Frequently Asked Questions about DF/HCC Breast …...Deborah Dillon. 1997-2011 – • No strict eligibility criteria for collection during this time period • 700-800 breast cancer

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FrequentlyAskedQuestionsaboutDF/HCCBreastDataandSpecimenUseWhatistheDF/HCCBreastUsersCommittee?WhatarethesourcesofDF/HCCBreastdataandspecimenforresearch?WhatarethepoliciesforDF/HCCBreastdataandspecimenuse?HowdoIsubmitaresearchproposal?HowdoIregisterforOncDRS?HowdoIcreateaprojectteamonOncDRS?WhatarethedifferentprojectswithintheDF/HCCBreastSPOREgrant?TheDF/HCCBreastUsersCommitteeComposition:TheBreastUsersCommitteeisthesupervisingbodyforuseofthebreastcancerdataand/orspecimensfromtheDF/HCC.TheUsersCommitteewillbecomposedofatleastonememberfromeachparticipatingorganizationwhichincludesDana-FarberCancerInstitute,BrighamandWomen’sHospital,BethIsraelDeaconessMedicalCenter,andMassachusettsGeneralHospital,representingthedisciplinesofpathology,surgery,andmedicaloncology,radiationoncologyandbiostatistics.Memberswillbeappointedbytheirrespectiveorganizationswithnopre-specifiedtermlimits.Thecurrentmembershipispresentedbelow.Purpose:ThemembersoftheDF/HCCBreastUsersCommitteearechargedwithreviewingthefeasibilityandscientificvalidityofproposedclinicalandhealthservicesresearchand/orqualitativeimprovement(QI)projectsandtranslationalandlaboratory-basedprojectsusingthespecimensandclinicaldataavailablethroughDF/HCCresearchprotocolswhichgovernitscollection.

DF/HCC BREAST USERS COMMITTEE MEMBERS (AS OF JUNE 15, 2016)

CO-CHAIRSNANCYLIN,MD;DFCI

DEBORAHDILLON,MD;BWHLAURACOLLINS,MD;BIDMC

USERSCOMMITTEEMEMBERSWILLIAMBARRY,PHD;DFCIMYLESBROWN,MD;DFCILEIFELLISEN,MDPHD;MGHJUDYGARBER,MD,MPH;DFCIMEHRAGOLSHAN,MD;BWHDIRKIGLEHART,MD;BWH

STEVENISAKOFF,MD,PHD;MGHTARIKING,MD;BWH

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IANKROP,MD,PHD;DFCIBEVERLYMOY,MD;MGHANNPARTRIDGE,MD,MPHSTUARTSCHNITT,MD;BIDMCBARBARASMITH,MD;MGHNADINETUNG,MD;BIDMCERICWINER,MD;DFCIJULIAWONG,MD,DFCIJEANZHAO,PHD,DFCI

PoliciesBiospecimensarebankedintheDFCI/BWHtissuebank(BankDirector:Dr.DeborahDillon).AllrequestsforbiospecimenshousedwithintheDF/BWHtissuebankmustbeapprovedbytheDF/HCCBreastUsersCommitteepriortorelease,asdorequestsforcuratedclinicaldata.IfthesamplesneedtobesentoutofDFCI/BWHtoanotherinstitutionaMaterialTransferAgreement(MTA)willalsoneedtobesignedandapprovedbyOfficeofGeneralCounselbeforeclinicaldataand/orspecimensarereleased.Researcherscanrequestde-identifiedtissueorbloodsamplesandlinkedclinicaldatafromthebankwithoutobtainingadditionalIRBapprovalforthespecificresearchquestion.Usersmustsignadatauseagreementstatingthatthebankwillnotprovide,andtheuserwillnotattempttolearn,theidentityofthepatients.Ifanidentifieddataset(e.g.adatasetthatcontainspatientnames,medicalrecordnumbers,etc)oralimiteddataset(e.g.adatasetthatcontainsdatesoftreatment)isrequested,thenDF/HCCIRBapprovalspecifictotheprojectmustbeobtainedbytherequestingresearcherbeforereleaseofclinicaldataorspecimens.ConsultationwiththeCo-ChairsoftheBreastData/TissueUsersCommitteeisavailabletoresearcherspriortoIRBsubmissionandduringtheIRBapprovalprocess.TheUsersCommitteewillrequiredocumentationofIRBapproval(ifneeded)priortoreleaseoftissueorclinicaldata.Administrativestaffwillmaintainaflowsheettofollowtheprogressofeachrequestandmaintaincontactwiththeinvestigatorsduringthereviewprocess.TheadministrativestaffforwardstheproposaltoallmembersoftheUsersCommittee(detailedbelow)forreviewandcomment. SourcesofDF/HCCBreastDataandSpecimensforResearch93-085:ProjectSHARE(SpecimensHelpAllResearchEfforts)CollectionofSpecimenandClinicalDataforPatientswithBreastCancerorHighRiskforBreastCancerPrincipalInvestigator:NancyLin,MD/DFCIOverallaccrual:21,500asofJune1,2016

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Bloodcollectionincludesbloodsamplesthatareonlydrawnonthosepatientsscheduledtohaveablooddrawforroutineclinicalpurposesatatimeperiodsoonafterpatientconsents.TenmLbloodwillbedrawnintoEDTAcontainingtesttube,andwholebloodwillbealiquotedintocryovials.FivemLwillbedrawnintoabluetoppedtube.Plasmawillbeseparatedfromcellularcomponentbycentrifugationandaliquotedintocryovials.BloodcollectioniscataloguedincaTissue.Notenotallpatientshaveabloodsampledrawnsincepatientsmaynotcomebacktobetreated.Onlyonebloodsampleperpatientiscollectedandthetimingofthebloodcollectionisnotbasedontimingbeforeoraftersurgery,progression,ortreatmentswitch.Tissuecollectionareobtainedonlywhenaprocedureisplannedforclinicalreasonsandwouldnormallybediscardedfollowingroutinepathologicalprocedures,mainlyamongpatientswithnewdiagnosisofprimarybreastcancer.TissuecollectionwillbecataloguedincaTissue.Fresh/frozentissuewillbethenbebankedandstoredundertheBreastTissueBankunderDr.DeborahDillon. 1997-2011–

• Nostricteligibilitycriteriaforcollectionduringthistimeperiod• 700-800breastcancertumorsamplesfrompatientsconsentedunder93-085to

allowforlinkagewithdetailedclinicalannotationinCRISdata.Basicretrospectivespecimen-levelannotationincaTissueongoingandincludespathologictumorsize,numberofpositivelymphnodes,histologicgrade,hormonereceptorstatus,HER2status

• Approximately750anonymizedsamplescollectedunderPartners#1148.Formoreinformation,contactDeborahDillondirectly.

2015-present-

• Eligibilitycriteria->=1.5cmand/orneoadjuvantchemotherapypatientswithatleast>1.0cmresidualdisease.

• 36breastcancertumorscollectedtodate.• Basicretrospectivespecimen-levelannotationincaTissueongoingandincludes

pathologictumorsize,numberofpositivelymphnodes,histologicgrade,hormonereceptorstatus,HER2status.Alsoincludeswhetherspecimenwasobtainedafterneoadjuvanttherapyandwhetheritislinkedtoaspecifictissuecollectionsub-study(i.e.inflammatorybreastcancer,clinicaltrial,etc.)

• CanbelinkedtoRedCAPdatafordetailedclinicalannotation.BOCClinicalDatabasesDemographic,clinicalandtreatmentdata

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1997-2012Demographic,clinical,andtreatmentdataofpatientswithnewlydiagnosedbreastcancerandreceivedsomeoralloftheirtreatmentforbreastcanceratDana-FarberCancerInstituteandMassachusettsGeneralHospitalfromJuly1997toAugust2012.DatawascollectedintheCRISdatabase.

• 4937and2590patientsatDFCIandMGH,respectivelywithdataandfollow-upupuntil2012.

• DataarecollectedinClinicalResearchInformationSystem(CRIS)database.• Thefollowingclinicalinformationwillbecollectedoneachstudyparticipant:

• Demographic(ageatinitialdx,race/ethnicity)• Primarybreastcancerhistory:stage,histology,grade,hormonereceptorstatus

andHER2status• Treatmenthistory:adjuvantchemotherapy,adjuvanthormonetherapy,adjuvant

radiationtherapy• Metastaticbreastcancerhistory:dateofrecurrentormetastaticdisease;

location;sitesanddatesofradiationtherapy,datesofsystemictherapy(linesoftherapyandfirstandlastdoes;response)

• Long-termfollow-updata

2013–2015-Nodatacollectedduringthistimeperiod2016–Collectionofdemographic,clinicalandtreatmentdataofpatientswithnewlydiagnosedbreastcancerandreceivedsurgeryatDF/BWCCwillresumeasofJanuary1,2016atDana-FarberCancerInstitute.DatawillbecollectedinRedCAPdatabase.

