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OCTOBER 2015
FRENCH NATIONAL CANCER INSTITUTE SCIENTIFIC REPORT / 2014-2015
RAPC
SAN
G15
For more informatione-cancer.fr
Institut National du Cancer52, avenue André Morizet
92100 Boulogne-BillancourtFrance
Tel. +33 (0) 1 41 10 50 00Fax +33 (0) 1 41 10 50 20
diffusion@institutcancer.fr
FREN
CH N
ATIO
NAL
CANC
ER IN
STIT
UTE
SCI
ENTI
FIC
REPO
RT /2
014-
2015
52, avenue André Morizet92100 Boulogne-Billancourt
France
Tel. +33 (0) 1 41 10 50 00Fax +33 (0) 1 41 10 50 20
diffusion@institutcancer.fr
FRENCH NATIONAL CANCER INSTITUTE SCIENTIFIC REPORT / 2014-2015
FRENCH NATIONAL CANCER INSTITUTE SCIENTIFIC REPORT / 2014-2015
The French National Cancer Institute is the health and science agency in charge of cancer control.
Published by the French National Cancer InstituteAll rights reserved – Siren 185 512 777
Conception: INCaRealised by
ISSN 2276-5751ISBN: 978-2-37219-150-0
ISBN net: 978-2-37219-151-7
DEPÔT LÉGAL OCTOBRE 2015
All rights reserved.This work may not be translated or copied in whole or in part without the written permission of Institut National du Cancer. According to the Code of intellectual property, only copies strictly reserved for private use and not for a collective one, or brief excerpts justified by the scientific nature or information of the work into which they are incorporated, are authorised.
This document was published in October 2015. It is available at the following address:Institut National du Cancer (INCa)Direction de la recherche52, avenue André Morizet – 92100 Boulogne-Billancourte-cancer.fr© 2015. Institut National du Cancer (INCa)
Since 2003, the fight against cancer in France has been structured around national plans to mobilise all stakeholders on prevention, screening, care, research and support for patients and their friends and families. The 2003-2007 Cancer Control Plan set up the first comprehensive strategy to fight cancer; the second Cancer Control Plan (2009-2013) introduced the notion of personalised care.The 2014-2019 Cancer Control Plan intends to give each and every person, all over France, the
same chances for recovery and implement innovation even faster for patient benefit. This plan includes 17 objectives, all gathered around four major health priorities:l Cure more patientsl Preserve continuity and quality of lifel Invest in prevention and researchl Optimise management and the organisations efficiencyThe Cancer Control Plan falls within the implementation of a national health strategy and the “France-Europe 2020” Strategic Agenda for research, technology transfer and innovation.
CancerPlan2014-2019
FRENCH NATIONAL CANCER INSTITUTE 2014-2015 SCIENTIFIC REPORT
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FRENCH NATIONAL CANCER INSTITUTE 2014-2015 SCIENTIFIC REPORT
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TABLE OF CONTENTS
PREAMBLE 6
Key figuresClinical trial indicatorsMolecular genetics platforms: activity indicatorsInternational framework
SUMMARY OF THE REPORT 17
Part 1. Summary of previous recommendations of the members of the international Scientific Advisory Board and corresponding achievements 19
Part 2. Report on 2014-2015 cancer research activity 23
1. SUPPORT IN BIOLOGY AND BASIC SCIENCES FOR CANCER RESEARCH 25
1.1. Research programmes 26
1.2. The International Cancer Genome Consortium ICGC and ICGCMed 32
2. TRANSLATIONAL AND INTEGRATED RESEARCH 37
2.1. Cross-disciplinarity and translation of knowledge into clinical practice 38
2.2. Strengthening of organisation and infrastructures dedicated to translational/integrated research in integrated cancer research sites (SIRICs) 43
3. CLINICAL RESEARCH AND DEVELOPMENT OF EARLY PHASE TRIALS FOR INNOVATIVE DRUGS 45
3.1. The clinical cancer research programmes 47
3.2. Organisation of clinical research, and strengthening of structures and infrastructures 56
4. RESEARCH IN HUMAN AND SOCIAL SCIENCES, EPIDEMIOLOGY AND PUBLIC HEALTH 61
4.1. The recurrent programme for Human and Social Sciences (HSS), Epidemiology and Public Health (EPH) Research 63
4.2. Population Health Intervention research 64
4.3. Initiatives developed to support research on environmental risks 66
4.4. PhD Programme in HSS-EPH 2015 in collaboration with academic partners 68
5. THE CANCEROPOLES 69
5.1. A new designation for the 2015-2017 period 69
5.2. Contracting and managing the Canceropoles 73
6. INTERNATIONAL DEVELOPMENTS 74
6.1. Strategic vision, mission and values 74
6.2. Synergy between the objectives of the French NCCP and INCa’s portfolio of European and International partnerships 74
6.3. INCa’s European and International portfolio 75
7. BIBLIOMETRIC STUDY AND EVALUATION PROCESS 80
7.1. Cancer Research in France – A bibliometric overview with an in-depth analysis of the 2010-2014 period 80
7.2. Strengthening of ex-ante assessment to draw up future guidelines 81
7.3. A pilot study for ex-post assessment of translational funded projects 81
7.4. Increasing involvement of INCa international networks of assessment of research impact 82
FRENCH NATIONAL CANCER INSTITUTE 2014-2015 SCIENTIFIC REPORT
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Part 3. Focus on strategic topics for advancing cancer research 83
1. CANCER RESEARCH PROGRAMMING 84
1.1. Context 84
1.2. INCa’s operational procedures and proposals regarding research 85
2. PRECISION MEDICINE IN ONCOLOGY PRACTICE AT NATIONAL LEVEL: DATA AND INFORMATION TECHNOLOGY 872.1. State of the art of Next generation sequencing
in oncology in France 87
2.2. Proposals for a national organisation for the analysis and storage of data generated 88
3. NEW PROGRAMME: FUNCTIONAL HETEROGENEITY OF TUMOUR CELL RELATIONSHIPS IN THEIR ECOSYSTEM 893.1. Scientific context 90
3.2. The new programme framework 91
4. EVOLUTION OF BIOLOGICAL RESOURCES: TUMOUR BANKS AND CLINICAL-BIOLOGICAL DATABASES 924.1. 10-year review and achievements 92
4.2. Development of the collections in the context of precision medicine 95
5. KEY SCIENTIFIC ISSUE IN PAEDIATRIC ONCOLOGY: CURING MORE CHILDREN MORE EFFECTIVELY 97
6. SCIENTIFIC AND HEALTH DEMOCRACY IN THE 2014-2019 CANCER CONTROL PLAN 996.1. An objective of the 2014-2019 Cancer Control Plan… 99
6.2. … and an obligation of the INCa institutional project 99
6.3. Breathing life into health democracy with INCa’s partners 100
APPENDICES 101
1. PROPOSALS FOR A NATIONAL ORGANISATION FOR THE ANALYSIS AND STORAGE OF DATA GENERATED 102
1.1. Screening strategy 102
1.2. Volumes 103
1.3. Sequencing and data organisation 104
1.4. Data sharing for improved treatment decision-making and for research 105
1.5. Training issues 105
1.6. Conclusion 105
2. CLINICAL TRIALS REGISTRY 107
3. CANCER RESEARCH FUNDING AND CSO CLASSIFICATION 109
4. 2014-2019 CANCER CONTROL PLAN ACTIONS PROGRESS RELATED TO CANCER RESEARCH 111
6FRENCH NATIONAL CANCER INSTITUTE 2014-2015 SCIENTIFIC REPORT
2015 is an important year for French Presidential Cancer Control Plans: it is the French National Cancer Institute’s (INCa) 10th anniversary. A flagship creation of the 2003-2007 Cancer Control Plan, INCa has remained a major actor of the two following cancer control plans. INCa’s crucial role as an agency providing expertise in oncology in the care, public health and research fields has been confirmed, and INCa is now in charge of steering the 3rd Cancer control plan and coordinating actions from several health agencies, research institutions and major charities.2015 is thus a pivotal year in which INCa has the duty to review past work and plan future action. Therefore, this Scientific Report, prepared by INCa’s Research and Innovation Division in close collaboration with Inserm and the Aviesan Cancer Institute (ITMO Cancer – Aviesan), adopts this approach. The scientific review is based not only on an analysis of each research programme but also on a critical view of the past scientific strategy which has benefited from the Scientific Advisory Board’s critical input and recommendations. In order to efficiently thrive in the future, INCa’s programmes should be based on a critical analysis of past actions’ strengths and weaknesses and should be challenged by scientific advances and societal needs.Analysis of past programs has shown that important breakthroughs were obtained by researchers with grants from INCa or Inserm. Moreover, INCa’s projects aiming to develop scientific site strategies (e.g. the SIRIC programme) or critical tools for translation and clinical research (e.g. genetics/genomic platforms, CLIP² programme) were of tremendous importance to federate multidisciplinary research and provide equal access to medical innovation for all patients. However, important progress remains to be made in several fields including cancer prevention and interventional research. The fight against smoking clearly showed positive results during the 2003-2007 Cancer Control Plan but progress deteriorated during the 2009-2013 Cancer Control Plan, especially in young people. This serious health issue prompted INCa to launch a comprehensive research programme (“PRIORITE TABAC”) aiming at understanding the causes of the unsuccessful prevention campaigns, so as to define the best strategy by enrolling all scientific actors in the design of this multi-year programme. It focuses, in the first instance, on epidemiology and social sciences. The second step will include research projects on biological specificities of tumours linked to tobacco and on factors which determine patients’ susceptibility to the various tumour localisations. During the past 10 years, basic oncology research priorities have changed. Since the beginning of the 21st century, development of the human genome project and subsequent technologies has allowed researchers to establish detailed molecular portraits of tumour cells. This OMICs approach was of tremendous importance in developing the therapy strategy which targets protein products
PREAMBLE
7FRENCH NATIONAL CANCER INSTITUTE
2014-2015 SCIENTIFIC REPORT
of mutated genes driving tumour development. Although substantial results were obtained using this type of therapy, only short-term remission was obtained in most patients due to resistance to treatment. Single cell approaches demonstrated that tumour cells cannot be considered as a homogenous clone in a given tumour. Indeed, a tumour is now considered as a Darwinian equilibrium between multiple competing and/or cooperating tumour cell sub-clones with instable genome and epigenome and functional differences in the context of a complex educated stroma. Knowledge of crosstalk between tumour cells and the various cells which populate the tumour stroma is growing, thus allowing better understanding of resistance to therapies targeting tumour cells or stromal cells. The critical importance of lymphoid cells and more generally of the immune system for controlling the disease was clearly proven by the use of immune checkpoint inhibitors in a growing number of patients in various types of tumours. Taking into account these scientific and medical breakthroughs, INCa, Inserm and ITMO Cancer - Aviesan proposed in September 2015 an integrative and multidisciplinary scientific programme on the tumour ecosystem. Connecting researchers in the fields of mathematics, physics and biology, in close contact with clinicians and pathologists, this programme aims to develop in-silico and ex-vivo/in-vivo models of the tumour in its ecosystem. We expect that this program will identify critical parameters of ecosystem evolution and ultimately define clinical algorithms for optimal care. In close coordination with this Inserm and Aviesan programme, INCa will foster translational and clinical programs in the immunotherapy field. INCa will encourage expert clinical centres to implement immuno-monitoring and set-up clinical trials associating immunotherapy with radiotherapy and/or targeted therapies.Our century is strikingly based on societal use of information technology. The medical field is no exception. It is clear that care and medical research have to be nurtured by an intelligent appropriation of Big Data. Understanding these massive and complex data in oncology is one among the challenging cancer control plan actions. In 2016, the Plan will help develop interoperability of information systems in hospitals and will implement the digital records and links between clinical, OMICs and immuno-monitoring data. The Plan will also fund research on systems biology and artificial intelligence aiming at defining algorithms to interpret the digital avatar of a given patient in the context of the data of the other patients. We expect that this research programme will ultimately support medical staff with the definition of evidenced-based therapeutic strategies, and lead to a global increase of cured patients and improved quality of life.The elaboration of this global programme is a collective work. All my thanks go to all colleagues from the INCa, Inserm and Aviesan for their critical contributions to the programmes and this report.
