available and emerging biomarkers to inform...
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AvailableandEmergingBiomarkerstoInformDecision-MakingforPatientswithEarly-StageProstateCancer(PC)and
UseofActiveSurveillance
RaoulSConcepcion,MDDirector
TheComprehensiveProstateCenterNashville,Tennessee
Disclosures
ConsultingAgreements AstraZenecaPharmaceuticalsLP,GenomicHealthInc,IntegraConnect
SpeakersBureauAmgenInc,Astellas PharmaGlobalDevelopmentInc,BayerHealthCarePharmaceuticals,DendreonPharmaceuticalsInc,JanssenBiotechInc,SanofiGenzyme
ProstateCancer:CurrentNeeds
• RefinePSA• Increasethelikelihoodofaninitialpositivebiopsythat willidentifysignificantprostatecancer
• Reduceunnecessaryrepeatbiopsies• Stratify lowriskfromhigherriskcancers
• WillPCMs(ProstateCancerMarkers)improveourmanagement?
3
PCMs
4
Tissue
Blood
Urine
Whatisabiomarker?Amoleculethatcanbefoundinblood,tissueorbodyfluidsthatisasignofanormalorabnormalprocess
ComparisonofMolecularTests
Test Description Validated Endpoint(s) Biomarker Selection Specific for Prostate Cancer Specimen Patient Access
Genomic Prostate Score (GPS)
Predicts the likelihood of adverse pathology using multiple genetic pathways
Adverse Pathology at RPLikelihood of high-grade disease
Likelihood of non-organ-confined disease5-year BCR
NCCN Guidelines®
YESPositive Biopsy
NCCN Very Low, Low, Low-intermediate risk
GS 3+3, 3+4
Medicare Reimbursed for NCCN Very Low/Low
Financial Assistance Available: Patient contacted if out-of-pocket
>$100
Prolaris®
Cell Cycle Progression Score (CCP)
Reports the risk of dying from untreated disease in 10 years, using a single pathway
In a biopsy setting: 10-year Untreated Mortality
in a post-RP setting: 10-year BCR
MetastasisNCCN Guidelines®
NOProstatectomy Positive
BiopsyAUA Low-High Risk
Medicare Reimbursed for NCCN Very Low/Low
Financial Assistance Available: Patient contacted if out-of-pocket
>$375
ProMark®ProMark Score
Predicts likelihood of adverse pathology using protein staining
Adverse Pathology at RPLikelihood of high-grade disease
Likelihood of non-organ-confined diseaseYES Positive Biopsy
GS 3+3, 3+4
Financial Assistance Available: Patient contacted if out-of-pocket
>$350
ConfirmMDx®ConfirmMDx result
Predicts likelihood of negative repeatbiopsy
Negative Repeat Biopsy YES Negative Biopsy HGPIN Biopsy
Medicare Reimbursed Financial Assistance Available: Patient contacted if out-of-pocket
>$500
Decipher®Genomic Classifier
Predicts the probability of metastasis after surgery
5-year Metastasis YES ProstatectomypT3 or pT2 w/positive margin
Medicare Reimbursed Financial Assistance Available: Patient contacted if out-of-pocket
>$395
4Kscore® 4KscoreProvides probability of aggressive cancer
Likelihood of GS 3+4 and higher at biopsy YES Blood
Biopsy-eligible patientsFinancial Assistance is not reported on website
Prostate Cancer Molecular Test Grid
Oncotype DX
• Biopsy-based,12prostatecancer-specificgenestestthathasbeenclinicallyvalidatedtopredictthelikelihoodofadversepathologyusingmultiplegenomicpathways,allowsbetterpersonalizedriskstratificationtodeterminewhoisbestsuitedforactivetreatmentvsactivesurveillance
• Usingtheoriginalneedlepositivebiopsy• Testindependentlypredicts:
• Likelihoodofhigh-gradedisease• Likelihoodofnon-organ-confineddisease• BiochemicalrecurrenceafterRP
• GenomicProstateScorefrom0to100• CoveredbyMedicareforqualifiedpatients
Klein,etal.Eur Urol.2014.Cullen,etal.Eur Urol.2014.
