Follow-up of patients with early breast cancer: Is it time to rewrite the story?

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Follow-up

of

patients

with

early

breast

cancer:

Is

it

time

to

rewrite

the

story?

Fabio

Puglisi

a,b,∗

,

Caterina

Fontanella

a

,

Gianmauro

Numico

c

,

Valentina

Sini

d

,

Laura

Evangelista

e

,

Francesco

Monetti

f

,

Stefania

Gori

g

,

Lucia

Del

Mastro

h

a_Department_of_Oncology,_University_Hospital_of_Udine,_Italy b_Department_of_Medical_and_Biological_Sciences,_University_of_Udine,_Italy c_Department_of_Medical_Oncology,_Azienda_USL_della_Valle_d’Aosta,_Aosta,_Italy

d_Surgical_and_Medical_Department_of_Clinical_Sciences,_Biomedical_Technologies_and_{Translational}_Medicine,_{“Sapienza”}_University_of_Rome,_Italy e_Radiotherapy_and_Nuclear_Medicine_Unit,_Veneto_Institute_of_Oncology_IOV_–_IRCCS,_Padova,_Italy

f_Department_of_Radiology,_IRCCS_AOU_San_Martino-IST,_Genova,_Italy g_Department_of_Medical_Oncology,_S.Cuore-Don_Calabria_Hospital,_Negrar_(VR),_Italy

h_Department_of_Medical_Oncology,_IRCCS_AOU_San_Martino-IST,_Genova,_Italy

Accepted11March2014

Contents

1. Introductionandterminology... 131

2. Surveillance... 131

2.1. Summaryofliteraturereviewandcurrentguidelines... 131

2.2. Usesandabusesofresources... 132

3. Advancesinmanagement... 132

3.1. Advancesinbiology ... 132

3.2. Advancesinsurveillancestrategies... 133

3.2.1. Locoregionalrecurrence... 133

3.2.2. Distantmetastases... 134

4. Biomarkersfordiseaserelapse... 135

5. Rationaletodesignnewstudies... 136

6. Conclusions... 137 Conflictofinterest... 137 Authors’contributions... 137 Reviewers... 137 Acknowledgements ... 137 References... 137 Biographies ... 140 Abstract

Theguidelinesforfollow-upinbreastcancersurvivorssupportonlyperformanceofperiodicphysicalexaminationandannual mammogra-phy.However,medicaloncologistsandprimarycarephysiciansroutinelyrecommendbothbloodtestsandnon-mammographicimagingtests inasymptomaticpatients,leadingtoanincreasedanxietyrelatedtofalse-positiveresultsandhighermedicalexpenses.Recently,advanced

∗_{Corresponding}_author_at:_Department_of_Oncology,_University_Hospital_of_Udine,_Piazzale_S.M._{Misericordia,}₃₃₁₀₀_Udine,_Italy.

Tel.:+390432552754/0432559309;fax:+390432552762.

E-mailaddress:fabio.puglisi@uniud.it(F.Puglisi).

http://dx.doi.org/10.1016/j.critrevonc.2014.03.001

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imagingtechnologieshaveimprovedsensitivity/specificitytodetectmetastaticlesionsbeforesymptomsarise.Consideringtheprogressmade inthetreatmentofmetastaticdiseaseandtherapidevolutionoftargetedtherapy,thatrequirescustomizationofthestrategyaccordingto molecularcharacteristicsofthedisease,patientscouldderiverealbenefittoearlydetectionofdiseaserecurrence.Thishypothesismustbe testedinaprospectiveclinicaltrial.

Keywords:Earlybreastcancer;Follow-up;Surveillance;Survivorshipcare

1. Introductionandterminology

Theoverall prevalenceof womenlivingwitha diagno-sisof breastcancer(BC)isincreasing intheindustrialized countries[1],thusmanagement of breast cancersurvivors representsadailypracticeproblemforbothoncologistsand primarycarephysicians(PCP).

Afteraradicalprimarytreatment,patientswithearlystage cancerenterinastructuredsurveillancephaseusuallycalled “cancerfollow-up”[2].According totheCochrane Breast Cancer Group, terms such as “routine testing”, “follow-up”or“surveillance”indicatetheregularuseoflaboratory or instrumental tests in otherwise asymptomatic patients to detect distant metastases earlier [3]. This definition is primarilyfocused onearlydetection of diseaserecurrence inpatients otherwise asymptomatic.However, considering that worldwide population is aging and 50–70% of BC survivors experience persistent impairment or limitations after primarytreatment [4,5],physicians alsohavetodeal withco-morbiditiesandlong-termsideeffectsoftreatment suchasanthracycline-relatedcardiacdamage, anti-estrogen-associated bone disease, chemotherapy-induced infertility, andriskofsecondmalignancies.Supportiveand psychologi-calinterventionsshouldbeanimportantpartoftheoncologist role.Thismorecomprehensiveactivityisusuallytermedas “survivorshipcare”.