• Thefollowingclinicalinformationwillbecollectedoneachstudyparticipant:• Demographic(ageatinitialdx,race/ethnicity)• Primarybreastcancerhistory:stage,histology,grade,hormonereceptorstatus



location;sitesanddatesofradiationtherapy,datesofsystemictherapy(linesoftherapyandfirstandlastdose;response).PleasenotethatpatientswhohadsurgeryanddrugtherapyelsewhereandsubsequentlywereseenatDFCIforthefirsttimeafteradiagnosisofmetastaticbreastcancerwasmadeareNOTincludedinthisdatabase.

• Long-termfollow-updata• Pleasenotethatinadditiontothebreast-specificdatabase,thereareefforts

underwayatDana-Farberasawholetocollectcommondataelementsacrossdiseasecenters.Thedatabaseiscurrentlyunderconstruction.

Comment [PHS IS1]: LeavespaceforMikeHassetttoinputBCCORDinfo...

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Table1.ExamplesofpatientinclusionwithinBOCclinicaldatabasesPatientvignette 1997-2012(CRIS) 2016-(RedCAP)_ NewdiagnosisofstageI-IIIbreastcancer,surgeryatBWH,chemotherapyatDFCI

Yes Yes

NewdiagnosisofstageI-IIIbreastcancer,surgeryatMGH,chemotherapyatMGH

Yes No

NewdiagnosisofstageI-IIIbreastcancer,surgeryatoutsidehospital,chemotherapyatDFCI

Yes No

NewdiagnosisofstageI-IIIbreastcancer,secondopiniononly,nottreatedatDFCIorMGH

No No

NewdiagnosisofstageI-IIIbreastcancer,surgeryatFaulknerHospital,chemotherapyatDFCI

Yes Yes

NewdiagnosisofstageI-IIIbreastcancer,surgeryatFaulknerHospital,notreatmentatDFCIorBWHmaincampus

No? Yes

Newdiagnosisofdenovometastaticbreastcancer,treatedatDFCI

Yes Yes

Newdiagnosisofrecurrentmetastaticbreastcancer,previoustreatmentforstageIIbreastcanceratoutsidehospital

No No

Presentingforsecondopinionforsecondlinetherapyformetastaticbreastcancer,consultonly

No No

Presentingforsecondopinionforsecondlinetherapyformetastaticbreastcancer(treatedelsewhereprior),andsubsequentlytransferscaretoDFCI

No No

11-104:Profile-ResearchonClinicallyAcquiredPatientMaterialinCancerPrincipalInvestigator–BruceJohnson,MDOverallAccrual:XXAccrualofpatientswithprimarydiagnosisofbreastcancer:XX11-104(Profile)istheumbrellaprotocolforclinicaldata,tissuecollectionandgenomictestingoftumorsacrossDFCI,BWH,andBoston’sChildren’sHospital.Patientshavebeenconsentedsince2011.Therehavebeendifferentversionsoftheassayusedsince2011.TheOncomapassaywasusedfrom8/01/2011throughtheendofSeptember2013fromDFCI(adultandpediatric),BWH(Adults)andconsultpatientsreferredfromotherhospitalstoDFCIandBWHareincluded.TwoversionsofOncoPaneltestsareincludedinthedatabase:OncoPanelVersion1(v1)dataincludespatientssequencedbetween6/26/2013and8/6/2014.Oncopanelv1

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includesaninitial275cancergenesand91intronsacross30genesforrearrangementdetection.ImplementedonAugust7of2014,Version2ofOncoPanelexpandsontheinitialversiontoincludetheexonicregionsofanadditional25genesassociatedwithdiseaseanddrugresponse,intronicregionsofanadditional4genes,aswellasothernon-codingregionsacrossseveralothergenes.AllDFCIpatientsareapproachedatregistrationforconsenttotheprotocol.Theconsentrate,however,hasvariedandoverallwithinbreastcancerpatientshasbeenlessthan50percent.Oncomap/Oncopaneltestinghasbeenorderedprimarilyonpatientswithmetastaticbreastcancerandtheconsentrateforthesepatientsishigher,basedontargetedconsenteffortsinthebreastoncologyclinicforthesepatients.Inaddition,itisimportanttonotethatbecauseofthetargetedmetastaticpopulation,analysesexaminingdisease-freesurvivalandrecurrenceratesarenotbefeasibleinthebreastcancerdataset.Therearesomenon-curatedclinicaldataelementsthatcanbelinkedtoOncomap/OncopanelresultsavailableinOncDRS(forexample,age,race,sex,chemotherapyorderedwithinEPIC),however,detailedcuratedclinicaldata,includingER,PR,andHER2status,andanyinformationfromoutsiderecords,arenotavailablethroughOncDRSforbreastcancerpatients.Otherdatasourcesoutlinedinthisdocumentwillneedtobeusedtoobtainthistypeofclinicaldata.09-204:EMBRACE:EndingMetastaticBreastCancerforEveryonePrincipalInvestigator:NancyLin,MD/DFCIOverallaccrual:1116metastaticbreastcancerpatientsDemographic,clinical,andtreatmentdataofpatientswithmetastaticbreastcancerenrolledinthestudyandhaveabaselineblooddrawdatingfromJanuary8,2010topresent.ThestudyenrollspatientsseenatleastonceatDFCIforadiagnosisofmetastaticbreastcancerandwhoconsenttothestudy.Incontrasttothe93-085databases,patientsseenasconsultsonlyandpatientswhoreceivedpartoralloftheirtreatmentatoutsideinstitutionsmaybeincludedinthisstudy,ifconsented.

• 656patientswithbaselinedataand69patientswithfollow-updata.• DataiscollectedinINFORMelectroniccasereportform.• Thefollowingclinicalinformationwillbecollectedoneachstudyparticipant:




hormonereceptorandHER2status;location;sitesanddatesofradiationtherapy,datesofsystemictherapy(linesoftherapyandfirstandlastdose)

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• RECISTresponsedataisNOTavailable.Archivalscansarealsonotcollectednorcataloguedprospectively.Clinicalresponsedataisannotatedwhenavailableasbestresponseasascertainedbyreviewofthemedicalrecord(e.g.Response,StableDisease,ProgressiveDisease,Unevaluable,Unknown).

• Long-termfollow-updataBloodcollectionincludes:

• Forallconsentedpatients,bloodiscollected:• Atbaseline:10mLintoEDTAtubeand10mLintoCPTtube• Attimeoffirsttreatmentswitch:10mLintoEDTAtubeand10mLintoCPTtube• At4to6weeksaftertreatmentswitch:10mLintoEDTAtubeand10mLinto

CPTtube• InJune2015,allconsentedpatientsalsohadabloodsampleatbaselineandateach

progressioneventfortheanalysisofcfDNA(One10mLsampleinCPTtube)andthenblooddrawseverythreemonthsattimeofclinicalblooddraws(Two10mLsamplesintoEDTA-containingorCellSavetubes).

827patientshavecompletedtheirbaselinedraw,282participationshavecompletedtheirfirsttreatmentswitchdraw,andthen247patientshavecompletedtheir4-6weekaftertreatmentswitchdraw.Tissuecollectionwillsoonincludearchivaltissuetobankforfuturestudiesinlate2016.05-246:CollectionofSpecimensandClinicalDataforPatientswithBreastCancerPrincipalInvestigator:NancyLin,MD/DFCITotalaccrual:358breastcancerpatientsThisstudyallowsustocollectresearchspecimensinthepreoperative,neoadjuvant,andlocallyadvancedandmetastaticsettings.Ifapatienthasconsentedtothestudy,anypatientwithsuspectedandconfirmedbreastcanceratallstagesofdiseasecanconsenttoprovidingtissuesamplesbyundergoingaresearchbiopsy–eitheratthetimeofaclinicalbiopsyorindependentofthetimingofaclinicalbiopsy.Thestudyalsoallowsforserialbiopsiestobeperformed.Intermsofbloodcollection,sampleswillbecollectedtomatchthetimeofbiopsyforisolationofCTCs,germlineDNAandcfDNA.Patientmayhaveserialblooddraws,ifpatientwasconsentedunder93-085andnewpatientbloodwastakenaccordingtothatprotocol,andthenbloodwasdrawnwiththebiopsyunder05-246.Inaddition,thereisasubstudyunder05-246calledCenterforCancerPrecisionMedicinethatisfocusedprimarilyonwholeexomeandtranscriptomesequencingoftumorsamplesfrom

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patientswithmetastaticbreastcancer.Tissuecollectionwillundergoadifferentprocessthatthoseconsentedunder05-246(3-6coreswillbecollected:1forclinicalpathology(FFPE)tobeusedforH&Eandclinicaltestingfirstandthenonceclinicaltestingiscomplete,Oncopanel;remainingcoreswillbefrozeninOCTandifclinicaltestingiscompleted,remainingcoreswillbesenttotheBroadInstitute).Inadditiontotheinitialblooddrawattimeofbiopsy,bloodcollectionwillalsooccurattimeoffirsttreatmentswitch,4-6weeksaftertreatmentswitchandattimeoftumorprogressionand/oratregularthreemonthintervals.06-169:HelpingOurselves,HelpingOther:TheYoungWomen’sBreastCancerStudyPrincipalInvestigator:AnnPartridge,MD,MPH/DFCIOverallaccrual:1302youngwomen(diagnosedage40oryounger)withbreastcancerStudyincludesbloodandtissuecollection,medicalrecordabstractionandserialquestionnaires(womenaresurveyedevery6monthsforthefirst3yearsafterdiagnosis,thenyearlyafterforanadditional7years).Thereareplanstocontinuethesurveycomponentofthisstudybeyondtheinitial10years.Clinicalandtreatmentdataisabstractedviamedicalrecordreview.

