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11/10/2017
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Organisation des plateformes de génétiquemoléculaire du cancer
Frédérique Nowak – 11 octobre 2017
Journées du GFCO
Predictive biomarkers for targeted therapies’ prescription
Biomarker Cancer type Targeted therapiesPatients nb
in 2016
KIT mutations GIST Imatinib 1 218
HER2 amplification Breast and gastric cancersTrastuzumab, lapatinib, pertuzumab,
trastuzumab emtansine
10 832 (B)770 (G)
RAS mutations Colorectal cancer Panitumumab, cetuximab 21 923
EGFR mutations Lung cancer Gefitinib, erlotinib, afatinib, osimertinib 28 563
ALK translocations Lung cancer Crizotinib, ceritinib, alectinib 23 434
ROS1 translocations Lung cancer Crizotinib 17 680
BRAFV600 mutation MelanomaVemurafenib, dabrafenib, trametinib,
cobimetinib5 583
BCR-ABL translocationChronic Myeloid Leukaemia/
Acute Lymphoblastic LeukaemiaImatinib, nilotinib, dasatinib, ponatinib, bosutinib 9 570
17p deletion / TP53mutation
Chronic Lymphocytic Leukaemia Ibrutinib, idelalisib2 8571 808
BRCA mutation (somatic)
Ovarian cancer Olaparib 1 608
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France organisation of molecular centres for personalised medicine
Provides nationwide molecular diagnostic tests
� Perform molecular testing for all patients;
� Whatever the healthcare institution status (public hospitals, private hospitals…);
� Perform high qualitytests;
� leukemia, solidtumours
� Perform molecular testing for all patients;
� Whatever the healthcare institution status (public hospitals, private hospitals…);
� Perform high qualitytests;
� leukemia, solidtumours
Objectives
� Partnerships betweenseveral laboratorieslocated in Universityhospitals and cancer centers
� Regionalorganization
� Cooperation betweenpathologists and biologists
� Partnerships betweenseveral laboratorieslocated in Universityhospitals and cancer centers
� Regionalorganization
� Cooperation betweenpathologists and biologists
28 regional centres
�xThe program is operated by INCa/French Ministry of Health since 2006
Financements
� Financements INCa pour la mise en œuvre des tests moléculaires
� Structuration initiale (AAP 2006 et 2007)
� Tests KRAS
� Tests EGFR
� AAP anapath
� Biomarqueurs émergents
� Implémentation du NGS
� Essai PAOLA1 et déploiement BRCA
� Financements annuels récurrents de la DGOS
� Enveloppes MERRI ciblées par test
� Puis passage au RIHN
� Financements INCa pour le programme AcSé Moléculaire
� Financements INCa pour l’assurance qualité
RIHN
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Benefit & swift access to innovation for all patients
Ensure that all patiets actuallybenefit from molecular testing
… as soon as a new therapy is available
Lung cancer :
� June 2009 : gefitinib approval by EMA for
patients with activating EGFR mutations intheir tumour
� INCa started funding the 28 centres by
the end of 2009 (€1.7M)
Lung cancer :
� June 2009 : gefitinib approval by EMA for
patients with activating EGFR mutations intheir tumour
� INCa started funding the 28 centres by
the end of 2009 (€1.7M)
1269
2667
16834
20750
2199523336
2455826614 28563
0
10000
20000
30000
2008 2009 2010 2011 2012 2013 2014 2015 2016
nb
of
pat
ien
ts
EGFR screening / lung cancer
Elaboration of guidelines for :
� the detection of mutations in solid tumours ;
� the organisation of molecular testing ;
� reports of molecular tests
Implementation of national External Quality Assessmentrounds for the main tests in the 28 centers
Ensure the best quality for molecular tests
Implementation of a quality assurance programImplementation of a quality assurance program
�xTowards ISO 15189 accreditation
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Targeted NGS in routine practice
Routine use of targeted NGS
in all the molecular genetics centres
Routine use of targeted NGS
in all the molecular genetics centres
� Rolling out started
in 2015 in all the
molecular centres
� Progressive shift
from the standard
approach towards
targeted NGS for all
patients
� Rolling out started
in 2015 in all the
molecular centres
� Progressive shift
from the standard
approach towards
targeted NGS for all
patients
� Pilot phase launched in 2013 with 11 molecular genetic centres :
�develop the necessary skills to use this new
technology
� Monitoring led by INCa :�increase the sharing of experiences
�Draft guidelines
� 5 referent teams in bioinformatics :
�Validate & release existing data analysis
pipelines, or develop better ones
�support wet labs and their “embedded”
bioinformaticians through network animation
and training
� Economic impact of NGS evaluated at the same time
Implementation of targeted NGS in routine practice
Next challenge: use the additional information obtained by NGS to improve patients outcome
� Assess the clinical significance of new variants ;� Define a strategy of treatment ;� Enroll patients in clinical trials.
