CaseComprehensiveCancerCenterStantonL.Gerson,MD,DirectorCancerMoonshotInitiative

Observations,RecommendationsandSuggestedFocusAreas

March30,2016

DiscussionOverview

Background

I. RecommendationsA. ProvideSupportforAcademicCancerCenter-basedDrugDevelopmentPipelinesB. Support“BigData”IntegrationTools

II. Enhancing the quality and value of community based networks operated bymajor CancerCenters

A. CoordinatedApproachB. QualityReportingC. ClinicalTrials

III. FocusAreasA. RecommendedFocusAreastoProduceSubstantialResults

§ ScreeningandPreventionØ HPVVaccinationtoReduceCervicalandHead&NeckCancersØ LungandColonCancerScreeningØ EsophagealCancerScreeningØ AspirinforColorectalCancerPreventionØ Exercise,WeightReductionandDiet

§ TranslatingGenomicInsightstoReducedRiskandImprovedTreatmentØ AdolescentandYoungAdultCancerGenomicsØ UniqueGeneticCausesofCancerinAfricanAmericansØ HighCancerIncidenceinFamiliesØ CancerRecurrenceandMetastasis

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CaseComprehensiveCancerCenterExecutiveCommitteeStantonL.Gerson,MD,DirectorCancerMoonshotInitiative

Observations,RecommendationsandSuggestedFocusAreas

March30,2016Background:

TheCaseWesternReserveUniversity(CWRU)ComprehensiveCancerCenterExecutiveCommitteehas been working under the guidance of Director Stan Gerson to develop recommendations toinformandguidetheworkoftheOfficeoftheVicePresidenttoadvanceprogressoncancer.

The Executive Committee brings together the Case Comprehensive Cancer Center (Case CCC)consortium partners – including University Hospitals (UH), Cleveland Clinic (CC), Case WesternReserveUniversity (CWRU)andmemberMetroHealth System– in a collaborativeeffort todriveprogressincancerresearchandtreatmentforthebenefitoftheservicepopulationinnortheasternOhio.

SetforthbelowareourobservationsandrecommendationsregardingtheCancerMoonshotwhichincludes matters of national applicability, issues of particular impact in Northeastern Ohio, andopportunitiesrelatedtoparticularareasofconsortiumexpertise.

Manybarriersexistinpreventingexpeditedtreatmentsolutionsforcancercare.Includedinthosebarriersarebothinfrastructureandpoliticalchallenges.

Someofthekeybarriersinclude:§ TheVeteransAdministrationasanindependentsystem§ Lowscreeningrates§ LowHPVvaccinationrate§ Universalconsentneeds§ Povertyandaccess§ Environmentalexposures§ Hospitalcompetition§ Restricteddatasharing

InNortheastOhio,theCaseComprehensiveCancerCenter:§ Captures2outofevery3oncologypatients§ Enrollsalmost10%ofpatientsinclinicaltrials

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I. Recommendations:

A. ProvideSupportforAcademicCancerCenter-basedDrugDevelopmentPipelines.

CaseCCCinvestigatorsandtheirsponsor institutions(CWRU,UHandtheClevelandClinic)have developed robust pipelines of new anti-cancer drugs that are in various stages ofdevelopment--rangingfromchemistrytopreclinicalmodelstophase1and2clinicaltrialsbeingconductedatconsortiumhospitals.Wemodelnewtargets,mechanismsoftreatmentresistance,andnoveldrugcombinations.

The National Cancer Institute (NCI), the institutions themselves, or philanthropic sourcessupportfundingforthispipelineactivity.Currently,17drugsand5nano-therapeuticsareinsomestageofdevelopment.Thismodelofdevelopmentprovidesanenvironmentwheredrugdevelopmentcanproceedinacostefficientandobjectivemannerfocusedonscienceandnotonedrivenbycommercialconsiderations.

Federal fundingshouldbeprovidedfor this typeofdevelopmentmodel. Inparticularwehaveexperiencedaneedforinfrastructureresourcestosupportearlytestingandmodeling,andtosupportlicensingtopharmaceuticalandbiotechnologyentities.

B. Support“BigData”IntegrationTools.

The Consortium partners have developed and implemented a solution to the big datasharingchallenge. It is a singleplatform for secureclinicaldata fromallmajorClevelandhospitals – UH, CC, MetroHealth System, which together account for 70% of the 4.3Mnorthern Ohio population -- including but not limited to EHR data, genomics, clinicaloutcomesandriskassessments.

