithneoadjuvantsystemictherapyfirst.

Forpatientswhoproceedwithprimarysurgery,basedonpathologicalresults,postoperativeradiationtherapy(RT)andadjuvanttreatmentshouldbeadministered.(See"Radiationtherapytechniquesfornewlydiagnosed,nonmetastaticbreastcancer"and'Adjuvanttherapy'below.)

AdjuvanttherapyTheuseofpostoperative(adjuvant)systemictherapyisguidedbythepatientsclinicalstatusandtumorcharacteristics:

Formostpatientswithhormonereceptorpositivedisease,werecommendchemotherapyintheneoadjuvantsettingratherthanendocrinetherapy.Chemotherapyisassociatedwithhigherresponseratesinashortertimeperiod.(See"Neoadjuvanttherapyforbreastcancer:Rationale,pretreatmentevaluation,andtherapeuticoptions",sectionon'Patientselection'.)

Forpatientswithhumanepidermalgrowthfactorreceptor2(HER2)positivebreastcancer,aHER2directedagent(eg,trastuzumabwithorwithoutpertuzumab)shouldbeaddedtothechemotherapyregimen.(See"Neoadjuvanttherapyforbreastcancer:Rationale,pretreatmentevaluation,andtherapeuticoptions",sectionon'HER2directedtherapy'.)

Werestrictendocrinetherapyintheneoadjuvantsettingtothetreatmentofpostmenopausalpatientswithhormonereceptorpositivediseasewhoarenotsurgicalcandidates(regardlessoftumorsize)witharelativeorabsolutecontraindicationtochemotherapy(ie,significantmedicalcomorbidities,advancedage,orpoorperformancestatus).(See"Neoadjuvanttherapyforbreastcancer:Rationale,pretreatmentevaluation,andtherapeuticoptions",sectionon'Endocrinetherapy'and"Neoadjuvanttherapyforbreastcancer:Rationale,pretreatmentevaluation,andtherapeuticoptions",sectionon'Patientselection'.)

Patientswhodidnotreceiveneoadjuvantsystemictherapyshouldreceiveadjuvanttreatment.Theuseofchemotherapy,biologictherapy,and/orendocrinetherapyisguidedbythesameprinciplesusedtodeterminetreatmentforearlystagebreastcancer.(See'Adjuvanttherapy'above.)

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Patientstreatedwithneoadjuvantendocrinetherapywhoundergosurgeryshouldcontinueendocrinetherapyintheadjuvantsetting.Whetherornottoadministeradjuvantchemotherapyshouldbeindividualized.(See"Neoadjuvanttherapyforbreastcancer:Rationale,pretreatmentevaluation,andtherapeuticoptions",sectionon'Objectives'.)

SPECIALCONSIDERATIONS

FertilitypreservationCliniciansshoulddiscusswithpatientstheriskofinfertilityandpossibleinterventionstopreservefertilitypriortoinitiatingpotentiallygonadotoxictherapy.Thisdiscussionshouldoccursoonafterdiagnosis,sincesomeinterventionstopreservefertilitytaketimeandcoulddelaythestartoftreatment.ThisisconsistentwithguidancefromtheAmericanSocietyofClinicalOncology[5].Thetopicoffertilitypreservationiscoveredindetailseparately.(See"Fertilitypreservationinpatientsundergoinggonadotoxictreatmentorgonadalresection".)

OlderwomenForsomepatientswithestrogenreceptor(ER)positivebreastcancer,inwhomsurgeryisnotanoptionorlifeexpectancyislimited,primaryhormonaltreatmentwitheithertamoxifenoranaromataseinhibitorwithoutsurgeryorradiationtherapy(RT)canbeused[6].Weprefertoindividualizetreatmentbasedonthepresenceofmedicalcomorbiditiesandpatientandclinicianpreference.(See"Generalprinciplesonthetreatmentofearlystageandlocallyadvancedbreastcancerinolderwomen",sectionon'Surgeryversusprimaryendocrinetherapyinwomenwithhormonereceptorpositivedisease'.)