� Organisation of molecular tumour boards (MTB)
� Initially designed in the context of genomic driven clinical trials ;
� Implementation of MTB in routine practice started in 2015 in some centres.
� Need to create shared databases to collect information about rare mutations in relation to
patients’ follow up.
� Development of new types of clinical trials with a large access on the territory : AcSé
programme
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The Biomarker France study is a cohort of #17,500 patients of French lung cancer patients who were routinely screened for EGFR mutations during a 1-year period (from April, 2012 to April, 2013).
It collected :
� Clinical data
� Molecular data
� The impact on treatment(s)’ decision and patients’ outcomes
A national database in lung cancer:The Biomarker France Study
� Only 3% of patients in this database were enrolled in clinical trials
- ELÉMENTS FONDATEURS & PRINCIPES -
Patients porteurs d’un cancer
au stade métastatique ou
réfractaires aux traitements
validés:
* cible identifiée dans leur
tumeur,
* une molécule disponible en
pré-AMM ou AMM mais dans
une indication différente
Prescriptions hors cadre réglementaire, donc non maitrisée,
non sécurisée
A PROSCRIRE!
PROGRAMME AcSé - Accès sécurisé aux thérapies ciblées
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� SÉCURITÉ DU PATIENT et recueil des données scientifiques.
La RECHERCHE BIOMÉDICALE permet :
� D’évaluer objectivement l’efficacité et les effets secondaires ;� D’arrêter un traitement non efficace dans une indication donnée ;
� Une organisation optimale pour la communauté scientifique, les patients
et les autorités de santé.
� EGALITÉ D’ACCÈS SUR LE TERRITOIRE (centres autorisés en cancérologie avec
acticité de recherche)
� OUVERT à tous les âges notamment AUX ENFANTS et adolescents si des données
de phase I sont disponibles
� NE PAS SE SUBSTITUER A LA RECHERCHE DE DEVELOPPEMENT:
� Si le patient est éligible pour un essai clinique de développement ouvert
en France il est dirigé préférentiellement vers celui ci
� La France doit rester attractive pour la recherche industrielle
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PHASE II
CLINICAL TRIALS
PHASE II
CLINICAL TRIALS
MOLECULAR SCREENING
MOLECULAR SCREENING
Molecular Genetic Centers (Routine
molecular
diagnosis)
Molecular Genetic Centers (Routine
molecular
diagnosis)
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DRUGS (Provided by
pharmaceutica
l firms
DRUGS (Provided by
pharmaceutica
l firms
THERAPEUTIC
NEED
DRUG (S) PROJECTS
THERAPEUTIC
NEED
DRUG (S) PROJECTS
Research of specific molecular alterations of the drug(s) target
ALK, ROS1, MET
BRAF V600
ONE DRUG PROJECT (FOCUSED ON A DRUG)MULTI-DRUGS PROJECT
(FOCUSED ON THE TARGETED POPULATION)
Targeted Therapies Immunotherapies
Research of a molecular
alteration in an identified cohort
(biomarkers potentially
predictive of efficacy )
MSI on non-colorectal
cancer diagnosis
Screening in two centersNATIONAL SCREENING COORDINATED AND FUNDED BY INCA
AcSé-TRIALSAcSé-TRIALS
Sponsor
Founder(s)
No molecular screening
Molecular matching
trial at relapse
PHRC-K
Molecular matching
trial at relapse
PHRC-K
PI
21
3Pangenomic research
programme / Extensive molecular analysis
Extensive targeted therapies (for Pediatrics population)
MAPPYACTS PROJECT
PROGRAMME ACSÉ au 10/10/2017 LES DIFFÉRENTS ESSAIS AcSé
Multi-agent from multi company
Since July 2016
Nivolumab Pembrolizumab
Nivolumab Pembrolizumab
Crizotinib Vemurafenib
Since October 2014Since July 2013
B. GEOERGERA. MARABELLE C. MASSARDJY. BLAYG. VASSAL
Since June 2017Since May 2017
- LE 1er ESSAI - -CRIZOTINIB
ALK, MET, RON , ROS110 000 – 18 000 patients
14 000 – 25 000 tests
ALK, MET, RON , ROS110 000 – 18 000 patients
14 000 – 25 000 tests
2013 20152014 2016
12 528 patients « AcSé Crizo » dans la base de données (juil. 2017)
12 528
5
229
2017
PI : G. Vassal
Autorisé – mai 2013
1er patient – Août 2013
21 cohortes, 463 patients, 3 ans d’inclusion
Durée totale de l’essai : 5-6 ans
Au 5 septembre 2017, 82 sites recruteurs (185