All data is stored in a secure, HIPAA compliant CWRU managed database called theCLEvelandAreaResearchPlatformforAdvancingTranslationalHealthcare(CLEARPATH)and

3-yearreturn(atCaseCCCalone):

• 5newcanceragentsbeginclinical trialsafterpreclinicaldevelopmentandFDAreview

• 3newpathwaysoftreatmentresistance identifiedwithtreatmentalternativesdescribed

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is available to any CWRU affiliated investigator under an overarching approved protocol;investigatorsmayalsorequesttore-identifyindividualsusingtheirownindividualapprovedprotocol. CLEARPATH is scalable for all diseases and can easily include more hospitalsand/oradditionalresearchnetworks.

Inaddition,CaseCCCinvestigatorshavedevelopedbigdatainterrogationtoolsofelectronicmedicalrecordsthatevaluatedrugrepurposingbyfindingwhichcommonlyuseddrugsareassociatedwithimprovedoutcomesinpatientswithcancer.Afindinginovariancancersisnowbeingevaluatedinclinicaltrial.

II. Enhancing the quality and value of community based networks operated bymajor CancerCenters:

A recognized need of theMoonshot effort is facilitating collaborations with researchers,doctorsandpatientstoovercomeinconsistentcare,excesscost,andpooroutcomes.

TheAmericanAssociationofCancerInstitutes(AACI)andtheNationalCancerInstitute(NCI)DesignatedCancerCentersrepresentapproximately92CancerCentersnationally.Throughthesecentersandtheirregionalcommunitybasednetworks, includingcare inruralareas,care for anestimated700,000patientswith canceroccurs, representingover40%of theentirecountryburdeninnewlydiagnosedcancerpatients.

By focusing efforts on coordinating care and emphasizing rapid introduction of newdiscoveriestopatientbenefit,throughtheAACI/NCIcancercenters,wecouldsubstantiallyaffectthequalityofcareandoutcomesforthesepatients.

Thisapproachrequires3maininitiatives:

A. CoordinatedApproach.

Through theAACIandNCIdesignatedcancer centers,modelsof care (carepaths) canbeagreed upon with strategy, infrastructure and business implication support. Consistentcare will improve quality and outcomes, and reduce costs. While the National Cancer

3-yearreturn:

• Reviewofthestructureandimpactofthisbigdatainitiativeonresearch,patientcareandqualityassessmentswillbenefitothercentersandregions

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CenterNetwork(NCCN)guidelinesareaconsistentstartingpoint,allmajorcancercentersarelinkingNCCNtodiagnosticandtreatmentstandards.

B. QualityReporting.

Qualityreportingisessentialtounderstandtheeffectaswellasdrivecompliance.SharingEMRanddatabasesarenecessarytoachievethisgoal.

C. ClinicalTrials.

Clinicaltrialsprovideaccesstonoveldrugs.Toimproveaccessacrosscommunitynetworksweneedto:

§ Reducebarrierstoenrollment§ Increasegenomicandotherspecialtestingformarker-basedtreatment§ Develop clinical trials that are appropriate for regional sites to improve patient

outcomes.

Attention to these approaches would enhance coordinated care, reduce competition,improveoutcomesandmanagecosts.

III. FocusAreas

A. RecommendedFocusAreastoProduceSubstantialResults:

CaseCCCisinsupportofthefocusareasidentifiedintheNCIbudgetjustification,andtheletterofsupportprovidedbytheAssociationofAmericanCancerInstitutes.

Basedonourexpertise,wehaveidentifiedanumberoftopicsofopportunitythatpertaintotheMoonshot’sgoalofsignificantlyadvancingprogressoncancer.ThesetopicsfallundertwoareasofConsortiumcorecompetency–ScreeningandPreventionandGenomics.

Specifically,we identify topicswherewewouldpropose federal support for collaborativeprojects using coordinated clinical and research databases. These projects wouldaccelerate,within3years,transferofdiscoveriesintomeaningfulimpactonpopulationsinareas of cancer screening, prevention, early detection, integrated care, personalizedmedicineandinspecificareasofpediatriccancers,youngadultcancersanddrugdiscoverytoclinicalapprovalofmoreeffectivetreatmentsforcancer.

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§ ScreeningandPrevention

TheCancerMoonshotshouldnotsolelyfocusonresearchanddevelopmentrelatedtotreatments and cures, but also embrace the areas where immense progress can bemadeinreducingcancerincidence,includingscreeningandprevention.

