ITIF-抓住癌早期篩查的變革機遇-2021.04正式版WN4

SeizingtheTransformativeOpportunityofMulti-cancerEarlyDetection

STEPHENEZELL|APRIL2021

Blood-basedmulti-cancerearlydetection(MCED)technologiesholdthepromisetorevolutionizeAmerica’scancer-screeningparadigm,dramaticallyexpandingtherangeofdetectablecancersandidentifyingthematearlierstageswhencancersaremoretreatable.Policymakersshouldprovideasupportiveregulatoryandcoverageenvironment.

KEYTAKEAWAYS

Multi-cancerearlydetectionapproachesmergeemergingbiologicalandinformationtechnologies—includingnext-generationgenesequencing,artificialintelligence,andbigdata—inarevolutionarynewapproachtocancerdetection.

MCEDcandetectsignalsfordozensofdifferenttypesofcancerswithaveryhighrateofaccuracy,alowfalse-positiverate,andtheabilitytotracethedetectedcancertoitslikelytissueoforiginwithahighdegreeofconfidence.

MCEDholdsthepotential,overtime,totransformAmerica’scancer-detectionparadigmfromoneinwhichmostcancersaredetectedwhenpatientspresentsymptomaticallytooneinwhichtheycanbescreen-detectedinadvance.

IfU.S.enterprisesaretoleadinthisfast-emerging,intenselygloballycompetitivetechnologyfield—andifcitizensaretoenjoythebenefits—thenpolicymakerswillneedtogettheregulatoryandcoverageenvironmentright.

CongressshouldpasstheMedicareMulti-CancerEarlyDetectionScreeningCoverageAct,whichauthorizestheCentersforMedicare&MedicaidServicestouseanevidence-basedprocesstocoverblood-basedMCEDtests.

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INTRODUCTION

Cancerremainsoneofhumanity’smostintractablediseases,andisexpectedtosurpassheartdiseaseastheleadingannualcauseofAmericanfatalitiesby2030.Theindividual,social,andeconomiccostscancerinflictareenormous,meaningtheneedforbotheffectivecancerscreeningandtherapeuticoptionsremainsparamount.Fortunately,anewslateofbiologicalandinformationaltechnologies—includinggenomesequencing,bigdataanalytics,artificialintelligence/machinelearning(AI/ML),andnanotechnology—areenablingbreakthroughinnovationsincancerdetectionandtreatment.

Indetection,blood-basedapproachesholdthepotentialtoscreenforsignalsofover50cancerssimultaneouslywithaveryhighrateofaccuracyandtheabilitytotracethedetectedcancertoitslikelytissueoforiginwithahighdegreeofconfidence.Multi-cancerearlydetection(MCED)screeningholdsthepromisetoradicallyexpandthenumberofcancersforwhichthereareavailablescreeningoptionsandtobroadencancerdetectiontotheasymptomaticpopulation.Itheraldsapotentialparadigmshiftfromtryingtotreatcancerinlaterstagestodetectingandtreatingthediseaseinitsearliestones.Butifthepromiseofmulti-cancerearlydetectionscreeningapproachesistoberealized,policymakerswillhavetogettheregulatoryandcoveragepoliciesrighttosupportdeploymentanduptakeofthistransformativetechnology.

Multi-cancerearlydetection(MCED)screeningholdsthepromisetoradicallyexpandthenumberofcancersforwhichthereareavailablescreeningoptionsandtobroadencancerdetectiontotheasymptomaticpopulation.

Thisreportbeginsbyexaminingthesocialandeconomiccostscancerinflicts.ItdiscussestheimportanceofearlycancerdetectionandmovesontoanexplorationofhowMCEDtechnologieswork,evidenceoftheireffectivenesstodate,thebenefitstheyarecapableofproviding,andwhyit’simportanttheUnitedStatesremainthegloballeaderinthisfield.Itthenanalyzestheregulatoryandcoverageenvironmentbeforeconcludingbyprovidingrecommendationsforhowpolicymakerscanenactpoliciesenablingthistransformativetechnologytoflourish,includingbypassinglegislationcreatingapathwaytoensuretimelyMedicarecoverageofMCEDscreeningexams.

THEINDIVIDUAL,SOCIAL,ANDECONOMICCOSTSOFCANCER

Cancerreferstoagroupofdiseasescharacterizedbytheuncontrolledgrowthandspreadofabnormalcells.