MalebreastcancerThetopicofmalebreastcancerisdiscussedseparately.(See"Breastcancerinmen".)

BreastcancerinpregnancyThetreatmentofbreastcancerinpregnancyisdiscussedseparately.(See"Gestationalbreastcancer:Treatment".)

PROGNOSISThemajorityofbreastcancerrecurrencesoccurwithinthefirstfiveyearsofdiagnosis,particularlywithhormonereceptornegativedisease.However,somerecurrencesoccurmuchlater.InonestudyofpatientswithstageI,II,orIIIbreastcancerwhowerewithoutevidenceofdiseasefiveyearsoutfromtheoriginaldiagnosis,therecurrencerisksinthesubsequentfiveandtenyearswerestill11and19percent,respectively[7].(See"Patternsofrelapseandlongtermcomplicationsoftherapyinbreastcancersurvivors",sectionon'Relapse

Forpatientswhoreceivedthefullcourseofplannedneoadjuvantchemotherapy(see"Neoadjuvantsystemictherapyforbreastcancer:Response,subsequenttreatment,andprognosis",sectionon'Chemotherapy'):

Patientswithhormonereceptorpositivebreastcancershouldreceiveendocrinetherapytoreducetheriskofbreastcancerrecurrenceandbreastcancerrelatedmortality.ThereisnoevidencethattheadditionoffurtherchemotherapyintheformofadjuvanttreatmentimprovesOS.Theselectionofendocrinetherapyismadeaccordingtomenopausalstatus.(See"Neoadjuvantsystemictherapyforbreastcancer:Response,subsequenttreatment,andprognosis",sectionon'Endocrinetherapy'.)

Patientswithhormonereceptornegativebreastcancerwouldtypicallynotreceivefurtherchemotherapyintheadjuvantsetting,asthereisnoevidencethattheadditionofadjuvantchemotherapyimprovesOS.Thesepatientsshouldbeginposttreatmentsurveillance.(See"Approachtothepatientfollowingtreatmentforbreastcancer",sectionon'Guidelinesforposttreatmentfollowup'.)

Insomeexceptionalcaseswherethetumorprogressedduringneoadjuvanttherapyorifthecompleteneoadjuvanttherapycouldnotbedeliveredatthenormallevelsofintensity,adjuvantchemotherapyshouldbediscussedandconsidered.

PatientswithHER2positivebreastcancershouldreceiveoneyearoftrastuzumabfollowingcompletionofsurgerywithouttheadditionoffurtherchemotherapy.ThisrecommendationisbasedonstudiesofadjuvantchemotherapywithorwithouttrastuzumabthatdemonstratedthattheadditionofoneyearoftrastuzumabsignificantlyimprovesdiseasefreesurvivalandOS.(See"Neoadjuvantsystemictherapyforbreastcancer:Response,subsequenttreatment,andprognosis",sectionon'HER2directedtreatment'.)

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patterns'.)

Patientswithearlystagebreastcancerhaveabetterprognosisthanthosepatientsdiagnosedwithlocallyadvanceddisease.AccordingtoTumor,Nodes,Metastases(TNM)stage,fiveyearrelativesurvivalratesbystageforpatientspresentingwithstageI,IIA,IIB,IIIA,IIIB,andIVdiseasewere95,85,70,52,48,and18percent,respectively[8].Bothyounger(age

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SUMMARY

PatientstratificationPatientswithanewdiagnosisofbreastcancercanbestratifiedbytheirextentofdisease(see'Patientstratification'above):

Earlystagebreastcancer

PatientswithclinicalstageI,IIA,orasubsetofstageIIBdisease(T2N1)areclassifiedashavingearlystagebreastcancer.

