2014-15 REPORT ANNUAL Understanding Precision Medicine and ... Meredith Irwin... · NF1. Metastatic...
Transcript of 2014-15 REPORT ANNUAL Understanding Precision Medicine and ... Meredith Irwin... · NF1. Metastatic...
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ANNUALREPORT2014-15
GFCC ANNUAL REPORT
UnderstandingPrecisionMedicineandGeneSequencingforNeuroblastoma
January20,2018MeredithIrwin,MD
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SickKids SequencingProgram
PrecisionTherapy
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Whatisprecisionmedicine?
• “personalized”vs.“individualized”vs.precision
• isanapproachfordiseasetreatment(andprevention)thattakesintoaccountindividualvariabilityingenes,environment,andlifestyleforeachperson.
• useofgenes/molecularcharacterization(+/- inconjunctionwithclassictumorclinicalandbiologicalfeatures)toinformtreatment
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PrecisionCancerTherapy
Earlyprecisionmedicine:Low,intermediateandhighriskneuroblastoma
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Whatcausescancer?
• Whatcausescancer?
– Changesingenesthatgivecellstheabilitytogrow
fast,continuouslydivide,spreadandformtumors
• GENETICS101
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Whatiscancer?
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Mutations/alterationsingenescausecancer
(1)Mutation
(2)Extracopies- oncogenes
(3)Missingcopies-suppressorgenes
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DNA
mRNA
protein
AUGGAGCCAACUAUUGAUGAA
FlowofgeneticinformationDNA RNA Protein
Met- Glu - Pro- Thr - Ile- Asp - Glu
ATGGAGCCAACTATTGATGAA
Genes
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DNA
mRNA
protein
AUGGAGCCAACUAUUGAUGAA
FlowofgeneticinformationDNA RNA Protein
Met- Glu - Pro - Thr - Ile- Asp - Glu
ATGGAGCCAACTATTGATGAA
Genes
X
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DNA
mRNA
protein
AUGGAGCCAACUAUUGAUGAA
FlowofgeneticinformationDNA RNA Protein
Met- Glu - Pro - Thr - Ile- Asp - Glu
ATGGAGCCAACTATTGATGAA
Genes
MUTANT WILD-TYPE
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DNA
mRNA
protein
AUGGAGCCAACUAUUGAUGAA
FlowofgeneticinformationDNA RNA Protein
Met- Glu - Pro - Thr - Ile- Asp - Glu
ATGGAGCCAACTATTGATGAA
Genes
MUTANT WILD-TYPEPrecisionTherapy
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Rolesforgenealterationsinpediatriccancer?
– Unlikeadultcancersitisraretogetpediatriccancerfromanexposuretosomethingtoxic(cigarettesmoke,sun)
– Althoughitcanbeinheritedfromparentsmostofthetimeitisnot
– Changesincancercellgenesleadtopropertiessuchasgrowth/survival,proliferation,invasion/metastasis…...
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Genemutationscanbeinheritedornew-what’sthedifference?
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Howtosequencegenes
• Sequencing=codeofgenesACTG…..
• Previously- checkonegeneafteranotherforalterations/mutations
• Nowcansequenceallgenes(DNAandRNA)
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Breakthrough:nextgenerationsequencing
• Cansequenceallofthegenesinacancercell
ratherthanoneatatime
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Thehumangenomestats
• 23chromosomepairs– 1x/y,other22
• Entiregenome=over3billionbasepairs– ACTG…..
• Approx20,000genesthatcodeforproteinsmadeincells– Alotmoreimportantinfointheothermillionsofbasepairs
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0
5,000
10,000
15,000
20,000
25,000
30,000
Cost per Human Genome
20122011 2013
$ R
eage
nt C
ost
Cost range
• ‘$ Cost’ of exome sequencing 1,000-2,000
Genome wide sequencing is becoming less expensive than existing genetic tests
Existing Genetic Dx Tests
Sequencing ALK ~ $1500
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MutationsinNeuroblastoma
• Mutation- changesinoneormoreDNAbases(eg A->C)resultingindifferentaminoacidthatchangestheprotein
• Veryheterogeneous• IncomparisontosomecancerswherethereisacommonmutationinmostpatientsinNBvarietyofdifferentgenemutations– ALK- mostcommonmutation(10%)– Others- ATRX,Ras,NF1,PTPN11,…..
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Targetedtherapiesbasedongenetics
– Chemotherapiesattackcancerandnormalcells
causingincreasedsideeffects
– “target”thedifferentgenes/proteinsonthe
cancercellthathelpittogrowandsurvive
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SickKids SequencingProgram
PrecisionTherapy
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KICSprogram
• 2016:sequenced–almost200completed• Someledtoidentificationoftargetedtherapiesandotherguidancefortreatmentdecisions– ALKinhibitordrugs,others
• DiscoveryofnewgenesinvolvedinNB• ExpandingtoallCanadiansites(PROFYLE)
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KiCS StudyObjectives• Establishtheutilityofsequencingforpatientcare(relapsedandrefractory)– PatientDiagnosticsandMonitoringDiseaseResponse– Prognosis– Guidingtherapeuticdecisions:
• suggestnewtargetsfortherapeuticinterventionbasedontumor-specificgeneticalterations
• Establishthevalueofsequencinginidentifyinginheritedgenes
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KiCS Consent- Overview• ReferraltoKiCS → eligible→ consent
• Consent– EntryPoint1(tumour andgermline/blood)
• Twopartconsentavailable– PartA– samples– PartB– sequencing
– EntryPoint2(germline only)– Parentconsentformsandassent
• Averageconsent:~90minutes
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Whywedorepeatbiopsiesatrelapse?