1

ItremainsoneofAmerica’s,andglobalsocieties’,greatesthealthchallenges.Cancerisresponsibleforalmostoneinsixdeathsglobally.

2

Theglobalcancerburdenisexpectedtosurpass20millionnewyearlycasesby2025.

3

Canceristhesecond-mostcommoncauseofdeathintheUnitedStates,exceededonlybyheartdisease,althoughcancerisexpectedtobecometheleadingcauseofAmericanfatalitiesby2030.Likewise,amongadultsages35to70,whilecardiovasculardiseaseremainstheleadingcauseofmortalityglobally,“mortalityfromcancerwillprobablybecometheleadingcauseofdeath”inthenearfuture.

4

Expertspredicttheyear2021willsee1.9millionnewcancercasesdiagnosedintheUnitedStates,withover600,000Americansexpectedtoperishfromthedisease,whichtranslatestoabout1,650deathsperday.

5

Approximately1outofevery200Americans

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receiveacancerdiagnosiseachyear.ForAmericansborntoday,oneintwowomen,andoneinthreemen,arelikelytodevelopcanceratsomepointintheirlifetimes(withoneinfiveperishingfromthem).

6

OneineightU.S.womenwillbediagnosedwithbreastcancerintheirlifetimes.

7

Onereasoncancerratesareincreasingisbecausecancerisprimarilyadiseaseofoldage,andasAmericanslivelongeringeneral,thelikelihoodoftheirdevelopingacancergrows.IntheUnitedStates,60percentofallcancercasesdiagnosedareinpeopleaboveage65,while80percentofallcancersintheUnitedStatesarediagnosedinpeople55yearsofageorolder.

8

Americansages65andolderaremorethanseventimesmorelikelythanyoungerAmericanstobediagnosedwithcancer.

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SeventypercentofallAmericancancerdeathsoccurwithpeopleages65orolder.

10

Yet,despitebeingmoreprevalentintheolderpopulation,cancerisactuallytheleadingcauseofdeathforAmericansunderage65.

11

IntheUnitedStates,healthexpertspredictthatbreast,prostate,andlungcancerswillaccountforthemostnewcasesdiagnosedamongAmericanmenandwomenin2021.(See

figure1.)

However,intermsofcancerfatalities,lungcancerisnowtheleadingcauseofdeathforAmericanmenandwomenalike,secondisprostatecancerformenandbreastcancerforwomen,followedbycolorectalandpancreaticcancer.(See

figure2.)

Figure1:EstimatednewU.S.cancercases,2021(bycancertype,bothsexescombined)

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Figure2:EstimatedU.S.cancerfatalities,2021

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Fortunately,Americancancerfatalityrateshavedecreasedoverthepasthalf-century,largelytheresultofacombinationofmore-effectivescreeningapproaches,anoveralldecreaseinsmokinginthepopulation,andmore-effectivetreatmentandtherapeuticoptions.Forsomeofthemostcommoncancers—lung,colorectal,breast,andprostate—reductionsinsmokingandimprovementsinscreeninghaveledto36percentfewerdeathsthanwouldhaveoccurredotherwise.

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Americans’deathsfromcancerhavefallenfrom193.9per100,000populationin1950to152.5today.

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Sincepeakingintheearly1990s(at215per100,000population),U.S.cancerdeathrateshavedeclinedby27percent.

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Thisdeclinetranslatedintomorethan2.9millionfewercancerdeathsfrom1991to2017.

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AndbreakthroughtherapiessuchasAvastinandHerceptinforbreastcancer,Keytrudaforlungcancer,andYervoyformelanomahelpexplainwhyAmericancitizensenjoythehighestcancersurvivalratesintheworld.Forinstance,over99percentofU.S.womensufferingfromlocalizedbreastcancerarestilllivingfiveyearslater.

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Onestudyestimatesthatapproximately73percentofsurvivalgainsincancerareattributabletonewtreatments,includingmedicines.

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Moreover,asLichtenbergexplains,“Duringtheperiod2000–2011,thepremature(beforeage75)cancermortalityrate…declinedbyabout9percent.…Intheabsenceofpharmaceuticalinnovationduringtheperiod

1985–1996,theprematurecancermortalityratewouldhaveincreasedabout12percentduringtheperiod2000–2011.”