PatientswithaT3tumorwithoutnodalinvolvement(T3N0,asubsetofpatientswithclinicalstageIIBdisease)andthosewhopresentwithstageIIIAtoIIICdiseaseareclassifiedashavinglocallyadvancedbreastcancer.

Approximately5percentofpatientswillpresentwithdistantmetastases(stageIV)atdiagnosis.

Thesurgicalapproachtotheprimarytumordependsonthesizeofthetumor,whetherornotmultifocaldiseaseispresent,andthesizeofthebreast.Theoptionsincludebreastconservingtherapy(breastconservingsurgeryplusradiationtherapy[RT])ormastectomy(withorwithoutRT).Bothapproachesresultinequivalentcancerspecificoutcomes.(See'Earlystagebreastcancer'aboveand"Breastconservingtherapy"and"Mastectomy:Indications,types,andconcurrentaxillarylymphnodemanagement".)

Theriskformetastaticdiseaseintheregionalnodesisrelatedtotumorsize,histologicgrade,andthepresenceoflymphaticinvasionwithintheprimarytumor.Althoughinternalmammaryorsupraclavicularnodesmayalsobeinvolvedattheinitialpresentation,theyrarelyoccurintheabsenceofaxillarynodeinvolvement.Thesurgicalapproachtotheregionalnodesdependsontheclinicalstatusoftheaxilla(see'Evaluationoftheaxillarynodes'above):

Forpatientspresentingwithclinicallysuspiciousaxillarynodes,apreoperativeworkupincludingultrasoundpluslymphnodebiopsycanhelptodeterminethebestsurgicalapproach.Ifthelymphnodebiopsyispositive,anaxillarynodedissectionshouldbeperformed.Ifthelymphnodebiopsyisnegative,asentinellymphnodebiopsy(SLNB)atthetimeofsurgeryshouldbeperformed.(See"Managementoftheregionallymphnodesinbreastcancer",sectionon'Axillaryultrasound'and"Managementoftheregionallymphnodesinbreastcancer",sectionon'Axillarydissection'and"Managementoftheregionallymphnodesinbreastcancer",sectionon'Sentinellymphnodebiopsy'.)

Patientswhopresentwithaclinicallynegativeaxilladonotrequireapreoperativeworkup.ThesepatientsshouldundergoanSLNBatthetimeofdefinitivebreastsurgery.Patientswhohave

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Locallyadvancedbreastcancer

adjuvantchemotherapyifthetumorsizeis>0.5cm.(See"Epidemiology,riskfactorsandtheclinicalapproachtoER/PRnegative,HER2negative(Triplenegative)breastcancer"and"Adjuvantchemotherapyforhormonereceptorpositiveornegative,HER2negativebreastcancer".)

PatientswithHER2positivebreastcancer>1cminsizeshouldreceiveacombinationofchemotherapyplusHER2directedtherapy.Followingchemotherapy,patientswithERpositivediseaseshouldalsoreceiveadjuvantendocrinetherapy.(See"AdjuvantmedicaltherapyforHER2positivebreastcancer"and"Adjuvantendocrinetherapyfornonmetastatic,hormonereceptorpositivebreastcancer",sectionon'PatientswithHER2positivetumors'.)

Mostpatientswithlocallyadvanced,inoperablebreastcancershouldreceiveneoadjuvantsystemictherapyratherthanproceedingwithprimarysurgery.Thesepatientsareusuallynotcandidatesforbreastconservationattheirinitialpresentation.Neoadjuvanttreatmentimprovestherateofbreastconservationwithoutcompromisingsurvivaloutcomes.(See'Neoadjuvantsystemictherapy'above.)

Formostpatients,werecommendchemotherapyintheneoadjuvantsettingratherthanendocrinetherapy.Chemotherapyisassociatedwithhigherresponseratesinafastertimeframe.AHER2directedagent(ie,trastuzumab)shouldbeaddedtothechemotherapyregimenfortumorsthatareHER2positive.(See"Neoadjuvanttherapyforbreastcancer:Rationale,pretreatmentevaluation,andtherapeuticoptions",sectionon'Eligibilityforprimarysurgery'.)