Ø HPVVaccinationtoReduceCervicalandHead&NeckCancers: Currently,onlyabout30%ofboysandgirls intheagerangeof11-15yearsoldarebeing vaccinated for HPV. In Northeast Ohio, the Consortium partners havecommittedtodevelopingprogramstoacceleratethatvaccinationratetowardagoalof70%orhigher.What will be needed to drive this level of improvement (both here and in othercommunities)issupportfor:

§ Populationstudies§ DevelopmentofmessagingandpubliceducationprogramsthattheHPV

vaccineisacancervaccine(withdisseminationofthatmessagethroughprimarycareandpediatricofficesandschool-basededucationprograms)

§ Vaccinationratemonitoringprograms.

Case CCC’s region-wide Pediatric Practice Based Research Network is ideallypositionedtorapidlyimplementsuchaninitiativewithappropriatefundingsupport.Community interest encouraging vaccination for all school-aged children shouldfacilitateimprovementinvaccinationrates.

Ø LungandColonCancerScreening:

The Cleveland area has high death rates from colon cancer and lung cancer, aproblemthat ismostpronouncedinourunderservedAfrican-Americancommunitywhere screening rates are low and smoking rates are 40% above the nationalaverage.Nationally,ratesoflungcancerscreeningforhigh-riskpopulations(thoseover50yearsofagewithahistoryofsmokingfor30yearsormore)arequite low(lessthan30%).Thissignificantlyraisesmortalityratesresultingfromlatediagnosisofthesecancers.Similarly,greatgains inpreventionandtreatmentofcoloncancercanbeachievedthrough improvements in screening. Better deployment of low-cost lung cancerscreeningaswellaspotentiallycoloncancerDNAtesting(atechniquedevelopedat

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CWRU)asanalternativetocolonoscopycanhelpwiththisimprovement.UHandCCadminister inexpensive CT screening programs for at-risk smokers and patientregistriesthatallowformonitoringoffollow-up.Significantadvancesinpreventionthroughscreeningcouldbepromotedbyfederalsupportto:

§ EvaluatewhetheraDNA test for colon cancerhasbetter acceptance inthepopulationthancolonoscopy

§ Offsetcostsofscreening,databasemaintenanceandfollow-up§ Developandevaluatenewsmokingcessationprograms

Additionally, support for novel imaging techniques (e.g., MRI fingerprinting), andscreening tests (e.g., DNA based blood and saliva testing) hold the promise ofbringingnoveltechnologiesintobroaderuse.

Ø EsophagealCancerScreening:

ObesityandBarrett’sEsophagusareassociatedwith increasedratesofesophagealcarcinoma (EC). Given that there has not been a great deal of improvement intreatment,earlydetectionofbothBarrett’s(topreventtheonsetofcancer)andofEC(whenstillcurable)isanimportantmedicalobjective.Case Comprehensive Cancer Center members have identified DNA changesdetectable fromabrushingof theesophaguswitha very simple self-administeredballoonswabthatcancollectasampleforDNAanalysisfromtheloweresophagusinamatterofminutes.Funding to support evaluation of this balloon brush as a tool for prevention andearlydetectioninpatientsthoughttohaveBarrett’sassociatedrefluxcouldrapidlyestablishanewmethodtoreducetherisksanddeathsofesophagealcarcinoma.

Ø AspirinforColorectalCancerPrevention:

CaseCCC,withcollaboratorsatHarvard,demonstratedthemolecularbasis forthedailyuseofaspirintoprotectagainstcoloncancer.WedemonstratedthatPGDH-15isariskstratificationbiomarkerthatpredictswhowillandwhowillnotbenefitfromaspirinchemoprevention.

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Population screening forPGDH-15 identify those (~50%)whobenefit fromaspirin,reducing the use for those without benefit, and is an example of personalizedprecisionpreventivemedicine.To capitalize on this advancement, funding is needed to initiate a multi-sitepopulation-based assessment screening and intervention trial that identifies whobenefitsfromaspirinusewithreducedincidenceofcoloncancer.

