endopredict expérience du cjp en 2017 · amplifié ni équivoque par fish) pt1b / c, pt2, pn0 -...
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Centre de Lutte contre le Cancer d'AuvergneClermont-Ferrand - France -
Centre Jean Perrin
Endopredict
ExpérienceduCJPen2017
Endopredict
ExpérienceduCJPen2017
Monaco le 31/01/2018
Frédérique Penault-Llorca, MD, PhD
Liensd’intérêts
• FrédériquePenault-Llorca:consultantepourAbbvie,AstraZeneca,Bayer,BMS,Lilly,Merck,Merck Lifa,Novartis,Pfizer,Roche,Sanofi,Takedadanslechampdebiomarqueurs
Contextedel’utilisationdessignaturesen2018
Tumeurluminales : A: PR>20%andKi67<14%B:PR<20%and/orKi67>14%*
– Risquesintermédiaires– Risquesélevéspouréviterlachimiothérapie–Mieuxdéfinirlerisquederécidiveà5et10ans– Eviterlessuretsous-traitements
• Adaptationthérapeutiqueadjuvante• HormonothérapievsHormonothérapie+Chimiothérapie
• Plusieurstestsdisponibles– priseenchargeRIHN(…..)
*StGallen A.Goldhirsch AnnOncol 2013
ParticularitésdutestEndopredict
EndoPredict(Sividon puis Myriad)
HR+ / HER2- , T1-2, N0
FFPEqRT-PCR
8 GENES SIGNATUREPROLIFERATION, OESTROGENES
« LOCAL » TEST(SPECIAL EQUIPMENT IS REQUIRED)
SCORE OF RECURRENCE EP SCORELATE AND EARLY RECURRENCES
(5 & 10 YEARS)PROGNOSIS
LOW RISK
HIGH RISK
UBE2CBIRC5DHCR7
STC2AZGP1IL65T
RBBP8MGP
5
EndoPredict:2° GenerationGeneExpression Test
6
Targeted patients• Early-stage breast cancer• ER+, HER2-• Node -, Node + (1-3 positive nodes)
Proven outcomes• 10-year risk of DR• Early and late metastasis• Low risk, high risk categories
Proven prognostic power• Combines molecular and clinical
information
7
RT-PCR-basedEndoPredictCanbeperformedinlocalmolecularpathologylabs
FFPE tissue sample:• ER +, HER2 -• 10 µm section• >30% tumour
content(adjacent HE slide)
RNA-Isolation:• Manually• Automatically
• 3h for 12 samples
RT-qPCR:• Pipetting of 96
well plates• RT-PCR run
• 2h per plate
Analysis and report:• Upload in software• Quality control• Print-out of report
• 15 min
RNA isolation EndoPredict-Test Test resultTumour sample
„Turn-around-Time“ < 8 h
8
EndoPredict isahighlyreproducibletestShowninanalyticalverificationandroundrobintrials
0 5 10 150
5
10
15
EP reference value
EP m
easu
red
by p
artic
ipan
t #1
R=0.998
0 5 10 150
5
10
15
EP reference value
EP m
easu
red
by p
artic
ipan
t #2
R=0.999
0 5 10 150
5
10
15
EP reference value
EP m
easu
red
by p
artic
ipan
t #3
R=0.987
0 5 10 150
5
10
15
EP reference value
EP m
easu
red
by p
artic
ipan
t #4
R=0.999
0 5 10 150
5
10
15
EP reference value
EP m
easu
red
by p
artic
ipan
t #5
R=0.997
0 5 10 150
5
10
15
EP reference value
EP m
easu
red
by p
artic
ipan
t #6
R=0.996
0 5 10 150
5
10
15
EP reference value
EP m
easu
red
by p
artic
ipan
t #7
R=0.998
1 2 3 4 5 6 70.9
0.92
0.94
0.96
0.98
1
participant
Pear
son
corre
latio
n co
effic
ient
Denkert etal.,2012
ENDOPREDICT
EP Score EPclin Score
Source : endopredict.comSource : endopredict.com
21
• TestavecunmarquageCEpourlediagnosticinvitroà Applicabledepuisle11Mai2015enFrance• Testd’expressiongéniqueàpartird’unéchantillondetissutumoralparRT-PCR(ARNm).• Analysede8gènestumorauxidentifiésdanslaprogressiondelamaladie