• 656patientswithbaselinedatafullyextracted(extractionongoing).• DataiscollectedinaMicrosoftAccessdatabase.Somesurveydata(year7is

manuallyenteredbystaff,years8,9,10canbeaccesseddirectlybythepatient)iscollectedinRedcap(onlinesurveyportal)

• Thefollowingclinicalinformationiscollectedoneachstudyparticipant:• Demographic(ageatinitialdx,race/ethnicity)• Primarybreastcancerhistory:stage,histology,grade,hormonereceptorstatus

andHER2status• Treatmenthistory:(neo-)adjuvantchemotherapy,adjuvanthormonetherapy,

surgicalhistory• Metastaticbreastcancerhistorydataisabstractedbasedonpatientself-

reportedsurveydata:dateofrecurrentormetastaticdisease• Long-termfollow-updata

Bloodcollectionincludes:

• Forallconsentedandactivepatients(asofJune21,2016,ofthe1116eligible,wehaveatleast1samplefrom91%ofourpatients.Asof6/21/16,837patientshavecompletedtheirbaselinedraw,984patientshavecompletedtheir1yeardraw,and356patientshavecompletedtheir4yeardraw.).Bloodisrequestedatthefollowingtimepoints:

• Atbaseline(Enrollmentto9monthspost-dx)• 1yearfromdiagnosis(9monthsto2yearspost-dx)• 4yearsfromdiagnosis(3.5yearsto5yearspost-dx)• Ifcollected,2(10mL)EDTAtubesaretakenateachtimepoint

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§ 10mLtubesyield6cryovials• 4(~2mLeach)aliquotsofwholeblood• 2(~2mLeach)aliquotsofplasma

*Notetheabovetimerangesareguidelines.Theprotocolonlyspecifiesthatbloodwillberequestedat3differenttimepoints.Therearesomeexistingdrawsthatwerecollectedoutsideoftheseranges.Tissuecollection:forallconsentedpatients(98%ofourcohort)wepursuethefollowing:originalH&EStainedslidesfromallspecimensandtissueblocksstoredinparaffin.Centralpathologyreviewandindividualswithtumorblocksbanked:AsofJune28th,(867/68%)and734/57%,respectively09-204:EMBRACE:EndingMetastaticBreastCancerforEveryonePrincipalInvestigator:NancyLin,MD/DFCIOverallaccrual:1116metastaticbreastcancerpatientsDemographic,clinical,andtreatmentdataofpatientswithmetastaticbreastcancerenrolledinthestudyandhaveabaselineblooddrawdatingfromJanuary8,2010topresent.ThestudyenrollspatientsseenatleastonceatDFCIforadiagnosisofmetastaticbreastcancerandwhoconsenttothestudy.Incontrasttothe93-085databases,patientsseenasconsultsonlyandpatientswhoreceivedpartoralloftheirtreatmentatoutsideinstitutionsmaybeincludedinthisstudy,ifconsented.

• 656patientswithbaselinedataand69patientswithfollow-updata.• DataiscollectedinINFORMelectroniccasereportform.• Thefollowingclinicalinformationwillbecollectedoneachstudyparticipant:




hormonereceptorandHER2status;location;sitesanddatesofradiationtherapy,datesofsystemictherapy(linesoftherapyandfirstandlastdose)

• RECISTresponsedataisNOTavailable.Archivalscansarealsonotcollectednorcataloguedprospectively.Clinicalresponsedataisannotatedwhenavailableasbestresponseasascertainedbyreviewofthemedicalrecord(e.g.Response,StableDisease,ProgressiveDisease,Un-evaluable,Unknown).

• Long-termfollow-updata

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Bloodcollectionincludes:

• Forallconsentedpatients,bloodiscollected:• Atbaseline:10mLintoEDTAtubeand10mLintoCPTtube• Attimeoffirsttreatmentswitch:10mLintoEDTAtubeand10mLintoCPTtube• At4to6weeksaftertreatmentswitch:10mLintoEDTAtubeand10mLinto

CPTtube• InJune2015,allconsentedpatientsalsohadabloodsampleatbaselineandateach

progressioneventfortheanalysisofcfDNA(One10mLsampleinCPTtube)andthenblooddrawseverythreemonthsattimeofclinicalblooddraws(Two10mLsamplesintoEDTA-containingorCellSavetubes).

827patientshavecompletedtheirbaselinedraw,282participationshavecompletedtheirfirsttreatmentswitchdraw,andthen247patientshavecompletedtheir4-6weekaftertreatmentswitchdraw.Tissuecollectionwillsoonincludearchivaltissuetobankforfuturestudiesinlate2016.LEAVESPACEFORJUDY’Sprojects/descriptionsSummary:Thefollowingclinicalinformationwillbecollectedoneachstudyparticipant(viathe09-204databaseforpatientswhoareconsentedtobothstudies.Forpatientswhodecline09-204,theinformationiscollectedandstoredinaseparatefilemaintainedbythestudyCRC).




location;sitesanddatesofradiationtherapy,datesofsystemictherapy(linesoftherapyandfirstandlastdose)

• RECISTresponsedataisNOTavailable.Archivalscansarealsonotcollectednorcataloguedprospectively.Clinicalresponsedataisannotatedwhenavailableasbestresponseasascertainedbyreviewofthemedicalrecord(e.g.Response,StableDisease,ProgressiveDisease,Unevaluable,Unknown).

• Long-termfollow-updataDatafromOncDRS

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Onaninstitute-widelevel,varioustypesofdataarealsoavailablethroughOncDRS(seebelow).ThetablebelowpresentsthetypeandsourceofdataandthenumberofpatientsacrossDFCIthathavedataavailablethroughOncDRS.AllOncDRSdataisupdatedeverytwoweeksandnewdataelementswillbeincludedovertime.Formoreinformationonspecificdataelements,pleaserefertoOncDRSDataGuide.Importantnote:ER,PRandHER2data,aswellasothercurateddataarenotavailablethroughOncDRS.

DataType Source(s) ApproxNumberPatients,2/1/16

Demographics Epic 285,500PatientVitalStatus Epic,CancerRegistry 281,500VisitDiagnosis Epic 246,600CancerRegistryDiagnosis CancerRegistry 67,200

OncologyMedicationsEpic,Pre-EpicPharmacy,Pre-EpicCOE,Pre-EpicLMR

53,000(notincludingEpic&LMRdata)

OncologyTreatmentPlan Epic,COE 39,600(notincludingEpicdata)LabResults–Chemistry&Hematology

SunquestLab 118,500Encounters Epic 281,500OncoPanelGeneticTestResultsfromTumorSpecimens CAMD 6,600

OncoMapGeneticTestResultsfromTumorSpecimens CAMD 4,900

11-104ProtocolConsent OnCore,Epic 62,500ProtocolRegistration OnCore 115,582DF/HCCBreastDataandSpecimenUsePolicyScope:AllpublicationsusingDF/HCCdataandspecimensmustbebasedonresearchproposalsthatwereapprovedordeemedexemptbytheUsersCommittee.Examplesofpublicationsdeemedexemptwouldbethoseresultingfromprospective,DF/HCCIRB-approvedtherapeuticclinicaltrials.Theprocessofsubmission,reviewandapprovalofresearchproposalaredescribedbelow.Allproposalsthatrequiretheuseofcurateddata(forexample,collectedaspartof93-085CRISorREDCAPdatabase,09-204metastaticdatabase,orproposedsecondaryanalysispreviouslyunplannedaspartofatherapeuticclinicaltrial)mustalsobeapprovedbytherelevantstudyPI.AllproposalsforsecondaryuseofclinicaldataorsamplescollectedunderanexistingDF/HCCIRB-approvedtherapeuticclinicaltrialmustalsobeapprovedbytherelevantstudyPI.