VERYLOW INTERMEDIATELOW
Likelihoodoffavorablepathology
More Less
727candidategenesinhighestGleasonsamples
727candidategenesindominantGleason
samples
GeneSelectionfortheOncotype DX® GPSAssay
8
374genespredictoutcome(dominant)
367genespredictoutcome(highest)
Final17GPSGenes
• Consistentperformance inbiopsies
• Representkeypathways• Analyticalperformance
• PredictPCdeath,adv.path,BCR• Valuebeyondexistingmeasures
288genespredictiveregardlessofsampled
Gleasonpattern
PC,prostatecancer;BCR,biochemicalrecurrence.
288Genes
GPSIncorporatesMultipleBiologicPathwaysPredictiveofProstateCancerAggressiveness
9
StromalResponseBGN
COL1A1SFRP4
ProliferationTPX2
AndrogenSignalingAZGP1FAM13CKLK2
SRD5A2
Cellular OrganizationFLNCGSN
GSTM2TPM2
Thecombinationofmultiplepathways
ismorepredictivethan
anysinglepathway
GenesAssociatedwithBetterOutcome
GenesAssociatedwithWorseOutcome
ARF1ATP5ECLTC
GPS1PGK1
ReferenceGenes
CCPScoreAddsSignificantPrognosticInformation
Study Endpoint
Multivariate model*
Hazardratio(95%CI)
CCPscorep-value
PSAp-value
GleasonScorep-value
TURPconservativelymanaged CaPdeath 2.6 (1.9,3.4) <10-10 <10-7 0.028
Needle Biopsyconservativelymanaged CaPdeath 1.7 (1.3,2.1) <10-4 0.017 0.0022
RadProstatectomy1 BCR 1.7 (1.4,2.2) <10-5 <10-8 0.015
RadProstatectomy2 BCR 2.0(1.4,2.8) <10-4 0.12 0.17
ExternalBeamXRT BCR 2.1 (1.0,4.2) 0.035 0.054 0.20
Prolaris• Uses31cellcycle-relatedgenes
• Predictsdisease-specificmortalityanddiseaseaggressivenessinprostatecancerpatientsfollowingneedlebiopsy
• Post-prostatectomypatientstobetterestimatetheriskofbiochemicalrecurrence
• Prolaris scoreiscombinedwithpatient’sclinical-pathologicvaluestoestimatea10-yearprostatecancer-specificmortalityrisk
• Endpointsofaggressiveness,mortalityriskandUSdistributionpercentile• Validatedinrelevantendpoints:BCR,metastasis,DSM
• Scoresfrom0to10
• ASzoneforhelpingwithASdecisioninuntreatedpatients
• Prolaris BiopsycoveredbyMedicareforqualifiedpatients
KochMO,etal.CancerBiomark.2016;17(1):83-88.
ProMark
• Proteomicassayutilizing automatedimageanalysistechnologythatidentifiestumorandbenigntissues
• Measuresthequantitativeexpressionlevelsof eightproteinbiomarkers- DERL1,CUL2,SMAD4,PDSS2,HSPA9,FUS,
pS6,YBOX1
• PatientswithbiopsyGleasonScores3+3and3+4
• Identifytumoraggressiveness• Scoresfrom0to100• CoveredbyMedicareforqualifiedpatients
Decipher
• Localizedprostatecancer• Usesabiopsytocalculatetheprognosistodetermineifactivesurveillance,localtherapyormulti-modaltherapyisneeded• Basedonthepatient’spersonaltumor-basedgenomics
• Postradicalprostatectomy• Usestheexpressionofbiomarkerstocalculatetheprobabilityofclinicalmetastasiswithin5yearsofradicalprostatectomy
surgery• Analyzesasmalltissuesamplethatwasremovedduringsurgery• Predictsprobabilityofmetastasisaftersurgeryandprovidesindependentassessmentoftumoraggression• Measurestheexpressionlevelsof22RNAbiomarkersinvolvedinmultiplebiologicalpathwaysacrossthegenomethatare
associatedwithaggressiveprostatecancer
• Endpointsofprobabilityofhighgradedisease,5-yearprobabilityofmetastasisand10-yearprobabilityofprostatecancerspecificmortality
• DecipherScore• 0– 0.45=LowRisk• 0.45– 0.6=AverageRisk• 0.6-1=HighRisk
• CoveredbyMedicareforqualifiedpatientspost-RP Karnes RJ, et al. J Urol. 2013. 190(6):2047-2053.