LesgènesdelasignatureEndopredict
8 gènes cibles et 3 gènes de référence
-Gène de la Voie de signalisation estrogéno-dépendante : AZPG1IL6ST MGPRBB8 STC2
-Voie de la prolifération et apoptose : BIRC5 DHCR7UBE2C
-Gènes de références : CALM2, OAZ1, RPL37A
RE&RP
KI67HER2
RT-PCR
Scoregénomique
NTC
CQ+
CQ ADN
Score génomiqueEP-score
0-15précisionde1%(0.15)
Unalgorithmeà3variables
Score génomiqueEP-Score
(0-15)
Statutganglionnaire
pN
TailleTumorale pT
(1-4)Un score Clinique
EPclin Score
è Tworiskgroupsè Geneselectiontopredict10-yearoutcome
EndoPredictAssayDesign
13
highrisklowriskNodalStatus(pN)+TumourSize(pT)
Cutoff value:10% distant recurrence (10y)AlgorithmRT-PCR
Filipitsetal.2011
3ProliferationGenesUBEC2,BIRC5,DHCR7
5HormoneReceptorGenesSTC2,AZGP1,IL6ST,RBBP8,MGP
3RNANormalizationGenesCALM2,OAZ1,RPL37A1DNAControlGene
HBB
EPScore EPClinScore
Endopredict summaryStudy PatientspopulationReferences
PROGNOSTICmorethan 2000patientsABCSG06et08ER+,HER2-,pN- orpN+Filipits,CCR2011
Tam5yrs orSequential 5yrsABCSG06et08Idem
butfocusonlate recurrences Dubsky,BJC2013ATACER+,HER2-,pN- orpN+,menop Sestak,JNCI2013
Tam5yrs orAA5yrsFocusonlate recurrence Buus, JNCI2016
GEICAM9906ER+,HER2-,menop ornotMartin,BCR20146FECor4FECthen 6hebdoP
PREDICTIONNostudies…
RetrospectivestudiesfromprospectivetrialsLOEIb
EP-clinic-score
98.20%(96.5- 99.8)
87.7%(82.8-92.5)
AllowtheidentificationofptswithanexcellentprognosisAfter5yrs,forwhomitshouldnotbenecessarytoproloungehormonalTTFortheotherHormonotherapymightnotbethebestTToption
62%basrisque
Lesétudesd’impact
ENDOPREDICT ADENDOM AT CJP
• ADENDOMstudy(startedJanuary2016)• Objective
EvaluationoftheimpactoftheEndopredict®ontreatmentdecision
• Population• N0• ER+• HER2-
• 202patientstested• Notechnicalfailure• 67ptsHIGHRISK(33%)• 135ptsLOWRISK(67%)
LowRISKER+/HER2-population
33%HIGHRISK
17
18
Penault-Llorca etalSABCS2016
EndoPredictchangedtherapydecisionsin35.8%ofpatients
Changesintherapyalignedwithtestresult
• EndoPredictavoided chemotherapyin28.4%ofpatients• EndoPredictresultedinadditional chemotherapyin7.5%ofpatients
Pre-testTherapyDecision
48%Endocrine&Chemotherapy
52%Endocrine therapyalone 67%EPclin LowRisk
33%EPclin HighRisk
EPclinTest Result
26%ET&Ctx
74%Endocrine therapyalone
Post-testTherapyDecision
ADENDOMStudyFrance(N=201) 9%N1mic17%G3
EndoPredictDecisionImpactStudies
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• Allstudiesresultedinasimilarproportionoftherapychange• 3outof4studiesshowed substantialreductionofchemotherapy
• UKstudy:substandardpresentationofresultwithoutanyinformationaboutclinicalcharacteristicsofpatientsè notcomparablewithotherstudies
NetreductioninChemotherapyinProspectiveRecurrenceScore®UtilityStudies
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*inthetotalstudypopulation1.Albanell etal,EJC2016;2.Eiermannetal,AnnalsOncol 2012;3.Pestalozzietal,BMCCancer2017;4.Bloomfieldetal.ASCO2017abstr e12002
Multigene assay /country StudydesignNumber
ofpatients
Netreductionof
chemotherapyuse
inthestudy*
OncotypeDXBreastRecurrenceScore®Test /EUMeta-Analysis1
Meta-analysis,prospective,multicenter 527 –21%