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Submissionpolicy:InvestigatorswithinDF/HCCmustsubmitaproposalformdirectlytotheBreastUsersCommitteeviaemaildirectlytotheprojectmanagerorviaOncDRSforaccesstodataand/orspecimens.Investigatorsmustcomefromaninstitutioninwhichsignificantcontributionisbeingmadeintermsofspecimenand/orclinicaldatacollectioninordertosubmitaresearchproposal.InvestigatorsthatareexternaltoDF/HCCmusthaveaninvestigator(collaborator)thatisafacultymemberatDF/HCCtosubmitonhis/herbehalf–eitherviaemaildirectlytotheprojectmanagerorviaOncDRS.TheprojectmanagerfortheUsersCommitteewillensuredistributionoftheresearchproposaltothemembersoftheUsersCommitteeforreviewandcommentviaemail.Memberswillreplywithadecisionwhetherto1)approve,2)reject;or3)requestrevisionandresubmission.Theprojectmanagerwillconveythedecisionand/oranyquestionsfromtheUsersCommitteetotheinvestigatorwithin4weeksaftertheproposalisdistributedtomembersforreview.

Approvalpolicy:Whenmakingfinalapprovalofaresearchproposal,alleffortswillbemadetocometoconsensus.Ifneeded,simplemajorityvotingwillbeusedandquorumwillbeatleasthalfofallactiveUsersCommitteeparticipantsand2ofthe3co-chairs.OnceapprovedbythecommitteeandtheDF/HCCIRBifrequired,theprojectmanagerwillforwardtheinvestigatoraletterstatingtheusers’committeefinalapproval.TheUsersCommitteegenerallytakesapproximately2-4weekstoissueapprovals.Theprojectmanagerthenwillworkwiththeappropriatestafftoidentifyandgeneratedatasetsandcollectionofspecimensbasedonthecohortspecifications.AllapprovedresearchproposalsarecataloguedintheBreastUsersCommitteelogforreference.AnnualRenewalPolicy:AsofMarch2016,wehaveinitiatedarequiredannualreviewofpreviouslyapprovedprojects.Thegoalsofanannualreviewareasfollows:

• Toreceiveaprogressreportontheprojectsthathavebeenpreviouslyapproved• Tounderstandhowthespecimensand/ordatahasbeenusedineachproject• Todeterminewhetheranypublicationshavebeengeneratedfromeachproject• Toassesswhetherprojectshavebeencompletedorarestillon-going,andongoing,

whatthetimelineisforcompletion.Theannualrenewalformshouldbesubmittedtotheprojectmanagereachyearuntiltheprojectiscompleted.Anupdatedapprovalletterwillbedistributeduponre-reviewandapprovalbytheUsersCommittee.GrantPolicy:FeasibilityrequestsIfaninvestigatorispreparingagrantproposal,aggregatedataand/orde-identifieddatatodeterminefeasibilitycanbeprovidedfortheapplication,ifavailable.Weencourageinvestigatorstoreachoutinadvancetotheco-chairsoftheUsersCommitteetodeterminewhetherthedesiredbiospecimens/clinicaldataareavailableandthetimelineforturnaroundofafeasibilityrequest.Moredetailsonthisprocesscanbefoundhere.

Comment [M2]: Doweinitiatetheannualreviewwithareminder?LC

Comment [PHS IS3]: Laura,Isentanemailtoeachpersonwhohashadtheirprojectapprovedmorethan1yearago(asofmid-May);Iwillcontinuethisprocessmovingforwardatthe1yearmarkforeachapprovedproject;IwillalsocollectrenewalapplicationsandsubmittotheUC,andthensendarenewallettertothePIs.LPK

Comment [PHS IS4]: Gotoparagraphonaggregatedataand/ordeidentifieddataforfeasibiltybelow.

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LettersofsupportUponreceiptofabriefsynopsis,listingofspecificaims,andifrelevantenumerationoftypesandamountoftissue/blood/clinicaldatarequiredfortheproposedstudy,theUsersCommitteeisabletoprovideagenericletterofsupporttoinvestigatorsingoodstandingwithinDF/HCC,whichoutlinestherelevantclinicaldataandbiospecimensthatcouldbeavailableandindicatestheprocessbywhichaconceptisvettedbytheUsersCommittee.Asampleapprovallettercanbefoundhere.Theturnaroundtimeforthisletteristwoweeks.Investigatorswhowishtoattachaletterforagrantapplicationwithamorefirmcommitment(e.g.UsersCommittee‘pre-approval’)mustsubmitafullUsersCommitteeapplicationatleastfourweeksbeforethegrantdeadline.DocumentationofIRBApprovalRecently,studiesand/orproposalssupportedwithNCIorDODgrantfundinghaverequireddocumentationofIRBapprovalandreviewofthegrantproposal/applicationbytheIRB.Forstudiesusingclinicaldataand/orspecimenscollectedunderanyofthedatasourcesoutlinedabove,theaimsofthestudyoutlinedinthegrantproposalwillneedtobeapprovedbytheUsersCommitteeand/orOHRS(dependingonthenatureofthestudyandneedforidentifieddataornot).IntermsofOHRSreview,youmaycontactOHRSastotheirrequirementsforreviewingthegrantproposaltomeettheNIHorDODpolicies.Insomecircumstances,IRBapprovalofthedataandtissuecollection‘umbrellaprotocol’anddocumentationofapprovalthroughtheUsersCommitteemechanismwillfulfillNCI/DODrequirements.However,increasingly,grantingagenciesarerequiringdocumentationofIRBreviewofthespecificresearchproposalinthegrant,evenitisusingde-identifiedsamplesandde-identifiedclinicaldataobtainedfromanIRB-approved‘umbrellaprotocol’.Pleasealsonotethatamendmentstotheexistingcohortstudyprotocolswillnotbesubmittedforeachproposedindividualgrantproposal.Instead,investigatorswillneedtosubmitalow-riskprotocolapplicationsummarizingtheproposedworktotheDF/HCCIRB.PleaserefertotheOHRSwebsitefordetailsofsubmissionandapplicationtemplatesforIRBreviewoflowriskprotocols.Publicationpolicy:Priortoabstractormanuscriptsubmission,investigatorsshouldnotifytheBreastUsersCommitteefordiscussionsregardingauthorshipandfundingacknowledgements.Ingeneral,aninvestigatorfromeachinstitutionrepresentedintheanalysisofclinicaldataand/orspecimensshouldbeincludedintheauthorship.Inaddition,forpublicationsthatincludecuratedclinicaldata(i.e.fromacohortdatabase),thePI/leadersoftherelevantdatabaseshouldbeincludedasanauthor(s).Forpublicationsincludingbiospecimens,thebankdirectorshouldgenerallybeincludedasanauthor.Forsecondaryuseofanexistingclinicaltrial’sclinicaldataorbiospecimens,thetrialPIshouldbeincludedasanauthor.Failuretoadheretothepublicationpolicymayresultinlossofprivilegestoaccessclinicaldataorbiospecimensforresearch.

Formatted: Font:Italic

Comment [PHS IS5]: GotoDataSourcessection

Deleted: is

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Allmanuscriptswhichincludetheuseofbio-specimensorclinicaldataabstractedfromProtocols93-085,09-204and/or05-246shouldreachouttotheUsersCommitteetodiscussacknowledgements,asfundingsourceshavevariedovertime.Inparticular,itisimportantthatallmanuscriptsexpressacknowledgementofthecontributiontotheDF/HCCBreastSPORE: SpecializedProgramofResearchExcellence(SPORE),AnNCIfundedprogram,Grant1P50CA168504.HowdoIsubmitaresearchproposal?Dependingontherequesttypeforclinicaldataand/ortissue,thesubmissionofyourresearchproposaltoUsersCommittee(andIRBifapplicable)willhavedifferentrequirements.Pleaserefertothesection,“DoIneedtosubmitthroughOncDRS,theUserscommittee,orboth”foradditionaldetails.RequestTypeforclinicaldataand/orspecimens

OncDRSRequestform

UsersCommittee

IRB

Aggregatedata(e.g.numberofeligiblepatientswithclinicaldata/specimens)

No,caneitherdirectlyaccessOncDRSaggregatequerytoolorcompleteClinicalResearchDataRequestform.