Giventherequiredlargeamountofresourcesandthe pos-sibleimportantconsequencesintermsofpatients’healthand survival,severalprospectivestudieswereconductedwiththe aimofdefiningthebestfollow-upstrategyinBCsurvivors [6–11]andclinicalguidelinesareconstantlyupdated[12,13]. Asurvivalbenefitderivedfromtheearlydetectionofdisease recurrencewas rarelydemonstratedinthegeneral popula-tion,although several otherneeds of cancer patients were pointedout,leadingtoawiderunderstandingofsurveillance andtoashifttowardsurvivorshipcare.Unfortunately,while oncologicalresearchisactivelypushedinthefieldof pharma-cologicaltherapy,littlehasdonetosolvethemanyquestions thatstillareopeninsurvivorshipcare.

2. Surveillance

2.1. Summaryofliteraturereviewandcurrentguidelines DataonBCfollow-updatebacktothe1990,whenresults from two randomized trials were published: the GIVIO

(GruppoInterdisciplinareValutazioneInterventiin Oncolo-gia,InterdisciplinaryGroupforCancerCareEvaluation)trial [6]andtheRossellidelTurcotrial[7].Theycomparatively evaluatedconventionalfollow-upbasedonregularphysical examinations andannual mammography withmore inten-sive investigations, such as chestX-rays, bone scan, liver ultrasound(US),andlaboratorytestsfortumormarkersin ordertosearchfordistantmetastases.Bothtrialsshowedno overallsurvival(OS)benefitarisingfromintensivefollow-up as comparedwithconventionalfollow-up[8,9].In particu-lar,thefirstanalysisoftheRosselliDelTurcotrialshowed anuncertainsurvivalbenefitarisingfromintensive follow-upcomparedwithconventionalfollow-up,butthedatawas notconfirmedafter10-yearfollow-up.The10-yearmortality cumulative rates were 31.5%for the conventional follow-up and 34.8% for the intensive ones (hazard ratio 1.05; 95%ConfidenceInterval(CI)0.87–1.26)[8].Similarly,the GIVIO at a median follow-up of 71 months, showed no differencesinsurvival,with132deaths(20%)inthe inten-sivegroupand122deaths(18%)inthecontrolgroup(odds ratio=1.12;95%CI=0.87–1.43).Moreover,theGIVIOtrial assessed a decreased health-related Quality-of-life (QoL) inthe intensive-screeninggroup[6].Recently, aCochrane review involving more than 2500 women, confirmed that intensivefollow-updidnotimproveOSanddisease-free sur-vival(DFS).Theseresultswereconsistentamongsubgroup analysesaccordingtopatientage,tumorsizeandlymphnode statusbeforeprimarytreatment[3].

Otherimportantissuesconcernfrequencyandlocationof follow-up visits. In 1997a singlecenter trialshowed that annualfollow-upvisitsaftermammographydidnotincrease theuseoflocalpractitionerservicesortelephonetriage com-paredwithvisitsscheduledevery3–6months.However,due tothesmallsamplesizeofthistrial,definitiveconclusions abouteffectivenessandcost-effectivenessofroutine follow-upwithrespecttodiseaseoutcomeswerenotassessable[9]. In1996and2006,twomulticenter,randomized,controlled trialsshowed nodifferencesinterms ofrecurrence-related clinicaleventsrateandhealth-relatedQoLbetweenfollow-up performedbyamedicaloncologistorbyaPCP[10,11]. How-ever,medianfollow-upofbothtrialswasshort(18months and3.5years,respectively)andstudieswereunderpowered toevaluatetheimpactonOS.

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periodichistoryandphysicalexamination(every3–6months for the first 3 years, then every6–12 months for 2 years or every 4–6 months for 5 years, respectively, then every 12 months). They also underline the importance of coun-seling about symptoms of recurrence and active lifestyle. Moreover,theyrecommendperiodicpelvicexaminationsfor everywoman,inparticularpatients takingtamoxifen, who areatincreasedriskofendometrialcancer,andbonemineral densitydeterminationforwomenundergoinganaromatase inhibitororwhoexperienceovarianfailuresecondaryto treat-ment.Physiciansshouldassessandencourageadherenceto adjuvantendocrinetherapy,andwomenathighriskfor famil-ialbreastcancersyndromesshould bereferred forgenetic counseling.

Inasymptomaticpatients,therearenodatatoindicatethat otherlaboratoryorimagingtests(e.g.bloodcounts,routine chemistrytests, chestX-rays, bonescans, liverUSexams, computedtomography(CT)scans,positronemission tomo-graphy(PET)scansoranytumormarkerssuchasCA15-3or CEA)canproduceasurvivalbenefit.

TheESMOguidelines[15]focusattentiontosurvivorship care,highlightingthatthepurposesoffollow-uparealsoto evaluateandtotreattherapy-relatedcomplications(suchas menopausalsymptoms,osteoporosisandsecondcancers)and toprovidepsychologicalsupportandinformationinorderto enhancereturningtonormallifeafterBC.Table1 summa-rizescurrentguidelinesonbreastcancerfollow-up.

Currently,no specifictrials wereconducted toevaluate thebestfollow-upstrategyinparticularpopulation,suchas maleBC,elderlypatients,veryyoungpatients,andBRCA1-2 mutationcarriers.

2.2. Usesandabusesofresources

In clinical practice intensive follow-upis awidespread reality and it costs 2.2–3.6 times more than guidelines-compliantfollow-up[16],asaresultofnon-mammographic testsperformedintheabsenceofanywarningsignsor symp-tomsofrecurrence[17].TheASCOincludedBCsurveillance in the top-five list of oncological practices that could be improvedandsimplifiedinordertoreducecosts[18].

