Benefits and Harms of Mammography Screening

25/9/2015
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BenefitsandHarmsofMammographyScreening
MagnusLbergMetteLiseLousdalMichaelBretthauerMetteKalager
BreastCancerRes.201517(63)
AbstractandIntroduction
Abstract
Mammographyscreeningforbreastcanceriswidelyavailableinmanycountries.Initiallypraisedasauniversalachievementtoimprovewomen'shealthandtoreducetheburdenofbreast
cancer,thebenefitsandharmsofmammographyscreeninghavebeendebatedheatedlyinthepastyears.Thisreviewdiscussesthebenefitsandharmsofmammographyscreeningin
lightoffindingsfromrandomizedtrialsandfrommorerecentobservationalstudiesperformedintheeraofmoderndiagnosticsandtreatment.Themainbenefitofmammography
screeningisreductionofbreastcancerrelateddeath.Relativereductionsvaryfromabout15to25%inrandomizedtrialstomorerecentestimatesof13to17%inmetaanalysesof
observationalstudies.UsingUKpopulationdataof2007,for1,000womeninvitedtobiennialmammographyscreeningfor20yearsfromage50,2to3womenarepreventedfromdying
ofbreastcancer.Allcausemortalityisunchanged.Overdiagnosisofbreastcanceristhemainharmofmammographyscreening.BasedonrecentestimatesfromtheUnitedStates,the
relativeamountofoverdiagnosis(includingductalcarcinomainsituandinvasivecancer)is31%.Thisresultsin15womenoverdiagnosedforevery1,000womeninvitedtobiennial
mammographyscreeningfor20yearsfromage50.Womenshouldbeunpassionatelyinformedaboutthebenefitsandharmsofmammographyscreeningusingabsoluteeffectsizesina
comprehensiblefashion.Inaneraoflimitedhealthcareresources,screeningservicesneedtobescrutinizedandcomparedwitheachotherwithregardtoeffectiveness,costeffectiveness
andharms.
Introduction
Theverb'toscreen'isdefinedas'tosiftbypassingthroughascreen'. [1]'To'sift'derivesfromanoldDutchword('zeef')a'utensilconsistingofacircularframewithafinelymeshedor
perforatedbottom,usedtoseparatethecoarserfromthefinerparticlesofanyloosematerial'. [1]
Thedefinitionsofscreeningvaryamongdifferentcultures,settings,andtimeperiods. [2,3]Ingeneral,alldefinitionsofscreeningincludeanidentificationofdiseaseordiseaseprecursor
amongpresumptivelyhealthyindividuals.Therearemainlytwodifferentapproachesofcancerscreening:preventionofdiseasebyfindingandremovingpremalignantprecursorsofcancer
andearlydetectionofcancerwherethegoalistotreattheinvasivecancerinanearlycurablestage. [4]In1968,theWorldHealthOrganizationsuggested10principlesthatshouldbe
fulfilledbeforeimplementingscreeninginapopulation(). [5]Someoftheprinciplesregardknowledgeaboutbiologicdevelopmentofcancer(principles4and7).
Table1.TheWorldHealthOrganization's10principlesofscreening
1.
Theconditionsoughtshouldbeanimportanthealthproblem
2.
Thereshouldbeanacceptedtreatmentforpatientswithrecognizeddisease
3.
Facilitiesfordiagnosisandtreatmentshouldbeavailable
4.
Thereshouldbearecognizablelatentorearlysymptomaticstage
5.
Thereshouldbeasuitabletestorexamination
6.
Thetestshouldbeacceptabletothepopulation
7.
Thenaturalhistoryofthecondition,includingdevelopmentfromlatenttodeclareddisease,shouldbeadequatelyunderstood
8.
Thereshouldbeanagreedpolicyonwhomtotreataspatients
9.
Thecostofcasefindings(includingdiagnosisandtreatmentofpatientsdiagnosed)shouldbeeconomicallybalancedinrelationtopossibleexpenditureonmedicalcareasa
whole
10. Casefindingshouldbeacontinuingprocessandnota'onceandforall'project
Screeningforbreastcancerwithmammographyaimsatdetectingbreastcanceratanearly,curablestage.Forearlydetectionbyscreeningtobebeneficial,weanticipateacontinuous,
lineargrowthpatternoftumors,andthatbreastcancerhasnotspreadatthetimewhentumorsaredetectableatmammography.Thus,iftheassumptionsoftumorgrowtharenotcorrect
orifgrowthoftumorsisheterogenic,screeningmammographymightnotbeanadequatetooltoreducetheburdenofbreastcancer. [6]
TheideaofearlydetectionstartedintheUSintheearly20thcenturywitheducationalmasscampaignswherethemessageof'donotdelay'seekingmedicalhelpforavarietyofcancer
signsandsymptomswascentral. [7]However,noneoftheseearlycampaignshadaneffectonthemortalityofbreastcancer. [8]In1963thefirstrandomizedtrialofmammography
screeningwaslaunchedwithintheHealthInsurancePlaninNewYork, [8]andseveralothertrialsfollowed. [9]Mostofthetrialswereperformedbeforewidespreaduseofantiestrogens
andmodernchemotherapywiththeexceptionoftheCanadianNationalBreastScreeningStudyandtheagetrial. [10,11]
Incontrasttoothercancerscreeningtools,mammographyscreeningwasevaluatedinrandomizedtrialsbeforeitwaswidelyrecommendedandimplemented.Nevertheless,therehas
beenacontinuousdiscussionofmammographyscreening,whichstartedinfullin2000afteraCochranereviewoftherandomizedtrialsindicatedlittleeffectofscreening. [12]More
recently,theeffectofmammographyscreeningoutsidetheexperimentalsetting,inthemodernerawithimprovementsinawareness,diagnostics,andtreatment,hasbeendiscussed.