No No

De-identifiedforfeasibilityanalysis(**Future6/16)

Yes NoMustagreenottopublishoridentifypatientswithoutUsersCommitteeapproval

No

De-identifiedforresearchproject

Yes Yes No

IdentifiedRetrospectivedataorpreviouslycollectedspecimens–ApplicationthroughOncDRS

Yes Yes Yes–completecombinedusercommitteeapplicationandIRBapplicationwithinOncDRS.Yourapplicationwillberoutedtotheuserscommitteeandonusercommitteeapproval,“NewProjectApplication:Researchuseofretrospectivemedicalrecordsorpreviouslycollectedspecimens”willbeforwardeddirectlytoIRBforapproval(onlyavailableforDFCI-basedinvestigators)

IdentifiedRetrospectivedataorspecimens(ApplicationtoUsersCommitteeviastand-aloneform)

Yes Yes Yes–completeUsersCommitteeApplicationandcomplete“NewProjectApplication:ResearchuseofRetrospectiveMedicalRecordsorPreviouslyCollectedSpecimens”.

Comment [PHS IS6]: http://www.dfhcc.harvard.edu/research/clinical-research-support/submission/forms-and-templates/

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SecondaryuseofIdentifiedProspective/ClinicalTrialdataorspecimens

Yes Yes Yes–FullIRBreviewedprotocolisrequired.Complete“NewProjectApplication:ProspectiveCollectionofHumanMaterialand/orClinicalDataforResearchPurposes”.

Aggregatepatientdata/specimensorde-identifieddata/specimensforfeasibilitystudy:Ifyouareinterestedinobtainingaggregatepatientdata/specimensorde-identifieddata/specimensforfeasibilitystudy,youdonotneedUsersCommitteeapprovalsincedatawillbeeitherprovidedinaggregateasapatientcountorde-identifiedandwillneverbepublished.FordataavailableinOncDRS–youcanusetheAggregateQueryToolwithOncDRS.FordatathatisnotavailableinOncDRS(CRIS,caTissue,datafrombreastoncologycohortstudies(e.g.09-204,05-246)oryouneedassistancewithOncDRS,completetheClinicalDataRequestForm.Onceyouwishtomoveaheadwiththeformalstudythatneedsidentifieddata,youwillneedtosubmitafullresearchproposaltotheusers’committee.

Researchprojectondeidentifieddata/specimens:Ifyouareinterestedinobtainingdeidentifieddataand/orspecimens,youwillneedtosubmitaresearchproposaltotheUsersCommitteeforapproval.TheproposalmaybesubmittedviaOncDRSoriftheclinicaldataisnotavailableviaOncDRS,youmaywishtoforwarddirectlytoprojectmanagerforUsersCommitteereview.Researchprojectonidentifieddata(retrospectiveorprospective):Ifyouareinterestedinobtainingidentifiedretrospectivedata(e.g.chartreview),youwillneedtosubmitaresearchproposaltotheUsersCommitteeforapproval.Inaddition,theinvestigatorwillneedtosubmitaprotocoltotheIRBforthestudy.ApprovalfromtheUsersCommitteeiscontingentonIRBapproval.IfyousubmityourproposalviaOncDRS,youwillalsoautomaticallybesubmittingtheapplicationtotheIRB(OHRS).ThereviewofyourproposalbytheIRBwillbean‘expeditedreview”,whichwilllikelytake2-3days.Forprospectivestudies,itisrequiredtocomplete“NewProjectApplication:ProspectiveCollectionofHumanMaterialand/orClinicalDataforResearchPurposes”foundontheOHRSwebsite.Othertypesofproposals:

§ Operationalandqualityimprovementdata:Ifthegoalistoexamineoperational,clinicalordataqualityimprovement,withnointenttopublish-youcanjustrequestareportusingthefollowinglinks:

a. ForresearchoperationaltaskssuchasdataqualityonCRIS,researchstatisticsorconsentingreports-usethislink:http://dfcionline.org/departments/informationsystems/clinres/coris/

b. Forclinicaloperationstaskssuchasclinicaloperationsmanagementorclinicalqualityimprovementusethislink:http://dfcionline.org/managerstoolkit/dart/

§ Noteonclinicaltrials:TheUsersCommitteemechanismisnotintendedtobeusedforthe

implementationofclinicaltrials.Ifyouareinterestedinstartingaclinicaltrial,pleaserefertotheOHRSwebsite:http://www.dfhcc.harvard.edu/research/clinical-research-support/

DoIneedtosubmitanapplicationtoOncDRS,UsersCommittee,orboth?InvestigatorsoutsideofDFCImustsubmitallrequestsviatheUsersCommitteeapplicationform.ForDFCIinvestigators,requestsforclinicaldataprojectsmaybesubmittedeitherthroughOncDRSorthroughtheUsersCommitteeviaemail.Theadvantageofsubmission


Comment [PHS IS8]: http://dfcionline.org/departments/informationsystems/clinres/coris/.

Comment [PHS IS9]: http://www.dfhcc.harvard.edu/research/clinical-research-support/


Comment [PHS IS11]: http://www.dfhcc.harvard.edu/research/clinical-research-support/

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throughOncDRSisthatasingleapplicationservesasthedocumentforbothUsersCommitteeandIRBreview.Otherwise,investigatorsmustsubmitanapplicationtotheUsersCommitteeandaseparatelowriskprotocolapplicationtotheIRB.AnystudythatincludesOncomap/OncopaneldatamustbesubmittedthroughOncDRS.HowdoIregisterforOncDRS?StaffRequesterRegistrationTosignupforaNewUserAccount:AttheSPARKSWebPortalLoginscreen,clicktheRegisternow!livelink.

EnteryourPartnersusernameandpassword,andclickNext.

SelectyourInstitution,Department,andAppointmentfromthedrop-downlistsontheRegistrationpage.

ReadandaccepttheUserAgreement

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Aconfirmationmessageappearsonceyourregistrationsubmissionissuccessful.Thismaytakeafewmoments.TheconfirmationmessagealsostatesthatyoumustbeaddedtoaprojectteambyaFacultyRequesterbeforeyoucanstartusingtheOncDRSapplications.

ClickOKtoreturntoexittheregistrationpageandreturntothemainOncDRSportalpage.OnceaFacultyRequesterhasaddedyoutoaprojectteam,youcanloginusingyourPartnerscredentialsanduseOncDRSapplicationsasamemberofaprojectteam.HowdoIcreateaProjectTeamonOncDRS?

1. Select‘ManageProjectTeams’fromtheSPARKS>OncDRSmenu

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2. Inthenewwindowthatappears,typeinanewprojectteamnameinthebox‘AddNew

ProjectTeam:’atthebottomrightofthescreenandclick‘Add’tocreatenewteam.

3. Clickonthenewlycreatedteamandanewwindowwillappear.Teammemberscanbeaddedbytypingintheirlastnameandclickingonthesearchbutton(magnifyingglasstotheright).ClickontheUserIDname,therowwillhighlightblue.Click‘Add’andthen‘Save’.Teammemberscanbeadded,activated,ordeactivatedatanytime.

4. ThenewProjectTeamisnowavailableforselectionwhenrunningAggregateQueries(SeeAggregateQueryToolInstructions)

DF/HCCBreastSPOREGrant1) Project#1-Androgens,androgenreceptorsignalingandbreastcarcinogenesis.Myles

Brown,MD&RullaTamimi,ScD.Specificaims:

§ Aim1.EvaluatetheroleofandrogenandARsignalinginbreastcancerriskintheNHS.§ Aim2.EvaluatetheroleofandrogensandARsignalingonbreastcancerprognosisinthe

NHS.§ Aim3.UsebreastcancersubtypespecificAR-targetgenesetstoconfirmARsignalingas

apredictorofprognosisinER+andER-/HER2+breastcancerinBIG-198andNeoAlto.2) Project#2-OvercomingResistancetoHER2-DirectedTherapiesforBreastCancer.Thomas

Roberts,PhD&IanKrop,MD,PhDAim1.Tousegeneticallyengineeredmouse(GEM)modelstoevaluatePI3K-targetedtreatmentstrategiesforHER2+breastcancerAim1A. Tocomparetheeffectsofp110isoform-specificandpan-PI3Kinhibitorsin

conjunctionwithHER2-directedtherapyinGEMmodelsofHER2drivenbreasttumors.Aim1B. ToexaminetheresponsetoHER2-andPI3K-targetedcombinationtherapiesof

HER2tumorswithconcomitantPIK3CAmutationsorPTENloss.