Prof. François Sigaux
Director Director of INCa’s Research and Innovation Programmes
Director of the Inserm cancer Institute
Director of ITMO Cancer - Aviesan
FRENCH NATIONAL CANCER INSTITUTE 2014-2015 SCIENTIFIC REPORT
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KEY FIGURES
2015 PROGRAMMES FUNDED BY INCa, INSERM FOR ITMO CANCER - AVIESAN AND MINISTRY OF HEALTH (DGOS) - MULTI-YEAR FUNDING
2007-2014 TRENDS IN FUNDING PER PROGRAMME TYPEANNUAL FUNDING OF CANCER RESEARCH PROGRAMMES AND STRUCTURATION OF RESEARCH* Provisional budget for the year 2015
0
20
40
60
80
100
120
20152014201320122011
INCaInsermDGOSTotal
€� M
54%
6%
4%7%
19%
24%
13%
24%
3%
5- Research training/young teams of excellence4- Platforms/resources/infrastructures3- Projects dedicated to a specific research issue2- Projects dedicated to specific type of cancer1- Investigator-driven calls
1- Investigator-driven calls (HSS-EPH)1- Investigator-driven calls (Translational)1- Investigator-driven calls (Biology)1- Investigator-driven calls (Clinical)
54%
6%
4%7%
19%
24%
13%
24%
3%
5- Research training/young teams of excellence4- Platforms/resources/infrastructures3- Projects dedicated to a specific research issue2- Projects dedicated to specific type of cancer1- Investigator-driven calls
1- Investigator-driven calls (HSS-EPH)1- Investigator-driven calls (Translational)1- Investigator-driven calls (Biology)1- Investigator-driven calls (Clinical)
0
10
20
30
40
50
60
70
DGOSInsermINCa
* Provisional
■ Investigator-driven projects ■ PRME-K* ■ PRT-K* ■ PHRC-K* ■ HSS-ESP ■ PRT-K* ■ PLBIO
■ Research training/young teams of excellence ■ Poste d'Accueil ■ FDV ■ ATIP-Avenir in the field of cancer ■ Translational Training ■ Research Chair in prevention ■ DOCHSS
■ Platforms, resources, infrastructures ■ IBiSA ■ Equipment in the field of cancer ■ CLIP² ■ Canceropole
■ Projects dedicated to a specific research issue ■ Anses* ■ Systems biology* ■ Environment ■ Multisarc-Acompli* ■ Epigenomic* ■ Physics, mathematics ■ Paola ■ Transcan ■ Innovative molecules
0
10
20
30
40
50
60
70
DGOSInsermINCa
* Provisional
■ Investigator-driven projects ■ PRME-K* ■ PRT-K* ■ PHRC-K* ■ HSS-ESP ■ PRT-K* ■ PLBIO
■ Research training/young teams of excellence ■ Poste d'Accueil ■ FDV ■ ATIP-Avenir in the field of cancer ■ Translational Training ■ Research Chair in prevention ■ DOCHSS
■ Platforms, resources, infrastructures ■ IBiSA ■ Equipment in the field of cancer ■ CLIP² ■ Canceropole
■ Projects dedicated to a specific research issue ■ Anses* ■ Systems biology* ■ Environment ■ Multisarc-Acompli* ■ Epigenomic* ■ Physics, mathematics ■ Paola ■ Transcan ■ Innovative molecules
FRENCH NATIONAL CANCER INSTITUTE 2014-2015 SCIENTIFIC REPORT
9
TRENDS IN THE NUMBER OF PROJECTS SELECTED IN INVESTIGATOR-DRIVEN CFPS MANAGED BY INCa * No translational research projects in 2008. 2015 clinical and translational projects not yet evaluated
TRENDS IN THE NUMBER OF PROJECTS SUBMITTED TO INVESTIGATOR-DRIVEN CFPS MANAGED BY INCa* No translational research projects in 2008
0
50
100
150
200
250
300
350
400
201520142013201220112010200920082007
Clinical* Translational*Human and Social sciences, epidemiology, public healthBiology and cancer sciences
Nb
of p
roje
cts
0
10
20
30
40
50
60
70
80
201520142013201220112010200920082007
Clinical* Translational*Human and Social sciences, epidemiology, public healthBiology and cancer sciences
Nb
of p
roje
cts
FRENCH NATIONAL CANCER INSTITUTE 2014-2015 SCIENTIFIC REPORT
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TRENDS IN FUNDING AWARDED TO INVESTIGATOR-DRIVEN CFPS MANAGED BY INCa* No translational research projects in 2008. 2015 clinical and translational projects not yet evaluated
TRENDS IN THE MEDIAN VALUE OF THE THREE MOST FUNDED INVESTIGATOR-DRIVEN CFPS MANAGED BY INCa – REQUESTED AND FUNDED AMOUNTS * No translational research projects in 2008
0
5
10
15
20
25
201520142013201220112010200920082007
Clinical* Translational*Human and Social sciences, epidemiology, public healthBiology and cancer sciences
€ M
0
100,000
200,000
300,000
400,000
500,000
600,000
20142013201220112010200920082007Med
ian
valu
e of
requ
este
d am
ount
(€)
0
100,000
200,000
300,000
400,000
500,000
600,000
20142013201220112010200920082007Med
ian
valu
e of
fund
ed a
mou
nt (€
)
ClinicalTranslationalBiology and cancer sciences
FRENCH NATIONAL CANCER INSTITUTE 2014-2015 SCIENTIFIC REPORT
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CLINICAL TRIAL INDICATORS
NUMBER OF CLINICAL TRIALS OPENED FOR PATIENT INCLUSION ADVERTISED IN THE NATIONAL REGISTRY (15 MAY 2015)
TRENDS IN PATIENTS INCLUSION IN CANCER CLINICAL TRIALS
0
10,000
20,000
30,000
40,000
50,000
201420132012201120102009200820072006200520042003
Nb
of p
atie
nts
enro
lled
24,037
26,003 28,16734,067 42,803
35,390 37,492
44,023
0
100
200
300
400
500
600
700
800
108233
417553
653687
517602
528509
Apr-0
7
Jul-0
7
Dec-
07
Jul-0
8
Dec-
08
Jul-0
9
Dec-
09
Jul-1
0
Dec-
10
Jun-
11
Dec-
11
Jun-
12
Dec-
12
May
-13
May
-14
May
-15
FRENCH NATIONAL CANCER INSTITUTE 2014-2015 SCIENTIFIC REPORT
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MOLECULAR GENETICS PLATFORMS: ACTIVITY INDICATORSPredictive molecular testing in France in 2014: activity of the 28 molecular genetics centres
Amiens
Lille
Rouen
Caen
Brest
Rennes
Angers
Nantes
Poitiers
Bordeaux -La Réunion
Source: INCa, 2015Drafted by INCa’s Research Division, 2015
Toulouse
Montpellier - Nîmes
Marseille
Number of patients who benefited from predictive molecular testing in 2014
10,000
5,000
2,500
1,000
Nice
GrenobleSt-Etienne
LyonClermont-Ferrand
Limoges
Tours - Orléans
Dijon
Besançon
Strasbourg
Nancy
Reims
Gustave Roussy
CurieAP-HP
Paris
Paris
FRENCH NATIONAL CANCER INSTITUTE 2014-2015 SCIENTIFIC REPORT
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EXAMPLE: SCREENING FOR K-RAS MUTATIONS IN PATIENTS WITH COLORECTAL CANCER
EXAMPLE: SCREENING FOR EGFR MUTATIONS IN PATIENTS WITH LUNG CANCER
0,0002,5005,0007,500
10,00012,50015,00017,50020,00022,50025,000
20142013201220112010200920082007
Nb
of p
atie
nts
1,100
10,012
17,246
16,581
17,00318,306
22,01119,347
0,000
5,000
10,000
15,000
20,000
25,000
2014201320122011201020092008
Nb
of p
atie
nts
1,269 2,667
16,83420,750
21,995
23,336 24,558
FRENCH NATIONAL CANCER INSTITUTE 2014-2015 SCIENTIFIC REPORT
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US NCI
US National Cancer Institute - Early phase
clinical research
Global Partnerships
Europe
National Agreements
Regional Networks
CANCON
Joint Action on Quality improvement in cancer
control
(WP8 - Survivorship and Rehabilitation)
EUROMED
Screening & early diagnosis in the mediterranean
countries
(WHO collaborative centre)
ICART
International Consortium for Action
and Research on Tobacco Control
CANCON
Joint Action on Quality improvement in cancer
control
(WP9 – Screening)
NCCP cross-cutting goals
IARC - GICR
International Agency for Research on Cancer – Global Initiative for
Cancer Registry
COFAC COL
Collaborative Network on Cervical
cancer Control in Francophone Africa
LAOS / THAILAND
Research and Public Health project on
cervical cancer
SENEGAL
Cooperation agreement on Cancer control (research &
public health)
Meet the needs of children, adolescents
and young adults
Reduce inequalities
Early diagnosis & screening
(Objective 1)
Collect data / support Public
Health (Objective 15)
INTERNATIONAL FRAMEWORK
FRENCH NATIONAL CANCER INSTITUTE 2014-2015 SCIENTIFIC REPORT
15
CANCON
Joint Action on Quality improvement in cancer
control
(WP6 - Research in comprehensive cancer
control network)
CANCON
Joint Action on Quality improvement in cancer
control
(WP8 - Survivorship and Rehabilitation)
European Commission EXPERT
GROUP on cancer control
US NCI
US National Cancer Institute - Global
coordination
International cancer research funders group
WHO
World Health Organisation –
Technical coordination
IARC
International Agency for Research on Cancer
– INCa sits at IARC Board of Directors
ICGC
International Cancer Genome Consortium
ICART
International Consortium for Action
and Research on Tobacco Control
CSA PerMed
Concerted and support action in personalised
medicine Eranet TRANSCAN 2
Coordination of national funding programmes in
translational research
ICRP
International Cancer Research Partnership
ICGC
International Cancer Genome Consortium
US NCI
US National Cancer Institute - Early phase
clinical research
IRCI
International Rare Cancers Initiative
JAPAN
Memorandum of Understanding with
Japan National Cancer Center on research
National Cancer Control Plan (NCCP) objectives
Innovation & Research
(Objectives 5 & 13)
Comprehensive and personalised
cancer care (Objective 7)
Personalised Medicine
(Objective 6)
Reduce smoking (Objective 10)
Global Partnership / Cancer Control (Objective 16)
FRENCH NATIONAL CANCER INSTITUTE 2014-2015 SCIENTIFIC REPORT
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17FRENCH NATIONAL CANCER INSTITUTE
2014-2015 SCIENTIFIC REPORT
This 9th report for INCa’s international Scientific Advisory Board (SAB) coincides with the first year of implementation of the new 2014-2019 Cancer Control Plan, which follows the two successive Cancer Control Plans, 2003-2007 and 2009-2013. It should be noted that the report reviews actions both from the INCa and Aviesan’s Multi-Organisation Thematic Institute for Cancer (ITMO Cancer - Aviesan).
In recent years, the research and health landscape in oncology has undergone a major upheaval, giving France major opportunities to strengthen its innovative programmes and initiate new ones. Among the key initiatives, the creation of 8 SIRICs (integrated cancer research sites), 16 CLIP2 (early phase clinical trial centres), 28 molecular biology platforms, and 13 designated cooperative intergroups has established a solid basis for excellence in cancer research in France. Some new major topics of the Strategic Research Agenda and the National Health Strategy now need to be promoted in order to achieve important objectives of the Cancer Control Plan, for the benefit of the patient, of which increasing the knowledge of cancers and promoting translational research, innovation and clinical trials are essential.
The first section of the present report summarises the recommendations made by INCa’s SAB, chaired by Prof. Daniel Louvard during the last annual meeting in 2014. The section describes how these recommendations have been implemented by initiating new actions or reinforcing existing major programmes. Eleven recommendations were made by the international SAB last year, which particularly emphasised the importance of the four following issues, based on basic and translational research: • Basic understanding of the tumour ecosystem; • Multidisciplinary research programme on tobacco-related cancers; • Precision medicine trials with tumour microenvironment and immune read-outs; • High-throughput genome sequencing and analysis facilities.
SUMMARY OF THE REPORT
18FRENCH NATIONAL CANCER INSTITUTE 2014-2015 SCIENTIFIC REPORT
The second section of this report presents a detailed review of the research programmes carried out in 2014 and 2015, and takes into account the actions undertaken since 2007 in the 4 following main research areas, for which the total investments over the 2007-2014 period are: • Biology and Basic sciences: €295 million; • Translational Research: €166 million; • Clinical Research: €185 million; • Research in Human and Social Sciences, Epidemiology and Public Health: €61 million.
As of July 2015, 845 proposals had been submitted (88 research projects selected) to all 2015 CFPs operated by INCa. Total 2015 multi-year investment should be €87 million at the end of the year. Considering all calls for proposals (CFPs) programmed by ITMO Cancer – Aviesan in 2015, more than 280 proposals had been submitted, and 48 projects have be selected. Total investment of Inserm on projects or resources selected by ITMO Cancer – Aviesan should be €30 million.
A chapter of this report is devoted to the initiative to promote the assessment of the research impact. An in-depth bibliometric study has been conducted by Inserm for the ITMO Cancer - Aviesan. A pilot study has investigated the impact of Translational research projects funded in 2007.
The third section of this report presents the definition of strategic research areas in line with previous recommendations of the SAB and with the 2014-2019 Cancer control plan, i.e.: • Strategic planning in cancer research, conducted by Aviesan; • Precision medicine in oncology practice at national level; • A new research support programme in the f ield of functional heterogeneity of tumour cell relations in their ecosystem. • Integration of tumour banks and clinical-biological databases in research for clinical management of patients; • One of the cross-cutting issues of the Cancer Control Plan: paediatric oncology with the main objective to improve the treatment of children. • Actions carried out by INCa to promote scientific and health.
19FRENCH NATIONAL CANCER INSTITUTE
2014-2015 SCIENTIFIC REPORT
With respect to INCa, the SAB‘s mission is to: • Ensure the consistency of INCa’ scientific policy; • Give its opinion on the INCa’s annual scientific report before its presentation to the Board; • Make recommendations and provide advice on INCa’s scientific lines of actions and on their implementation.
This chapter compiles the advice and recommendations issued by the international Scientific Advisory Board, and summarises the subsequent actions undertaken by INCa and ITMO Cancer - Aviesan. These are compiled in Table 1 below, which also points to the corresponding objectives of the Cancer Control Plan. Additional details of the progress of research actions linked to the Cancer Control Plan may be found in Appendix 4.
Part 1. SUMMARY OF PREVIOUS RECOMMENDATIONS OF THE MEMBERS OF THE INTERNATIONAL SCIENTIFIC ADVISORY BOARD AND CORRESPONDING ACHIEVEMENTS
FRENCH NATIONAL CANCER INSTITUTE 2014-2015 SCIENTIFIC REPORT
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Table 1. Recommendations of the 2014 international Scientific Advisory Board and corresponding actions in the 2014-2019 Cancer Control Plan
Recommendations from the 2014 international scientific advisory board
Progress and implementationCorresponding actions in
the 2014-2019 Cancer Control Plan
1. The Board acknowledges Agnès Buzyn, Fabien Calvo and INCa teams for their exceptional work in achieving the actions of the 2009-2013 Cancer Control Plan and in formulating the forward looking goals of the 2014-2019 Cancer Control Plan. More specifically, the Board appreciates that the research priorities are integrated into this last Cancer Control Plan. The Board congratulates François Sigaux on his appointment as Director of Research and Innovation.
Done • First report sent to the President of France.
In progress • Strengthening of priorities and links between actions (INCa, ITMO Cancer - Aviesan and ITMO Public Health - Aviesan). • Monitoring of the 2014-2019 Cancer Control Plan activities by INCa in association with the Government’s partners and charities.
-
2. The Board endorses the outlines of the seventeen objectives set out by INCa. With respect to the programmes of the 2009-2013 Cancer Control Plan, the Board agrees with the proposed programme changes outlined by François Sigaux during the meeting and as part of the 2014-2019 Cancer Control Plan.