The higher-than-recommended intensity involves both clinicalexaminationsandimaging.ACanadian population-based analysis showed that the mean number of visits in thefirst5yearsafterprimarytreatment wasusuallyhigher thanrecommendedbythe ASCOguidelines.Forexample, duringthe secondyearpatients underwentamean of11.2 visitsbydifferentphysicians,includingPCP,medical oncolo-gist,radiationoncologist,surgeonandothers,comparedwith 2–4visitsrecommended[19].Thesenumbersareacommon resultofawidespreadduplicationofcare.

Inlinewiththeseresults,KeatingandColleaguesobserved that 13.3%of the 37,967patients collectedinthe Surveil-lance,Epidemiology, andEndResults(SEER) –Medicare databasehadatleastonebonescan,29.2%hadatumor anti-gentest, 10.9%had chest/abdominal imaging,and 58.8%

hadachestX-rayinthefirstyearoffollow-up,andpatients followedbymedicalandradiationoncologistshadthehighest chance of undergoing non-recommended tests [20]. Simi-larly, a National survey conducted among Italian medical oncologistsshowedanabuseofimagingandtumormarkers testinasymptomaticBCsurvivors[21].

Therearemultiplepossiblereasonsofoveruseof imag-ingandlaboratorytesting.Thefirstoneisthepatient-driven anxietyandthefeelingofreassuranceinducedby examina-tions.Patientsarepronetoassociatethefrequencyofclinical examinationsandtestingwithimprovedoutcomes[22]due totheunrealisticbeliefthatmoretestingcouldanticipatethe diagnosisofrecurrenceandimprovetreatmentoutcomes.A secondissuetobetakenintoaccountisthedearthof prospec-tivetrialswithnewgenerationimaging(CTandPETscans) ororientedtospecialpopulations(forexamplewomenunder 40yearsoldorpatientswithtriple-negativeorHER2-positive disease).Finally,animportanttriggerofunnecessary exami-nationsandvisitsmaybetheabsenceofaclearcoordination amongalltheprofessionalsinvolvedinthesurvivorshipplan [23].Bycontrast,uncoordinatedcarecanalsobethecause of underuse ofappropriate visitsandtests:theSEERdata [20]showed thatinUnitedStatesonly27%of breast can-cer survivors’aged65yearsoroldersawtheironcologists annuallyfor3yearsafteractivetreatmentandacasecontrol studyconductedinOntario[24]highlightedthatamongBC survivorsonlyaminorityunderwentcolorectalandcervical cancerscreening,despitebeingseenbymultiplespecialists duringthefirst5yearsafterprimarytreatment.These exam-plesoflower-than-standardpracticesupportthehypothesis thatresourcesmaynotbeequallydistributedamong surviv-ingpatients.

3. Advancesinmanagement

3.1. Advancesinbiology

AhugeamountofevidencesuggeststhattheriskofBC recurrenceanddeathisinfluencednotonlybystageatinitial presentationbutalsobytheunderlyingbiologyofthetumor [25].Overall,thehazardrate variesovertimeaccordingto predictiveandprognosticfactors[25].Abetter understand-ingofpatternsofrecurrenceisanimportantmedicaldriver forboththetreatmentandthesurveillancecliniciandecision process.

Currently, BCis classifiedinto five differentmolecular subtypes[26–28]accordingtoimmunohistochemical(IHC) classification:

• Luminal A (characterized by hormone receptors (HR)-positive tumor cells and low Ki-67 expression; human epithelialgrowthfactorreceptor2(HER2)-negativestatus) • LuminalB(HR-positivecellsandhighKi-67expression;

HER2-negativestatus)

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Table1

Summaryofcurrentguidelinesonbreastcancerfollow-up. Scientificsociety Historyand

physical examination Mammography Breast self-examination Intensive follow-up Bonemineral density Gynecologic assessment

ESMO2011[15] Notspecified Every12months Notspecified Notrecommended Notspecified Notspecified ASCOUpdate

2013[6]

Every3–6months forthefirst3 years,every6–12 monthsforthe next2years,then annually

Every12months Monthly Notrecommended Notspecified Allwomen

NCCNVersion 3.2013[14]

Every4–6months for5years,then annually

Every12months Notspecified Notrecommended Womenon aromatase inhibitororwho experienceovarian failuresecondary totreatment Womenon tamoxifen:every 12months

AIOM2013[126] Every3–6months for5years,then annually

Every12months Notspecified Notrecommended Ifclinically indicated

Womenon tamoxifen:if clinically indicated

• HER2enriched(HR-negativeandHER2-positivestatus) • Triplenegative(HR-negativeandHER2-negativestatus) Thehazardratesfor relapseamongHR-negativeand/or non-luminalAtumorsshowasharppeaksoonafterinitial diagnosis.Conversely,hazardratesforHR-positiveand lumi-nalAtumorsarepersistinglowoverthetime[25].Arecent analysisshowedthatpatientswithLuminalBbreastcancer hadacontinuouslyhigherhazardofbreastcancerrecurrence overtimeandashorterOScomparedwithLuminalApatients [29,30].Moreover,LuminalBpatients hadhigherrates of bone as first recurrence site than othersubtypes. Visceral recurrenceasfirsteventwassimilaramongLuminalB,HER2 enrichedandtriplenegativeBC.

