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

19

• Allstudiesresultedinasimilarproportionoftherapychange• 3outof4studiesshowed substantialreductionofchemotherapy

• UKstudy:substandardpresentationofresultwithoutanyinformationaboutclinicalcharacteristicsofpatientsè notcomparablewithotherstudies

NetreductioninChemotherapyinProspectiveRecurrenceScore®UtilityStudies

20

*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

22

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%

23

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