Done • Establishment of working groups at Aviesan.
In progress • Definition of action plans (call for proposals, organisation).
-
3. The Board is fully impressed by the achievements made by the molecular screening programme (28 genetics platforms), and wishes to proceed to this ‘omics’ programme since this is a unique programme. We strongly endorse the proposal to establish a network linking the major established platforms.
Done • Harmonisation of the practices.
In progress • Working group on collection and integration of sequencing data performed by molecular genetics platforms.
Actions 6.1, 6.2, 6.3, 6.4, 6.5, 6.6 and 6.7
4. If INCa pursues its goal of obtaining whole genome sequences of a large number of tumour patients, it should present a strategic plan for high-throughput genome sequencing and analysis facilities, connected to the restricted number of designated comprehensive cancer centres and in conjunction with international programmes.
Done • Proposal of an organisational model for high-throughput genome sequencing and data management.
In progress • ACOMPLI and MULTISARC trials. • Reply to a mission letter from the Prime Minister to the President of Aviesan, for recommendations on implementation of clinical and research sequencing in France.
Actions 6.1, 6.2, 6.3, 6.4, 6.5, 6.6 and 6.7
FRENCH NATIONAL CANCER INSTITUTE 2014-2015 SCIENTIFIC REPORT
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Recommendations from the 2014 international scientific advisory board
Progress and implementationCorresponding actions in
the 2014-2019 Cancer Control Plan
5. The Board acknowledges INCa’s efforts to build capacity in the area of prevention/intervention research implementation. However, it is concerned that this multidisciplinary area still needs to be further developed in collaboration with other relevant agencies. The Board strongly suggests that the priority given to tobacco control should be used to strengthen this field.
Done • International symposium on November 2014 and then launch of a call for proposals on Intervention Research. • Designation of a chair of cancer prevention with IReSP and EHESP.
In progress • Setting-up a multi-year research programme, Cancer Tobacco PRIORITY (PRIORITÉ Cancers Tabac) with InVS, MIDELCA, LNCC and ARC Foundation. • Continuation of the collaboration between INCa and Canadian Health Research Institutes. • Integration of the research component into the platform of the National Programme to Reduce Smoking (PNRT). • Working group for the Biology component of the Cancer Tobacco PRIORITY programme for 2016.
Actions 8.7, 11.14
6. The Board strongly encourages INCa to continue to call French authorities to account to ensure they meet all their obligations as signatories to the WHO Framework Convention on Tobacco Control.
Done • INCa member of the French delegation at the 6th Conference of the Parties (COP 6) of the Framework Convention on Tobacco Control (FCTC), held in Moscow from 13 to 18 October 2014. • Agreements on electronic nicotine delivery systems and the adoption of guidelines and tax measures to reduce the demand for tobacco. • Launch of the National Programme to Reduce Smoking (PRNT).
In progress • Implementation of selected measures, such as plain packaging.
Actions 11.14, 16.11
7. The Board believes that validation of potential therapeutic targets emerging from academic/public research laboratories and their transition to early phase clinical trials should be facilitated. Further, it stresses the need to refocus the CLIP2 initiative toward phase I trials.
Done • New designation of 16 CLIP², 6 of them with a paediatric component. • Recommendations made to the experts for designation of CLIP² regarding the need for phase 1 clinical trials. • 6 new drugs proposed for calls for proposals. • 10 clinical trials ongoing or ready for enrolment.
In progress • 7 clinical trials due to begin.
Actions 5.2, 5.3
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Recommendations from the 2014 international scientific advisory board
Progress and implementationCorresponding actions in
the 2014-2019 Cancer Control Plan
8. The Board strongly supports the efforts of INCa to partner with the private sector in order to facilitate access of patients to innovative therapeutics.
Done • Meetings with companies for new partnerships. • Availability of new drugs by pharmaceuticals: among them, 5 from Novartis and 6 from AstraZeneca. • AcSé Crizotinib: 5,000 patients screened, 132 patients enrolled (from 23 July 2013 to 9 June 2015), 22 cohorts created. • Market approval filing by the company for a new indication.
In progress • AcSé Vemurafenib (started on October 2014). • Reflection on targeted therapy-based clinical trials for children affected by refractory or recurrent cancers according to the molecular profile of the tumour.
Actions 5.5, 5.6
9. The Board encourages INCa to leverage the ongoing precision medicine trials involving the tumour microenvironment and immune read-outs.
In progress • Restructuring of the translational medicine platforms including immunomonitoring.
Action 13.2
10. The Board strongly supports the priority on basic understanding on tumour ecosystem and looks forward to seeing specific implementation plans.
Done • Establishment of a joint ITMO Cancer - Aviesan and ITMO Cell Biology, Development and Evolution - Aviesan working group. • Summary of proposals for actions.
In progress • Preparation of a new call for proposals dedicated to functional heterogeneity of cell-cell interactions in the tumour ecosystem.
Action 6.6
11. The Board acknowledges the potential of the Canceropoles and the SIRICs; however, both programmes should undergo regular international peer-review and possibilities for interaction between these organisations should be implemented.
Done • Strengthening of Human and Social Sciences in the SIRIC programme.
• Bilateral partnerships for SIRIC-Canceropoles cross-participation. • Bilateral strategic discussions for joint actions and effective use of regional strengths in research.
In progress • Working group for a Human and Social Sciences chair dedicated to Cancer and shared by Lille 3 University/SIRIC OncoLille and INCa. • Joint actions for communication, research training, meetings and symposia. • Monitoring of the Canceropoles through the Contract of Objectives and Performance. • Mid-term assessment by an international Committee for the designated SIRICs (2015), and final assessment for the designated Canceropoles (2017).
Actions 16.6, 16.7, 16.8
23FRENCH NATIONAL CANCER INSTITUTE
2014-2015 SCIENTIFIC REPORT
Part 2.REPORT ON 2014-2015 CANCER RESEARCH ACTIVITY
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Table 2. Recurrent calls for proposals programmed by INCa and ITMO Cancer - Aviesan
Call for proposals (funders)Number of proposals
submittedNumber of projects
selected (% selection)Funding (€M)
2014 2015 2014 2015 2014 2015
Biology and basic sciences (INCa) 284 267 38 (13.4%) 34 (12.7%) 19.9 17.2
PHRC-K Programme for Hospital Clinical Cancer Research (DGOS)
196 186 45 (22.9%) Pending 21.1 Pending
PRME-K Programme for Medico-Economic Cancer Research (DGOS)
17 16 4 (23.6%) Pending 0.98 Pending
PAIR Integrated Research Action Programme (INCa-ARC Foundation-LNCC)
42(breast)
Pending(Tobacco)
8 (19%) (Breast)
Pending (Tobacco)
3.7 (Breast)
Pending (Tobacco)
PRT-K Programme for Translational Research (INCa-DGOS)
138 162 16 (12%) Pending 8.5 Pending
Training in Translational Research (Inserm)
103 97 36 (35%) 25 (26%) 2.5 2
Human and Social Sciences, Epidemiology and Public Health (INCa)
102 66 22 (22%) 17 (26%) 4.1 4.3
Population Health Intervention Research (INCa)
N/A 29 N/A 30 N/A Pending
Epigenomics (Inserm) 34 42 12 (35%) Pending 4.6 Pending
Physics, Mathematics, Engineering Sciences and Cancer (Inserm)
47 79 12 (25%) 15 (19%) 4 4.9
Cancer and Environmental Risks (Inserm) 24 31 7 (29%) 8 (26%) 3.2 3.2
Systems Biology (Inserm) 24 35 6 (25%) Pending 2.9 Pending
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1 SUPPORT IN BIOLOGY AND BASIC SCIENCES FOR CANCER RESEARCH
10 years of structuring actions in biologySince its creation, the Institute has operated through competitive calls for proposals to fund research projects, either investigator-driven or on specific topics.
Since 2005, INCa has launched regular call for investigator-driven research proposals. This annual call for proposals represents 25-30% of the Institute’s total annual expenditure on cancer research. Dedicated to basic research and leaving the initiative to the investigators’ creativity, the call for investigation-driver proposals in biology and basic sciences for cancer research (PLBIO) is aimed at funding innovative projects, strengthening multidisciplinary research, and developing research in emerging areas. Since 2007, 307 projects have been selected for funding from 1,987 proposals submitted, for a total budget of nearly €145 million.
Since 2011, three calls for proposals for multidisciplinary research on specific topics have been initiated by ITMO Cancer - Aviesan. The first was implemented on 2011, and focused on the interface between cancer biology, mathematics and physics. The second was implemented on 2012, to provide support for systems biology. The main objectives are to advance in the modelling of complex processes or integrative biology in the cancer area. An “Epigenetics and Cancer” call for proposals was implemented in 2013, for improving the understanding of epigenetic mechanisms associated with cancer. The calls for proposals dedicated to systems biology, epigenetic and cellular biophysics will evolve into a programme supporting interdisciplinary (biology, physics, mathematics) research projects in the area of tumour heterogeneity. The call for proposals “Physics, Mathematics and engineering sciences related to cancer” will be refocused on radio physics.
INCa and ITMO Cancer- Aviesan are also involved in initiatives aimed at supporting young researchers. Since 2007, INCa and more recently ITMO Cancer - Aviesan have provided financial support to the ATIP programme initiated by CNRS, the Avenir programme of Inserm, and subsequently the joint CNRS/Inserm ATIP-Avenir programme amounting to €9.4 million. The programme’s goal is to promote mobility and attract excellent team leaders, from France or abroad, to French laboratories. This enables young researchers to build and lead a research team. The purpose of these teams is to strengthen the research of the host laboratory while independently developing their own theme. Funding is provided for three years, with the possibility of extension for two years.
In addition, INCa, and more recently ITMO Cancer - Aviesan have supported the Frontières du Vivant (FdV, Frontiers in Life Sciences) PhD programme since 2010. The latter recruits students with training in at least two disciplines (such as biology, physics, mathematics, medicine, economics) and is open to international applicants. Finally, INCa is a founding member of the International Cancer Genome Consortium (ICGC), created in 2008 to comprehensively analyse genomic, transcriptomic and epigenomic alterations in 50 different types of tumours, and make the data available to the scientific community. Eight ICGC projects have been funded in France, and have already resulted in several high-level scientific publications. INCa has committed to the next ICGC programme (ICGC Med), dedicated to the clinical genomic. INCa has also participated in the international consortium.Global Alliance for Genomics and Health, since its creation in 2013. The objective of this consortium is to establish a framework for the responsible sharing of genomic and clinical data at international level.
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1.1. RESEARCH PROGRAMMES
1.1.1. “BIOLOGY AND BASIC SCIENCES FOR CANCER RESEARCH (PLBIO)” PROGRAMME The programme in 2015Since 2005, INCa has opened to the French scientific community an investigator-driven call for proposals in order to fund original and promising projects in different areas and disciplines of cognitive research in oncology. This annual call for proposals represents 25-30% of the Institute’s total expenditure on investigator-driven calls for proposals every year.
In 2015, 34 projects out of 267 proposals submitted were selected for funding. The selection rate of approximately 12.7% tends to be in line with the recommendations of the INCa’s international SAB and international standards. In 2015, the total funding allocated to the 34 selected projects is €17.2 million.
Table 3. Features of the “Biology and Basic Sciences for Cancer Research (PLBIO)” programme
Objectives
To acquire new knowledge and develop new tools to create new therapeutic approaches.Open to all areas of cognitive research and to scientific disciplines involved in tumour biology research, this call has been launched to: • enable the achievement of original projects; • strengthen multidisciplinary collaborations; • develop research in emerging areas.
Programming institution INCa
Operating institution INCa
Funding institution INCa
Year 2014 2015
Funding (in €M) 19.9 17.2
Proposals submittedProjects selectedSelection rate
28438
13.4%
26734
12.7%
To comply with the objectives of the call, nearly 91% of the projects funded aim to study the biological mechanisms of cell transformation and disease progression, according to the international CSO classification (Figure 1).
Fig. 1. Distribution of funding to projects awarded grants under the PLBIO programme in 2015
6%
3%
91%
Biology= €15.65MAetiology= €0.45MTreatment= €1.11M
Figure 2 presents a more detailed analysis, and shows that nearly 34% of the projects in the Biology category (CSO 1) specifically concern mechanisms of DNA repair and the regulation of gene expression (epigenetic regulation or transcription, CSO 1.2). Approximately 32% of projects funded are focused on processes linked to the development and spread of cancer, and the interaction between the tumour and its microenvironment (cell mobility, tumour invasion, metastasis, cancer stem cells, immunological microenvironment, or angiogenesis, CSO 1.4), whereas 23% of them study oncogenes, tumour suppressor genes and signalling pathways involved in cell proliferation and cell transformation (CSO 1.3).
The second area of interest in the CSO classification deals with treatment. Thus 7% of projects study either molecular mechanisms of response and resistance to treatments, or identification of new therapeutic targets (CSO 5.3).
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It is interesting to note that nearly 19% of the projects concern breast tumours, and 16% of them concern haematological diseases (this proportion is quite stable over the years). In accordance with the objectives of this call, nearly 30% of the projects are nonspecific to a tumour type, highlighting the fact that the projects are more focused on general mechanisms of cancer initiation and/or development, together with research on molecular targets and therapies that can be applied to several pathologies.
Fig. 2. Detailed analysis of the distribution of projects funded under the PLBIO programme in 2015
5.3 Systemic Therapies - Discovery and Development
2.1 Exogenous Factors in the Origin and Cause of Cancer
1.4 Cancer Progression and Metastasis
1.3 Cancer Initiation: Oncogenes and Tumor Suppressor Genes
1.2 Cancer Initiation: Alterations in Chromosomes
Trea
tmen
tAe
tiolo
gyBi
olog
y
33.8%
23.5%
32.4%
2.9%
7.4%
The programme over the 2007-2015 periodSince 2007, 307 projects have been selected from the 1,987 proposals submitted to the PLBIO programme, for a total budget of €145 million (Table 4). The number of letters of intent (LoI) submitted in 2015 remains very high. This is the Institute’s most attractive programme in terms of number of applications. These observations lead to two conclusions: • This programme is fulfilling its goals, namely by supporting research in a number of diverse areas in cancer-related basic sciences;
• INCa is consolidating its position as the major funding agency for cancer-related research programmes.