Ø Exercise,WeightReductionandDiet:

It is well known that obesity is a major cause of heart disease, diabetes andmetabolic syndrome. Less recognized is its profound effect on increasing risks ofcolon,endometrial,breastandovariancancers. Conversely,exercisereducesrisksofrecurrenceforthesecancers.Programs to reduce obesity through exercise in children and young adults, andprogramsthatincreaseexerciseafterthediagnosisofcancercanhaveasignificantimpact. The link between healthy foods and lower cancer incidence is also wellestablished,andimprovingdietaryhealthbyattackingtheproblemofhealthyfooddesertsinurbanareasneedstoberecognizedaspartofananti-cancerstrategy.CaseCCChasfundedinvestigatorsevaluatingobesityandcancer;studyingexercise--bothinschoolagechildrenasaprimarycancerpreventionmethod,andincancersurvivors(includingtheelderly)asitpertainstoreoccurrence;withinterventionstocorrecteachoftheserisksforcancer.Anadditionalfocusareahasinvolvedstudyingandremovinghealthyfooddesertsinourcommunity,analyzingtheinterventionforimprovedhealthoutcomes.Fundingisneededforeducationprograms,skilledfitnesstrainerstoimplementandevaluateexerciseinterventions,andbiomarkermonitoringoftheimpactofexerciseoncancerrisk.

§ TranslatingGenomicInsightstoReduceRiskandImproveTreatment:

Ø AdolescentandYoungAdultCancerGenomics:

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Advances inoutcomes forpatientswithcanceraged15-30years lagsbehindbotholder and younger individuals and there is a lack of ongoing focus on research incancers in this age group. Further understanding of the etiology and biology ofAdolescentandYoungAdult(AYA)cancerisnecessarytomakesignificantadvancesinthispopulation.Through philanthropic support, Case CCC has developed a scientific focus on theetiology and biology of AYA cancers -- with special attention from these youngpatients.Federalfundingshouldbedirectedtosupportgeneticanalysisandinterpretationtoidentifybothknownandnovelpathwaysleadingtocancerinthisagegroup.

Ø UniqueGeneticCausesofCancerinAfricanAmericans:

For the first time, Case CCC investigators have identified unique genetic changesresponsible for colon cancers and for myelodysplastic syndrome and acutemyelogenous leukemia in African Americans living in northern Ohio, includingCleveland.Thisfindingprovidesdirectevidencethatcancertreatmentsareinadequateforthispopulation,sincecurrentFDA-approvedtreatmentsareorientedtowardadifferentsetofgeneticchangesseeninCaucasians.Fundingshouldbedirectedtovalidatetheseuniquegeneticandpotentialepigeneticchanges inminoritypopulationsacrosstheUS,andtoevaluatenewscreeningandtreatment paradigms for African Americans carrying these mutations in theirtumors.

Ø HighCancerIncidenceinFamilies:

Therearemanyfamilieswithaveryhighincidenceofcancerthatcannotbetiedtoanycommonlyknowngeneticindicators(astheBRCA1,2genesandbreastcancer).CaseCCC,workingthroughbothUHandCCF,supporthigh-riskcancerfamilyclinicsthatareservingfamilieswithhighratesofcancer,includingbysupportingextensivescreeningandgenetictesting.Thistypeofselectionandextensivegenomicanalysisof complex cancer families is critical to determine risk and treatment options forthesefamilies.

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Fundingtocontinuetocollectthesefamilymembersacrossthetwohealthsystemsand select complex cancer families for complete and extensive genomic anddatabase analysis to uncover the genetic cause of cancer in that family is badlyneeded.

Ø CancerRecurrenceandMetastasis:

Thegreatestfearforanycancerpatientisthewordrecurrence.Understandingthebiology behind tumor metastasis, and spread to other organs remains critical todevelopingnewmethodsofearlydetectionandtreatments.In Cleveland, investigators are evaluating metastasis samples to understand theirgeneticabnormalities,inordertoimprovedetectionandtreatmentstrategies.Fundingisneededtoexpandresearchinthisareausingpatientderivedsamplesthatwillrepresentamajoradvancewhenthecausesandtriggersareidentified.

ContactStantonL.Gerson,MD

DirectorCaseComprehensiveCancerCenter

Cleveland,Ohio216-844-8562

Stanton.gerson@case.eduhttp://cancer.case.edu/

3-yearreturn:

• ImprovedratesofcancerscreeningandHPVvaccination• Identificationof newgenesassociatedwithAYAcancersandcancers in

families• ValidationofcancerriskgenesinAfricanAmericanswithcoloncanceror

AML/MDSwith newdiagnostic approaches and new therapies directedtowardsthesegeneticchanges

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