Werestrictendocrinetherapyintheneoadjuvantsettingtothetreatmentofpostmenopausalpatientswhoarenotsurgicalcandidatesatthetimeofpresentationandhavearelativeorabsolutecontraindicationtochemotherapy(ie,significantmedicalcomorbidities,advancedage,orpoorperformancestatus).(See"Neoadjuvanttherapyforbreastcancer:Rationale,pretreatmentevaluation,andtherapeuticoptions",sectionon'Endocrinetherapy'and"Neoadjuvanttherapyforbreastcancer:Rationale,pretreatmentevaluation,andtherapeuticoptions",sectionon'Eligibilityforprimarysurgery'.)

Followingsurgery(withorwithoutneoadjuvantsystemictherapy),allpatientswhoundergobreastconservingsurgeryshouldundergoadjuvantRTtomaximizelocoregionalcontrol.(See"Adjuvantradiationtherapyforwomenwithnewlydiagnosed,nonmetastaticbreastcancer".)

SomepatientstreatedbyamastectomyshouldreceivepostmastectomyRT.TheadministrationofadjuvantRTshouldbebasedupontheoriginalpretreatmentstage,regardlessofthepathologicresponsetoneoadjuvanttherapy.(See"Neoadjuvantsystemictherapyforbreastcancer:Response,subsequenttreatment,andprognosis"and"Adjuvantradiationtherapyforwomenwithnewlydiagnosed,nonmetastaticbreastcancer".)

Theuseofchemotherapy,biologictherapy,and/orendocrinetherapyisguidedbythesameprinciplesusedtodeterminetreatmentforearlystagebreastcancer.(See'Adjuvanttherapy'above.)

Forpatientswhoreceivedneoadjuvantchemotherapy:

Patientswithhormonereceptorpositivebreastcancershouldreceiveadjuvantendocrinetherapy.Theselectionofendocrinetherapyismadeaccordingtomenopausalstatus.(See"Neoadjuvantsystemictherapyforbreastcancer:Response,subsequenttreatment,andprognosis",sectionon'Endocrinetherapy'.)

Patientswithhormonereceptornegativebreastcancershouldnotreceivefurthertreatmentprovidedtheycompletedtheplannedneoadjuvantchemotherapyregimen.Thesepatientsshouldbeginposttreatmentsurveillance.(See"Approachtothepatientfollowingtreatmentforbreastcancer",sectionon'Guidelinesforposttreatmentfollowup'.)

Patientswithhormonereceptornegativebreastcancerwhodidnotcompleteplannedneoadjuvant

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treatmentpriortosurgeryarecandidatesforfurtherchemotherapyinthepostoperative(oradjuvant)setting.

PatientswithHER2positivebreastcancershouldreceiveoneyearoftrastuzumabfollowingcompletionofsurgery.(See"Neoadjuvantsystemictherapyforbreastcancer:Response,subsequenttreatment,andprognosis",sectionon'HER2directedtreatment'.)

Patientstreatedwithneoadjuvantendocrinetherapywhoundergosurgeryshouldcontinueendocrinetherapyintheadjuvantsetting.Whetherornottoadministeradjuvantchemotherapyshouldbeindividualized.(See"Neoadjuvanttherapyforbreastcancer:Rationale,pretreatmentevaluation,andtherapeuticoptions",sectionon'Endocrinetherapy'and"Neoadjuvanttherapyforbreastcancer:Rationale,pretreatmentevaluation,andtherapeuticoptions",sectionon'Eligibilityforprimarysurgery'.)

ForsomepatientswithERpositivebreastcancer,inwhomsurgeryisnotanoptionorlifeexpectancyislimited,primaryhormonaltreatmentwitheithertamoxifenoranaromataseinhibitorwithoutsurgerycanbeused.(See'Olderwomen'aboveand"Generalprinciplesonthetreatmentofearlystageandlocallyadvancedbreastcancerinolderwomen",sectionon'Surgeryversusprimaryendocrinetherapyinwomenwithhormonereceptorpositivedisease'.)