Fromabiologicalpointof view,the observationof dif-ferent patterns of relapse suggests different mechanisms involved in early and late BC events. As a consequence, itistemptingtohypothesize thatscheduleandintensityof surveillanceshouldvaryaccordingly.

3.2. Advancesinsurveillancestrategies 3.2.1. Locoregionalrecurrence

Thesurvivalofwomensufferinglocoregionalrecurrence is markedly different compared to those suffering distant metastases(80%5-yearrelativesurvivalrateversus25% 5-yearrelativesurvivalrate,respectively)[31]andpatientswith isolated locoregional or contralateralbreast cancer recurr-ences detected without symptoms have a better survival comparedtopatientsinwhomalatesymptomaticdetection isperformed.Overthelasttwodecades,ithasbeen demon-stratedthatpatientswithsolitaryfirstlocoregionalrecurrence aftermastectomymayachievea5-yearDFSrateof61–79% iftheyunderwentaradicallocoregionaltreatmentcombined withsystemicadjuvanttherapy[32,33].

Unfortunately,the first siteof relapseis representedby localrecurrence inonlyone-thirdofrecurrentBCpatients [34].Evenifsomeretrospectiveanalysessuggestedthat hav-ing an inflammatoryBC at the primary diagnosis [35] as wellas the tumorstageandpathological nodalstageafter neoadjuvant treatment [36] may predict for a higher risk of locoregional recurrence, no strategy are current avail-abletoidentifypatientswhoaremorelikelytohavealocal relapse.

The detectionof isolated locoregional andcontralateral recurrenceornewbreastprimaryinasymptomaticpatients bymammographyleadstoanabsolutereductioninmortality of 17–28%[37].Nevertheless,surveillancemammography is affected by both false-negative (approximately 10% of palpabletumorsare not clearlyvisibleonmammography) and false-positive results, which require further investiga-tions, especiallywhen deleteriouschangesin breasttissue havebeeninducedbysurgeryandradiotherapy[38–40].In suchcases,thereliabilityofthediagnosismightbeimproved by the use of US or magnetic resonance imaging (MRI) [41–43].Inparticular, MRI of thebreastcanbe usedas a problem-solvingtoolintheevaluationofpatientsinwhom equivocalabnormalitiesareidentifiedbymammographyor physicalexamination[44,45].MRIisparticularlyappealing for surveillance ofyoung women duetoitsproven higher sensitivitycomparedtomammography,especiallyindense breasts[46–50].However,duetotherelativelylowspecificity ofMRIforBCrecurrence(rangefrom66to100%)[51–58] andthecurrenthighcostofthistechnique[59],MRIcould not beconsideredarecommendabletool inBC follow-up. Moreover,arecentstudyshowedthatMRIdidnotreducethe riskofbothlocalanddistantdiseaserelapse[60].

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3.2.2. Distantmetastases

Intheearly1990sithasbeenreportedthatasmall percent-ageofmetastaticbreastcancer(MBC)patientswhoachieved a complete remission after systemic treatment remained disease-free over 20 years. Overall, these long-survivors representedonly 1–3%of allmetastatic patients,but they challengedaparadigm:MBCwasnolongeralwaysafatal condition[61,62].

Lookingintothepatientandtumorcharacteristicsofthe long-survivorswerealizedthattheysharedsomeimportant features:theywereyoung,withgoodperformancestatusand withalimitedburdenof metastaticdisease[63,64].In par-ticular,havingan oligometastaticdiseaseseemedtobethe strongestpredictorforlongsurvival.

Overthelastthreedecades,severalstudiesconfirmedthis assumption.Theimplementationofmultidisciplinary aggres-siveapproachinpatientswithasinglemetastaticlesionhas leadtoadisease-freeintervallongerthan15years[65–69], andaretrospectiveanalysisofpatientswith1or2metastatic sitesshowedacompleteresponsewithsystemictreatmentof 48%anda20-yearOSrateof53%[62].

These impressive results can be related with both an improvementintreatmentforMBCandanimprovementin earlydetectionofmetastaticdiseaselimitedto1–2sites.

However,morethan20%ofpatientshaveamultiplesites diseaseatpresentationofmetastaticspread[70].According toarecentretrospectiveanalysis,themostcommonsitesof distantrecurrence were bone (41.1%), lung(22.4%), liver (7.3%),andbrain(7.3%)[62].Interestingly,differentpatient and tumor characteristics underlined different patterns of distantrelapse:bonemetastasesweremorelikelytobe diag-nosedin patients withHR-positive disease,lung andliver metastasesinpatientswithamoreadvancedstageatthetime ofprimarydiagnosis,andbrainmetastasesinpatientswith HR-negative disease [29,62].The worse survival outcome overtheinitialyearsafter diagnosiswasobservedintriple negativeBCpatientsandinpatientswithHER2-positive dis-ease whodid not received any anti-HER2treatment [29]. Moreover, even if the introduction of drugs targeting the HER2 hasled toanimpressive improvementinbothDFS andOS[71–74], datafromthe firsttrial withtrastuzumab inmetastaticsettingshowedthat patientswhoreceivedthe anti-HER2treatmentupfronthadasurvivaladvantage com-pared with who received it after progression [70]. These findings suggest that an early diagnosis and treatment of HER2-positivediseaserecurrencemayimproveoutcomeof thesepatients.