• Evidencethattherearemore(anddifferent)mutationsatrelapse(clonalevolution)– MostcommontargetablemutationinNB(ALK)increasedattimeofrelapsevs.diagnosis
Ramaswamy andTaylor,NatureGenetics2015
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NGSPlatformsandAnalyses
Tumour DNA+RNA
Non-tumour DNA
Focused, deep sequencing
Broad, shallowsequencing
HiSeq 2500NextSeq 500
800+genes Wholegenome
HiSeq XTen
Libraryprep:2daysSequencing:1day
Libraryprep:2daysSequencing:3day
+6to30hrs
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SickKidsChildhoodCancerPanel
18,950exonannotations
Covering3.9millionbases
Focuseddeepsequencingof886genes
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SickKidsChildhoodCancerPanel
18,950exonannotations
Covering3.9millionbases
MOLECULARTUMORBOARD
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TheKiCS MolecularTumorBoard• Multi-disciplinaryandweekly• AtMeeting:
– datapresented,interpretedanddiscussed:• “actionability”determined
– linktopotentialagentsortrialsmade– challengesornextstepsreviewed– directcommunicationwithprimaryoncologistàfamily
• Attendance:– CoreKiCS team(oncologists,geneticists,pathologists,genomescientists,bioinformaticians,geneticcounsellors,researchassociates,MRP,etc)
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Drivervs.passengermutations
- Manygenevariantsthatcanbeconsidered- Teamincludingbioinformaticians needtoidentifypossible
“drivermutations”sincemanyarejustpassengers
- DRIVER:mutationthatgivesthecancercellaselectivemutation(togrowfaster,spreadetc)=ENGINE
- PASSENGER:manyothermutationsorvariantsincancercellsthatarealongforridebuthavenofunctionaleffect
ALK,MYCN
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ResearchReportsfromCancerPanel
30
Ledia Brunga
0
2
4
6
8
10
12
14
AMLrelapse
ALL
CMLandALL
Undiffe
rentiatedleukem
iaPe
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aMPA
LAM
KLRe
nalcellcarcino
ma
Wilm
stum
orRe
lapsed
hep
atob
lastom
aParagangliomaw/n
euroblastic…
Metastaticpapillarythyroidcarcinom
a…Follicular-Va
riantPapillaryThyroidCA
Prim
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atologicneo
plasm,…
NF1and
GBM
Embryonalrhabd
omyosarcom
aSyno
vialsa
rcom
a,and
pasth
istoryof…
Myofib
roblasticsa
rcom
aFron
toparie
talrhabd
oidmen
ingiom
a…NF1.M
etastaticrhabd
omyosarcom
a.Astrocytom
aGliosarcom
aNeu
roblastomaandCN
Stumor
Epen
dymom
aGB
MGlioma
Med
ulloblastoma
AT/RT
Intracranialund
ifferen
tiatedsarcom
aCo
loncancer
ProstateRMS
Chordo
ma
Osteo
sarcom
aCh
ondrob
lasticosteo
sarcom
aGIST
Undiffe
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aAlveolarRhabd
omyosarcom
aYo
lkSacTum
orMyofib
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rcom
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S-rearranged
prim
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rcom
Ewingsarcom
ametastaticto
thelungs
Desm
oidtumou
rMPN
STNeu
roblastoma
Ovaria
nmucinou
scarcino
ma
Ovaria
nsertolileydigtumou
rBreastcancer
Epith
eloidsarcom
aParagangliomaandpo
ssiblere
nalcell…
PapillaryThyroidCA
SampleCo
unt
Tumourtype
121patientsenrolled
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Incorporatinggeneticsintotreatmentandcareofpatients
- Insteadofpathology(neuroblastoma,sarcomaetc)treatmentisbasedonageneabnormalityintumorthatcanbetargeted
- PhaseIandIItrialsforonedrugorcombinationthatrequireagenemutation/alterationtoenroll
- Trialswithmanyregimensthatusebiopsyresultstoassignpatientstodifferentarmsofathetrial
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6monthslater
TargetingALKmutationwithALKinhibitor
protein
MUTANT WILD-TYPE
1275mutation
ALKi
ALKinhibitor
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CLINICALTRIALS
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Umbrella Trial UMBRELLA and BASKET TRIALS rial.
Woodcock J, LaVange LM. N Engl J Med 2017;377:62-70
Woodcock J, LaVange LM. N Engl J Med 2017;377:62-70
-One(orfewtumortypes)
-themutationidentifieddetermineswhichtreatment
-commoninbreast,lung
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Umbrella Trial UMBRELLA and BASKET TRIALS rial.