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14. SwainSM,JeongJH,GeyerCEJr,etal.Longertherapy,iatrogenicamenorrhea,andsurvivalinearlybreastcancer.NEnglJMed2010362:2053.

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GRAPHICS

Tumornodemetastases(TNM)stagingsystemforcarcinomaofthebreast

Primarytumor(T)*TX Primarytumorcannotbeassessed

T0 Noevidenceofprimarytumor

Tis Carcinomainsitu

Tis(DCIS) Ductalcarcinomainsitu

Tis(LCIS) Lobularcarcinomainsitu

Tis(Paget's) Paget'sdisease(Pagetdisease)ofthenippleNOTassociatedwithinvasivecarcinomaand/orcarcinomainsitu(DCISand/orLCIS)intheunderlyingbreastparenchyma.CarcinomasinthebreastparenchymaassociatedwithPaget'sdiseasearecategorizedbasedonthesizeandcharacteristicsoftheparenchymaldisease,althoughthepresenceofPaget'sdiseaseshouldstillbenoted.

T1 Tumor20mmingreatestdimension

T1mi Tumor1mmingreatestdimension

T1a Tumor>1mmbut5mmingreatestdimension

T1b Tumor>5mmbut10mmingreatestdimension

T1c Tumor>10mmbut20mmingreatestdimension

T2 Tumor>20mmbut50mmingreatestdimension

T3 Tumor>50mmingreatestdimension

T4 Tumorofanysizewithdirectextensiontothechestwalland/ortotheskin(ulcerationorskinnodules)

T4a Extensiontothechestwall,notincludingonlypectoralismuscleadherence/invasion

T4b Ulcerationand/oripsilateralsatellitenodulesand/oredema(includingpeaud'orange)oftheskin,whichdonotmeetthecriteriaforinflammatorycarcinoma

T4c BothT4aandT4b

T4d Inflammatorycarcinoma

PosttreatmentypT.Theuseofneoadjuvanttherapydoesnotchangetheclinical(pretreatment)stage.Clinical(pretreatment)Twillbedefinedbyclinicalandradiographicfindings,whileypathologic(posttreatment)Twillbedeterminedbypathologicsizeandextension.TheypTwillbemeasuredasthelargestsinglefocusofinvasivetumor,withthemodifier"m"indicatingmultiplefoci.Themeasurementofthelargesttumorfocusshouldnotincludeareasoffibrosiswithinthetumorbed.

Regionallymphnodes(N)

Clinical

NX Regionallymphnodescannotbeassessed(eg,previouslyremoved)

N0 Noregionallymphnodemetastases

N1 MetastasestomovableipsilaterallevelI,IIaxillarylymphnode(s)

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N2 MetastasesinipsilaterallevelI,IIaxillarylymphnodesthatareclinicallyfixedormattedorinclinicallydetectedipsilateralinternalmammarynodesintheabsenceofclinicallyevidentaxillarylymphnodemetastases

N2a MetastasesinipsilaterallevelI,IIaxillarylymphnodesfixedtooneanother(matted)ortootherstructures

N2b MetastasesonlyinclinicallydetectedipsilateralinternalmammarynodesandintheabsenceofclinicallyevidentlevelI,IIaxillarylymphnodemetastases

N3 Metastasesinipsilateralinfraclavicular(levelIIIaxillary)lymphnode(s)withorwithoutlevelI,IIaxillarylymphnodeinvolvementorinclinicallydetectedipsilateralinternalmammarylymphnode(s)withclinicallyevidentlevelI,IIaxillarylymphnodemetastasesormetastasesinipsilateralsupraclavicularlymphnode(s)withorwithoutaxillaryorinternalmammarylymphnodeinvolvement