20

Yet,asAzraRaza,aprofessorofmedicineanddirectoroftheMDSCenteratColumbiaUniversity,writes,“Cancerisstillbeatingus…Ihavebeenstudyingandtreatingcancerfor35years,andhere’swhatIknowabouttheprogressmadeinthattime:Therehasbeenfarlessthanitappears.”

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Shepointsoutthat,forallthisprogress,overallcancerdeathratesarenotdramaticallydifferentfromwhattheywereinthe1930s,beforetheybeganincreasingalongsidetheriseinsmoking.Indeed,whiletheage-adjusteddeathrateper100,000U.S.populationfromheartdiseasefellbyroughlytwo-thirdsfrom1950to2010,thesimilarrateforcancerjustbarelydecreased.(See

figure3.)

As.Dr.BertVogelstein,aprofessorofoncologyatJohnsHopkinsUniversity,explains,partofthisdisparitycanbeattributedtothefactthattheheartdiseaseresearchcommunityhaslargelyfocusedonearlydetectionandprevention,“whereastheoncologycommunityhasbeenmorefocusedoncuringadvanceddisease.”

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Or,asRazaputsit,

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“Wenowinvestalotofeffortintofindingminimalresidualdisease.Whynotapplythesamerigorandfocustofindingminimalinitialdisease?”

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Figure3:Age-adjustedrateofdeathper100,000population

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Thus,despitesomeprogress,cancerstillafflictsmillionsannuallyandimposestremendouscostsontheU.S.healthcaresystem,aswellasthebroadereconomy.Canceristhesecond-most-costlydiseaseintheUnitedStates.

25

Canceraccountsforanestimated5to11percentoftheannualtotalU.S.healthcarebudget.

26

In2017,cancercarecosttheUnitedStatesanestimated$177billion(anincreaseofapproximately39percentsince2010),equivalentto1percentofU.S.grossdomesticproduct(GDP).

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Medicare—thefederallyadministeredhealthcareprogramthatcoversmorethan60millionseniorsandpersonswithdisabilities—shouldersroughlyone-thirdofthiscostannually.

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TheUnitedStatesinvestsabout$27billionannuallyoncancerscreeningtests.

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Canceristhesecond-mostcommoncauseofdeathintheUnitedStates—exceededonlybyheartdisease—althoughitisexpectedtobecometheleadingcauseofAmericanfatalitiesby2030.

Morethan$94billioninearningswerelostintheUnitedStatesin2015duetocancerdeaths.

30

A2008studyestimatedthatthevalueoflifelostfromallcancerdeathsintheyear2000totaled$960.6billionandpredictedthatthetotalvalueoflifelostin2020fromcancerdeathsintheUnitedStateswouldreach$1.5trillion.

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Thetremendouscostscancerimposesconverselysuggesttremendousbenefitsifcancerscouldbedetectedearlierwhentreatmentsaremorelikelytosucceedandasmore-effectivetreatmentsandtherapeuticsforcancerareinvented.Infact,MurphyandTopel,consideringthebenefitsofincreasedlongevityandimprovedqualityoflife,findthata1percentreductioninmortalityfromcancercoulddeliverroughly$500billioninnetpresentbenefits,whileacure(ifonecouldbeachieved)coulddeliver$50trillioninpresentandfuturebenefits.

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Similarly,Lakdawallaetal.examinedtrendsinsurvivalaftercancerdiagnosisfrom1988through2000andarguedthatimprovementsin

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treatmentsledtoapproximately24millionmorelifeyearsforpatients,ataneconomicvalueof$1.9trillion.

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Theirresearchfindsthattheoverwhelmingamountofeconomicvalueproducedfrominvestmentsincancerresearchanddevelopment(R&D)madebythepublicandprivatesectorhaveflowedtopatients,withhealthcareprovidersandpharmaceuticalcompaniesappropriating5to19percentofthetotaleconomicvaluecreated,withtherestaccruingtopatients.

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THEIMPORTANCEOFEARLYCANCERDETECTION

Earliercancerdetectiongeneratessignificanthealthandeconomicbenefits,asthetwofollowingsectionsattest.

HealthBenefits

Cancerismosteffectivelyandefficientlytreatedwhenitiscaughtearly,whenitislocalized,andbeforeithasmetastasizedtodistantpartsofthebody.Asonereportexplains,“Survivalratesimprovedramaticallywhencancerisdiagnosedearlyandthediseaseisconfinedtotheorganoforiginbeforeithashadachancetospread,andthecancerismorelikelytobetreatedsuccessfully.”