Table 4. Trends in selection and funding of the research programme in Biology and Basic Sciences for Cancer Research
Year 2007 2008 2009 2010 2011 2012 2013 2014 2015 TOTAL
Funding (in €M) 14.4 13.5 13.5 20.8 14.4 15.9 15.1 19.9 17.2 144.7
Proposals submitted Projects selectedSelection rate
10640
37.70%
14530
20.70%
34227
7.90%
24143
17.80%
20330
14.78%
19132
16.75%
20833
15.80%
28438
13.40%
26734
12.73%
1987307
15.45%
Analysis of the projects funded for the 2007-2015 period according to the CSO classification shows that the projects, as expected, mainly focus on tumour biology. This trend is quite stable over the years (Figure 3).
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Fig. 3. Distribution of the projects funded under the PLBIO programme over the 2007-2015 period
0%
20%
40%
60%
80%
100%
CSO1Biology
CSO2Aetiology
CSO3Prevention
CSO4Early detection,
diagnosis and prognosis
CSO5Treatment
CSO6Cancer control
and Survivorship
CSO7Scientific
models
200720082009201020112012201320142015
0%
10%
20%
30%
40%
50%
60%
1.1 Normal Functioning 1.2 Cancer Initiation: Alterations in Chromosomes
1.3 Cancer Initiation: Oncogenes and Tumour
Suppressor Genes
1.4 Cancer Progression and Metastasis
1.5 Resources and Infrastructure
200720082009201020112012201320142015
The distribution of the projects among the various sub-categories in the biology section has changed since 2007, especially in the CSO 1.2 section (Cancer initiation: alterations in chromosomes), dedicated to regulation of gene expression. Indeed, we observe that the proportion of projects studying DNA repair mechanisms, epigenetic regulation and microRNA-dependent regulation of transcription has increased over time.
This trend can be linked to the proliferation of tools available for carrying out this type of research, such as gene expression profiling, as well as the identification of new mechanisms
and regulators involved in the fine tuning of gene expression. Moreover, gene regulation is a dynamic and competitive field. For instance, France’ epigenetics research area is particularly rich and strong, and many teams have been established in this field in recent years. With the United Kingdom, France ranks at the top in Europe for research in epigenetics.
The number of projects studying tumour suppressor genes, oncogenes and signalling pathways involved in cell transformation and cell proliferation has remained quite stable over the 2007-2015 period (CSO 1.3).
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The initiative is also part of the strategy of the two major French charities, French National Cancer League (LNCC) and ARC Foundation for Cancer Research (ARC Foundation) and has allowed the funding of 2 more promising candidates per year, in cancer field.
ATIP-Avenir model: a five-year supportIn 2014, 4 ATIP-Avenir projects dedicated to cancer research and awarded in 2010 were extended for 2 years. Two candidates awarded grants in 2011 will be evaluated in September 2015 for a further two years of funding. These prolongations highlight that a 3 years-grant is not suitable for supporting a new team, its research programme and developing international initiatives, according to the 2013-2014 priority actions. This extension is relevant with the five-year programme of the European Research Council (ERC) Junior. Moreover, in the 2014-2019 cancer control plan, the action 13.1 recommends to fund young teams for longer periods, until 6 years. Since 2009, the total amount allocated to the ATIP-Avenir programme in the field of cancer supported by ITMO Cancer - Aviesan is €7.7 million for 24 teams (Table 5).
Table 5. Features of the ATIP-Avenir programme in the field of cancer
ObjectivesTo develop an innovative independent research programme with talented and promising candidates.
Programming institution Inserm - CNRS
Operating institution Inserm
Funding institution INCa
Inserm for ITMO Cancer - Aviesan
Year 2009 2010 2011 2012 2013 2014 2015
Funding (in €M) 0.75 0.66 1.20 0.90 1.20 1.80 1.20
Projects selected 2 3 4 3 4 4 4
With respect to overall programmes since 2007, INCa and ITMO Cancer- Aviesan supported Avenir, ATIP and then, ATIP-Avenir programmes for a total amount of €9.4 million (Figures 4 and 5).
Studies related to the development and progression of cancer, based on interactions with the tumour microenvironment (mainly on the regulation of processes in tumour invasion, metastasis, angiogenesis and immune microenvironment) also remain strongly represented (CSO 1.4).
The number of projects focusing on early cancer detection and cancer treatment has decreased steadily since the Institute launched a call for proposals dedicated to translational research (CSO 4 and CSO 5). However, it should be pointed out that the projects coded CSO 5.3 are specifically directed at understanding molecular mechanisms of action and resistance, the characterisation of molecular signatures of treatment response, and the identification of new drug targets.
1.1.2. FOSTERING INDEPENDENCE FOR YOUNG RESEARCHERS AND SUPPORTING EXCELLENCE IN CANCER BIOLOGY AREAS: ATIP-AVENIR PROGRAMMESince their creation, these two programmes (ATIP by CNRS and Avenir by Inserm) have enabled the establishment of independent research teams in the area of life sciences and health. Thus, more than 406 researchers (234 for CNRS and 172 for Inserm) have benefited from considerable support. Following the success of both of the original Avenir and ATIP programmes, Inserm and CNRS established a partnership and linked their own programmes to a new programme called “ATIP-Avenir”, launched in 2009.
Holding a competitive selection process to develop an innovative independent research programme is an excellent means for supporting talented and promising candidates that have obtained their PhD degree less than 10 years before applying to the programme, within the French scientific community.
In 2015, the ATIP Avenir programme has been continued. Projects in this current programme cover different issues of cancer development, including fundamental research on modulation of the chromatin environment and nuclear organisation, molecular mechanisms that regulate centromere formation, and faithful chromosome segregation and the link to genome stability and integrity, or to epigenetic factors and the mechanisms operative in dormant leukaemic stem cells.
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Fig. 4. 2007-2015 ATIP, Avenir and ATIP-Avenir programme funding in the field of cancer *Renewals not included
0200400600800
1,0001,2001,4001,6001,8002,000
201520142013201220112010200920082007
€K
Fig. 5. Trends in the recruitment of new ATIP, Avenir and ATIP-Avenir teams acting in the field of cancer (2007-2015)
0
1
2
3
4
5
6
201520142013201220112010200920082007
Nb
of te
ams
fund
ed
ATIP-Avenir ATIPAvenir
A workshop day on the impact of the ATIP Avenir programme in the field of cancerA workshop day, held on 26 June 2015, organised in collaboration with both the French National Cancer League and ARC Foundation, on the research impact of cancer projects funded from 2009 to 2011, welcomed 90 participants.
It was an opportunity to make an assessment, based on experience feedback from successful candidates, on the impact
of the ATIP-Avenir programme on their current activity, the development of national and international collaborations and their incorporation into cancer networks.
It demonstrates that the programme promotes research excellency and subsequently helps the candidates to succeed in their career track (100% of the 2009-2010 candidates have succeeded in securing a permanent position , and 6 out of 7 of the 2011 candidates) and funding such as ERC grants (3 recipients) or from the international ANR programme (2 recipients).
Specific actions in the Cancer Control Plan could be proposed in 2016 to help the recipients to join cancer networks and to develop their knowledge on funding strategies.
1.1.3. Programme for Research in Physics, Mathematics and Engineering Sciences related to CancerFollowing the success of the first call in 2011, the “Physics and Cancer” call for proposals was renewed, with a significant increase in budget for the 2nd, 3rd, 4th and 5th editions (+60%).
The number of projects submitted in 2015 has increased up to and reaches 80 submissions. The overall multi-year budget
(€4,8 million in 2015) has also increased (+20%). The selection rate (19%) is therefore lower, and 15 projects were selected.
This call for proposals is programmed by ITMO Cancer- Aviesan as part of the actions of the Cancer Control Plan. Since the launch of this initiative, a total of 84 research projects (€19.7 million) have been funded at the interface of biology, mathematics and physics in the field of cancer.
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The majority of the projects address new approaches in physics for improving the therapeutic management of cancer, which will have a direct impact on patients.
They are aimed at: • targeting the delivery of encapsulated chemotherapeutic drugs detected by MRI to the tumour cells;
• addressing unresolved issues of using MR images directly in radiation therapy planning;
• providing information on the elasticity and viscosity of human tissues and clues for understanding tissue heterogeneity;
• understanding tissue interactions in order to improve deep tumour treatment using electroporation/electrochemotherapy;
• investigating cancer cell invasion and characterising adhesion and tension dynamics in apoptotic cells versus mesenchymal cells during cell extrusion;
• developing minimally invasive tools for in vivo or in situ tissue analysis, such as endoscopic or laparoscopic probes for in vivo tissue analysis using mass spectrometry for guided surgery, or for obtaining quantitative information about chemo-induced apoptosis and the impact of tumour cells interacting with their environment;
• combining several state of the art methods in imaging, image analysis and microfluidics to generate images, making it possible to simultaneously collect useful information regarding the metabolic and morphologic status of the tissues, or to understand the metastatic cascade, or to understand the spatiotemporal dynamics of critical molecules involved in cellular transformation and migration.
1.1.4. SUPPORT FOR TRAINING IN INTERDISCIPLINARY RESEARCHSupport for interdisciplinary research is a priority set out in the 2009-2013 Cancer Control Plan and subsequent 2014-2019 Cancer Control Plan. Training PhD students to participate in an interdisciplinary community is a first step in further developing their potential as young researchers in interdisciplinary research, and acquiring skills that are increasingly needed in the area of cancer research.Since 2010, INCa, and since 2011 ITMO Cancer- Aviesan, have been supporting the PhD programme “Frontiers in Life Sciences,” (FDV) as part of the Paris Descartes and Paris Diderot PhD Programme in Life Sciences. This programme (funded with the help of the Bettencourt-Schueller Foundation) recruits In
Table 6. Research in Physics, Mathematics and Engineering Sciences Related to Cancer
Objectives
To attract physicists, mathematicians and engineers toward cancer research in order to improve the understanding, diagnosis or therapeutic management of cancer.
Programming institution ITMO Cancer - Aviesan
Operating institution Inserm
Funding institution Inserm for ITMO Cancer - Aviesan
Year 2011 2012 2013 2014 2015
Funding (in €M) 2.62 4.17 4.02 4.07 4.89
Proposals submittedProjects selected Selection rate
6417
26%
5721
37%
5419
35%
4712
25.5%
7915
19%
Of the 79 proposals examined in 2015, 15 had been submitted in previous years. The number of participating teams increased considerably, to 257 (double that of previous years).
Ambitious risky projects with a high potential impact for social policy-makers were selected. The main impact of their results will be earlier and better diagnosis, and improved monitoring of the response to anticancer therapy. They are expected to lead to new scientific strategies in the area of research on metastasis, as well as promising technical perspectives in the field of radiation therapy and instrument features for microscopy technique, with the potential for commercial development.
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convinced of the benefits of this training programme, ITMO Cancer - Aviesan decided for the first time to fund 3 projects. Two of these projects are concerned with the role of the immune system in the development of tumours, and the third evaluates circulating microRNA as an early biomarker for cancer.
A workshop day on 19 June 2015, for assessing the outcome of projects funded from 2010 to 2012 • 50 participants (senior scientists, post-doctoral fellows, PhD students);
• 70% of the participants were external to the FdV programme, indicating a great interest in the projects developed within this doctoral school;
• Topics included EMT inducers, cell reprogramming and tumour initiation, mechanotransduction in cancer-associated fibroblasts, and the history of the discovery and development of anticancer drugs.
1.2. THE INTERNATIONAL CANCER GENOME CONSORTIUM ICGC AND ICGCMED
The international genome consortium (ICGC) was established in 2008 to bring together researchers worldwide to comprehensively analyse the genomic, transcriptomic and epigenomic changes in 50 different tumour types or subtypes that are of clinical and societal importance across the world, and to make the data available to the entire research community as rapidly as possible, and with minimal restrictions, in order to accelerate research into the causes and control of cancer.
ICGC facilitates communication among its members, and provides a forum for coordination with the objective of maximising efficiency among the scientists working to understand, treat, and prevent these diseases.
2015, students from all over the world who have been trained in various disciplines (e.g. biology, physics, mathematics, medicine, economics).
Table 7. PhD programme “Frontiers in Life Sciences” in the field of cancer
Objectives
To promote ambitious research projects using a broad range of academic disciplines in order to understand living systems.
Programming institution PhD School “Frontiers in Life Sciences’’
Operating institution PhD School “Frontiers in Life Sciences’’
Funding institution INCa Inserm for Aviesan ITMO Cancer
Year 2010 2011 2012 2013 2014 2015
Funding (in €M) 0.21 0.21 0.21 0.21 0.21 0.35
Proposals submittedProjects selected
42
72
52
62
42
43
13 PhD students have been selected since 2010 in cancer research, and awarded a total amount of €1.37 million.
Projects in this current system, at the interface of cancer cell biology and physics, combined with recent advances in optics, address issues oriented toward “cancer” applications such as unravelling the fundamental mechanisms of cancer cell invasion, deciphering constraints of complex environments including “social rules” of collective stability, or identifying new cancer biomarkers responsible for the emergence of resistance to specific therapies.
In 2014, the selected projects address fundamental mechanisms of cancer invasion, with an emphasis on the role of tumour microenvironment in tumour progression and metastasis. These studies are in line with the recommendation of the SAB, and address the changes in the mechanical properties of the extracellular matrix leading to invasion, and how physical forces involved in basement membrane removal contribute to the invasive process.
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As of February 2015, the consortium received commitments from funding organisations in Asia, Australia, Europe, and North and South America for 85 projects (Figure 6). Ultimately, over 25,000 tumour genomes will be sequenced to provide a comprehensive catalogue of genomic abnormalities associated with cancer, a collection of data
that will reveal the repertoire of mutations that cause a wide-range of diseases and help define clinically relevant cancer subtypes. The data will also provide a rich resource for the world’s researchers working on the development of new treatments to advance patient care.