[13,14]
Themammographydebatehasnotonlybeenaboutthebeneficialeffectsofmammographyscreening,butmorerecentlyalsotheharms.Inthelast10yearsincreasingawarenessof
overdiagnosisinmammographyscreeninghasemerged.Overdiagnosisisdefinedasthedetectionoftumorsatscreeningthatmightneverhaveprogressedtobecomesymptomaticor
lifethreateningintheabsenceofscreening.Thisisadirectharmofscreeningbecausemarkerstodistinguishtheoverdiagnosedtumorsfromthepotentiallifethreateningtumorsare
lackingand,thus,alltumorsaretreated.Womenwithoverdiagnosedtumorsonlyexperiencetheharmsandsideeffectsoftreatment,withoutanybenefit.Inthisreviewwediscussthe
benefitsandharmsofmammographyscreeningandgiveanoverviewofthefindingsfromrandomizedtrialsandfrommorerecentobservationalstudiesfromtheeraofmodern
diagnosticsandtreatment.Weaimatpresentingthebenefitsandharmsper1,000womeninvitedtomammographyscreeningwhostartedscreeningatage50yearsandwerescreened
everysecondyearuntilage69yearsscreeningofthisagegrouphasbeenshowntoachievemostofthebenefitwithlessharm. [15,16]
ScreeningMammography
AttendanceRates
Mammographyscreeningisrecommended(andinEuropeofferedthroughorganizedprograms)inmostWesterncountries.However,inSwitzerlandanindependentpanelofexperts(the
SwissMedicalBoard)reviewedtheevidenceonmammographyscreeningandconcludedthatharmsoutweighedthebenefitsandrecommendedagainstmammographyscreening [17]that
is,thatscreeningprogramsshouldnotbeimplementedinareaswheresuchprogramsdonotexistandthattheongoingprogramsshouldbephasedout.Whenscreeningis
recommended,theeligibleagerangediffersindifferentcountriesfrom40to74years. [4,18,19]Therecommendedintervalbetweentwoscreensvariesfrom1to3years. [18]Mammography
screeningiswellacceptedonaverage,morethanhalfofeligiblewomenattendscreeningmammography.Inmostcountries,attendanceratesarehigherthan70%.Womenaged50to
69yearshavethehighestattendancerate. [18,19]Theattendanceratevariesbetweencountries(19.4%to88.9%),andindifferentagegroups.Mostwomenwhohaveparticipatedonce
continuetoparticipate.
FalsePositiveTests
Aswitheverydiagnostictestthesensitivityandspecificityofmammographyscreeningarenotperfectvariouslevelsofsensitivityandspecificityfordetectingbreastcancerhavebeen
published. [20,21]Theriskofexperiencingafalsepositivemammogramforwomenundergoingbiennialscreeningfromage50to69yearsinEuropeisabout20%, [21]andtheriskof
experiencingabiopsyduetoafalsepositivetestis3%. [21]BasedondatafromtheUK,2.3%ofallwomenwithafalsepositivetesthadalumpectomy,representing76outof100,000
womenscreenedinonescreeninground. [22]TheriskisevenhigherintheUS,wherethe10yearfalsepositiverateis30%,and50%ofallwomenwillexperienceafalsepositive
mammogramatonetime. [23,24]Thechallengeswithafalsepositivetest,apartfromthemonetarycosts,areimpairedpsychologicalwellbeingandchangesinhealthbehavioramong
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womenwiththefalsepositivetest.After6months,only64%ofthoserecalledduetoafalsepositivetestweredeclaredcancerfreeafter1yearapproximately90%weredeclared
cancerfree,andonlyafter2yearswereallthosewhowereinfactfreeofcancerdeclaredcancerfree. [25]Researchhasshownthatfalsepositiveresultsnegativelyinfluencewomen's
psychologicalwellbeingduringtheperiodimmediatelyafterthetests,andarecentstudyshowedthatwomenwithfalsepositivefindingsexperiencepsychologicalharmforatleast3
yearsafterscreening. [26]Womenwithfalsepositivefindingshadhigheruseofhealthcareservices55%ofwomenwhoexperiencedapositiverecallreturnedtotheoutpatientclinicin
thefirstyearafterscreening,someuptoeighttimes, [27]andreportedlowerqualityoflifethanthosewithout. [27,28]Somewomenmayalsohavealteredhealthbehaviorandtrustinthe
healthcaresystem. [28]
FalseNegativeTests
Intervalcancersarecancersdetectedafteranormalscreeningmammogramandbeforethenextscheduledmammogram.Intervalcancerseitherwereoverlookedatthelastmammogram
orarerapidlygrowingcancersthatbecomeapparentinthescreeninginterval. [29]Inareinterpretationofintervalcancers,around35%wereoverlooked, [30]while65%werenotvisibleat
thelatestmammogramandappearedintheintervalbetweenscreeningmammograms.Ofallbreastcancersdetectedamongwomenwhoparticipateinscreening,28to33%areinterval
cancers, [20]andthisproportionseemstobestableinthedifferentscreeningrounds. [29]Useofdigitalmammographyisincreasing,anddetectionratesofductalcarcinomainsitu(DCIS)
andinvasivecancersarehigher.Whetherthiswilldecreasetheproportionofintervalcancersisunknown,buttherateofmissedcancersseemstobesimilartothatofanalogue,screen
filmmammography. [31]Onemightanticipate,therefore,thattheproportionofintervalcancerswithdigitalmammographywillbecomparabletothatwithanaloguescreenfilm
mammography.However,theincreasingdetectionrateswithdigitalmammographymightincreasetheamountofoverdiagnosis.