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Aim2.ToidentifyandtestresistancemechanismstoHER2-andPI3K-targetedtherapiesinGEMmodelsAim2A. TotesttheabilityofrecentlyidentifiedmechanismsofresistancetoPI3K

inhibitorstoblockresponsetocombinationsofHER2andPI3Ktargetedtherapies Aim2B. ToidentifygenescapableofconferringresistancetoHER2-targetedinhibitionin

aGEMmodelAim3.ToevaluatetheroleofPI3KinhibitioninconjunctionwithHER2-targetedtherapyinpatientswithHER2+breastcancerAim3A. TotestthehypothesisthattheadditionofaPI3Kinhibitorovercomesresistance

topreoperativepertuzumab/trastuzumabbasedtherapyAim3B. ToidentifyPI3K-dependentandPI3K-independentresistancepathwaysenriched

inresidualtumorsafterpreoperativeHER2-andPI3K-directedtherapyAim3C. ToassessPI3K-dependentandPI3K-independentpathwaysassociatedwith

resistancetoHER2-and/orPI3K-directedtherapiesinhumanbreastcancerspecimens.3) Project#3-NovelStrategiestoextendDNARepairTherapiesforTripleNegativeBreast

Cancer.AlanD’Andrea,MD&JudyGarber,MD,MPHTheoverarchinggoaloftheprojectistoutilizenovelstrategiestodisrupthomologousrecombination(HR)repairinBRCA-proficienttriple-negativebreastcancers(TNBC)inordertosensitizethemtopoly(ADP-ribose)polymerase(PARP)inhibition.TheProjectincludespreclinicalworkinTNBCcelllinesandpatient-derived(PDX)modelswithultimatetranslationtoclinicaltrial.SpecificAim1.EvaluatethecombinationofaCDK1inhibitor(dinaciclib)andaPARPinhibitor(veliparib/ABT-888)inthetreatmentofBRCA-proficientTripleNegativeBreastCancerSpecificAim2.EvaluatethecombinationofaPI3Kinhibitor(BYL719)andaPARPinhibitor(olaparib)inthetreatmentofBRCA-proficientTripleNegativeBreastCancer(seemodificationsoforiginalaimsdescribedbelow)4) Project#4-BETbromodomainproteinsasnoveltherapeutictargetsinTripleNegative

BreastCancer.KorneliaPolyak,MD,PhD,EricWiner,MDAim1.TodefineandcharacterizethedrugtargetanddownstreamtargetsofJQ1/BETbromodomaininhibitorsinTNBCs.

Aim1A. ToidentifykeymediatorsofJQ1’seffectsinTNBCsbyglobaltagged-compound-bindingassays(Chem-seq).

Aim1B. ToanalyzethegeneexpressionprofilesofTNBCsfollowingJQ1/BETbromodomaininhibitortreatmentandafterdownregulationofBRD4orotherrelevantbromodomainproteins.

Aim1C. ToperformChIP-seqforBRD4orotherrelevantbromodomainproteinsinTNBCtoidentifyJQ1/BETbromodomaininhibitorgenomictargets.

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Aim1D. TointegrateanalysisofallgenomicdatatodefinemajordownstreammediatorsofresponsetoJQ1/BETbromodomaininhibitorsinTNBCs.

Aim2.ToconductaclinicaltrialtotestJQ1/BETbromodomaininhibitorsinTNBCpatients.

Aim2A. ToconductaphaseIItrialofJQ1/BETbromodomaininhibitorsinpatientswithmetastaticTNBC.TheprimaryobjectiveofthetrialistodetectasignalofresponsetoabromodomaininhibitorinmetastaticTNBC.Baseline,ontreatment,andpost-progression(inrespondingpatients)tumorbiopsieswillbeperformedtofacilitatemechanisticstudiesandthedevelopmentofpharmacodynamicbiomarkersandbiomarkerspredictiveofclinicalresponse.

Aim2B. ToanalyzetheexpressionofthetargetsofJQ1/BETbromodomaininhibitorsinprimaryhumanbreasttumorsamples.Wewillanalyzetheexpressionofdirectdrugtargets,criticaldownstreameffectors,andpredictorsofresponseidentifiedinAim1byimmunohistochemistryandmulti-colorimmunofluorescence.

Aim2C. Toderivexenograftmodelsfrombiopsiesofpatientsenrolledintheclinicaltrial.Thesewillbeusedtotesthypothesesregardingbiomarkers,targets,resistancemechanisms,andcombinationtherapies.

Aim3.Todevelopcelllinesresistanttobromodomaininhibitorsandcharacterizecombinationtherapiestoimprovetherapeuticresponsesandovercomeacquired.

Aim3A. Todevelopresistantcelllines.WewillstartwithsensitiveTNBCcelllinesanddevelopresistantderivativesbyprolongedgrowthingraduallyincreasingJQ1concentrationsincellcultureorxenograft-bearingmice.

Aim3B. ToinvestigatewhethercombiningG2/Marrestinducing-drugsortargetedagentseffectiveinTNBCwithJQ1/BETbromodomaininhibitorsleadstomoreefficientpre-clinicaltherapeuticresponses.

SPORECareerEnhancementProgram(CEP)&DevelopmentalResearchProgram(DRP)CEPProjectsAwarded2016:HarnessingtumorassociatedmacrophagesforbreastcancertherapyInvestigator:JenniferGuerriero,PhD(DFCI)Aim1:TestthehypothesisthatTMP195treatmentenhanceshormoneandmonoclonalantibodytherapyintheMMTV-PyMTmousemodelofbreastcancer.TestthehypothesisthatTMP195treatmentwillenhanceanti-estrogentherapyintheMMTV-PyMTmousemodelofbreastcancer.TestthehypothesisthatTMP195treatmentwillenhanceanti-HER-2/neumonoclonalantibodytherapyintheMMTV-PyMTmousemodelofbreastcancer.Aim2:TestthehypothesisthatTMP195-activatedTAMswillbenefitpatientswithtriplenegativebreastcancer.TestthehypothesisthatTMP195inducestumorregressioninamousemodeloftriplenegativebreastcancer.TestthehypothesisthatTMP195willenhancePARPinhibitortherapyinamousemodeloftriplenegativebreastcancer.

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BreastcancersubtypespecificriskpredictionmodelstoinformprecisionmedicineapproachestopreventionandearlydetectionInvestigator:AnneMarieMcCarthy,PhD(MGH)Existingbreastcancerriskmodelsdonotconsidertumorsubtypeandhavelimitedpredictiveability.Improvingriskpredictionmodelstoestimatesubtypespecificriskusingepidemiological,clinical,andimagingfeaturescouldenablepredictionofaggressivetumorsandbeusedtoguidemoreintensivepreventionandscreeningstrategiesforwomenathighriskforpoorprognosiscancers.Aim1:Examinetherelationshipofepidemiologicriskfactorsandimagingfeatures(e.g.breastdensity,masscharacteristics,calcifications,asymmetry,architecturaldistortions)withaggressivebreastcancersubtypes(TNBC,HER2+)amongwomenundergoingroutinescreeningmammography.Aim2:Adaptexistingbreastcancerriskpredictionmodelstogeneratesubtypespecificriskestimates.EtiologyandpreventionofbreastandovariancancersInvestigator:MeganRice,ScD(MGH)BreastcanceristhemostcommonlydiagnosedcanceramongUSwomenandistheleadingcauseofcancerdeathforwomen<45yofage.Pregnancypriortoage35confersalong-termprotectiveeffectagainstbreastcancer,withagreaterbenefitforwomenwhowereyoungeratfirstbirth.Despitetheriskreduction,pregnancyisassociatedwithatransientincreaseinbreastcancerrisk;themagnitudeanddurationofthisincreasedriskisgreaterinolderfirst-timemothers.Aim1:Investigatetheassociationbetweenlifestylefactorsrelatedtoinflammation,specificallysedentarybehaviorandapro-inflammatorydietpattern,andriskofbreastcancerdiagnosed≤10yearsafterchildbirth.Secondarily,wewillcomparethestrengthofassociationbetweenthesefactorsandtotalbreastcancerriskstratifiedbyparityandtimesincechildbirthinpremenopausalwomen(i.e.,nulliparous,≤10years,>10years).Aim2:Assesstherelationshipbetweenaspirinandnon-aspirinNSAIDsuseandriskofbreastcancerdiagnosed≤10yearsafterchildbirth.Secondarily,wewillcomparethestrengthoftheassociationbetweenNSAIDsuseandtotalbreastcancerriskstratifiedbyparityandtimesincechildbirthinpremenopausalwomen.Aim3:Comparetheexpressionofinflammationpathwaymarkersinbreasttumortissuefromwomendiagnosed≤10yearssincechildbirthtotissuefromthosediagnosed>10yearssincechildbirthortonulliparouswomen.Awardedin2015MinoritySupplementAwardInvestigator:ShawnJohnson,PhDThegoalofthisprojectwastofurthercharacterizetheabilityofCDK12inhibitiontosensitizetriplenegativebreastcancer(TNBC)models,bothBRCA-wildtypeand–mutated,toPARPinhibitors.Aim1:Furtherelucidatethestructuralmechanismbywhichdinaciclib,apan-CDKinhibitor,inhibitsCDK12withgreaterefficacythanotherknownCDK9inhibitors.Aim2:Improveinvivopharmacodynamicassaysforassessinghomologousrecombination(HR)inFFPE-samples.Specifically,thequantificationofRAD51fociinductioninFFPE-samplesfrompatientderivedxenografts(PDX)models.Aim3:Developandcharacterizenovelcovalent