Fig. 6. Map of ICGC Projects
1.2.1. 10TH ICGC SCIENTIFIC WORKSHOPDuring the last ICGC Scientific Workshop, held in Verona in February 2015, the progress of ongoing ICGC programmes worldwide was presented.
Processed data are available via the Data Coordination Centre (DCC), and are updated every 6 months. The latest version, 19, in June 2015, comprises data from 12,979 cancer genomes from 55 ICGC projects (Figure 7).
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Fig. 7. ICGC data portal
The consortium has also conducted benchmarking studies to improve sequencing and analysis results. The conclusions of these exercises were presented and discussed during the workshop.
The ICGC workshop was also the opportunity to report on the progress of the PanCancer Analysis of Whole Genomes (PCAWG) project. This programme is the result of the commitment of the ICGC and TCGA (The Cancer Genome Atlas) to analyse non-coding DNA, which represents 98% of the human genome.
The main objective of this work is to identify mutations in non-coding regions that may be involved in and coordinate cancer specific processes. More than 600 researchers are contributing to the interpretation and analysis of the data for 4,000 whole genome sequences. For this purpose, the PCAWG project involves a cloud environment using computing centres in Asia, Europe,
and USA that fulfil the technical requirements of the project and the bioethical framework of ICGC and its member projects.
During the last ICGC workshop, the launch of ICGC Med was announced. The objective of ICGC Med is to link genomic data to clinical data to improve diagnostic and prognostic tools with genomic testing, and to make further progress in patient treatment and care.
1.2.2. FRANCE’S INVOLVEMENT IN THE ICGC PROGRAMMEThe Liver programme, directed by Prof. Jessica Zucman-Rossi Initiated in 2008, this project is aimed at identifying the mutations and rearrangements in liver cancers related to alcohol and metabolic syndrome. This programme has enabled the
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Table 8. Trends in the ICGC Breast Cancer programme
Number of HER2-positive samples
Collected 289
With adequate quality for sequencing 131
Whole genome sequencing 67
Whole exome sequencing 20
Transcriptome sequencing 49
Methylome analysed 48
The Prostate Cancer project, directed by Prof. Olivier Cussenot Launched in 2011, the project is aimed at identifying, through an integrative approach, genomic factors which characterise or allow targeting of the various phenotypes of aggressiveness of early stages of prostate cancer. The project advances the hypothesis that molecular events leading to aggressive forms are present at the earliest stages of the disease, and are modulated by microenvironment and genetic background. It proposes a multiple-stage study design, initially involving the generation of a primary set of genomic data to catalogue differences and target regions, in order to validate the clinical relevance on different and larger independent sets. Whole genome and whole exome sequencing of 25 pairs (normal/tumours) has been performed by the CNAG platform. Data analyses are ongoing and the first results highlight 4 predominant mutational signatures.
The Ewing Sarcoma project, directed by Prof. Olivier DelattreEwing sarcoma (ES) is the second most common primary malignant bone tumour in children and adolescents after osteosarcoma. Clinically, the survival of ES patients has considerably benefited from chemotherapy and radiotherapy. However, the prognosis of patients with metastasis at diagnosis or at relapse remains very poor. This disease is characterised by recurrent translocations involving members of the EWS and ETS gene families. The goal of the project is to establish the catalogue of somatic mutations that may cooperate with EWS-ETS fusion in the development and progression of the tumour, and to compare signatures between local and metastatic tumours.
identification of 4 new genes in hepatocellular carcinomas, which has in turn led to the launch of 4 projects focused on functional validation. The results were published in Nature Genetics in May 2012.
Further investigations, published in March 2015 Nature Genetics, show: • Specific mutational signatures associated with exposure to risk factors (alcohol, tobacco, aflatoxin B1);
• Each tumour is the result of a unique combination of mutations affecting approximately 40 genes. This large panel of genetic alterations may be involved in resistance mechanisms;
• TERT promoter mutations are earlier events in hepatocyte transformation.
Additional studies, published in August 2015 in Nature Genetics, show that the integration of defective virus AAV2 within cancer driver genes is observed in non-cirrhotic HCC. These results highlight the importance of infectious agents in cancer aetiology.
The Breast Cancer programme, directed by Dr Alain Viari and Prof. Gilles Thomas (†)Launched in 2008, this project is aimed at identifying somatic mutations present in breast cancers with HER2 gene amplification. By the end of 2014, the French Breast Cancer network, comprising twelve centres involved in the ICGC programme, had achieved significant results: • the sample collection was closed; • the target sample sequencing terminated and bioinformatics software developed;
• more than 800 tumour and matched blood samples were stocked in the common repository in Lyon;
• 289 of them are HER2-positive and are analysed on behalf of the French project;
• some 150 other HER-positive samples are transferred to the BASIS project team directed by the Sanger Institute.
The results will be published in at least two separate papers: one addressing all breast cancer subtypes and the other the HER2-positive French population (submission pending).
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The Gynaecological Carcinosarcoma project, directed by Prof. Alain PuisieuxCarcinosarcomas are rare tumours with poor prognosis that often occur in the uterus, but can also affect the ovaries, fallopian tubes and vagina. The clinical management of carcinosarcoma is complex due to poor scientific understanding of these tumours.
Launched in December 2013, the carcinosarcoma project aims, through an integrative approach, to decipher the cellular and molecular mechanisms for the development and progression of these gynaecological cancers by combining descriptive and functional analyses.
The Leiomyosarcoma project, directed by Dr Frédéric ChibonLeiomyosarcoma (LMS) is an uncommon group of malignant mesenchymal tumours composed of cells showing distinct smooth muscle differentiation that occur mainly in adults in any location of the body (soft-tissue, viscera or uterus). Soft-tissue LMS present very complex genetics and intra-tumour heterogeneity.
Initiated in December 2013, this programme is aimed at improving our understanding of the pathogenesis of malignant smooth muscle lesions, identifying new alterations driving oncogenesis, and addressing the clonal evolution of these heterogeneous tumours by combining genomic and transcriptomic analysis.
The Prolymphocytic B-Cell Leukaemia project, directed by Dr Olivier BernardProlymphocytic B-cell leukaemia is a rare blood cancer characterised by the presence of B prolymphocytes in peripheral blood, bone marrow and spleen. This is an aggressive blood cancer that shows a poor response to treatments.
Launched in December 2014, this project aims to identify somatic mutations using exome sequencing and cellular biology approaches. These studies may help to determine the cell of origin, the oncogenesis, and clonal organisation of the tumour, and then to develop specific treatments.
The project was launched in 2012, and the f irst results were published in Cancer Discovery in September 2014, in collaboration with the Bioinformatics department of St. Jude Children’s Hospital.
The results show that a combination of two alterations is necessary to identify the aggressive forms of Ewing sarcoma. Indeed, STAG2 mutation is present in 17% of cases (sign of tumours with a poor prognosis), CDKN2A in 12% of cases, and mutations in p53 and in genes involved in chromatin modifications are present in 7% of cases. In 3% of cases, both STAG2 and p53 are mutated, and those tumours have a very poor prognosis.
Further analyses are in progress to confirm these results, to identify additional mutations and to study the functions of STAG2 and its association with the p53 pathway.
The Retinoblastoma project, directed by Dr François RadvanyiRetinoblastoma is a paediatric cancer that develops rapidly in the cells of the retina. It is the most common intraocular cancer of infancy and childhood, with an incidence of one case per 15,000–20,000 live births. Most patients are diagnosed before the age of five years. In developed countries, patients have an excellent prognosis. However, in the majority of cases, enucleation of the affected eye has to be performed. An early event in retinoblastoma genesis is the functional loss of both alleles of the RB1 gene. However, other genes are likely to be involved in the development of this cancer. This project is aimed at identifying additional events that lead to retinoblastoma development, whether they are genetic or epigenetic. The first results show that different cell populations are involved in retinoblastoma development, confirming that it is a heterogeneous disease. Indeed, transcriptome and methylome analysis make it possible to identify two sub-groups with different genomic alterations corresponding to different types of disease progression among patients.Launched in 2013, this project belongs to the rare tumour programme, together with the Gynaecological Carcinoma, the Leiomyosarcoma and the B-Cell Prolymphocytic Leukaemia projects.
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2 TRANSLATIONAL AND INTEGRATED RESEARCH
10 years of structuring actions by INCa in translational researchUnder the first two Cancer Control Plans, INCa promoted the continuum between research and care. This support to translational research has been reflected in funding for research projects and the development of various structures and infrastructures.
From 2011 and 2012, 8 Integrated Cancer Research Sites (SIRIC) were designated for a 5-year period. The budget allocated to this programme is €64 million, which is jointly provided by INCa, Inserm for ITMO Cancer - Aviesan and the French Ministry of Health (DGOS). The SIRIC programme aims at strengthening the links between various research areas (basic, clinical, public health, epidemiology and human and social sciences), by bringing together a critical mass of scientists (physicists, researchers, engineers, carers and patients) committed to work on the specifications and constraints of translational research.
Availability of and access to human biological samples is critical for the development of translational research activities. Since its creation, INCa has contributed to the establishment of a multidisciplinary and multi-centre organisation, through both the creation of biological resource collections via the tumour banks, and the centralisation, management and exploitation of all clinical, biological and epidemiological data in the clinical and biological databases dedicated to one pathology or cancer site.
To support translational research projects, INCa has gradually put in place several calls for proposals, investigator-driven or oriented, to address topical areas and/or spur the creativity of investigators.
In 2005, the Institute thus initiated National Specialised Programmes of Excellence (PNES; Programmes Nationaux
d’Excellence Spécialisés) devoted to research on lung and kidney cancer. These federative national research networks have brought together some of the most effective teams of researchers and clinicians working on these two areas of pathology. The lung and kidney PNES have been in place for 2 years, with respective budgets of €1.8 million and €1.4 million.
In 2007, INCa established an annual specialised programme entitled Integrated Research Action Programme (PAIR; Programme d’Actions Intégrées de Recherche), to gather the scientific and medical communities specialising in a specific pathology, in order to address all aspects of research related to that pathology. Since 2007, 8 programmes have been conducted and 71 projects have been funded for a total of €37.6 million by ARC Foundation, the French National Cancer League and INCa.
Alongside these targeted calls for proposals, INCa, in partnership with DGOS, has, since 2007, launched a competitive call for proposals in translational research. The goal of this action is to promote interdisciplinary projects involving laboratory researchers and clinicians. Since 2007, 128 projects have been funded for a total budget of €51.5 million.
This support for translational research has been extended at European level since 2011, through the TRANSCAN network, which conducts Europe-wide calls for proposals for translational cancer research. Four joint calls for proposals have thus been launched since the start of this initiative.
Finally, appropriate training for physicians and researchers is essential to encourage them to collaborate on the same translational research project. In this context, INCa, has in 2007, launched a call for applications from students or young graduates in medicine, pharmacy, odontology and veterinary sciences who wish to complete their initial training with a translational cancer research project. This call for proposals is supported by ITMO Cancer - Aviesan since 2011.
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2.1. CROSS-DISCIPLINARITY AND TRANSLATION OF KNOWLEDGE INTO CLINICAL PRACTICE
Translational research is supported through dedicated calls for proposals and a policy of designated multidisciplinary integrated research sites. This support for translational research has also been extended at European level via coordinated actions against cancer, particularly through the TRANSCAN network, and calls for proposals dedicated to this area of research.
2.1.1. THE TRANSLATIONAL RESEARCH PROGRAMME (PRT-K)The objective of this call for proposals launched for the first time in 2007 and recurrent since 2009 in partnership with the Ministry of Health (DGOS), is to promote interdisciplinary projects, bringing together laboratory researchers and clinicians. Sharing of specific expertise, skills and knowledge should foster the translation of scientific and medical discoveries into clinical advances for cancer patients. In 2014, 16 projects have been selected for funding representing a global budget of €8.5M (€5.5M INCa + €3M DGOS). In 2015, 162 letters of intent have been received and 47 preselected and applicants invited to submit full proposals.
Table 9. Features of the PRT-K programme
Objectives
To hasten the transfer of knowledge with a view to its prompt application in clinical practice for the benefit of patients, by giving researchers an incentive to develop multidisciplinary projects in close collaboration with clinical players, in order to improve prevention, early detection, diagnosis, treatment and comprehensive care of cancer patients.
Programming institution INCa/Ministry of Health (DGOS)
Operating institution INCa
Funding institution INCa/Ministry of Health (DGOS)
Year 2014 2015
Funding (in €M)
8.533INCa: 5.572
DGOS: 2.960Pending
Proposals submitted Projects selected Selection rate
13816
11.6%
162PendingPending
Numerous tumour sites are studied in the projects selected in 2014: high incidence cancers (breast, colorectal, lung, liver) as well as rarer tumours (adrenal cancer, neuroendocrine tumours, and uveal melanoma).
Since 2007, 868 proposals have been submitted in response to this call for proposals, and 128 have been selected and funded (2015 results not included, final selection in progress). The overall selection rate for this call for proposals is 14.7%. The total amount invested in these projects since 2007 is €51.5 million (Figure 8).
Fig. 8. Trends in selection for the Translational Research Programme
0
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2014201320122011201020092007 /
Tota
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Total funding in €M Nb of projects
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of p
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The typology of projects funded since 2007 corresponds to the characteristic profile for translational research (Figure 9), with most of the budget allocated to two main categories of research projects: • projects that involve developing techniques for early detection, diagnosis and prognosis using biomarkers (genetic, biological, immunochemical and microbiological);
• projects based on improving patient care by developing new therapeutic strategies and greater understanding of mechanisms of treatment resistance.
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Table 10. Features of the Translational Research Training Programme 2014-2015
Objectives
To promote training of students or young medical, pharmacy and veterinary science graduates in translational research by funding master’s degrees, doctoral theses or post-doctoral research.
Programming institution ITMO Cancer - Aviesan
Operating institution Inserm
Funding institution Inserm for ITMO Cancer - Aviesan
Year 2014 2015
Funding (in €M) 2.3 2
Proposals submittedProjects selected Selection rate
10330
29%
9725
26%
In 2014 and 2015, the number of proposals submitted has doubled compared to 2013, which indicates interest of student or young clinicians, pharmacists and veterinarians for research career.