Womendiagnosedwithintervalcancerdonotbenefitfromearlydetection,butcouldbefalselyreassuredbytheirlastnormalmammogramanddelayseekingmedicalcare.However,this
mightnotseemtobethecaseaswomenwithintervalcancerdonothavepoorerprognosisthanwomenwhochosenottoutilizemammographyscreening. [29]
For1,000womeninvitedtomammographyscreeningeverysecondyearfor20yearsfromage50,200willexperienceafalsepositivemammogram,30willundergoabiopsyduetoa
falsepositivemammogram,and3willbediagnosedwithintervalcancer[32,33](Figure1).
Figure1.
Summaryofbenefitsandharmswhen1,000womenarescreenedeverysecondyearsfor20yearsstartingatage50.Numberofwomenwithfalsepositivemammogramsand
falsepositivebiopsiesarebasedonareview[32].NumberofintervalcancersarebasedonreportednumberofintervalcancerintheNationalHealthServicebreastscreeningprogramme
[33].Thenumbersofoverdiagnosedandpreventedbreastcancerdeathsareestimatedbasedon31%overdiagnosis[19]and13to17%reductioninmortalityfrombreastcancer[35].
Theserelativenumbersareappliedtotheobservedincidenceofinvasivebreastcancer(womenaged50to69years)andmortality(womenaged55to74years)intheUKin2007[32]
thisresultedin15overdiagnosedwomenand2to3preventedbreastcancerdeathsper1,000women.Nodeathsarepreventedoverall[9].
Overdiagnosis
Mammographyscreeninginevitablyentailsincreasedbreastcancerincidence[36]duetoearlierdetectionofcancersthatwouldotherwisehavebeendiagnosedlaterinlifeanddueto
diagnosisofcancersthatwouldnothavebeenidentifiedclinicallyinsomeone'sremaininglifetime.Thelattercategoryiscommonlyreferredtoasoverdiagnosis.Theoretically,
overdiagnosiscanoccurbecausethetumorlackspotentialtoprogresstoaclinicalstage,orevenregresses, [37]orbecausethewomandiesfromothercausesbeforethebreastcancer
surfacesclinically.Inreality,thesethreealternativescannotbereliablydisentangled.Inanyofthethreescenariostheindividualwomanwouldbediagnosedandtreatedwithnopossible
survivalbenefit.Hence,overdiagnosisrepresentsasubstantialethicaldilemmaandburdensthepatientandthehealthcaresystem.Treatmentforbreastcancerincludessurgery,
radiotherapy,chemotherapy,andantiestrogentreatment.Riskofdeathfromcardiovasculardiseaseisincreasedinwomentreatedwithradiotherapy, [38]andadjuvanttreatmentmaybe
cardiotoxic(forexample,taxanes,anthracyclines,ortrastuzumab). [39]Itispossiblethatovertreatmentcausesincreasedmortalitybyothercausesbesidesbreastcancer.Thismayexplain
whythereisnoreductioninmeasurableoverallmortalitywithscreeningmammography[9](Figure2).
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Figure2.
Scenariosfordifferentoutcomesofscreeningmammography.(A)Screeningisineffective.(B)Screeningiseffective.(C)Screeningleadstooverdiagnosis.(D)Screeningleadsto
overdiagnosisthatcausesdeathfromsideeffectsoftreatment.
Overdiagnosisdoesapplytobothcarcinomainsituandinvasivecancerthelifetimeriskofprogressionofcarcinomainsitutoinvasivebreastcancerisunknown,butprobablylessthan
50% [40]andtheleadtimeislongerforinsituthaninvasivecancers.Thus,itislogicalandintuitivethatcarcinomainsitucanbeoverdiagnosed.However,pathologicalverifiedinvasive
cancerscanalsobeoverdiagnosed.Thiscontradictswhatmostcliniciansweretaughtinmedicalschool,andcanbehardtounderstandforbothcliniciansandthepublic.Onewayof
lookingatthischallengeisbyusingthe'icebergmodel': [40]thedevelopmentofcancerisalengthyandcomplexprocess,whereunrepairedgeneticinstabilityandchangesintumor
microenvironmentcouldleadtodistinct,heterogeneoussubpopulationsofabnormalcells.Cancercanbeenvisionedasanicebergofdisease,wherethevisibletipabovethewaterline
comprisesthemostaggressivelesionsthosethatproducesymptomsandclinicaldisease.Themajorityofourbodyofknowledgeconcerningthenaturalhistoryofmalignanciescomes
fromobservationsfromthese'topoftheiceberg',symptomaticlesionsabovethewaterline. [40]Underneaththewater'ssurface,however,theremightbemultiple,indolentcancer
subpopulationsofcells.Thesesubpopulationswilllooklikecancertothepathologistifdetectedthroughscreening. [40]Earlydetection(suchasmammographyscreening)divesunderthe
surfaceandpicksupsilentlesions.Thenaturalhistoryoftheseasymptomaticlesionshasnotbeenstudiedandisthereforeessentiallyunknown,butmanyofthesemaybeindolentover
timeandnevergeneratesymptomsordiseasewithoutscreening.