OncotypeDXBreastRecurrenceScoreTest/Germany2 Prospective,multicenter 366 –33%
OncotypeDXBreastRecurrenceScoreTest/Switzerland3 Prospective,multicenter 222 –13 %
ExpérienceduCentreJeanPerrinetd’autresCLCC
ENDOPREDICT CJP UNIRADstudy
• UNIRADstudy(started,June2015è2019)• Objective
EvaluationofDFSbenefitat2yearsofAfinitor® afterastandardtreatmentinER+HER2-negativeEBC
• Population• Invasiveearlybreastcancer(anyT)• Primarysurgery• ER+• HER2-• EPclin score≥3.3
• 434patientstested• Notechnicalfailure• 373ptsHIGHRISK(86%)• 61ptsLOWRISK(14%)
HighRISKER+HER2-population
è86%HIGHRISK
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ENDOPREDICT au CJP depuis le RIHN
Englobal :• Nbr decas :432• RisqueElevé :246cassoit57%• RisqueFaible :186cassoit43%
En2016:• Nbr decas :176• RisqueElevé :88cassoit50%• RisqueFaible :88cassoit50%
2017(dec-septembre):• Nbr decas :256• RisqueElevé :158cassoit62%• RisqueFaible :98cassoit38%
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endopredict
basrisque
hautrisque57%
43%
2016-17
endopredict
basrisque
hautrisque
33%
67%
Adendom
N = 317 %Mean Age 58yrs [29-91]
MenopausalYesNoUnknown
4314260
75%25%
pT1pT1abpT1cpT2pT3pT4
143414795121
5%11%48%31%4%0%
pN0pN1pN2unknown
21377126
73%26%0%
SBRGrade1SBRGrade2SBRGrade3NC
45243236
15%78%7%
ER(IHC)NC
Mean %of +cells =94%[56-100]N=61(19%)
100%positive
PR(IHC)NC
Mean %of +cells =70%[0-100]N=82(26%)
93%positive (≥10)
Proliferation (Ki67/%IHC)NC
Mean =18%[1-50]N=96(30%)
142≥15%(64%)105≥20%(48%)
AuCJPMaiàdécembre 2017317tests
CRITERIA ThresholdSCOREMeanET
3,540,65
3,3
10years risk ofreccurencemeanET
14,3%[3-51]8,7%
10%
EPCLINLowHighND
1471673
47%53%
CJP:Maiàdécembre 2017:317testsendopredict
basgrade
hautgrade
NR51%
Données nationales 2016
Endopredict: sur294cas :165HRsoit56%• 70N+soit23.8%,dontè22mi• Nbdecasentre3.2et3.4 :41dont8N+parmilesquels4mi• Nbdecasentre3.1et3.5 :80dont15N+parmilesquels8mi
ExpérienceCJP
27
Données InstitutCurieAVincent-SalomonSFSPM2017
56/44
IGRExperience (Endopredict)M Lacroix-Triki SFSPMNovember 2017
28
2016:AverageTimetoresults5days(1to9)36cases(Medianriskat10years:12,5%)MedianEPclin score:3,6(2,4– 5,1)è Chemo:67%;6patientsrefusedchemo,1HT
2017:Averagetoresults9days(3to25)132cases(Medianriskat10years:12%)MedianEPclin score:3,5(2,3– 5,8)è Chemo:58%;6patientsrefusedchemo,1HT
33/67%
42/58%
168patients
65%postmeno
pT1c– pT2(>90%)
pN0(>70%)
gradeII/III(>90%)
Conclusion
Conclusions
• Testbienimplantéetsimpleàréaliser• ToujoursinterpréteraveclesdonnéesdeEPScoreetEPclinetdiscuterlescasprochesdelacut off
• Importancedeconstituerdesregistres• IncertitudesquantaufinancementRIHNetauxmodalités« déclarationparlecentreprescripteur ».
Critères devraie viepourutilisationEndopredict inRIHN:COHORTE• CancerduseininvasifER+(ER≥10%parIHC),HER2- (0,1+,ouninonamplifiéniéquivoqueparFISH)pT1b/c,pT2,pN0- pN1mique,pN1(1à3N)
• Avec:PR<20%• ouluminal degrade1à2avecKi67>10%ouindexmitotique(IM)2à3• ougradeluminal 3avecKi67<30%ouscoreIM1à2
• EndehorsdecessituationsletestpeutêtreprescritaprèsdesdiscussionsenRCPenparticulierpourlesfemmespréménopausées oupourdéciderd'uneprolongationdutraitementhormonalaprès5ans
• Unregistrenationalestenplace