N3a Metastasesinipsilateralinfraclavicularlymphnode(s)

N3b Metastasesinipsilateralinternalmammarylymphnode(s)andaxillarylymphnode(s)

N3c Metastasesinipsilateralsupraclavicularlymphnode(s)

Pathologic(pN)**

pNX Regionallymphnodescannotbeassessed(eg,previouslyremoved,ornotremovedforpathologicstudy)

pN0 Noregionallymphnodemetastasisidentifiedhistologically

pN0(i) Noregionallymphnodemetastaseshistologically,negativeimmunohistochemistry(IHC)

pN0(i+) Malignantcellsinregionallymphnode(s)nogreaterthan0.2mm(detectedbyH&EorIHCincludingisolatedtumorcellclusters(ITC))

pN0(mol) Noregionallymphnodemetastaseshistologically,negativemolecularfindings(RTPCR)

pN0(mol+) Positivemolecularfindings(RTPCR),butnoregionallymphnodemetastasesdetectedbyhistologyorIHC

pN1 Micrometastasesormetastasesin13axillarylymphnodesand/orininternalmammarynodeswithmetastasesdetectedbysentinellymphnodebiopsybutnotclinicallydetected

pN1mi Micrometastases(greaterthan0.2mmand/ormorethan200cells,butnonegreaterthan2.0mm)

pN1a Metastasesin13axillarylymphnodes,atleastonemetastasisgreaterthan2.0mm

pN1b Metastasesininternalmammarynodeswithmicrometastasesormacrometastasesdetectedbysentinellymphnodebiopsybutnotclinicallydetected

pN1c Metastasesin13axillarylymphnodesandininternalmammarylymphnodeswithmicrometastasesormacrometastasesdetectedbysentinellymphnodebiopsybutnotclinicallydetected

pN2 Metastasesin49axillarylymphnodesorinclinicallydetectedinternalmammarylymphnodesintheabsenceofaxillarylymphnodemetastases

pN2a Metastasesin49axillarylymphnodes(atleastonetumordepositgreaterthan2.0mm)

pN2b Metastasesinclinicallydetectedinternalmammarylymphnodesintheabsenceofaxillarylymphnodemetastases

pN3 Metastasesintenormoreaxillarylymphnodesorininfraclavicular(levelIII

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axillary)lymphnodesorinclinicallydetectedipsilateralinternalmammarylymphnodesinthepresenceofoneormorepositivelevelI,IIaxillarylymphnodesorinmorethanthreeaxillarylymphnodesandininternalmammarylymphnodeswithmicrometastasesormacrometastasesdetectedbysentinellymphnodebiopsybutnotclinicallydetectedorinipsilateralsupraclavicularlymphnodes

pN3a Metastasesintenormoreaxillarylymphnodes(atleastonetumordepositgreaterthan2.0mm)ormetastasestotheinfraclavicular(levelIIIaxillarylymph)nodes

pN3b Metastasesinclinicallydetectedipsilateralinternalmammarylymphnodesinthepresenceofoneormorepositiveaxillarylymphnodesorinmorethanthreeaxillarylymphnodesandininternalmammarylymphnodeswithmicrometastasesormacrometastasesdetectedbysentinellymphnodebiopsybutnotclinicallydetected

pN3c Metastasesinipsilateralsupraclavicularlymphnodes

PosttreatmentypN

Posttreatmentyp"N"shouldbeevaluatedasforclinical(pretreatment)"N"methodsabove.Themodifier"sn"isusedonlyifasentinelnodeevaluationwasperformedaftertreatment.Ifnosubscriptisattached,itisassumedthattheaxillarynodalevaluationwasbyaxillarynodedissection(AND).