EstimatesofOverdiagnosis
Preciseestimationofoverdiagnosisisacomplicatedanddifficulttask.Thereisnoperfectanalysisthatwouldbeuniversallyapplicabletothisproblem.Consequently,recentstudiesshow
alargevariationintheestimatedoverdiagnosisofbreastcancer,fromnoneto54%. [41]Instudiesbasedonstatisticalmodelingtoadjustforleadtime,estimatesofoverdiagnosisare
consistentlybelow5%. [42,43]Incontrast,observationalstudieshavepublishedhigherestimates,between22and54%, [37,41,42]dependingontheuseofthedenominator. [44]In,we
presenttheamountofoverdiagnosisandreductioninmortalityestimatedwithdifferentdenominators(incidence/deathfrombreastcancerindifferentagegroups).Itclearlyshowsthat
differentdenominators(rows2to4in)resultindifferentamountsofoverdiagnosisandmortalityreduction.Thus,itisimportantthatbenefitsandharmsofmammographyscreeningare
presentedusingsimilardenominators(in).
Table2.Differentpercentagesofoverdiagnosisandmortalityreductionbasedonthenumberofcancersoverdiagnosedanddeathsavoidedfrombreastcancerusingdifferent
denominators(incidence/deathfrombreastcancerindifferentagegroups)inNorwayin2010
Age(years) Expectednumberofcancers Percentageofoverdiagnosis(n=714.4) Expectednumberofbreastcancerdeaths Percentageofmortalityreduction(n=53.7)
5099
2,208
19.4
693
7.8
5079
1,571
27.3
506
10.6
5069
942
45.5
334
16.1
TheexpectednumberofbreastcancersandbreastcancerdeathsisestimatedastheobservedincidenceandmortalityratesinNorwayfrom1980to1984multipliedbytheNorwegian
femalepopulationin2010[4547].Thenumberofoverdiagnosedcancers(714.4cancers)isbasedonstudiesbyFalkandcoworkers[45]andKalagerandcoworkers[44]andthenumber
ofreducedbreastcancers(53.7avoideddeathsfrombreastcancer)isestimatedbyreducingthenumberofexpected(358)breastcancerdeathsby15%intheagegroup55to74years
(3580.15=53.7).
5099
2,208
19.4
693
7.8
5079
1,571
27.3
506
10.6
5069
942
45.5
334
16.1
(3580.15=53.7).
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5099
2,208
19.4
693
7.8
5079
1,571
27.3
506
10.6
5069
942
45.5
334
16.1
(3580.15=53.7).
Overdiagnosismightbeunderestimatedinthestatisticalmodelingstudiesbecausetheytestedonlyoneassumptionatatime,basedeitheronassumptionsfortheriskofprogression
fromcarcinomainsitutoinvasivecancer, [42]oronsojourntimewithadjustmentforleadtime. [42,43]Instatisticalmodelsbasedonsojourntimeandleadtime,overdiagnosishasbeen
disregardedintheestimationofleadtime,sincetheassumptionofgrowthhasbeenbasedonaprogressivedisease.This,however,isnotthecaseforoverdiagnosiswherethediseaseis
nonprogressiveorperhapsevenregressive. [37]Thus,whenusingtheseestimates,overdiagnosisislikelytobeunderestimated. [48]
Sincewedonothaveanydirect,biologicalevidenceofnonprogressionorregressionofbreastcancer,assumptionscannoteasilybetested,andrepresentonlya'guess'.Evidencefrom
observationalstudiesismoreconvincing.Thedifferenceintheestimatesfromobservationalstudies(22to54%)mightbeduetodifferentassumptionsofexpectedchangesinbreast
cancerincidenceduetochangesinbreastcancerriskfactors,differentfollowuptimeafterintroductionofscreening,anddifferencesinaccountingforleadtime.After25yearsoffollow
up,theCanadianNationalBreastScreeningStudy, [10]comparingphysicalbreastexaminationwithcombinedphysicalbreastexaminationandannualmammographyinwomenaged40
to59years,foundanexcessofinvasivecancerinthescreeningarm,resultingin22%overdiagnosis.Whenthenumberofbreastcancersdetectedatscreeningisusedasthe
denominator(asintheCanadianstudy),theamountofoverdiagnosisobservedinthepreviousrandomizedtrialsisstrikinglysimilar(22to24%)[10,49]andinlinewiththe30%reportedin
theCochranereviewofscreeningforbreastcancerwithmammography. [9]TheamountofoverdiagnosismightevenbehigherbecauseDCIS,whichaccountsforoneoutoffourbreast