Diagnostictoolscurrentlyusedinthesurveillance,such asPET,MRI,andCT,haveawiderangeofaccuracyinthe detectionofallthesitesofrelapse[75];consequentlyitisnot likelytoassumeaoneshotdiagnosticexaminationthatcanbe appropriatelyusedforthesurveillanceofdistantrelapsebut ratherthissurveillanceislikelytocompriseacombination of thesetechnologies.The poorprognosis ofpatients with distantrelapsejustifyastrongefforttoidentifya“systemic surveillancestrategy”effectiveinimprovingoutcome.

3.2.2.1. Conventionalworkup. Conventionalimagingtests (CITs) available to detect distant metastases include con-ventionalX-rays,CTscan,US,bonescanand,inalimited number of settings, MRI. Diagnosticaccuracy of CITsin surveillancesettingofBCsurvivorsismainlyextrapolated fromstudiescomparingconventionalworkupandPETscan andtheyarefartobecompletelyassessed[40].Forexample, CT scan is widely used in clinical practice but diagnos-tic accuracy of CT imaging in detecting recurrent and/or MBC,rangesfrom40to92%insensitivityandfrom41to 100%inspecificity [76–79].Moreover,abdominalUShas theundoubtedadvantageofminoreconomicalandbiological costsbutitsuseinBCisnotsupportedbyadequate scien-tific evidences;mostofthe studiesassessedthe diagnostic accuracyofUSinthediagnosisoflocalrecurrenceandnot oflivermetastases[41].

Aparticularmentionshouldbemadeforthebone involve-ment.Boneisthe mostcommonsiteof distantmetastases fromBC[80];complicationsresultingfrombonemetastases includehypercalcemia,bonepain,pathologicalfractures,and spinalcordcompression[81].Earlydetectionofmetastatic disease may prevent skeletal complications,offer a better chancetocontrolthediseaseprocess,andimprovepatients’ QoL[82].

From arecentreview,emerged thatthe absence of risk stratification in published data does not adequately eval-uate the benefit of intensive surveillance among patients withknownhigh-riskdisease,thereforetoplanstudiesfor assessing an accurate surveillance strategy in aggressive tumorsisarealneed[83].

ConventionalX-rayhasalowsensitivityindetectionof bonemetastases.Ithasbeenestimatedthata30–75% reduc-tioninbonedensityisrequiredtovisualizeametastasison radiographs.Inthesameway,aconsiderablecortical destruc-tionisrequiredforvisualizationofametastasisbyCTscan; sensitivityandspecificityofthismodalityindetectingearly malignantboneinvolvement[84,85]arerelativelylow.Bone scanoffersarelativelysensitiveandreasonablypriced eval-uationofthewholeskeletoninasingleimagingexamination but it is affected by a poor anatomic resolution [86] that mayresultsinnot-detectinglyticlesionsordifficultyin dis-tinguishing tumorfromdegenerative/traumaticevents. The detectionrate of bonemetastasesby bonescaninpatients withearly-stageBCisverylow(0.82and2.55%instageI andII,respectively),butitincreasesto17%inpatientswith stageIIIdisease.Therefore,bonescanshouldbeperformed insymptomaticpatients, whenthereisaclinicalsuspicion formetastaticboneinvolvement[87],andinadvanced-stage disease.

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3.2.2.2. PETandPET/CTscanning. Thediagnostic poten-tialofwhole-body18-fluoro-2-deoxy-d-glucose(FDG)-PET canbe consideredinpatients withhighrisk of recurrence [89,90].Moreover,theadvantagesofFDG-PET/CTin iden-tifyinglocoregionalrecurrenceare thehighsensitivityand theabilitytodifferentiatepost-surgical/radiotherapychanges fromtruerecurrence.AnimportantroleofFDG-PETseems tobethedetectionofdistantmetastasesinpatientswith sus-pectedrecurrence disease, e.g.when biochemicalmarkers (CA15.3orCEA)increase[91,92].

ArecentpaperbyParmaretal.[93]reportedanincrease inuseofcrosssectionalimaging,suchasCTandMRIandin particularPETorPET/CTinasymptomaticpatientsduring thesurveillanceperiod. Fromthisstudy appearsthatthere wasasignificantincreaseinPET/PET-CTusefrom2%to9% ina6-yearperiodandaconcomitantdecreaseinbonescan from21%to13%inthesameperiod.TheriseinPETuse andattendantdecreaseinbonescanimplicatesapopulation receivingPETscaninlieuofbonescanforsurveillanceof asymptomaticmetastaticdisease.Comparedtoconventional imaging,FDGPEThasbeenshowntobemoresensitiveand specificindetectingdistantmetastaticdisease[94].Mostdata arederivedfromtheassessmentofpatients withsuspected recurrent or metastaticdisease comparingFDG PET with conventionalimaging[95–99],althoughonlyonestudyhas included asymptomaticpatients aswell[97].On the other hand,asymptomatictumormarker increasewas correlated withan elevatedsensitivityfor thedetectionofmetastases byPET or PET/CT also incomparison withconventional imagingmodalities[100].