35

Earlydetection,especiallyresultingfromeffectivecancerscreeningprotocols,isparamounttoreducingmortalityfromcancer.AstheAmericanCancerSocietyexplains,“Screeningisknowntoreducemortalityforcancersofthebreast,colon,rectum,cervix,lung(amongcurrentorformerheavysmokers),andprobablyprostate.”

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Overall,patients’survivalratesare5to10timesgreaterwhencancerisdetectedatanearlystageratherthanatalatestage.

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Whencancerisdiagnosedafterithasspread,thefive-yearcancer-specificsurvivalrateis21percent,comparedwith89percentwhenthecancerisdiagnosedearlyandstilllocalized.

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AccordingtoastudybyClarkeetal.,“ProjectedReductionsinAbsoluteCancer–RelatedDeathsfromDiagnosingCancersBeforeMetastasis,2006–2015,”detectingcancerswithdistantmetastasesatearlierstagescouldpotentiallyreducecancer-relatedfive-yearmortalitybyatleast15to24percent.

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ThestudyfoundthatdetectionofmultiplecancertypesearlierthanstageIVcouldreduceatleast15percentofcancer-relateddeathswithinfiveyears,affectingnotonlycancer-specificbutall-causemortality.StageIVcancersrepresented18percentofallestimateddiagnosesbut48percentofallestimatedcancer-relateddeathswithinfiveyears.AssumingallstageIVcancerswerediagnosedatstageIII,51fewercancer-relateddeathswouldbeexpectedper100,000,areductionof15percentofallcancer-relateddeaths.Assumingone-thirdofmetastaticcancerswerediagnosedatstageIII,one-thirddiagnosedatstageII,andone-thirddiagnosedatstageI,81fewercancer-relateddeathswouldbeexpectedper100,000,areductionof24percentofallcancer-relateddeaths.

40

Earlierdetectionofcancerssavesbothlivesandcostsforhealthcaresystemsandeconomiesmorebroadly.

Theimportanceofearlydetectionbecomesevenclearerwhenexaminingitsimpactonsurvivalratesforcertainformsofcancer.Wellmorethan90percentofwomendiagnosedwithbreastcancerattheearlieststagesurvivetheirdiseaseforatleastfiveyears,comparedwithabout15percentforwomendiagnosedwiththemost-advancedstageofdisease.Morethan80percentoflungcancerpatientswillsurviveforatleastoneyearifdiagnosedattheearlieststage,comparedwitharound15percentforthosediagnosedwiththemost-advancedstagesofthedisease.

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Unfortunately,onlyabout15percentoflungcancersarediagnosedatthelocalizedstage,whenclinicalinterventioncanmarkedlyimprovepatientoutcomes.

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Ninetypercentofwomendiagnosedwithearliest-stageovariancancersurvivetheirdiseaseforatleastfiveyears,comparedwitharound5percentforwomendiagnosedwiththemost-advancedstageofdisease.Andmorethannineintenbowelcancerpatientswillsurvivethediseaseformorethanfiveyearsifdiagnosedattheearlieststage.

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Earlierdetectionmakesallformsofcancerinterventionmoreeffectivethanwhencancersarediagnosedatlaterstages.AsDr.Vogelsteinnotes,patientswithstageIIIcolorectalcancer,iftheyhavemicrometastases(i.e.,averysmallmicro-metastaticdisease,evenifalreadyspreadtootherorgans),givenchemotherapy,canrecoveralmost50percentofthetime;whereasifthecancerbecomesvisibleandbulky(visiblemetastases),therecoveryrateisclosetonil.Thisalsoholdstrueforthenewest,mostcutting-edgeinterventions,suchastargetedimmunotherapies(i.e.,immunecheckpointinhibitors)andCAR-T-based(chimeric-antigenreceptorTcell)therapies:Recoveryratesarefarhigherinpatientswithlowtumorburdensthanwithhigh.

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Indeed,inquitemanycases,thesetechnologiesmeanthatpatientswithlocalized(i.e.,StageI-II)solidtumorsarepotentiallycurable.AsRazawrites(aboutwhatthisevidencemakesclear):

Whatweneednowisaparadigmshift.Today,thenewestmethodsgeneratingthemostresearchandexpensetendtobefocusedontreatingtheworstcases—chasingafterthelastcancercellsinend-stagepatientswhoseprognosesaretheworst.