cancersdetectedatmammographyscreening,wasnotincludedintheseestimates. [10]IfDCISisaprecursorofinvasivebreastcancer,wewouldexpectadropinincidenceofinvasive
breastcancerafterdetectionandremovalofDCIS.Thereisnoevidenceforthis.Onthecontrary,incidencerateskeepincreasingincountrieswithmammographyscreening. [50]
Giventheuncertaintyoftheestimatesfrommodelingandobservationalstudies,weusedthebestavailableestimateofoverdiagnosisfromobservationaldatafromaUSstudywhere
DCISandinvasivecancerwereincluded,followupwasmorethan25yearsafterscreeningwasinitiatedandnoextensiveuntestableassumptionsweremade. [19]However,intheUS
thereisnomammographyscreeningprogram,andtherateoffalsepositivesishigherthaninEuropeandAustralia.Thus,itmightbepossiblethattheamountofoverdiagnosisdiffers
betweentheUSandEuropeandAustralia.SincenoneoftheestimatesofoverdiagnosisfromEuropeorAustraliawerebasedonfollowupaslongasintheUSstudy,wechoosetouse
theUSestimateof31%overdiagnosis(inlinewithwhatisobservedintherandomizedtrials). [19]Weestimatedthenumberofoverdiagnosedwomenbasedontheobservedincidenceof
invasivebreastcancerinwomenaged50to69yearsintheUKin2007. [19,34,49]For1,000womeninvitedtobiennialmammographyscreeningfor20yearsfromage50,15willbe
overdiagnosed(Figure1).Basedondifferentmetaanalysesandreviewsofbenefitsandharmsofmammographyscreening[9,22,32]andourbestestimate, [19,34,35]wepresentafigure
showingthedifferentestimatesofoverdiagnosisandpreventeddeathsfrombreastcancer(Figure3).
Figure3.
Differentestimatesofoverdiagnosedwomenandsavedlivesfrombreastcancerindifferentmetaanalysesandtrials.Euroscreen:estimatesderivedfromareviewof
observationalstudies,whereestimatesofmortalityreductionfromcasecontrolstudiesareincluded[32].UKIndependentreview:estimatesonrelativeeffectderivedfromrandomized
trialsofmammographyscreeningandappliedtoUKnationalratesforwomenaged55to79years[22].UKObservational:estimatesbasedon31%overdiagnosis[19]and13to17%
reductioninmortalityfrombreastcancer[35]andappliedtotheobservedincidenceofinvasivebreastcancer(womenaged50to69years)andmortality(womenaged55to74years)in
theUKin2007[34]thisresultedin2to3preventeddeathsfrombreastcancer.Cochranereview:estimatesfromtherandomizedtrialsofmammographyscreening[9].TheCochrane
reviewdoesnotassumetheeffectofmammographyscreeningtolastfor20yearsasisassumedintheotherestimates,butrelatestowhatwasobservedintherandomizedtrials[9].
Tobeabletodifferentiatebetweenpotentiallethalandnonlethalcancers,experimentalstudieshavetobeperformed,preferablyasaninterdisciplinarycooperationbetweenthe
biomedicalandclinicalcommunities.First,however,onehastoacceptthatoverdiagnosisdoesoccur,andperhapsalsochangetheterminologyofnonlethalcancerto'IDLEtumor'
(InDolentLesionsofEpithelialorigin),asrecentlysuggested. [6]
BreastCancerMortality
Accordingtotherandomizedbreastcancerscreeningtrials,therelativereductioninmortalityfrombreastcancerrangesbetween15and25%[9,22,36,51]forwomenaged50to69years.
Thedifferencesintheseestimatesareduetodifferencesininclusionofrandomizedtrialsinpooledestimates.Forthe25%estimatedreduction,mammographyscreeningversusno
screeningiscomparedthus,theCanadiantrialwasnotincludedbecausetheycomparedphysicalbreastexaminationtocombinedphysicalbreastexaminationandannual
mammography. [10,36]Forthe15%estimatedreduction,methodologicallimitationsinsomeoftherandomizedtrialswasaccountedfor [9]withoutthis'adjustment',a20%reductionwas
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found. [9,22,52]Noneoftherandomizedtrialsshowedanyeffectoncancermortalityorallcausemortality. [9]Giventhenumberofwomenenrolledintherandomizedtrials(660,000)anda

20%reductioninbreastcancermortality,a2%reductioninallcausemortalityshouldhavebeendetectable. [52]Theabsenceofareductioninallcausemortalityindicatesthatwomendie
ofotherdiseasesataboutthesametimeinlifewithandwithoutscreening.