sites ouverts), 229 inclusions
PI : G. Vassal
Autorisé – mai 2013
1er patient – Août 2013
21 cohortes, 463 patients, 3 ans d’inclusion
Durée totale de l’essai : 5-6 ans
Au 5 septembre 2017, 82 sites recruteurs (185
sites ouverts), 229 inclusions
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BRAF V60010 000 – 18 000 patients
14 000 – 25 000 tests
BRAF V60010 000 – 18 000 patients
14 000 – 25 000 tests
- LE 2ème ESSAI - -VEMURAFENIB
1791 patients testés pour BRAF dans la base de données (juil. 2017)
1791
HORS cancers du poumon,
cancers colorectaux et
mélanomes
⇒ routine diagnostique
6
174
PI : JY. Blay
Autorisé – Août 2014
1er patient – Octobre 2014
11 cohortes, 500 patients, 3 ans d’inclusion
Durée totale de l’essai : 5-6 ans
Au 6 septembre 2017, 66 sites recruteurs (115
sites ouverts), 174 inclusions
PI : JY. Blay
Autorisé – Août 2014
1er patient – Octobre 2014
11 cohortes, 500 patients, 3 ans d’inclusion
Durée totale de l’essai : 5-6 ans
Au 6 septembre 2017, 66 sites recruteurs (115
sites ouverts), 174 inclusions
Targeted therapies
Molecular analysis of
tumour cells
Change of paradigm in cancer treatment : a fast evolving scientific and medical environment
PARP inhibitors
Germline genetics analysis
2014 : Market autorisation of olaparib in
ovarian cancer for patients with BRCAmutations (either somatic or germline)
New challenges :
1. Patients information on the personal and familial impact of a positive BRCA test : ethics+++
2. Molecular tests integrating 3 complementary expertises : pathology, somatic genetics and
germline genetics
3. Complex samples circuit (blood & tumour) / turnaround time
⇒ Need to make current organisational framework evolve
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French organisational framework for germline genetics in oncology
���� Brest
���� Limoges
Clermont-Ferrand (2)����
Amiens ����Le Havre
�������� Rouen
La Rochelle
Niort����
Poitiers
Angoulême
���� Lille (2)Boulogne-sur-Mer
LensValenciennes
���� Nancy (2)
Metz
����
Tours Bourges
Orléans
����
Caen
Cherbourg
Bordeaux (2) ����
Bayonne Toulouse (3) ����
Rodez
���� Lyon (7)
Saint-Etienne �������� Grenoble (2)
���� Chambéry
Nîmes ����
Perpignan
Montpellier (2) ����
Béziers
���� Reims (4)
Charleville Mézières
Troyes
���� Angers
Le Mans
Cholet
���� Dijon
Auxerre
Mâcon
Chalon-sur-Saône
(2)����
Nantes(2)
���� Besançon
���� Colmar
���� Strasbourg (3)
���� Mulhouse
Thonon-les-Bains
Avignon����
���� Nice
Gap
Ajaccio
Aubagne
DraguignanAix-en-Provence
Marseille(3)
Bastia���� Toulon
����
ValenceAurillac
Martigues
Belfort-Montbéliard
(2)
(2)
���� Fort de France
Cayenne���� Sainte-Clotilde
Saint-Denis����
���� Saint-Pierre
Clichy ����
Saint-Cloud ����
���� Paris (13)
Bobigny����
Briis-sous-Forges
Levallois-Perret
���� Kremlin Bicêtre����
Villejuif
Lorient
Saint-Nazaire(2)
Bondy (2)
Tarbes
Corbeil-Essonnes
����Pointe à Pitre
Saint-Brieuc
���� Rennes (2)
Grasse
Bonifacio
Corté
����
Montargis����Vannes
����
CHU de Rennes ����
����
����
���� CHU de Lille
����
Centre François Baclesse, Caen
Institut Bergonié, Bordeaux ����
����
����
����
����
���� CHU d’Angers����
����
CHU de Nantes
CHU de Nancy
Centre Jean Perrin, Clermont-Ferrand
CHU-CLCC de Reims
CHU de Rouen
CHU de Montpellier
Centre Oscar Lambret, Lille
APHM
Institut Claudius Regaud, Toulouse
CHU de Lyoncancers non fréquents
CHU-CLCC de Lyoncancers fréquents
Centre Georges-François Leclerc,Dijon
���� ����
Centre Paul Strauss, Strasbourg
CHU de Strasbourg
����
Institut Paoli Calmettes, Marseille
���� Paris����
Institut Gustave Roussy, Villejuif
APHP Hôpitaux Universitaires La Pitié-Salpêtrière
APHP Hôpitaux Universitaires Paris Nord Val de Seine
APHP Hôpitaux Universitaires Paris Centre et Paris Ouest
Institut Curie
130 genetic counseling sites in 90 cities 25 laboratories for genetic testing
Perform genetic tests prescribed by clinical geneticists
Objectives :
� identify people with genetic predisposition to cancer
� offer specific prevention programmes including risk-adjusted screening, preventive surgery and
medicines.