Fig. 10. Trends in the number of projects submitted and selected in the Training for Translational Research programme 2011-2015
0
20
40
60
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20152014201320122011
Nb of projects submittedNb of projects selected
35
1927 25
3025
36
52
10397
Fig. 9. Distribution of budget allocated to the Translational Research Programme since 2007
0
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30
TreatmentEarly detection, Diagnosis
and Prognosis
AetiologyBiology
Budget in €M Budget in %
16%9%
50%
25%
0%
10%
20%
30%
40%
50%
60%
2.1.2. THE TRANSLATIONAL RESEARCH TRAINING PROGRAMMESThe Translational Research Training Programme for students and young investigatorsAs part of their strategy for translational research, INCa first, and then ITMO Cancer - Aviesan offer a specific recurrent call for applications, initiated in 2007, to facilitate the training of medical students, pharmacists, odontologists and vets who wish to complete their studies by performing translational cancer research. This support is provided through the competitive awarding of grants to applicants for one to three years to complete a master’s degree, post-doctoral residency, or to prepare a doctoral thesis on an outstanding research topic.
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Table 11. Features of the translational cancer research positions through the “Poste d’Accueil” initiative in the field of cancer
Objectives
Provide training to research through research and strengthen the links between basic and clinical research, therapeutic and public health for young medical doctors.Strengthen links between research laboratories as part of biology and animal and comparative pathology.
Programming institution Inserm
Operating institution Inserm
Funding institution Inserm for ITMO Cancer - Aviesan
Year 2011 2012 2013 2014 2015
Funding (in €M) 0.08 0.15 0.3 0.09 Pending
Projects selected 1 2 3 1 Pending
There is a complementarity between the Inserm “Poste d’Accueil” initiative and the translational research training call, since several students funded by “Poste d’accueil” in 2009, were awarded a PhD position in 2011 and for a post-doctoral position in the 2015 translational research training call.
2.1.3. THE EUROPEAN TRANSLATIONAL CANCER RESEARCH PROGRAMMEThe translational cancer research network established under ERA-NET TRANSCAN currently involves 29 organisations (INCa included) from 19 countries, including 15 EU Member States. The purpose of TRANSCAN is to establish coordination at European level and support joint projects in translational cancer research. The 1st TRANSCAN programme, funded by the European Commission for a 4-year period (January 2011 – December 2014), allowed three calls to be launched for joint proposals (Table 12), topics for which were defined by the TRANSCAN partners based on the recommendations of the TRANSCAN Scientific Advisory Board.
From 2007 to 2015, 180 training grants have been awarded for translational research, for a total of €12.5 million including 15 to postdoctoral candidates and 71 to PhD students.
The analysis of the trajectories of the recipients indicates that they continue working in translational research after their training, suggesting that the programme is achieving its objective.
It is noteworthy that some students who received a training grant in translational research were able to submit, years later, research projects as coordinator or associated team, to the national call for proposals PRT-K, indicating their ongoing commitment in this area.
In 2015, the projects selected aimed at better understanding of the mechanism of resistance to treatment such as radiotherapy or demethylating agents. They involve research in the area of stem cells, their radiation-induced migration or their genetic instability, to avoid the development of resistant subclones. The important role of stromal stem cells, and cells of the immune system and angiogenic microenvironment is also raised. Finally, the local delivery of radioinducers and nanoparticles for more effective radiotherapy is also a topic of growing interest.
Temporary translational research positions programmeAs part of its policy on translational research training programmes, the Cancer Control Plan supports the Inserm initiative of offering a temporary position for a medical doctor, pharmacist, odontologist or veterinary physician (“poste d’accueil”) working in the field of cancer. The objective is to allow them to complete their medical degree and simultaneously taking part in research, and thus, to promote translational research. Full-time positions are targeted to pharmaceutical, odontological or practising medical students who have obtained the diploma giving access to doctoral studies or young qualified people from veterinary schools. Funding is provided for one or two years, renewable for one year, to complete their PhD thesis, or to obtain a post-doctoral position immediately after they received their PhD. In total, 6 positions have been supported for €0.6 million since 2011, including 5 doctors and 1 pharmacist (Table 11).
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Table 12. Calls for proposals of the 1st ERA-NET TRANSCAN programme
1st call for proposals:JTC 2011
Topic: Validation of Biomarkers for Personalised Cancer MedicineBudget (15 funding partners): €10.6 M (INCa €1.3 M)Results:10 projects selected among 117 submitted pre-proposals;7 French teams (including 1 coordinator) participating in 6 selected projects.
2nd call for proposals:JTC 2012
Topic: Translational Research on Primary and Secondary Prevention of CancerBudget (15 funding partners): Total budget of €11.2 M (INCa €1.3 M - ARC Foundation €0.5 M)Results: 10 projects selected among 55 submitted pre-proposals;9 French teams (including 1 coordinator) participating in 7 selected projects.
3rd call for proposals:JTC 2013
Topic: Translational Research on Tertiary Prevention of CancerBudget (15 funding partners): €11.4 M (INCa €0.8 M - ARC Foundation €0.57 M)Results: 10 projects selected among 68 submitted pre-proposals;4 French teams (including 1 coordinator) participating in 3 selected projects.
Focus on projects funded through JTC 2013For its 3rd call on translational cancer research focused on tertiary prevention, TRANSCAN received 68 applications that met the eligibility requirements. This topic was subdivided into 3 specific aims:
1. Assessment of the impact of health behaviours (diet, smoking, alcohol intake, etc.) on clinical outcomes in cancer patients
This aim will be explored in 2 projects out of the 10 selected: 1) An intervention study to evaluate the impact of diet on tertiary prevention of head and neck cancers; 2) A study on folate-dependant metabolism in colorectal cancer.
2. Optimisation of the quality of life of cancer patients (side effects, co-morbidity, etc.)
This topic will be studied in one project aimed at analysing the influence of treatments and co-morbidity on the clinical course of breast and colorectal cancer.
3. Prevention of recurrence and second cancer
Five projects will study this topic and 2 are interested in the evaluation of chemoprevention: 1) Metformin and/or aspirin in colorectal cancer and 2) Metformin in breast cancer. Two other projects will explore immunological phenomena: 1) Validation of an Immunoscore in colorectal cancer; 2) Identification of novel tumour- associated antigens for immunotherapy in atypical teratoid/rhabdoid tumours. Three projects are interested in the development of genetic and epigenetic biomarkers: 1) Biomarkers for recurrence of pancreatic cancer; 2) Biomarker predictive of distant metastases in breast cancer and 3) Markers predictive of metastatic risk or 2nd cancer in melanoma.
In 2014, INCa, in collaboration with all the partners, participated in the submission of a 2nd TRANSCAN proposal. The European Commission selected this application for funding using the new ERA-NET Cofund scheme in the framework of Horizon 2020, which allows the European Commission to top-up the total research funding allocated the TRANSCAN2 partners by 33% for the 1st call for proposals (JTC 2014). This 33% additional
budget should help increase the number of research projects funded under JTC 2014. Similarly to the previous programme, INCa is actively involved in the TRANSCAN-2 network activities as well as in the funding of the French teams participating in the selected research projects. INCa coordinates Work package 4 on strategy and scientific research priorities and holds the position of chair for the network in 2015.
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Table 13. ERA-NET TRANSCAN-2 in Translational Cancer Research
Objectives of TRANSCAN-2
To coordinate the funding organisations’ activities at European level for implementing joint actions in Translational Cancer research, including joint transnational calls for proposals (JTCs).Website: http://www.transcanfp7.eu/transcan/index.php
Call for proposals (JTCs)
4 calls for proposals scheduled within 5 yearsProcedure in 1 or 2 stages: Pre-proposals + full proposalsPublication of results in October of year N + 1Start of funding in April of year N + 2
1st call for proposals: JTC 2014
Topic: Translational research on human tumour heterogeneity to overcome recurrence and resistance to therapyBudget: Tentative total budget of €17.4 M (INCa €1.5 M and ARC Foundation €0.5 M)Results: 117 submitted pre-proposals; Nb of selected projects: pending (October 2015)
2.1.4. RESEARCH AND ACTIONS PROGRAMME TO REDUCE SMOKING AND CHANGE CURRENT PREVALENCE OF TOBACCO-RELATED CANCERS (PRIORITE CANCERS TABAC) Smoking remains the leading avoidable risk factor for cancer in France. The latest estimate of the number of cancer deaths attributable to tobacco in France is approximately 44,000, not including cancers associated with passive smoking, which also promotes lung cancer. Tobacco is the primary causal factor for 80% of deaths from lung cancer, and is associated with an increased risk of at least 17 other types of cancer, especially bladder, pancreas, urinary and kidney, stomach, cervical, etc.
Despite a large number of initiatives launched in recent years, the prevalence of smoking in France remains high compared with other developed countries. More than 30% of 15-75 year olds smoke daily in France, i.e. 13 million people, whereas this figure is 19% in Great Britain, below 20% in the United States, and 16% in Australia. This “unfavourable” situation could be explained by the inadequate place still given to prevention in our health system, and by the lack of strong measures to support and help smoking cessation. Furthermore, few French research teams are interested in tobacco-related issues, and it is therefore crucial to renew research efforts on this topic.
In this context, INCa, in collaboration with the other agencies, ministries and research teams, set up a multidisciplinary partnership programme in order to establish research and actions priorities on tobacco and tobacco-related cancers. This programme is part the 2014-2019 Cancer Control Plan and will be linked with the “Programme National de réduction du tabagisme” announced by the President when launching this Cancer Control Plan. The tobacco-related cancer research priorities were defined in 2014 through thematic workshops completed by feedbacks from experts (not belonging to the task force). A national meeting was held in January 2015 in order to present research priorities for the call of proposals before its release. The call of proposals was published in late May and the scientific committee is scheduled for early 2016. This call concerns all cancers related to tobacco and its components, and covers a wide range of disciplines, from basic and clinical science to public health, via information and communication technologies, economics and political science, sociology, law, epidemiology, etc.
The projets are expected to fall under one of the following defined axes: • Axis 1: Determinants and trajectories of smoking; • Axis 2: Consumers and stakeholders behaviours; • Axis 3: Electronic nicotine delivery systems (electronic cigarettes);
• Axis 4: Smoking cessation in patients with cancer; • Axis 5: Screening for tobacco-related cancers and innovative research on new screening methods.
The call also intended to promote intervention research projects on this topic, and welcome studies on specific populations including women, teenagers and young adults and vulnerable populations. Social, economic, cultural and spatial inequalities should also be considered as cross-cutting topic for all these axes.The ARC Foundation and LNCC (charities) are partners in this first edition. In addition, the intention will be to build a pluridisciplinary network
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of researchers and field actors. This network will aim to ensure a scientific animation of the programme and will enable dialogue between field actors and research communities.
2.2. STRENGTHENING OF ORGANISATION AND INFRASTRUCTURES DEDICATED TO TRANSLATIONAL/INTEGRATED RESEARCH IN INTEGRATED CANCER RESEARCH SITES (SIRICs)
Under the 2009-2013 Cancer Control Plan, 8 cancer research sites were designated as Integrated Cancer Research Sites (SIRIC) for a 5-year period (starting from 2011 and 2012), and then became national centres of reference for translational cancer research.
The budget allocated to this programme is €64 million, jointly funded by INCa, Inserm for ITMO Cancer - Aviesan and the Ministry of Health (DGOS). This designation is aimed at spurring translational cancer research, helping to optimise and hasten the production of new knowledge and promote its dissemination and application to cancer care.This SIRIC programme increased the link between the different areas of research (basic, clinical, public health, epidemiology, and human and social sciences), by creating a critical mass of experts (physicians, researchers, engineers, healthcare workers and patients) working within the constraints of translational research. Each SIRIC is involved in specific integrated research programmes, representing the expertise and strategies of the site.
Fig. 11. Location of the 8 SIRICs in France
Guadeloupe Guyane
Martinique
La Réunion Mayotte
SIRIC ONCO Lille
SIRIC BRIO (Bordeaux Recherche intégrée Oncologie)
SIRIC CARPEM(CAncer Research andPErsonalized Medicine)
SIRIC SOCRATE(Stratified Oncology Cell DNA Repair And Tumor immune Elimination)
SIRICInstitut Curie
SIRIC MontpellierCancer
SIRIC MarseilleCancérologie
SIRIC LYRIC (Lyon Recherche intégrée en Cancérologie)
Source: INCa, 2012Drafted by INCa’s Research Division, 2015
Paris
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The SIRIC programme will undergo an assessment under the 2014-2019 Cancer Control Plan.
INCa coordinates regular annual meetings with SIRIC directors (September seminar) and project managers (3 meetings per year).
During the 2014-2015 period, inter-SIRIC working groups were established to explore shared issues. OSIRIS, the working group on data (clinical, biological, omics) sharing and integration, was particularly active on Information Technology solutions, ontology, ethical and regulatory aspects. This collaborative effort will be maintained, to facilitate the development of research projects by facilitating data sharing and integration in a high quality environment that complies with regulations.
SIRICs are organising a workshop on Drug Design and Development to be held in November 2015 to strengthen their collaboration, while simplifying R&D process and optimising public-private collaborations.
Other inter-SIRIC exchanges have resulted in the organisation of workshops on “Onco-immunology and Immunotherapy” in June and “Clinical Trials and Precision Medicine” in September.
INCa promotes the development of health democracy and involvement of patient advocacy in management activities and scientific programmes of the SIRICs. The Institute also tries to foster research in human and social sciences within the SIRICs. A workshop was organised at the end of March, where SIRIC representatives presented their actions and objectives in this area before discussing common needs and priorities for developing national collaborations. Another important point in terms of coordination, promoted by INCa, is the long and fruitful dialogue between the SIRICs and Canceropoles for coordinating their regional/local strategies and actions.
INCa, in collaboration with its partners (Ministry of Health and ITMO Cancer - Aviesan), is organising a midterm evaluation procedure for the 8 SIRICs in 2015. This evaluation is based on an international scientific committee of renowned experts in the field of integrated cancer research. SIRICs will have the opportunity to present and discuss the progress of their activities during hearings, which will be organised in December 2015.