ClassifiesmenintoDecipherHigh orLowgenomicriskfor:
1. %likelihoodHighGradeDisease(Gleason4or5)
2. %likelihoodofMetastasis5yearspostprostatectomy
3. %likelihoodProstateCancerSpecificMortality(PCSM)10years
PatientInclusionCriteria:Ø NCCNVeryLowRiskØ NCCNLowRiskØ NCCNIntermediateRiskØ NCCNHighRisk
WhatisDecipherBiopsy?
DecipherBiopsyhaspredictivevalueforvariousendpoints(Feb2016- May2017)
Publication Institution Patients(n) PrimaryObjective/KeyResults
Kleinetal.,Urology2016 ClevelandClinic 57patients
Decipherwasshowntopredictriskofmetastasis10yearspostRPusingneedlebiopsytissue.DecipherhadthehighestAUC(0.80;95%CI,0.58-0.95)comparedtoNCCN(0.75;95%CI,0.64-0.87)at predicting10yearspost-RPmetastasis.The AUC was0.88whenDecipherwascombinedwiththeNCCNmodel.Pre-operatively,40%and47%ofpatientswereNCCNlowandintermediaterisk,respectively.Deciphercategorized67%,25%and9%ofpatientsaslow(<0.45),intermediate(0.45-0.60)andhigh,respectively.Furthermore,Decipherreclassified48%ofNCCNintermediateriskmenaslow.
Leeetal.,UrologyResearch&Reports2016 UCSD 22patients
Decipherwasshowntopredictthepresenceoflymphnodeinvolvement(LNI)uponradicalprostatectomy.DecipherhadanAUCof0.78forpredictingLNI,significantlyhigherthanGleasonscore,pathologicalstageandpreoperativePSA(allAUC<0.7).OnMVA,forevery10%increaseinDecipherscore,theoddsofhavingLNIonRPincreasedby43%.TheconcordancebetweenthebiopsyDecipherandRPDecipherriskgroupswas86%.
Nguyen etal.,PCPD2016 DanaFarber/Harvard 100patients
StudysuggeststhatpatientswiththehighestGCrisk(GC>0.6)hadhighratesofmetastasisdespitemulti-modaltherapyandcouldbeconsideredforlongerdurationADTand/orclinicaltrials.TheDeciphergenomicclassifier’s(GC)abilitytopredictdistantmetastasesafterradiationandshort-courseandrogendeprivationtherapy(ADT)usingneedlebiopsytissuewasexplored.100patients(NCCNintermediateandhighrisk)receivedRT+[median]6moADT.GCsignificantlyandindependentlypredictedmetastasis(HR.1.41onMVA)andperformedwithac-indexof0.77.
Nguyenetal.,EuropeanUrology,2017
Multiple (UCSF,ClevelandClinic,JHU+more)
235patients
BiopsyDecipherwasasignificantpredictorofPCSMwitha5-yearPCSMrateas wellas5-yearmetastasis.PatientswithbiopsyDecipherlow-,intermediate- andhigh-riskhadametastasisrateof4.1%,7.8%and21%by5yearspost-biopsy.Theriskof5yearPCSMwas0%,0%,and9.4%forDecipherlow,intermediate,andhigh,respectively (HR1.5756per10%increaseinscore,5795%CI1.03-2.48,P=0.037).