StudyDesigns
Thereareanumberofmethodstoinvestigatetheeffectofmammographyscreeninginanonexperimentalsetting.Cohortstudies,casecontrolstudies,andtrendstudiesshowdifferent
estimatesofmortalityreduction,rangingfromnoeffectto50%reductioninbreastcancermortality. [53,54]
CohortStudies.Theoptimalnonexperimentaldesigntoinvestigatetheeffectofmammographyscreeningisacohortstudyofwomeninvitedandwomennotinvitedtomammography
screeningwhohavesimilarbaselineriskforbreastcancerandbreastcancerdeathandsimilaropportunitiesforoptimalbreastcancertreatment.Onlyfewsuchstudiesexist,andthe
estimatedeffectofmammographyscreeningonbreastcancermortalityvariesfrom10to25%reduction. [35]Apooledestimateofthesetrialsshowedareductioninbreastcancer
mortalityof13to17%. [35]
CaseControlStudies.Incasecontrolstudies(sometimescalledcasereferentstudies)casesarewomenwhodieofbreastcancerandcontrolsarewomenwhoarealivestratifiedby
whethertheyhaveundergonescreeningmammographyornot.Thus,thesestudieswhenperformedinsettingswheremammographyscreeningisrecommendedorwherescreening
programsexistarecomparisonsofwomenwhoparticipateandwhodonotparticipateinmammographyscreening.Thevalidityofthesestudiesislowbecauseofhealthyscreeneeand
selfselectionbias,aswomenwithbreastcancerarenoteligibletomammographyscreeningortobecontinuedtobescreened(selectionofthemosthealthy),andwomenwhochooseto
participateinmammographyscreening(selection)maydifferwithregardtoriskofdeathfromthosewhodonotparticipate. [55]Attemptstoadjustforthesebiaseshavebeendoneby
adjustingfortherelativeriskinbreastcancermortalitybetweenthenonparticipantsandthenoninvitedcomparisongroup. [7,56]Theunderlyingassumptionoftheseadjustmentsisthat
wedoknowtheriskofuninvitedwomen.Inrandomizedtrials,wecaneasilyfindtheriskofbreastcancerdeathforthosenotinvitedtomammographyscreening(thecontrolgroup).
However,inobservationalstudieswhereeverybodyisinvitedorrecommendedtoundergomammographyscreening,wehavetomakeassumptionsonriskofdeathfrombreastcancer
amongtheuninvitedwomen.Theseassumptionscannotbetestedandarethereforebasedon'bestguess'estimates.Incasecontrolstudies,a50%reductioninmortalityfrombreast
cancerisfound,andsimilarreductionsarefoundincohortstudiesofparticipantsandnonparticipantsinmammographyscreening. [54,57]WhentherandomizedtrialfromMalmwas
analyzedasacasecontrolstudy,a58%reductioninmortalityfrombreastcancerwasfound,whereasthereal,observedreductioninthetrialwasonly4%(8%whentheresultswere
adjustedfornoncomplianceandcontamination). [36]Thus,estimatesfromcasecontrolstudiessystematicallyoverestimatetheeffectofscreening.
TrendStudies.Trendstudiesarestudiesofpopulationbasedbreastcancermortalityovertimeindifferentages(agestandardization)andgeographicareas.Dataonpopulationbased
breastcancermortalityareeasytoretrieve,butastheyearlymortalityrateisnotreflectiveoftimeofdiagnosis,deathsfrombreastcancerdiagnosedbeforeinvitationinfluencesthe
mortalityratesomeyearsafterscreeningisimplemented.Further,whenalleligiblewomenareinvitedandascreeningprogramhasbeenrunningforsometime,themortalityrateis
expectedtoreachasteadystateandfurtherreductioncannotbeexpected.After7yearsoffollowupintheHealthInsurancePlanstudy,themortalityreductionwasnolongerapparent,
[58]indicatingthatscreeninghasnoeffectifnolongeroffered.Foracontinuingprogram,however,themortalityeffectwillnotdisappear,butreachasteadystate.Thus,inthefirstyears
afterscreeninghasbeenintroducedandreachedfullcoverageintheareastudied,thecauseofchangeintrendsofbreastcancermortalitycanbedifficulttostudyandinterpret.Most
trendstudiesshowthatbreastcancermortalityhasdeclinedinmostEuropeancountriessincetheearlytomid1990s.Thedeclineinmortalityisevenhigheramongwomenyoungerthan
theeligibleagerangeforscreeningandforsomecountriesareductionisobservedalsoforwomenolderthantheeligibleagerange. [59]Theinterpretationoftheseresultscouldbethat
heightenedawarenessandimprovedtherapyratherthanmammographyscreeningareresponsiblefortheobservedreduction. [53,59,60]
TumorStage
Anotherbenefitofmammographyscreeningcouldbethatbreastcancersdetectedatscreeningaresmallerandthuslessadvancedthanthosedetectedclinically.Ingeneral,smaller
tumorsaremorelikelytoberesectedbylumpectomy,andwithlessnodepositivedisease,lessadjuvanttherapyisneeded.Basedontherandomizedmammographyscreeningtrials,
however,thisisnotthecasescreeningwasassociatedwithanincreaseinthenumberofmastectomiesofabout20%. [9]Thereasonisthatmammographyincreasedboththenumberof
womendiagnosedwithinvasivebreastcancerandthenumberfoundtohavemultiplemicroscopiccancersdistributedthroughoutthebreast,forwhichmastectomyisrecommended.