A new competitive call for applications will be launched at the end of the 5-year period; this competitive process will be open to the existing designated sites and to new ones.
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3 CLINICAL RESEARCH AND DEVELOPMENT OF EARLY PHASE TRIALS FOR INNOVATIVE DRUGS
10 years of clinical research and organisation, structures and infrastructures by INCaINCa has implemented actions, within the framework of the successive Cancer Control Plans, to support clinical research via calls for proposals (CFPs) and the setting up of infrastructures.
CLINICAL RESEARCH PROGRAMMES
• Clinical Research call for proposals: In 2005, INCa launched a CFP aimed at supporting: therapeutic research, including tumour banks and key translational research issues, large clinical trials with major public health objectives, early phase clinical trials using innovative statistical methodologies, and clinical trials in rare cancers that had been insufficiently investigated or had a particularly poor prognosis. Seventeen projects were funded for a total of €3 million.
• Programme for Hospital Clinical Cancer Research (PHRC-K): Under the 2003-2007 Cancer Control Plan, the Cancer component of the PHRC programme was individualised by the Ministry of Health, and its management entrusted to INCa. Since then, INCa has organised a competitive evaluation of proposals submitted to PHRC-K on a yearly basis. Under the subsequent Cancer Control Plans, the annual funding for PHRC Cancer was increased to €20 million.
• Programme for Medico-Economic Cancer Research (PRME Cancer): Since 2005, the Ministry of Health has individualised the funding and assigned to INCa the management of the Cancer part of its national Medico-Economic Research Programme. This programme was consecutively named the Programme for Innovative and Costly Techniques (STIC), Programme for Innovative Techniques (STI) in 2012 and then PRME in 2013. Currently, it has two strands: Innovation in Care and Care Management Pathways. The annual budget for PRME Cancer is €2 million.
• Programme for Early Phase Cancer Clinical Trials: Based on the collaboration between INCa and NCI/CTEP launched in 2009, and the early phase clinical trials network (CLIP2) set up in 2010, it was possible to develop a collaborative programme in France between INCa and international pharmaceutical companies, and set a CFP specifically dedicated to CLIP2. This programme has been reinforced by the 2014 - 2019 Cancer Control Plan.
• AcSé Programme started in 2013 and bases treatment decisions on relevant biomarkers in non-approved malignancy applications, with different treatment arms bringing together similar organ/histologies of cancer. It aims at providing patients with access to targeted oncology therapies based on molecular testing, improving safety and evaluating efficacy for a targeted drug.
CLINICAL RESEARCH TRAINING PROGRAMMES
In 2006 and 2007, INCa launched annual calls for applications (CFA) in several cancer research areas with a €1 million and €450,000 budget, respectively. The CFA were aimed at supporting young researchers’ activity and outstanding research projects, and offering a one- or two-year period of training after they graduated.
In 2006, the objectives of the clinical research strand of the CFA were: conception, design, follow-up and data analysis of national or international clinical trials, particularly in innovative areas, and with important public health impact, or in orphan cancer diseases. Four applications were funded. In 2007, the objectives of the clinical research strand of the CFA were: conception and management of clinical projects including genomic, proteomic, functional imaging or pharmacological data, biomarker identification and validation, statistical methodology for biomarkers and surrogate criteria use with data listed above. Teams from hospital molecular genetics platforms were encouraged to participate.
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CLINICAL RESEARCH ORGANISATIONS, STRUCTURES AND INFRASTRUCTURES
Their main objectives are to:
• provide support for the development of early phase clinical research projects with better coordination and organisation, and designation of clinical centres CLIP2;
• reinforce cooperation between cooperative groups;
• strengthen research capacity by coordinating clinical research teams and providing support for data processing centres;
• increase awareness of clinical trials, and increase patient enrolment in studies.
1/ CLINICAL RESEARCH MANAGEMENT STRUCTURES
• CLIP2: Initiated by the 2009-2013 Cancer Control Plan and strengthened by the 2014-2019 Cancer Control Plan, this network aims at promoting access to innovative drugs. Therefore, since 2009, INCa has implemented:
– a collaborative agreement with US NCI/CTEP;
– the designation for 4 years of 16 CLIP2 in 2010, and subsequently in 2015 (some of the latter to conduct clinical trials in paediatric cancers).
2/ CLINICAL RESEARCH COORDINATION STRUCTURES
• Designation of cooperative intergroups: This action was prepared during two of INCa’s earlier consecutive clinical research coordination initiatives:
– the creation and development, between 2005 and 2007 of 28 clinical study groups organised by medical speciality, organ or cancer type, to identify and validate ongoing clinical trials, and propose new ones;
– the creation and development, between 2007 and 2012, of 9 multidisciplinary clinical research groups, organised by organ or cancer type, to identify and validate ongoing clinical trials, promote access to innovative drugs, help to develop innovative clinical research projects, participate in INCa’s clinical and translational research planning, and gather clinical research teams together into intergroups.
Thus, between 2012 and 2014, INCa designated, for a two-year period, 13 French cooperative intergroups with an international dimension.
• PHARE/SIGNAL Clinical Trial: Sponsoring national clinical trials and studies in breast cancers. As a sponsor, INCa has coordinated more than one hundred of investigators in several French centres for both a therapeutic trial comparing trastuzumab treatment for 12 vs 6 months in 3,384 patients enrolled between 2006 and 2010, and a clinical study of genetic alterations in 9,400 patients enrolled between 2009 and 2011. Several results from these studies have been published or are expected.
3/ STRUCTURES PROVIDING SPECIFIC TOOLS AND MEANS FOR CANCER CLINICAL RESEARCH
• Data processing centres network (CTD): INCa designated 11 CTD in 2007 to provide logistical and methodological support, especially in data management, quality control and analysis of results in clinical research projects.
The CTD were initially funded by INCa and subsequently, from 2008 on, by the Ministry of Health with a €1 million total annual budget. The CTD have developed collaborative research projects and facilitated access to available clinical research data within the network. INCa has sponsored and funded collaborative projects selected in its competitive CFPs.
• Mobile Clinical Research Teams network (EMRC): Under the 2003-2007 Cancer Control Plan, INCa and the Ministry of Health created 26 Mobile Clinical Research Teams (EMRC) to enable community hospital investigators to participate and enrol their patients in clinical trials. This programme has been strengthened by the subsequent Cancer Control Plans. About 70 full-time equivalent (FTE) of clinical research associates and clinical study technicians carrying out their role in more than 160 centres throughout France have been funded by the Ministry of Health with an annual budget that was increased to €3.4 million in 2012.
• Cancer patient enrolment in clinical trials: Initiated under the 2003-2007 Cancer Control Plan and strengthened by the 2009-2013 Cancer Control Plan, INCa’s annual survey of funded centres to support patient enrolment in clinical trials has assessed cancer clinical research activity in France. Hence, between 2008 and 2014, the number of patients enrolled in clinical trials has increased by 97% (122% in academic trials, 22% in industrial trials), up to 44,023 patients enrolled (4 out of 5 in academic trials). The objective of the 2014-2019 Cancer Control Plan is to enrol 50,000 patients a year in therapeutic trials.
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• Research projects addressing individual or collective behavioural modification, or exploring drug-based approaches for the prevention of cancer risks;
• Projects that include assessment of the quality of life (during and/or after illness);
• Combination of several targeted drugs, or combinations of targeted drugs with chemotherapy or radiotherapy;
• Clinical validity of the efficacy of innovative health technologies in the areas of treatment or diagnosis;
• Increase of patient survival; • Reduction in the toxicity of medium- and long-term treatments, and assessment of toxicity, especially for children and young adults;
• Palliative care; • Meta-analyses addressing controversial issues in treatment efficacy.
As recommended by the 2014-2019 Cancer Control Plan, strong participation from cooperative clinical groups is expected, particularly with regards clinical trials aimed at responding to the major therapeutic questions of increasing survival and reducing the side-effects and delayed effects of treatments.
Approximately 50% of the budget will be devoted to large-scale projects conducted by cooperative groups.
3.1. THE CLINICAL CANCER RESEARCH PROGRAMMES
Academic clinical research is organised through 2 annual calls for proposals managed by INCa, and funded by Ministry of Health (DGOS).
3.1.1. THE NATIONAL PROGRAMME FOR HOSPITAL CLINICAL CANCER RESEARCH (PHRC-K)PHRC funds research projects with the following objectives: • Evaluation of the safety, tolerance or feasibility of the use of health technologies1 in humans;
• Measurement of the efficacy of health technologies. In this objective, priority for funding will be given to research that, using controlled comparative methods, randomised or not, will contribute to achieving recommendations with a high score.
The call’s areas of PHRC-K 2015 have been drawn up in the context of the recommendations of the 2014-2019 Cancer Control Plan and particularly concern: • Areas pertaining to advanced forms of tumour diseases, geriatric and paediatric oncology;
1 – A health technology is defined as an intervention that may be used to promote health, to prevent, diagnose or treat acute or chronic disease, or for rehabilitation. Health technologies include pharmaceuticals, devices, procedures and organisational systems used in health care.
• INCa’s cancer clinical trials register (RECF): INCa developed RECF freely accessible from its website from 2007 under the 2003-2007 Cancer Control Plan. The subsequent Cancer Control Plans have reinforced RECF. It has provided updated information on cancer clinical trials conducted in France, and allowed comprehensive and targeted searching of clinical trials using a multi-criteria search engine and a geolocation module. Data collection has been performed mainly through collaboration with NCI in 2007-2008, AFSSAPS-ANSM (French Medicine Agency, equivalent to US FDA) since 2009, sponsors and principal investigators, and visits to the clinicaltrials.gov website. The number of clinical trials in RECF has increased from about 100 in 2007 to about 2,000 in 2015. The number of visits to RECF has increased over the years, from 15,000 to 27,000 a month.
4/ MONITORING AND EVALUATION OF INCA’S CLINICAL RESEARCH STRUCTURING ACTIONS
During the past 10 years, INCa has monitored and evaluated its clinical research structuring actions using reports on research projects in dedicated seminars, especially during scientific meetings, analysis and review of activity reports of structures, budget follow-up, and real- time monitoring of funded projects in progress. These activities have been performed in collaboration with funders or co-funders of programmes, e.g. the Ministry of Health for PHRC-K and PRME-K or ARC Foundation, for the CLIP2 programme.
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In 2015, of 186 letters of intent submitted to PHRC-K, 91 proposals were shortlisted for final review in November 2015.
Sixty seven percent of these letters of intent are for projects involving therapeutic studies: • Half (50%) of these therapeutic projects involve systemic treatments;
• Surgery, radiotherapy and combined treatments, including at least either surgery or radiotherapy, account for the remaining (50%) proposals involving therapeutic projects.
Early detection, diagnosis, prognosis and management of patients are the objectives of 33% of letters of intent selected.
For the 2014 PHRC-K call for proposals, for a total of 196 projects submitted, 14 were in the field of paediatrics and 6 have been selected: the aims of these clinical trials are the evaluation of therapeutic efficacy, specially in high risk neuroblastoma, atypical teratoid rhabdoid tumour and rhabdomyosarcoma. Two clinical trials aim at decreasing treatment morbidity and mortality in acute myeloid leukemia, and morbidity of GnRH and alkylating agents in teenagers, respectively. Another clincal trial aims at determining the molecular profile of tumours in order to propose a targeted therapy. In the field of geriatrics, 12 proposals have been submitted and 4 projects selected. Three phase III clinical trials plan to evaluate overal survival, quality of life and the presevation of autonomy: among them, two are therapeutic clinical trials planning to specifically include patients aged 75 years and over, in diffuse large B cell lymphoma and rectal adenocarcinoma, respectively. The third therapeutic clinical trial is a phase I-II (chimioradiotherapy) trial that aims at including oesophagus cancer patients. All of these projects reach some objectives of the 2014-2019 Cancer Plan.
For the 2015 PHRC-K call for proposals, for a total of 186 projects submitted, 12 are in the field of paediatrics and 5 in the field of geriatrics.
Table 14. Main features of the Programme for Hospital Clinical Cancer Research
Objectives
To validate new medical or scientific knowledge in the clinical area. To improve quality of care by evaluating new methods for diagnosis and treatments.
Programming institution INCa/ Ministry of Health (DGOS)
Operating institution INCa
Funding institution Ministry of Health (DGOS)
Year 2014 2015
Funding (in €M) 21.06 21*
Proposals submittedProjects selectedSelection rate
19645
22.9%
186PendingPending
*Provisional
In 2014, of 196 letters of intent submitted to PHRC-K, 45 projects were finally selected for funding in November 2014.
Table 15. Types of projects selected in 2014
Number of projects selected
Drug therapy 19
Management strategy 7
Surgery or other innovative techniques
8
Biotherapy 2
Radiotherapy 2
Imaging (including PET) 3
Biomarkers (diagnosis, prognosis)
2
Nuclear medicine (excluding PET) 2
Total 45
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Fig. 12. Trends in selection and funding for PHRC-K 2007-2014
0
5
10
15
20
25
20142013201220112010200920082007
€M
Funding in €M Nb of projects
Nb
of p
roje
cts
0
10
20
30
40
50
60
70
80
Fig. 13. Distribution of total funding allocated to PHRC-K in 2007-2014: €146 million
67%
1%
22%
10%
Prevention
Early detection, diagnosis, and prognosis
Treatment
Cancer control
Note: The “early detection, diagnosis and prognosis” category includes early phase trials (see the CSO classification in Appendix 3).
2014-2015 Highlights• 50% of the budget devoted to large-scale projects
conducted by cooperative groups.• Research fields for PHRC-K defined according to the
2014-2019 Cancer Control Plan.• PHRC-K results:
– 2014: 45 projects funded for a total of €21.1 million; – 2015: 186 letters of intent submitted, 91 proposals pre-
selected for final review.