AsrecentlyreportedbyGroheuxetal.[101],the aggres-siveness of BC, based on histological features, is directly correlated with the glucose metabolism. Triple negative tumorsandnon-differentiatedcancer(Grade3)demonstrated ahigheruptakeofFDGatPET/CTthantheotherhistological typeandfeatures.

Isasietal.[102]performedameta-analysistoassess FDG-PETfor the evaluation of BC recurrences andmetastases andreportedtheseresults:thesensitivityandspecificitywere approximately92%(56–100%)and82%(0–100%), respec-tively.

AllstudiescomparingthediagnosticaccuracyofPETwith PET/CT, consistentlyshowed that PET/CThave improved sensitivitycomparedwithPETbutnotsignificantdifferences inspecificity.Inthesestudies,PET/CTwasusedforthe diag-nosisoflocaldisease andmetastasesindifferentlocations andtheadvantageof PET/CToverPETappearstobetrue whenconsideredforthedetectionofdiseaseoverarangeof locations.

Several studies investigated the diagnostic accuracy of CITs compared with PET or PET/CT on a patient basis [78,97,103–108]; in 2010 Pennant and Colleagues give pooledsummaryestimatesrelatedwiththetwo diagnostic strategies: PET had significantly higher sensitivity [89%, 95% confidence interval (CI) 83%–93% vs 79%, 95% CI 72%–85%, relative sensitivity 1.12, 95% CI 1.04–1.21,

p=0.005]andsignificantlyhigherspecificity(93%,95%CI 83%to97%vs83%,95%CI67%–92%,relativespecificity 1.12,95%CI1.01–1.24,p=0.036)[75].

For bone involvement this gain in diagnostic accuracy obtainedwithPETiscontroversialandcertainlylessevident. In 2011,Houssami andCostelloe [86] reported a system-atic review that updatesthe evidence on comparative test accuracyfor imagingof boneinvolvementinwomenwith BC;themediansensitivity(basedonsevenstudies)forPET was 84%(range77.7%–95.2%), andfor bonescan,it was 80%(67.0%–93.3%).Themedianspecificity(sevenstudies) forPETwas92%(88.2%–99.0%)andforbonescan82.4% (9.1%–99.0%).

Overall,PETandPET/CTappeartogiveimproved diag-nosticaccuracycomparedwithCITandinthepatient-based analysis,absoluteestimatesofsensitivityandspecificitywere around10%higherforPETcomparedwithCIT.Despitethis, theimpactoftheseresultsonpatientmanagementis uncer-tain.Individualstudiesemphasizethatthesetechnologiesdo leadtochangesinmanagement, butitisdifficultto deter-minetowhatextentthesechangeswould havetakenplace with CITs and, more significantly, whether they modified finalpatientoutcome.

FurthermoretherearetwoimportantlimitationsofPET andPET/CT:economiccost,andbiologicalcost.

In Europe, a PET and a PET/CT scan range between approximately D600 ($885) and D1000 ($1474), and reimbursement for these examinations varies significantly dependingontherespectivehealthcaresystems[109].

Withregardstobiologicalcosts,Huangetal.[110] calcu-latedthattheeffectivedosefromFDGPET/CTscanningwith a diagnostic CTprotocol andan administered FDG activ-ityof370MBqwasupto32.18mSv,althoughthestandard employedPETor PET/CTprotocolregisteredan effective doserangedbetween6.24and9.38(lowdoseCTscanand lessFDGadministeredactivity).Moreover,Chineseauthors reportedthattheassociatedlifetimecancerincidence associ-atedwiththisdosewasestimatedtobeupto0.5–14%only fortheU.S.population[111].

4. Biomarkersfordiseaserelapse

Sinceoligometastaticpatientshavethehighestprobability tobelong-survivorafteramultimodalitytreatment,theearly recognitionofminimalresidualdiseaseshouldbeoneofthe majorgoalsofBCsurvivorsfollow-up.

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appropriatelevelofsensitivity[112],itisnoteasytoidentify theperfectbiomarkerforBCrelapse.However,anumberof differentprognosticbiomarkershavebeenevaluatedoverthe lastyears.

Mutationswithinthegeneswhoseproductsparticipatein DNArepair,suchasBRCA1,BRCA2,andP53,predispose thepatientstoanincreasedriskofdevelopingBC[113,114]. In particular,it hasbeendemonstratedthat p53 accumula-tionisastrongpredictorofbothearlyandlaterecurrencein HR-positiveBCpatientstreatedwitharomataseinhibitorsas adjuvantendocrine therapy[113].Therefore,patients with mutations identified within the mentioned genes mightbe consideredforapersonalizedfollow-upstrategy.

Circulating tumor cells (CTCs) in peripheral blood of patients with early BC have been shown to be an inde-pendentprognostic factorfor diseaserecurrenceanddeath [115].Arecentstudy providedevidenceof astrong corre-lationbetweendetectionofCTCsduringthefirstfiveyears offollow-upandincreasedrisk of latedisease relapseand deathinpatientsearlyBC,regardlessfromHRstatus[116]. Moreover,theAuthorssuggestedthatthepresenceofCTCs mayindicatechemo-andhormonotherapy-resistanceinthe microscopicresidualdiseaseafterprimarytreatment.These findings may support the role of CTCs monitoring as an adjuncttostandardfollow-upstrategy.