Further,intheNationalHealthServicebreastscreeningprogramintheUK,30%ofDCISand24%ofinvasivebreastcancersweretreatedwithmastectomy,soearlierdetectiondoesnot
necessarilymeanlessaggressivetreatment. [61]Asmentionedabove,anotherbenefitofmammographyscreeningcouldbelessaggressiveadjuvanttherapy,duetosmallerandless
aggressivetumors.AsseeninthestagedistributioninscreeningandnonscreeninggroupsinNorway, [41]screeningledtothediagnosisof58%morestageI(localizedcancer)and22%
morestageII(regionalcancerorcancerinvolvingthelymphnodes)cancers,withoutanyreductioninadvancedstagedisease(stagesIIIandIV).Sinceallthesepatientsreceivesurgery
(eithermastectomyorbreastconservingsurgerywithradiation)andmoststageIIpatientsarerecommendedtoreceiveadjuvantchemotherapy,screeningmayhaveledto58%more
womenundergoingbreastsurgeryand22%morewomenundergoingadjuvantchemotherapy. [41]Thus,screeningmammographydoesnotseemtoreducetheburdenofreceivingmore
aggressivetreatment.
CauseofDeath
Thenumberofwomensavedfrombreastcancerdeathmightbeoutweighedbydeathfromothercausesduetoharmsoftreatmenthowever,duetouncertaintyabouttheoverallnumber
ofwomensaved,wepresentdifferentestimatesofwomensavedfrombreastcancerindifferentmetaanalysesofrandomizedandobservationalstudiesofbreastcancer[19,22,32,34,35]
(Figure3).Thenumberneededtobeinvitedtomammographytosaveorharmwomenishighlydependentontheunderlyingriskofbreastcancerordeathfrombreastcancer(Figures4
and5,showingriskofbreastcanceranddeathfrombreastcancerintheUSandUK [49,62]).IntheestimatesshowninFigure1,weuseUKdatafrom2007formortalityfrombreast
cancerinwomenaged55to74years, [34]andtherelativereductionof13to17%inbreastcancermortalitybasedonametaanalysisofobservationalstudies. [35]For1,000women
invitedtomammographyscreeningeverysecondyearfor20twentyyearsfromage50,2to3womenarepreventedfromdyingfrombreastcancer(Figure1).
Figure4.
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Benefitandharmwithscreeningmammographyanduseofaspirinover10years[62].Shownarethe10yearriskofdeathfrombreastcancer(barsabove0)andthe10yearrisk
ofthediagnosisofbreastcancer(barsbelow0)amongwomenaged40yearsand50years,withandwithoutmammographyscreening.Alsoshownarethe10yearriskofdeathfrom
cancer(barabove0)andthe10yearriskofmajorextracranialbleeding,definedasbleedingnecessitatingtransfusionorresultingindeath(barbelow0),associatedwiththeuseornon
useofaspirinasaprimarypreventivemeasure(onthebasisoffindingsfromrandomizedtrials).Ineachpair(noscreeningversusscreeningandnoaspirinversusaspirin),thedifference
betweenthepercentagesrepresentedbythebarsshowstheabsolutebenefitorharmassociatedwithscreeningmammographyortheuseofaspirin.Backgrounddataarederivedfrom
theliterature.
Figure5.
Twentyyearriskfordiagnosisof,anddeathfrom,breastandprostatecancerwithandwithoutscreeningintheUnitedKingdom[49].Displayedare20yearabsoluterisksfor
incidence(includingoverdiagnosis)andmortalitywithandwithoutscreening.Overdiagnosisissetto45%forprostatecancerand22%forbreastcancer,respectively(age50to69years).
Mortalityreductionissettobe20%forbothcancers(age55and74years).Forprostatecancer,theestimatesarebasedontheobservedincidenceandmortalityin1998(beforeany
widespreaduseofprostatespecificantigen(PSA))andforbreastcancerin2007(latestdataavailable).
InformationtoWomen
Screeningdiffersfromclinicalpractice.Individualswhoundergoascreeningprocedureareinvitedtoparticipatewiththeimpliedexpectationthattheywillbenefit.Thiscontrastswith
clinicalpractice,wherethepatientsapproachthemedicalpractitionerwithasymptomorcomplaintforhelp. [3]Thus,itisofutmostimportancethatinformationaboutbenefitsandharms
ofmammographyscreeningisbalanced.However,theharmsofscreeninghavenotbeencommunicatedtothepublicaswellasthebenefits. [63,64]Withincreasingevidenceof
overdiagnosis,thisisofconcernandviolatestheindividual'spossibilitytomakeaninformedchoice.
However,properinformationonrisksandbenefitsisnoteasy.Firstly,howdoclinicianscommunicatebenefitsandharms?Theuseofrelativerisksmaysuggestgreatereffectsthanexist,
whereastheuseofabsoluterisks(orequivalents,suchasthenumberneededtoscreen)preventsthismisunderstanding.Theuseofrelativerisksshouldbeavoidedoremployedonlyin
combinationwithmorecomprehensibleformsofcommunicatingrisk,suchasabsoluterisksornumbersneededtoscreen. [65]Secondly,manycannotinterpretnumbersaswellaswords
andhavedifficultyunderstandingnumericalexpressionsofrisk. [66]Inmedicalschools,coursesinstatisticsusuallydonotgofarenoughinteachingstatisticalorprobabilisticthinking,and
fewteachstrategiesforeffectivecommunication.Hence,mostphysiciansarepoorlyequippedtodiscussriskfactorsinawaythatisreadilycomprehensibletotheirpatients.This
deficiencyputstheidealofinformedconsentinjeopardy. [65,67]
Framingisthepresentationoflogicallyequivalentinformationindifferentforms.Positiveframingemphasizestheabsenceofdiseasenegativeframingemphasizesthepresenceof
disease[65](Figure6).Basedonthe20yearriskforawomanintheUKtodieofbreastcancer,theriskofdyingfrombreastcancerwithmammographyscreeningwouldbe15per1,000
womenand17to18per1,000womenwithoutmammographyscreening. [49]Positiveframingwouldbethatthenumberofwomenthatwillnotdiefrombreastcancerrisesfrombetween
982and983to985per1,000womenwiththeadditionofscreeningforbreastcancer. [34,35]AnexampleofpositiveframingisillustratedinFigure6.