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CDK12inhibitorsincollaborationwiththeNathanealGreylab.Aim4:FinalizeandsubmitmanuscriptdetailingcombinedCDK12/PARPinhibitorcombinationpreclinicalwork.Awardedin2014IntegrativeSubtype-SpecificPrognosticModelsforPrecisionBreastCancerDiagnosticsInvestigator: Andrew H Beck, MD, PhD (BIDMC) Wehypothesizethattheexpressionofmolecularsignaturesandmorphologicphenotypesdrivebreastcancerprogressioninasubtype-specificmanner.Todiscovermorphologicphenotypesassociatedwithbreastcancerprogression,wedevelopedtheComputationalPathologist(C-Path)system.Toidentifyrobustmolecularsignaturesassociatedwithbreastcancerprogression,wedevelopedSignificanceAnalysisofPrognosticSignatures(SAPS).Inthecurrentproject,wewillintegratetheuniquestrengthsofthesemethodsandapplythemtoalargeandwell-annotatedcollectionofbreastcancersamplestobuildrobust,biologicallyinformative,data-driventoolsforprecisionbreastcancerdiagnostics.Thegoalofthisprojectistoidentifymorphologicalandmolecularbiomarkersofinvasivebreastcancer(IBC)prognosisinbreastcancermolecularsubtypesandtoconstructintegrativesubtype-specificprognosticmodels.Aim1:Todiscovermorphologicbiomarkersassociatedwithpatientprognosisinbreastcancermolecularsubtypes.Aim2:Tovalidatesubtype-specificprognosticexpressionbiomarkersinbreastcancermolecularsubtypes.Aim3:Tobuildintegrativesubtype-specificprognosticmodelscomprisedofmorphologicphenotypes,expressionbiomarkers,andhostlifestylefactorstopredictsurvivalinbreastcancermolecularsubtypes.Estrogenreceptormutations:thefunctionalrolesinendocrineresistanceandpotentialasatherapeutictargetInvestigator: Rinath Jeselsohn, MD (DFCI) Theestrogenreceptorisanucleartranscriptionfactorthatdrivesproliferationandgrowthofluminaltypebreastcancersandisthemajortargetofhormone-basedtherapiesforbreastcancer.WehaveidentifiedESR1mutationsinupto20%ofmetastaticendocrineresistanttumorsamples.Thesemutationsareallclusteredintheligand-bindingdomainandourfunctionalstudiesindicatethatthesemutationsconferconstitutiveactivityandrelativeresistancetoendocrinetreatments.Aim1:EstablishstablecelllinesandpatientderivedxenograftsharboringtheESR1mutationsanddeterminethefunctionalrolesoftheERmutationsintumorgrowth,invasiveness,metastasisandendocrineresistance.Aim2:DecipherthemolecularmechanismsmediatingthephenotypeoftheESR1mutations.Aim3:TesttheefficacyofestrogenreceptordegraderscombinedwithPI3K,CDK4/6orHSP90inhibitorstoinhibitESR1mutationaldriventumorgrowthinpre-clinicalmodels.SapacitabineandSeleciclibinBRCA-DeficientBreastCancerInvestigator: Sara Tolaney MD, MPH (DFCI) Thespecificaimsofourproposalfocusonassessinghomologousrecombination(HR)proficiencyinclinicalsamplesofBRCAcarrierpatientsenrolledtothesapacitabine/seliciclib

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combinationtrial.Enrollmenttothiscohorthasnotyetbegun,sowehavenotbeenabletobeginworkoneitherofthespecificaimstodate.Aim1:AssessHRproficiencyoftumorsamplesusingtheMyriadGeneticsHR-deficiency(HRD)assayAim2:Performwholeexomesequencingtodeterminethemutationalsignatureoftumorsamples AssessingmethodstoimprovetheefficacyofPI3KinhibitorsinPIK3CAmutatedbreastcancersInvestigator:SadhnaVora,MD(MGH)ThegoalofthisprojectistoimprovetheefficacyofPI3Kinhibitors(PI3Ki)inbreastcancersdrivenbytheoncogenicmutationofthePIK3CAgene.OurpreliminarydatasuggestedthateithermTORiorCDKi,whencombinedwithPI3Ki,couldovercomeresistancetosingleagentPI3Ki.OurworkoverthefirstyearofthegranttermhasfocusedmoreonCDK/PI3KithanmTOR/PI3KiduetofindingsfromtheclinicoftoxicitiesassociatedwiththemTOR/PI3Kicombination(notablyhyperglycemiaandgastrointestinalissues).Aim1:InvivostudiesofPI3KinhibitionwitheithermTORCorCDK4/6inhibitorstodeterminewhichtreatmentstrategyisamoreeffectiveinitialPI3Kibasedtherapy.Aim2:PerformpooledshRNAscreenondenovoresistantestablishedandpatientderivedPIK3CAcelllines.Aim3:toassesspatientsamplesforbiomarkersofresistancetoPI3Kinhibitors.IdentifyingresistancemechanismsinER+breastcancerbytranslationalgenomicsInvestigator:NikhilWagle,MD(DFCI)Thegoalofthisresearchistoapplybothcomprehensivegenomicprofilingandsystematicfunctionalapproachestotestthehypothesisthatsomaticgeneticdifferencesmaycontributetoendocrine-resistanceinbreastcancer.Aim1:toconductanear-genomescalelentiviralopenreadingframe(ORF)screenforgeneswhoseoverexpressionissufficienttoconferresistancetoanti-estrogentherapyinbreastcancercelllines.Aim2:Toperformcomprehensivegenomiccharacterizationofpre-treatmentandpost-progressionbreastcancersamplesobtainedfrompatientswhohavedevelopedresistancetohormonaltherapy.DRPProjectsAwardedin2016Award8:SupramolecularnanotherapeuticsforpreferentialimmunemodulationofthetumorMicroenvironmentInvestigator:AshishKulkarni,PhD(BWH)Aim1:UseSNPstoswitchimmunosuppressiveM2tocytotoxicM1macrophages,andstudytheeffectinbreastcancer.Basedonpreliminaryobservations,wewill(a)useasyngeneicimmunocompetent4T1andanathymicMDAMB-231TNBCxenograftmurinemodeltotesttheefficacyoftheSNPvsaCSFR1antibodyandsmallmoleculeinhibitorsofCSF1R;and(b)dissectthemechanismsunderlyingtheswitch

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fromaM2toanM1subtypeinresponsetoSNPmediatedsustainedCSF1Rinhibition;Aim2:TestforsynergybetweentheSNPandanimmunecheckpointinhibitorinabreastcancermodel.Morespecifically,wewilltestthehypothesisthatacombinationofaCSF1R-inhibitingSNPandanimmunecheckpointinhibitor,administeredintherighttemporalsequencecanresultinanenhancedoutcomeintermsofsurvival.Award9:RapidfunctionalanalysisofBRCA1VUSallelesInvestigator:NicholasWillis,PhD(BIDMC)TheprojectwilltestthehypothesisthatSuppressionofaberrantDSBrepaircontributestoBRCA1tumorsuppressorfunction.Aim1:PerformageneticanalysisofapanelofBRCA1variantsinHRrepairandLTGCsuppression.SurveytheremainingBRCA1VUSallelesforsuppressionofLTGC.GenerateandtestefficacyofRFP-SCRbreastcancerHRreportercelllines.Aim2:RelateHRfunctionsofVUSallelestoPARPisensitivityandcisplatinsensitivity.StudytheimpactofBRCA1variantsinreversalofPARPinhibitorsensitivityofBRCA1mutantcells.Awardedin2015ComplimentingBMN-673withPD-1PathwayBlockadetoImproveResponsesAgainstBrca1-/-BreastCancerInvestigator:MichaelGoldberg,PhD(DFCI)Immunotherapycanaddressrefractorydiseaseandrepresentsanexcitingapproachtoachievedurableresponses.Whiletheantitumoreffectsofconventionaltherapies–suchasradiationandchemotherapy–aregenerallyattributedtotheircyotoxicity,theirefficacyisatleastpartlyattributabletotheirpartialinductionofantitumorimmunity.Still,evenimmunotherapyhasdemonstratedonlymodestbenefitagainstadvancedbreastcancertodate.Acombinationofcancercell-intrinsicand-extrinsicinterventionsmayberequiredtoimproveoutcomes.ThegoalofthisSPOREprojectistoconfirmthatcombiningthePARP1inhibitorBMN-673withanti-PD-1oranti-PD-L1willyieldasynergisticantitumorresponseagainstbreasttumorsthatexhibitimpairedhomologousrecombination,acommonfeatureoftriple-negativebreastcancer.Wearethefirsttoshowthat,BMN-673hasimmunoregulatoryeffects,providingamechanisticrationalefortheproposedcombination.WeidentifiedseveralimmunoregulatorygenesthatareupregulatedfollowingtreatmentwithBMN-673andhypothesizedthatBMN-673mayinfluencethecompositionandfunctionofimmunecellsinthetumormicroenvironment.WeconfirmedthatBMN-673significantlyincreasesthenumberoftumor-associatedCD8+TcellsandNKcellsaswellastheirproductionofIFN-γandTNF-α.ThesedatasuggestthatBMN-673maythereforeserveasanadjuvanttherapytoimmunotherapyinmice–andultimatelypatients–whosetumorsharbordefectsinhomologousrecombination.Totestthishypothesis,wewillcompletethefollowingAims:1)confirmsynergybetweenBMN-673andanti-PD-1/PD-L1inBrca1-/-breasttumors,and2)definemechanismofcooperativitybetweenPARPinhibitionandPD-1pathwaycheckpointblockade.Thisprojectiswellalignedwiththescope,investigators,andprojectselectionoftheSPOREinBreastCancer.TheworkishighlycomplementarytoProject3(NovelStrategiestoExtendDNARepairTherapiesforTriple-NegativeBreastCancer).Ifsuccessful,theapproachdescribedhereincouldbereplicatedwithinhibitorsfromProject4(BETBromodomainProteinsasNovelTherapeuticTargetsinTriple-NegativeBreastCancer).WewillworkwithCoreD(TissueandPathologyCore)andhopetoworkwithCoreC(ClinicalTrialsCore).NeutralizationofBCL2/BCL-XLenhancesthecytotoxicityofT-DM1invivoInvestigator:JasonZoeller,PhD(HMS)