Asalreadymentioned,fivedifferentBCsubtypescould bedetected byIHCandused as adriverfor daily clinical practice.However,gene expressionanalysesmaypermita moreaccuratestratificationofpatientswithmoreaggressive formsof BC.Forexample,the MammaPrintSymphonyis a 70-gene panel that allowed the stratification of patients intogroupsofhighandlowriskofrelapse[117].Similarly, the Oncotype DX is a 21-gene panel developed to assess the probability of relapse of BC within 10 years by the analysisofgenesinvolvedinproliferationandinvasiveness [118].Overtheyears,anumberofnewgenesignatureshave beendevelopedandseveralcomparisonsbetweendifferent panelandtechniquehavebeenpublished[119–121].Having a genetic fingerprint of the tumor could be an optimal solutiontodriveamoreaggressive follow-upstrategy,but theavailabledataarestillinhomogeneousandthebestpanel hasnotbeenidentifiedyet.

MicroRNAs (miRNAs) are a class of small (18–22 nucleotidesinlength),non-codingRNAsthatregulategene expressionon apost-transcriptionallevel [122].The iden-tificationofapatternofmiRNAsderegulationinBCtissue comparedwithnormalbreasttissuewasfirstreportedin2005 [123].Sincethen,severalstudieshavebeenfocusedonthe expressionofvariousmiRNAsandtheirrolesinBC devel-opmentandbehavior.The analysisof circulatingmiRNAs mightprovideadditionalindividualizedinformationon prog-nosisandmetastaticpotential of BCineachpatientatthe timeofprimarydiagnosis.SeveraldifferentpanelofmiRNAs havebeenevaluatedandan association withboth disease-free andoverall survival has beenreported inmany cases [124,125],howevernovalidatesignatureisavailableyetand

theimplementationofmiRNAsinafollow-upstrategyshould befurtherinvestigated.

5. Rationaletodesignnewstudies

Surveillance ofBCpatients withannualmammography andclinicalexaminationisthecurrentstandardofcare.Over thelastfewdecades,randomizedclinicaltrialshavefailedto demonstratearealbenefitofanintensivefollow-upstrategy. Incontrastwithpatientsandphysiciansperceptions,literature datadonotsupporttheintroductionof regularbloodtests, tumor markers, CT scan, bone scanand other imagingin thesurveillancesetting.Inaddition,theabuseofthesetools in clinicalpractice could increaseanxiety relatedto false-positiveresultsandunnecessaryexpenses.

However,therecouldbesettingsinwhichaninstrumental, aggressivefollow-upschedulecouldanticipatethediagnosis ofrelapseandimprovetreatmentoutcomes.

The first possible application of an intensive follow-up programistheMRIsurveillanceoflocoregionalrecurrence ofyoungandBRCApositivewomen.Asalreadydescribed,a combinedlocalandsystemictreatmentcanofferreal advan-tagestopatientswithlocoregionalrelapse.Asecondfieldof interest is the search of early systemic relapse in patients with HER2 positive tumors. The recent improvement in screeningtechniques,combinedwiththeavailabilityofactive targetedtherapy,mayleadtoaneffective“rescue”treatment inpatientswithearlydetectionoftumorrelapse.Moreover, theincreasedknowledgeinbreastcancerbiologysuggeststhe needofasubtype-tailoredsurveillancestrategy,focusedon thedifferentpatternsofrelapseintrinsicineverybreast can-cer molecularsubtype. HER2positivebreastcancersseem particularlysuitable foranintensivesurveillanceofdistant recurrence:treatmentanticipationhasshowntoconfera sig-nificant survival advantage.Fortestingthese hypothesesa newprospective clinicaltrial shouldbedesigned inwhich conventional surveillance strategyis comparedwitha CT-PET-basedstrategy.Afurtherscientificneedisthesearchfor diagnostictoolsabletoanticipatetheradiologicalevidence ofrecurrence:serummarkersandcirculatingtumorcellsare promisinganddeservestronginvestment.

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standardized, symptom-driven diagnostic assessment with thescreeningofasymptomaticwomenisanotherunanswered question.

6. Conclusions

Outsidefromtheexperimentalsettingthereiscurrentlyno reasontoperformanyexaminationinasymptomaticpatients otherthanannualmammography:nosingleimaging modal-ityhastherequiredcharacteristicsofsensitivity,specificity andcost-effectivenessratiotobeconsideredsuitableforBC follow-up. Intensive surveillance is associated with false-positivefindings,induction of anxiety, risk ofexposure to radiation,andunjustifiedcosts.Informationofpatientsand educationofphysiciansshouldbepursued.However,the bio-logicalknowledgeandthemanagementimprovementshould beconsidered the basisfor arenewed interestof research inthefieldoffollow-up.Areprobablydefinitivelygonethe timesofa“onesizefitsall”strategy:BCisaheterogeneous diseaseanddifferentapproachesshouldbeadaptedtothe dif-ferentdiseasesubtypes.Thecombinationofthebestcurrent diagnostictoolswiththebesttherapiesmaydemonstratethat theanticipationofrelapsedetectionandtreatmentisworth ofvalueinspecificsettings.Thisresearchiseagerlyawaited.

Conﬂictofinterest

Theauthorsdeclarenoconflictofinterest.

Authors’contributions

Allauthorsdrafted,readandapprovedthefinalversionof themanuscript.