Weneedinsteadtocommittoanticipating,finding,anddestroyingthefirstcancercells.

44

Unfortunately,onlyfivetypesofcancer—breast,cervical,colorectal,prostate,and“high-risk”lung—haveguideline-recommendedscreeningoptionsavailabletoday,whereasthevastmajorityofcancers,includingblood,headandneck,pancreatic,ovarian,andlivercancers,havenoguideline-recommendedscreeningtestsavailable.

45

Thefivetypesofcancerwithguideline-recommendedscreeningoptionsrepresentapproximately40percentofthetotalcancerincidenceintheUnitedStates,yetonly15to20percentofcancerdiagnoseswhentestperformanceandcomplianceareaccountedfor,accordingtoananalysisof2006to2015datafromtheNationalInstitutesofHealth’s(NIH)Surveillance,Epidemiology,andEndResults(SEER)Program.

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Overall,about70percentofallU.S.cancerdeathsoccurincancerswithnorecommendedscreeningoptions.

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Thisisaglobalstory:Ofthe9.5millioncancerfatalitiesrecordedgloballyin2017,thevastmajorityhadnoscreeningtestavailabletodetectthecancerpriortotheonsetofsignsorsymptoms.(See

figure4,

wherecancerswithscreeningtestsavailableareshowninorange,andthosethatdonotareinblue.)

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Figure4:Globalcancerfatalities,bytype,2017

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Tracheal,bronchus,andlungcancer

Colonandrectumcancer

Stomachcancer

Livercancer

Breastcancer

Pancreaticcaner

EsophogealCancer

Prostatecancer

Leukemia

Cervicalcancer

Brainandnervoussystemcancer

Bladdercancer

Lipandoralcavitycancer

Ovariancancer

Gallbladderandbiliarytractcancer

Kidneycancer

Larynxcancer

Otherpharynxcancer

Multiplemyeloma

Othercancers

Uterinecancer

Nasopharynxcancer

Non-melanomaskincancer

Malignantskinmelanoma

Thyroidcancer

Hodgkinlymphoma

Testicularcancer

0 500,000 1,000,000 1,500,000 2,000,000

However,effectivescreeningcandelivertremendousbenefits:Sincethepapsmeartestwasintroduced,thecervicalcancerdeathrateintheUnitedStateshasdeclinedbyabout70percent.

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ThefirstU.S.trialofbreast-cancerscreening,launchedin1963,reducedmortalityby25percentinitsfirst18years.

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Andanalystsestimatethat,since1998,thenumberofU.S.breastcancerdeathspreventedduetomammographyincreasedfrom384,000to614,000.

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Earlierdetectionmakesallformsofcancerinterventionmoreeffectivethanwhencancersarediagnosedatlaterstages.

Accordingtoa2016studybySeaburyetal.,“QuantifyingtheGainsintheWaronCancerDuetoImprovedTreatmentandEarlierDetection,”anexaminationofthe15most-commontypesofcancersfoundthatthethree-yearcancer-relatedmortalityofcancerpatientsfellby16.7percentfrom1997to2007,withadvancesinearlydetectionresponsiblefor4.5percentagepointsofthatdecline(inotherwords,27percentofthedecline)andadvancementsintreatmentforareductionof12.2percentagepoints.

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Astheauthorswrote,“Cancerdetectionhasseensignificantbreakthroughs,suchasdigitalmammogramsandthedevelopmentofgeneticprofiletests.”

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Theirstudyfoundthattherelativeimportanceoftreatmentanddetectioninreducingmortalityvariedacrosscancertypes.Improvementsindetectioncontributedtoreducedmortalityratesforall15typesofcancersstudied,butweremostsignificantforthyroid,prostate,andkidneycancer.

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Improvedearlydetectionaccountedfor60percentofthereductioninthethree-yearmortalityrateforprostatecancerandjustabouthalfthereductionforkidneyandrenalpelviscancers.

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Earlierdetectionofcolorectalcanceraccountedfor42percentofthegainincolorectalcancersurvivalratesfrom1997to2007,abettedbythefactthatthepercentageofadultsreceivingrecommendedscreeningforcolorectalcancerrosefrom44to65percentfrom2000to2010.(Thatfigurestoodat68.8percentasof2018.)