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Figure6.
Positiveframing.Outof1,000womenaged50to69yearsinvitedeverysecondyear,781arealivewithscreeningandthesamenumberwithoutscreeningoverthecourseof20years.
Correspondingly,985womenand982to983womenwithoutscreeningwillnotdieofbreastcanceraged55to74years.Negativeframing:outof1,000womenaged50to69years
invitedeverysecondyear,204womenwilldiewithscreeningandthesamenumberwithoutscreening.Correspondingly,15womenwithscreeningand17to18womenwithoutscreening
willdieofbreastcancerbetween55and74yearsold.Numberofwomendyingamongwomenaged55to74yearsisbasedontheobservedmortalityratesinEnglandandWalesin2007
[68].Thenumberofwomendyingovera20yearperiodisestimatedbysummingthemortalityratesfortheages55to74[68].
Womenarenotonlyoverestimatingtheirriskofbreastcancer,butalsosubstantiallyoverestimatingthebenefitofmammographyscreening. [67,6971]Over50%ofallwomenasked
thoughtmammographyscreeningreducedtheriskofdyingfrombreastcancerbyatleast50%. [67,69]Further,womenwantedtohavebalancedinformationandsharethedecisionwith
theirphysician, [71]butmanyreportedtheywereneverprovidedinformationonfalsepositivesandsideeffects. [71]AreportfromNorway,wherewomenareinvitedwithaprescheduled
timeanddateofascreeningmammographyappointment,showedthatiftheinvitationletterincludedaninformationleafletaimedatenablingwomentomakeafreeandinformed
choice,theprescheduledappointmentunderminedtheoptionofnotparticipating. [72]Theauthorsconcludedthatthecurrentrecruitmentproceduresgaveprioritytoscreeninguptakeat
theexpenseofinformedchoice. [72]Thus,theprincipleofinformedchoicemightbeinjeopardy. [72]
Conclusion
Womenshouldbecorrectlyinformedaboutthebenefitsandharmsofmammographyscreening(Figures1and2).Acomprehensiblewayofcommunicatinginformationonbenefitsand
harmsofmammographyscreeningispresentedinFigure1:among1,000womenwhostartscreeningatage50andarescreenedfor20years,2to3willavoiddyingfrombreastcancer
and200womenwillhaveatleastonefalsepositivetest,30willundergoabiopsy,3willbediagnosedwithanintervalcancer,andbreastcancerwillbeoverdiagnosedin15.
Inaneraoflimitedresourcesforhealthcareandpreventiveservices,weneedtoscrutinizeoureffortsinscreeningandprevention.Oneoftheoverarchinggoalsofscreeningisthe
reductionofincidenceormortalityofdisease.Currently,wedorecommendsomescreeningservices(suchasmammography),whileothersaredebatedordiscouraged(suchasprostate
specificantigenscreeningforprostatecanceroraspirinforprimarypreventionofcardiovasculardiseaseandprematuredeath).However,asFigures4and5show,thesedifferencesin
recommendationsdooftennotreflectdifferencesineffectivenessorharmsbetweenthedifferenttests. [49,62]
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Abbreviation
DCIS:Ductalcarcinomainsitu
Acknowledgements
ThestudywassupportedbygrantsfromtheNorwegianCancerSociety(PhDscholarshipMagnusLberg,grantnumberHS0220090082),USNorwayFulbrightFoundationfor
EducationalExchange(FulbrightfellowshipMagnusLberg),andHelseSorOst(ResearchgrantMetteKalager,grantnumber2014106).
BreastCancerRes.201517(63)2015BioMedCentral,Ltd.
Copyrighttothisarticleisheldbytheauthor(s),licenseeBioMedCentralLtd.ThisisanOpenAccessarticle:verbatimcopyingandredistributionofthisarticlearepermittedinallmedia
foranypurpose,providedthisnoticeispreservedalongwiththearticle'soriginalcitation.
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Age(years) Expectednumberofcancers Percentageofoverdiagnosis(n=714.4) Expectednumberofbreastcancerdeaths Percentageofmortalityreduction(n=53.7)

Age(years) Expectednumberofcancers Percentageofoverdiagnosis(n=714.4) Expectednumberofbreastcancerdeaths Percentageofmortalityreduction(n=53.7)

Age(years) Expectednumberofcancers Percentageofoverdiagnosis(n=714.4) Expectednumberofbreastcancerdeaths Percentageofmortalityreduction(n=53.7)

found. [9,22,52]Noneoftherandomizedtrialsshowedanyeffectoncancermortalityorallcausemortality. [9]Giventhenumberofwomenenrolledintherandomizedtrials(660,000)anda

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