Reviewers

JavierCortès,M.D.Ph.D.,HospitalValleHebron, Oncol-ogyDepartment,Barcelona,Spain.

ChristophC.Zielinski,Professor,M.D.,Chairman, Med-ical University of Vienna, Department of Medicine I, WaehringerGuertel18-20,A-1090Vienna,Austria.

NatalieTurner,MBBS,PratoHospital,ViaUgoFoscolo, I-59100Prato,Italy.

Acknowledgements

ThisreviewispartofaspecialprojectoftheAIOM (Asso-ciazioneItaliana diOncologia Medica)working groupon follow-upofbreastcancer.

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Biographies

FabioPuglisi(MD,PhD)isresearcherandprofessorof MedicalOncologyattheUniversityofUdine,Italyandsenior staffmemberoftheDepartmentofMedicalOncology, Uni-versity Hospitalof Udine, Italy. Since 1998, prof. Puglisi has heldhis teachingactivitymainlyfor the University of Udine,Italyandinregionalandnationalcourses.Heisauthor of severalpublicationsinscientificpeer-reviewedjournals, especially in his main fields of interest (i.e. clinical trials on breastcancer treatmentandresearchonprognosticand predictivefactors).HeisanactivememberofInternational Breast CancerStudyGroup(IBCSG),Michelangelo Foun-dation, GruppoItaliano Mammella (GIM). Puglisi is also nationaltreasurer ofItalianAssociationof Medical Oncol-ogy(AIOM).Asanexpertonclinicaltrialsinoncology,he servedontheBoardoftheEthicalCommitteeoftheGeneral HospitalofTrieste,Italy.

Caterina Fontanella received her Medical Degree in 2010from theUniversity ofTrieste,Italy.Since 2011,Dr. FontanellaworksaspostgraduatestudentattheDepartment of Medical Oncology,University Hospitalof Udine, Italy. Todate,sheisafellowshipresearcherattheGermanBreast GroupinstituteinNeu-Isenburg,Germany.Dr.Fontanellais theco-authorofdifferentpublicationsinpeer-reviewed jour-nalsandsheisamemberofItalianAssociationofMedical Oncology(AIOM).

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isthereferenceinthePiemonteandValled’Aosta Oncolo-gicalnetwork.Survivorshipcareisoneofhismainfieldof interest.

ValentinaSinireceivedherMedicalDegreein2006from “TorVergata”University of Rome, Italy.In 2011she spe-cialized in Oncology, “Tor Vergata” University of Rome. Since 2011 she is a PhDs in PhD University Grant Pro-gram“ClinicalandExperimentalResearch Methodologies in Oncology” provided by the Faculty of Medicine and Psychology, “Sapienza” University of Rome. She is an assistant at the Oncology Unit, Department of Oncology “Sant’Andrea”HospitalofRome.Sheauthored/coauthored different papers published in peer-reviewed international journals.Currentareasofresearchincludenewtreatmentsof breastcancer,cardiacandendocrine-relatedtoxicityof tar-getedandcytotoxicagents,optimizationofendocrinetherapy inbreastcancer.

LauraEvangelista,MDPhD,isanuclearmedicine physi-cianatIstitutoOncologicoVenetoIOV–IRCCSPadova,Italy. FollowingherresidencyinNuclearMedicineatUniversity “FedericoII” of Napoli Italy, sheworked as research fel-lowatUniversity“FedericoII”ofNapoliItaly(fromJanuary 2009toJune2009)andMemorialSloanKetteringof New YorkCity,USA(fromJanuary2011toApril2011)focusing onPET/CTinbreastcancerandmolecularimaging. More-over,in2009shemovedatIstitutoOncologicoVenetoIOV – IRCCSPadova,Italy, wheresheis currentlyworkingas anuclearmedicinephysician,withaspecial interestinthe nucleardiagnosticevaluationofbreastcancer.

Francesco Monetti received his M.D. degree with full marksfromtheUniversityofGenoa,Italyin1996.Hetook thespecialtyinRadiologyin2000attheUniversityofGenoa. Heworkedas radiologistinthe DepartmentofRadiology, BreastImagingSection,SanMartinoHospital-IST-National Cancer Institute, Genoa since 2001 until now. He is also theQualityManagerofthedepartmentsince2011.Hewas RadiologyReviewerforEORTCinEORTCphaseIIstudy:

The activity of raltitrexed (Tomudex)inmalignantpleural mesothelioma.HeisOECIauditorsince2013.Heismember ofItalianSocietyofMedicalRadiology(S.I.R.M.).

StefaniaGoriiscurrentlyDirectoroftheMedical Oncol-ogy Division inthe Departmentof Oncology atthe Sacro Cuore–DonCalabriaHospital, Negrar,Verona,Italy.She specializes in Internal Medicine and in Medical Oncol-ogy.StefaniaGori’sresearchinterestsincludeexperimental studies on basic and clinical applied research on breast cancer. She has been the Principal Investigator of many industry-sponsoredclinical trials.StefaniaGori is a mem-ber of numerous scientific societies, including the Italian Association of Medical Oncology (AIOM), the European Society of MedicalOncology (ESMO), andthe American Society of Clinical Oncology (ASCO). She is the author orco-authorofmorethan60publicationsinpeer-reviewed journals.