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Overall,thestudyestimatesthatthebenefitsofearlierdetection(forthissuiteof15cancers)duringtheyears1997to2007generated$19billioninsocietalvalue(evenwithoutconsideringthebenefitsofhavingidentifiedpatientsbeforetheydevelopedmalignancies).

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EconomicBenefits

Earlierandbetterscreeningyieldseconomicbenefitsaswell.The2018report“MedicalCareCostsAssociatedWithCancerinIntegratedDeliverySystems”examinedthecostsassociatedwithtreatingcancerfromJanuary1,2000toDecember31,2008inapopulationofover45,000patientsdiagnosedwithoneofthefourmost-commonlydiagnosedcancersintheUnitedStates(breast,colorectal,lung,andprostate)whoweremembersofoneofthefourhealthcareplanswithintheCancerResearchNetwork.Thereportshowssignificantpotentialeconomicsavingsfromearliercancerdetection,andthatmeantotalone-yearcostsforlungcancerrangedfrom$50,700(stageI)to$97,400(stageIV)amongpatientsages<65yearsandfrom$44,000(stageI)to$71,200(stageIV)amongpatientsages≥65years.Forcolorectalcancerpatientsunderage65,thefive-yearcostoftreatmentforapatientwithstageIVcancerwas$205,100,comparedwith$65,000forastageIpatient.(Forindividualsover65diagnosedwithcolorectalcancer,thefive-yeartotalcostsrangedfrom$67,900forastageIpatientto$141,000forstage

patients).Similartrendswereapparentforlungandprostatecancer,withthefive-yeartotalcostsforastageIlungcancerpatientundertheageof65estimatedat$93,800andforastageIVpatientat$200,300;forprostatecancer,five-yeartotalcostsfortheunder-65stageIprostatepatientstoodat$51,800comparedwith$72,300forastageIVpatient.

Overall,thereportobserves“highercostsamongpatientsdiagnosedwithadvancedversusearlier-stagediseaseinthefee-for-servicesetting.”Itconcludesbynotingthat“netcostsofcarewerehighestforpatientsaged<65yearswithadvanced-stagecancers,suggestingthatearlydetectionandpreventionstrategiesarekeytocurtailinghighlong-termcostsassociatedwithlate-stagedisease.”Thereport“emphasizestheneedforcontinuedeffectivecancerscreening”especially“toreducethenumberofinvasivecolorectalandlate-stagefemalebreastcancerdiagnoses.”

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Thestudy’smessageisclear:Earlierdetectionofcancerssavesbothlivesandcostsforhealthcaresystemsandeconomiesmorebroadly.

Similarly,a2017study,“EstimatingCostSavingsforEarlyCancerDiagnosis,”soughttoexaminethecostsavingsfromearlycancerdiagnosisfor19cancers,assumingthatallstageIIIandIVcasesweredetectedatstageIorIIinstead(usingcurrentincidenceratesforthesecancers).Asthereportnotes,“Inmanycases,itismuchlesscostlytotreatcancerwhenitisdiagnosedearlier.”

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Inpart,that’sbecausecancerpatients’costsofcareinthelastyearoflifearesizablyhigherthanduringearlystages.Thestudyconcludedthatearlierdiagnosisofthosecancerscouldgenerate$26billionincostsavingsannually,equivalentto17percentoftotal

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estimatedyearlyexpendituresoncancertreatment.

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Forbreast,lung,prostate,andcolorectalcancers,andmelanoma,whicharethetop-fivecancersintheUnitedStatesbyincidence,withanestimated859,110newcasesin2017(accountingfor50.9percentofthe1,688,780cancercasesdiagnosedthatyear),thestudyestimated$10.7billioninsavingsfromearlierdiagnosis(about41.5percentofcostsavingsfromallcancers).

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Onestudyestimatedthatearlierdiagnosisofasuiteof19cancerscouldgenerate$26billionincostsavingsannually,equivalentto17percentoftotalestimatedyearlyexpendituresoncancertreatment.

Thosefindingsalsoconcordwitha2016studywhichexaminedthecostofbreastcancercoverageacrossvariousstagesofthedisease.Thestudyconcludedthat“thecostswerehigherforpatientswhosecancerwasmoreadvancedatdiagnosis,forallcumulative6-monthperiods(months0–6,0–12,0–18,and0–24).”Itfoundthattheaveragecostsperpatient(asallowedbyinsurancecompanies)intheyearafterdiagnosiswere$60,637,$82,121,$129,387,and