Woodcock J, LaVange LM. N Engl J Med 2017;377:62-70
Woodcock J, LaVange LM. N Engl J Med 2017;377:62-70
-One(orfewtumortypes)
-themutationidentifieddetermineswhichtreatment
-commoninbreast,lung
-Multiplecancerseligible(histologyagnostic)
-mutationidentifiedallowseligibility
-CAPTUR,MATCH,many
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NCIPediatricMATCHMolecularAnalysisforTherapyCHoice
• BaskettrialforrelapsedsolidtumorsandlymphomasinUS– 200- 300/year;estimated5-10%Match
• Biopsyandsmall%willhavegeneabnormalityandcanenrollon1of8trialsofsingleagentthattargetsmutation
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NCIPediatricMATCHschema
MASTERPROTOCOL
Sub-protocols
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40
totransformthecareofCAYApatientsacrossCanadaby
usingnext-generationmoleculartoolsandcancermodel
systemstoidentifydisease- andpatient-specificbiomarkers
thataretractabletargetsfortherapytoimproveoutcomes.
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ThePROFYLEPrecisionMedicinePlatform
POG
KiCS
MUGQICandTRICEPS
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Buildingonthesuccessof3regionalprograms
Dec2015enrollment Sept2017enrollment
POG(Vancouver) 32 (incl.21youngadults)
98 (incl.29youngadults)
TRICEPS(Montreal) 21 (upto 21yrs.) 81 (upto 21yrs.)
KiCS (Toronto) 33 158 (incl.10youngadults)
157newcasesin13months~12permonth
AdamShlien
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43
Goals:
• Enroll and molecularly profile 450 patients over 5 years
• Analyze the tumour genome, transcriptome, and proteome to look for treatment targets
• Develop strategies to access therapies for CAYAs with ‘hard to treat’ cancers
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4444
MolecularProfiling&
PrecisionMedicineClinicalTrials
Biospecimen
EfficacyofPrecisionMedicine
IMPROVEOUTCOMESFORHARD-TO-TREAT
CAYACANCERS
Children,Adolescents,andYoungAdults(CAYA)withHard-to-TreatCancers
Modelsof
CAYACancers
•DiscoverNewTargets•DevelopTherapies• UnderstandBiology
CanadianCAYACancerBiobank
&
DataRepository
•BiomarkersofResponse•NewProfilingTools• FuelFutureDiscoveries
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ThePROFYLEPrecisionMedicinePlatform
Toestablishanationalmulti-institutional
cooperativenetworkforgenomics,withthe
goaltoensurethatALLeligiblepatientsinthe
countrywillhaveaccesstothisresource.
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Identify,screen,consent/assent
Tissuecollection,pathologyreview,
Biobanking
MolecularTumourProfiling,Data
Analysis
MolecularTumourBoard
QualityAssuranceandEthicsOversight
PROFYLE CLINICAL NODE
ActionableGenomicFinding(s)
NoactionableGenomicFinding
≥18y <18y
CAPTURclinicaltrial
CAPTURpediatriccohort
CAPTURadultcohort
CAPTURdrugs
ALKinhibitorPDGFRinhibitormTORinhibitorBRAFinhibitorMEKinhibitor?Checkpointinhibitor
HealthCanadanof1trialconcept
Compassionate/SAPaccess
PediatricphaseI/IItrials
PR,CR,SDPD
Continuetherapy
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Sequencingalsoidentifiesgermlinemutations(inherited)
• Mayhavesomeimplicationsfortreatment• Mayhaveimplicationsforotherfamilymembers– Counselling– Screening/surveillance
• Newscientificdiscoveries
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Howtousegenomics/sequencingtoguidetreatment
Modified from Lillian L. Siu et al. Clin Cancer Res 2015;21:4536-4544
“OMICS”tofindtarget-genomics(DNA,RNA)-proteomics-other
Molecular+clinical,radiology,histology,…
1. Othertrials2. SpecialAccess3. Nof14. Informtherapy
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ChallengestoPrecisionMedicineinChildren,AYA
• Pediatriccancersarerare(relatively)• Eachsubset– byhistologyand/orbygeneticalterationisevenrarer• ClinicaltrialschallengesofsmallN,endpoints,controls
• Drugaccessforchildren<18yo (<12)• Regulatory
– US,EUsomelegislationtohelpfacilitate• Pharma• Formulation
• Ethics• (Gen)omics
– Differentsetsofalterationsthatmaynotbeeasytointerrogatesincemostdataisadult
- Needresearchtounderstandnewvariants
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TheFuture• MorebaskettrialsandphaseI/IItrialsinwhicheligibilityisthegeneticorothermolecularalteration(histologyagnostic)
• Usesequencingmoreatdiagnosis,beforerelapse
• CellFreeDNA– DNAthattumorsshedintheperipheralbloodthatcanbeisolatedfromafewmlofblood
• Usetodetectmutationandtoquanitfy before/aftertreatment
• Abilitytomakemodelsusingpatientsamplesandtestdrugsinrealtime…..
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THANKS!
NEUROBLASTOMARESEARCHPROGRAMS