TheXclassificationwillbeused(ypNX)ifnoypposttreatmentSNorANDwasperformed

NcategoriesarethesameasthoseforpN

Distantmetastasis(M)M0 Noclinicalorradiographicevidenceofdistantmetastases

cM0(i+) Noclinicalorradiographicevidenceofdistantmetastases,butdepositsofmolecularlyormicroscopicallydetectedtumorcellsincirculatingblood,bonemarrow,orothernonregionalnodaltissuethatarenolargerthan0.2mminapatientwithoutsymptomsorsignsofmetastases

M1 Distantdetectablemetastasesasdeterminedbyclassicclinicalandradiographicmeansand/orhistologicallyprovenlargerthan0.2mm

PosttreatmentypMclassification.TheMcategoryforpatientstreatedwithneoadjuvanttherapyisthecategoryassignedintheclinicalstage,priortoinitiationofneoadjuvanttherapy.Identificationofdistantmetastasesafterthestartoftherapyincaseswherepretherapyevaluationshowednometastasesisconsideredprogressionofdisease.Ifapatientwasdesignatedtohavedetectabledistantmetastases(M1)beforechemotherapy,thepatientwillbedesignatedasM1throughout.

Anatomicstage/prognosticgroups0 Tis N0 M0

IA T1 N0 M0

IB T0 N1mi M0

T1 N1mi M0

IIA T0 N1 M0

T1 N1 M0

T2 N0 M0

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IIB T2 N1 M0

T3 N0 M0

IIIA T0 N2 M0

T1 N2 M0

T2 N2 M0

T3 N1 M0

T3 N2 M0

IIIB T4 N0 M0

T4 N1 M0

T4 N2 M0

IIIC AnyT N3 M0

IV AnyT AnyN M1

*TheTclassificationoftheprimarytumoristhesameregardlessofwhetheritisbasedonclinicalorpathologiccriteria,orboth.Designationshouldbemadewiththesubscript"c"or"p"modifiertoindicatewhethertheTclassificationwasdeterminedbyclinical(physicalexaminationorradiologic)orpathologicmeasurements,respectively.Ingeneral,pathologicdeterminationshouldtakeprecedenceoverclinicaldeterminationofTsize.Sizeshouldbemeasuredtothenearestmillimeter.IfthetumorsizeisslightlylessthanorgreaterthanacutoffforagivenTclassification,itisrecommendedthatthesizeberoundedtothemillimeterreadingthatisclosesttothecutoff.Multiplesimultaneousipsilateralprimarycarcinomasaredefinedasinfiltratingcarcinomasinthesamebreast,whicharegrosslyormacroscopicallydistinctandmeasurable.Tstageisbasedonlyonthelargesttumor.Thepresenceandsizesofthesmallertumor(s)shouldberecordedusingthe"(m)"modifier.InvasionofthedermisalonedoesnotqualifyasT4dimplingoftheskin,nippleretraction,oranyotherskinchangeexceptthosedescribedunderT4bandT4dmayoccurinT1,T2,orT3withoutchangingtheclassification.Thechestwallincludesribs,intercostalmuscles,andserratusanteriormuscle,butnotthepectoralismuscles.Inflammatorycarcinomaisaclinicalpathologicentitycharacterizedbydiffuseerythemaandedema(peaud'orange)involvingathirdormoreoftheskinofthebreast.Theseskinchangesareduetolymphedemacausedbytumoremboliwithindermallymphatics.Althoughdermallymphaticinvolvementsupportsthediagnosisofinflammatorybreastcancer,itisneithernecessarynorsufficient,intheabsenceofclassicalclinicalfindings,forthediagnosisofinflammatorybreastcancer.Ifacancerwasdesignatedasinflammatorybeforeneoadjuvantchemotherapy,thepatientwillbedesignatedtohaveinflammatorybreastcancerthroughout,evenifthepatienthascompleteresolutionofinflammatoryfindings.Clinicallydetectedisdefinedasdetectingbyimagingstudies(excludinglymphoscintigraphy)orbyclinicalexaminationandhavingcharacteristicshighlysuspiciousformalignancyorapresumedpathologicmacrometastasisbasedonfineneedleaspirationbiopsywithcytologicexamination.Confirmationofclinicallydetectedmetastaticdiseasebyfineneedleaspirationwithoutexcisionbiopsyisdesignatedwithan(f)suffix,forexample,cN3a(f).Excisionalbiopsyofalymphnodeorbiopsyofasentinelnode,intheabsenceofassignmentofapT,isclassifiedasaclinicalN,forexample,cN1.Informationregardingtheconfirmationofthenodalstatuswillbedesignatedinsitespecificfactorsasclinical,fineneedleaspiration,corebiopsy,orsentinellymphnodebiopsy.Pathologicclassification(pN)isusedforexcisionorsentinellymphnodebiopsyonlyinconjunctionwithapathologicTassignment.Classificationisbasedonaxillarylymphnodedissectionwithorwithoutsentinellymphnodebiopsy.