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ResistancetoT-DM1representsamajorobstacleintheeffectivetreatment.UsingtwoPDXmodelsofadvancedHER2+resistantdisease,weobtainedpreliminaryevidencedemonstratingthatblockadeofBCL2/BCL-XLanti-apoptoticactivitydramaticallyenhancestheeffectivenessofT-DM1.Thisproposalwillcharacterizethiscombinationtreatmentinadditionalmodelsofadvancedand/ormetastaticHER2+breastcancer,toaddressitseffectivenessindistinctERtumorsubtypes,characterizetheneedforBCL2-and/orBCL-XL-specificinhibition,andassesstumorresponseattheprimaryandsecondarysites.Suchinsightcouldinformafutureclinicaltrial.ImprovingtheinitialcytotoxiceffectivenessofT-DM1mayprovideatherapeuticapproachtoreduceand/oreliminatedrugresistanceintheclinic.Aim1.ToevaluatetheeffectivenessofT-DM1plusBCL2/BCL-XLinhibitionacrossmultiplemodelsofHER2+resistantdisease.ForT-DM1/ABT-263invivoexperiments,PDXtumorfragmentsorcellswillbetransplantedintothemammaryfatpadoffemaleNOD/SCIDmice.Micewithhormonereceptorpositivetumorswillrequiresub-cutaneousimplantationofaslow-releaseestrogenpellet.TheBCL2/BCL-XLinhibitorABT-263willbeadministered,andpathologicalresponsewillbedeterminedviaanalysisoftheH&Estainedsections.TumorcellswillbevisualizedbyHER2IHC.Tumorswillalsobeanalyzedformarkersofcellproliferation(Ki67)andcelldeath(cleavedcaspase-3).Aim2.TodeterminetheeffectivenessofcombinationT-DM1plusBCL2-orBCL-XL-selectiveinhibitors.WewillinitiatethesestudiesinHER2+ER-PDX12andHER2+ER+PDX5.Experimentswillincludeeighttreatmentarms:(1)T-DM1,(2)BCL2/BCL-XLinhibitorABT-263,(3)BCL2inhibitorABT-199,(4)BCL-XLinhibitorABT-133,(5)T-DM1+ABT-263,(6)T-DM1+ABT-199,(7)T-DM1+ABT-133and(8)placebocontrols.ABT-133willbeprovidedthroughcollaborationwithAbbvie.Bloodandtumorswillbecollectedandanalyzedatthe14-dayendpointasdescribedabove.DiscoveringhowPhosphoinositide3-Kinase(PI3K)regulatesDNAsynthesisandrepair,andexploitingthisdualfunctionofPI3Ktodesigncombinationtreatmentsfortriple-negativebreastcancerInvestigatorGerburgWulf,MD,PhDAim1:NucleosidesynthesisdownstreamfromPI3KisnotregulatedviaAKTbutviatheRac/PAKaxisandultimatelyregulationofglycolyticflux.PI3KdirectlycoordinatesglycolysiswithcytoskeletaldynamicsinanAKT-independentmanner.GrowthfactorsorinsulinstimulatethePI3K-dependentactivationofRac,leadingtodisruptionoftheactincytoskeleton,releaseoffilamentousactin-boundaldolaseAandanincreaseinaldolaseactivity.Consistently,PI3K-,butnotAKT-,SGK-ormTOR-inhibitors,causeasignificantdecreaseinglycolysisatthestepcatalyzedbyaldolase,whileactivatingPIK3CAmutationshavetheoppositeeffect.Aim2:DNAdamageinducedbyPI3KinhibitorsisaconsequenceofimpairedproductionofnucleotidesneededforDNAsynthesisandDNArepair.InhibitionofPI3Kcausesareductioninallfournucleotidetriphosphates,whileinhibitionofAKTislesseffectivethaninhibitionofPI3KinsuppressingnucleotidesynthesisandinducingDNAdamage.CarbonfluxstudiesrevealthatPI3K-inhibitiondisproportionatelyaffectsthenon-oxidativepentosephosphatepathway(non-oxPPP)thatdeliversribose-5-posphaterequiredforbaseribosylation.InvivoinamousemodelofBRCA1-linkedtriple-negativebreastcancer(K14-CreBRCA1f/fp53f/f)thePI3K-inhibitorBKM120ledtoaprecipitousdropinDNAsynthesiswithin8hoursofdrugtreatment,whileDNAsynthesisinnormaltissueswaslessaffected.InthismousemodelcombinedPI3K-andPARP-inhibitionwassuperiortoeitheragentalonetoinducedurableremissionsofestablishedtumors.

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Awardedin2014DevelopingmicroRNA‘signatures’asbiomarkersforoptimaltherapeuticuseofPARPinhibitorsinTripleNegativeBreastCancer(TNBC)Investigator:DipanjanChowdhury,Ph.D.(DFCI)Aim1istoassesstheabilityofSENSMiRNAstoabrogateHR-mediatedDSBrepairusingtwocomplementaryassayswhichhavebeenoptimizedinmylaboratoryAim2isfocusedonunderstandingthemechanismbywhichthesemiRNAsinfluenceHR,thatis,identifyHRpathwaymembersthatmayberegulatedbySENSMiRNAs.AimistoassesstheabilityofSENSMiRNAstoenhancesensitivitytoPARPinhibitorsaloneandincombinationwithCDKinhibitorinvitroinTNBClines.Aim4istoassesswhetherexpressionofSENSMiRNAsareassociatedwithresponsetoPARPi/CDKinhibitor(PhaseIItrial,SPOREprogram)orwithcisplatin(PhaseIItrial,MyriadGeneticLaboratories)intumorspecimensfromTNBCpatients.IdentifyingDisseminatedTripleNegativeBreastTumorCellsthatareResponsibleforDiseaseRelapseInvestigator:SandraS.McAllister,PhD(BWH)Aim1istoIdentifydisseminatedtumorcellsthatrespondtosystemicsignalstoformovertlungmetastasesAim2istoobtainmolecularsignaturesofdisseminatedtumorcellsbeforeandaftertheyformoverttumors.PalbociclibinBreastCancer:ResistanceMechanismsandSyntheticLethalitywithNHEJInhibitionInvestigator:GeoffreyShapiro,M.D.,Ph.D.(DFCI)Aim1:determinethemechanismsofresistancetotheCD4/6inhibitorpalbociclibinbreastcancercelllinesandinvestigatestrategiestoovercomeresistanceAim2:assessthecombinedinhibitionofCDK4/6andnon-homologousendjoining(NHEJ)inbreastcancercellsElucidationoftheroleofMELK,anoveloncogenickinase,inbasal-likebreastcancerInvestigator:JeanZhao,PhD(DFCI)Aim1:Todeterminethemechanism(s)underlyingtheoncogenicroleofMELKinbasal-likebreastcancer.Aim2:ToevaluatetheroleMELKinthetumorigenesisofbasal-likebreastcancerinaGEMmodel.Aim3:TodevelopaGEMmodelofbreasttumordrivenbyoverexpressionofMELK.

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Frequently Asked Questions about DF/HCC Breast …...Deborah Dillon. 1997-2011 – • No strict eligibility criteria for collection during this time period • 700-800 breast cancer