PARP inhibitors : impact on the national organisational framework
Setting up a pilot phase within the framework of the European PAOLA1 clinical trial
o Five screening centres granted by INCa for BRCA testing
o The molecular screening started in May 2015
o In two years : 1100 patients screened for BRCA
� 18,7% germline mutations
� 6,3% somatic mutations
Rolling out in the molecular genetics centres in collaboration with the oncogenetics laboratories
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Towards a more integratedorganisational framework
Pathology Somatic
genetics
Germline
genetics
Moleculargeneticscentres
Oncogeneticprogramme :
geneticcounseling and
laboratories
Towards a more integratedorganisational framework
Pathology Somatic
genetics
Germline
genetics
Integrated organisational
framework
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Targeted therapiesMolecular analysis of tumour cells
PARP inhibitorsGermline genetics analysis
Change of paradigm in cancer treatment : a fast evolving scientific and medical environment
ImmunotherapyCheckpoint inhibitors : � Anti-CTLA4
� Anti-PD1 and anti-PDL1
Market authorization and ongoing clinical trials in melanoma,
lung cancer, mesothelioma, kidney cancer, bladder cancer….
=> Specific predictive biomarkers are under development and will enter soon into clinical practice
Change of paradigm in cancer treatment : immunotherapy
Blank et al. Science 2016 ; 352:658-660
MSI & déficience MMR: AcSé Nivolumab
Expression PD-l1AMM pembrolizumab, Cancer du poumon
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Towards next ajustment integrated of the organisational framework
Pathology Somatic
genetics
Germline
genetics
Immunotherapy
ADN tumoral circulant : AMM de l’Osimertinib
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ADN tumoral circulant : test EGFR
Déploiement du test dans les laboratoires
���� 3 697 tests réalisés au cours du 1er semestre 2017
4
3
31
32
Non prévu
En projet
En cours de
validation de
méthodePour des projets de
recherche
uniquementRésultats rendus en
routine clinique
19
14
9
42
2 2 1NGS
PCR digitale
PCR spécifique d'allèle
sondes Taqman
Mass Array
Analyse de fragments
Pyroséquençage
HRM
Techniques d’analyse utilisées
Launch of the Plan in June 2016
Objectives :
o integrate genomic medicine into the patient’s care pathway
o allow equal access to whole genome sequencing, first for rare diseases and cancers and then for common diseases, as new therapeutic indications are validated
o create a momentum for innovation in a number of areas
National « France Genomic Medicine Plan 2025 »
From targeted NGS to tumour genomesanalysis in clinical pratice
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Call for proposals launched by the Ministry of Health for the set up of the first two ultra high-throughput clinical sequencing facilities
⇒ Generic activity: rare diseases and cancer, then common diseases
⇒ Sizing : sequencing of the equivalent of 18,000 genomes per year
⇒ Access for all of the patients in France
⇒ Integration into the patient’s healthcare pathway and the existing healthcare networks
France Genomic Medicine Plan 2025
SEQOiA
AURAGEN
Two selected applications among the 10 submitted :
o SEQOiA : joint application of Assistance Publique-Hôpitaux de Paris
(APHP), Institut Curie and Institut Gustave Roussy
o AURAGEN : joint application of Hospices Civils de Lyon, CHU de
Grenoble, CHU de Saint-Etienne, CHU de Clermont-Ferrand, Centre Léon
Bérard, Centre Jean Perrin and Institut de cancérologie de la Loire
Conclusion
France’ organisational framework for precision medicine in oncology :
– has been operating for 8 years;
– offers an equal access to molecular testing for all patients in
France;
– shows that molecular stratification can be successfully integrated
into the healthcare system;
– shows that such a national organisation has to be continuously
adjusted in a context of a fast evolving scientific, medical and
technological environment
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Institut national du cancer ● 52, avenue André Morizet ● 92513 Boulogne-Billancourt Cedex ● France ● Tél. +33 (0) 1 41 10 50 00 ● e-cancer.fr
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