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Classificationbasedsolelyonsentinellymphnodebiopsywithoutsubsequentaxillarylymphnodedissectionisdesignated(sn)for"sentinelnode,"forexample,pN0(sn).**Isolatedtumorcellclusters(ITC)aredefinedassmallclustersofcellsnotgreaterthan0.2mm,orsingletumorcells,oraclusteroffewerthan200cellsinasinglehistologiccrosssection.ITCsmaybedetectedbyroutinehistologyorbyimmunohistochemical(IHC)methods.NodescontainingonlyITCsareexcludedfromthetotalpositivenodecountforpurposesofNclassificationbutshouldbeincludedinthetotalnumberofnodesevaluated.RTPCR:reversetranscriptase/polymerasechainreaction."Notclinicallydetected"isdefinedasnotdetectedbyimagingstudies(excludinglymphoscintigraphy)ornotdetectedbyclinicalexamination."Clinicallydetected"isdefinedasdetectedbyimagingstudies(excludinglymphoscintigraphy)orbyclinicalexaminationandhavingcharacteristicshighlysuspiciousformalignancyorapresumedpathologicmacrometastasisbasedonfineneedleaspirationbiopsywithcytologicexamination.Anatomicstage:M0includesM0(i+).ThedesignationpM0isnotvalidanyM0shouldbeclinical.IfapatientpresentswithM1priortoneoadjuvantsystemictherapy,thestageisconsideredStageIVandremainsStageIVregardlessofresponsetoneoadjuvanttherapy.Stagedesignationmaybechangedifpostsurgicalimagingstudiesrevealthepresenceofdistantmetastases,providedthatthestudiesarecarriedoutwithin4monthsofdiagnosisintheabsenceofdiseaseprogressionandprovidedthatthepatienthasnotreceivedneoadjuvanttherapy.Postneoadjuvanttherapyisdesignatedwiththe"y"prefix.Forpatientswithapathologiccompleteresponse(pCR)toneoadjuvanttherapy,nostagegroupisassigned(ie,yT0N0M0).T1includesT1mi.T0andT1tumorswithnodalmicrometastasesonlyareexcludedfromStageIIAandareclassifiedStageIB.

UsedwiththepermissionoftheAmericanJointCommitteeonCancer(AJCC),Chicago,Illinois.TheoriginalsourceforthismaterialistheAJCCCancerStagingManual,SeventhEdition(2010)publishedbySpringerNewYork,Inc.

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Disclosures:AlphonseTaghian,MD,PhDNothingtodisclose.MoatazNElGhamry,MDNothingtodisclose.SofiaDMerajver,MD,PhD[Breastcancer(Palbociclib)]AstraZeneca[Breastcancer(Circulatingtumorcells)].Speaker'sBureau:LillyOncology(Breastcancer).Consultant/AdvisoryBoards:Pfizer[Breastcancer(Palbociclib)].OtherFinancialInterest:JanssenR&D,LLC[Breastcancer(CellSearch)].DonSDizon,MD,FACPNothingtodisclose.Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.Conflictofinterestpolicy

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