3.1.2. THE NATIONAL PROGRAMME FOR MEDICO-ECONOMIC CANCER RESEARCH (PRME-K)The PRME-K comprises two main strands: • “Innovation in Cancer Care” aimed at validating the efficiency of innovative health technologies for cancer care in anticipation of their evaluation by the French National Authority for Health (HAS);
• “Cancer Care Management Pathways” aimed at comparing in real life the efficiency of alternative care strategies involving health technologies in order to optimise cancer care.
Table 16. Main features of the PRME-K programme
Objectives
Enhance efficiency of validation of innovative health technologies through medico-economic studies for evaluation by the Authority for Health (HAS).
Programming institution INCa/ Ministry of Health (DGOS)
Operating institution INCa
Funding institution Ministry of Health (DGOS)
Year 2014 2015
Funding (in €M) 0.976 2*
Proposals submittedProjects selectedSelection rate
184
22.2%
16PendingPending
*Provisional
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The AcSé programme shows the feasibility of a new methodology for an informed access programme in the era of a paradigm shift to molecular markers to guide treatment. It provides equal access across France to molecular testing and targeted therapies outside their approved indication, and generates valuable data within the therapy area.
The AcSé programme is managed by a scientif ic steering committee with 3 main tasks: • To choose the drugs eligible for the programme; • To define the guidelines for the programme; • To communicate with patients and oncologists.
The steering committee is currently considering other clinical trials.
The next AcSé project, which is currently in preparation, should address the specific needs of children and teenagers with a relapsed life-threatening malignancy, and their access to investigational drugs that match the molecular profile of their tumour.
INCa works closely with other member organisations of the AcSé steering committee (e.g. Unicancer, the sponsor of these first protocols conducted under the AcSé programme or the ARC Foundation as a co-funder of the programme).
Moreover, INCa interacts extensively with the French Medicine Agency (ANSM), which is in charge of authorisation and monitoring of clinical trials.
In 2015, of 16 letters of intent submitted to PRME-K, 7 were shortlisted for final review of full proposals in November 2015, with a provisional budget of €2 million.
3.1.3. THE ACSÉ PROGRAMME The ongoing treatment paradigm is that cancer patients with histology expressing certain biomarkers may benefit from targeted therapies. However, biomarkers may be present in malignancies other than that indicated on a drug’s label. Patients with those malignancies have hence no access to potentially effective drugs. To tackle this situation the French National Cancer Institute (INCa) has developed the AcSé Programme in 2013 (Secured Access to innovative therapies) programme as part of the National Cancer Control Plan.
AcSé address the question of safety issues in patients who are administered drugs that are not authorised for their specific condition, and equal access to treatment for those denied such drugs. Besides AcSé organises the collect of data to guide future treatments, and support evidence of drug activity.
The programme started in 2013 and base treatment decisions on relevant biomarkers in non-approved malignancy applications, with different treatment arms bringing together similar organ/histologies of cancer. The programme aims at improving safety and evaluating efficacy for a targeted drug outside its approved indication. This programme provides patients with access to targeted oncology therapies based on molecular testing in the 28 INCa molecular genetic centres. All patients in France with advanced malignancies harbouring the drug biomarker are eligible for inclusion, provided no other active clinical trial in France exists in which they could be included. Trials may also include patients <18 years if safe dosing data are available.
Proof of concept is being demonstrated through crizotinib, which is approved for treatment of ALK positive non-small cell lung cancer. However, ALK, MET and ROS1, the crizotinib targets, are altered in over 20 other malignancies. The Phase II trial began in 2013, and 132 patients have received crizotinib treatment so far. A second trial started in 2014 with vemurafenib, authorised been enrolled so far, with more than10 other malignancies known to present BRAF mutations.
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2014-2015 HighlightsCrizotinib clinical trial, on June 2015 (Starting July 2013):• Molecular genetics screening on almost 5,000 patients;• About 6% of positive screening responses.132 patients
enrolled as of 9 June 2015;• 7 children enrolled;• 22 cohorts created;• 3 cohorts closed: 2 because target number of patients
enrolled (NSCLC ROS1 translocation and NSCLC MET mutation), 1 because no effect (MET amplification in colorectal cancer);
• Initiative for an authorisation based on NSCLC ROS1 translocation by the pharmaceutical company.
Scientific disseminationThis programme was presented at the American Society of Clinical Oncology meetings both in 2014 and 2015, and an article has been submitted for publication in Nature Reviews Clinical Oncology.
3.1.4. PUBLIC-PRIVATE PARTNERSHIPS: 21 INNOVATIVE DRUGS OFFERED FOR EARLY PHASE CLINICAL TRIALSThe previous collaboration set up with NCI CTEP from 2009 (Table 17), and the creation of the early phase clinical trial centres network in 2010 are the two key elements that paved the way for this national initiative.
Table 17. Milestones in the cooperation between US NCI and INCa
2010Signature of an agreement to facilitate access to new drugs for patients in France.INCa is the only European institution involved in the cooperation with NCI for these early-phase academic trials.
CHONDROG AKTIL CABONE AMC-085
2011-2012
February: proof of concept established for the
CHONDROG trial (inhibitor of the hedgehog signalling pathway
tested in advanced stage chondrosarcomas): enrolment
complete (45 patients) and initial results presented at the
ASCO meeting in 2012
November: AKTIL trial (diffuse large B-cell lymphomas) open
for enrolment
2013CHONDROG trial published
in Ann Oncol
AKTIL study: 22 patients enrolled to date
(51 patients planned)
2014Following interim
analysis, enrolment was stopped
A study testing cabozantinib in Ewing sarcomas and relapsed
osteosarcomas is in preparation
2014-2015
Final analysis, publication planned
October
CABONE study: 3 patients enrolled
(90 patients planned)
AMC-085 study, testing brentuximab in in the
treatment of stage III/IV HIV-associated Hodgkin lymphoma
is ready for enrolment
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Under the NCI/CTEP collaboration, public-private partnerships between INCa and pharmaceutical companies allow drugs undergoing development to be supplied to the designated early clinical phase trial centres (CLIP²). Through calls for proposals, the CLIP² submit proposals for academic clinical trials designed to test drugs for indications or pathologies different to those intended in the companies’ development plans. After signing collaboration agreements with different pharmaceutical companies, INCa launched, between 2011 and 2014, 12 calls for proposals regarding 21 innovative drugs. Seventeen studies were selected to be funded in partnership with ARC Foundation (Figure 14).
Fig.14. Annual trend in public private partnerships for innovative drugs
02468
101214161820
20152014201320122011
Nb of projects initiated
2
69
13
17 (expected)
Table 18. Establishment of collaboration between INCa and the pharmaceutical companies
2010 2011-2012 2013 2014 2014-2015
Several meetings organised to discuss a direct collaboration between INCa and the pharmaceutical companies.
Implementation of the process.
June: positive opinion from the Ethics Committee.
November 2011: 1st call for proposals launched by INCa.
End of 2012: 6 calls for proposals launched.
1st trial opened for recruitment: PIK ORL for cancer of the head and neck.
3 new calls for proposals launched.
5 clinical trials due to begin.
6 new drugs were proposed for calls for proposals.
5 clinical trials are ongoing.
4 clinical trials are due to begin.
6 new drugs were proposed for calls for proposals.
10 clinical trials are ongoing or ready for enrolment.
7 clinical trials are due to begin.
To launch these calls for proposals for early phase clinical trials, 5 steps are necessary from the identification of the drug to the beginning of the trial.
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Fig. 15. Scheme for organisation of public-private partnerships
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Table 19 shows the different collaborations established to date.Table 19. Drugs offered to the early phase clinical trials programme
Date of launch of CFP Innovative drugsProposals presented
Projects selected
November 2011PI3K/mTor inhibitor 18 1 (Kaposi’s sarcoma)
PI3K inhibitor 4 1 (Cancer of the head and neck)
April 2012PI3K/mTor inhibitor 13 1 (Myeloid leukaemia and myelodysplasia)
Anti CDK 4/6 7 2 (GIST/metastatic melanoma)
July 2012 p70/AKT inhibitor 20 2 (Solid tumours/breast cancer)
August 2012 Anti-EGFR monoclonal antibody 14 Suspended
April 2013 Oncolytic virus 7 1 (Breast and soft tissue sarcomas)
May 2013 p38 MAPK inhibitor 8 2 (Breast/glioblastoma)
July 2013 Anti HER3 8 Suspended
December 2013 Antineoplastic 12 1 (Endometrial adenocarcinoma)
May 2014
HSP90 inhibitor
20 Pending
New ALK inhibitor
Smo antagonist
MEK inhibitor
New B-RAF inhibitor
September 2014
Anti-PD-L1
50
5 (metastatic renal cell carcinoma, advanced pancreatic and colorectal cancer, locally advanced head and neck squamous cell carcinoma, metastatic hormone receptor-positive endometrial adenocarcinoma, in locally advanced/unresectable soft tissue sarcoma, recurrent advanced/metastatic endometrial cancer patients)
Dual mTORC1 and mTORC2 inhibitor
PARP inhibitor
MEK ½ inhibitor
EGFR inhibitor
2014-2015 Several contacts in progress with other companies
2014-2015 Highlights• One study (CABONE) in Ewing sarcomas and
osteosarcomas is open to enrolment of children aged 12 years and over;
• 17 studies have been selected since the start of the public-private partnerships, including 6 studies recently;
• An increasing number of drugs are being offered by pharmaceutical companies, which reflects the attractiveness of the programme.
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Focus on next generation clinical trials
MULTISARC AND ACOMPLI
The development of new technologies for next generation sequencing, analysis and data storage, as well as continuously falling costs, allow to consider sequencing tumour genomes in clinical practice, and more particularly sequencing the exome and transcriptome (RNASeq).
While these technologies are now mature as research tools, clinical use of exome sequencing and RNASeq of tumours for all patients requires establishing the following conditions:
• setting up organisations, in appropriate numbers, to carry out exome sequencing and RNASeq for clinical cases, and able to adapt rapidly to technological developments;
• setting up structures to store the large volumes of data generated;
• acquiring tools and human resources needed to analyse the sequencing results;
• implementing conditions that will enable clinicians to make the best possible use of the NGS results to benefit patients, particularly by developing tools as decision- making aids and setting up a specific organisation;
• allowing the integration of clinical data (diagnosis, epidemiology, therapeutic response) with the molecular biology data and sharing the data in order to contribute to improve knowledge and developing tools as decision-making aids.
To respond to these major issues, action 6.3 of the 2014-2019 Cancer Control Plan recommends implementing, from 2014, clinical trials that include tumour exome analysis for 3,000 patients with breast cancers, colon cancers, lung cancers and sarcomas, in order to demonstrate the large-scale feasibility of these approaches and their utility in patient care. It is in this context that INCa and Inserm for ITMO
Cancer - Aviesan have decided to implement exome and transcriptome sequencing in the framework of two clinical trials guided by genomics, MULTISARC in soft-tissue sarcomas, and ACOMPLI in advanced colon carcinomas that will compare biology-driven therapies to standard treatments. Three pharmaceutical companies agreed to provide drugs which will allow to target a maximum number of molecular anomalies. These trials should start early 2016 and screen around a total of 1,500 patients.
The aim of these Programmes is to assess the benefit of this approach for the decision relating to treatment and to assess if treatments guided by biology improve patient survival.
PAOLA1
Olaparib, a PARP inhibitor of AstraZeneca, has obtained its European market approval late 2014 for maintenance treatment of high grade ovarian cancer patients, fallopian tube and primitive peritoneal cancer patients, having a BRCA mutation (germline and/or somatic). In this context, the patient’s BRCA, both somatic and germline genetic status, will have to be acquired, within time lines consistent with the patient therapeutic management. The entry of a somatic component will require the development of NGS on tumour sample.
Considering these constraints, setting up a pilot phase is essential, building on the oncogenetic laboratories (germline genetics) and the platforms of molecular cancer genetics (somatic genetics). Hence, all patients enrolled in the PAOLA1 clinical trial will be tested for their BRCA status. PAOLA1 is a comparative clinical trial of olaparib-bevacizumab vs bevacizumab (Roche) in maintenance treatment (following a first line chemotherapy) including 612 European patients having a BRCA mutation or not. Five centres have been selected for BRCA testing and the analysis have started in May 2015. This program also shows the importance of closely involving the activity of molecular genetics platforms and cancer genetics laboratories.
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3.2. ORGANISATION OF CLINICAL RESEARCH, AND STRENGTHENING OF STRUCTURES AND INFRASTRUCTURES
The main objectives are: • To provide support for the development of early phase clinical
research projects through measures that facilitate coordination and organisation, one such measure being the designation of the CLIP2 clinical trial centres;
• To increase cooperation between the cooperative groups; • To increase research capacity by coordinating clinical research staff and providing support to the data processing centres;
• To publicise ongoing clinical research projects, and increase enrolment in trials.
3.2.1. NEW DESIGNATION OF EARLY PHASE CLINICAL TRIAL CENTRES – CLIP² Extending efforts to structure clinical and translational research implemented during the 2009-2013 Cancer Control Plan is part of Objective 5 of the current Cancer Control Plan.In October 2014, the designation and funding of the CLIP² planned for a 4-year period was over.Following a new phase of designation, 16 early phase clinical trial centres (CLIP²) in cancer were selected, for a term of four years. Six of these centres have also been designated for paediatric activity, to strengthen early phase clinical research in children. The 16 CLIP² receive funding for their operation from INCa in partnership with the French National Cancer League for the paediatric component (Figure 16).
Fig. 16. The 16 early phase clinical trials centres (CLIP²)
Adults + Paediatrics
Adults
GCS C2RC LilleCHU Lille/ Centre Oscar Lambret
GCS IRCNACHU Nantes / Institut de Cancérologie de l’Ouest
Institut Bergonié
Centre Eugène Marquis
Centre Georges-François Leclerc
Centre François Baclesse
Hôpital Saint-Louis
Hôpital Pitié-Salpétrière / Hôpital Henri MondorGustave Roussy
Institut Curie
Centre Léon Bérard
Hospices Civils de Lyon
Institut Paoli-Calmettes
Assistance Publique des Hôpitaux de Marseille
Institut Régional du Cancer Montpellier — Val d’Aurelle
Institut Universitaire du Cancer de Toulouse — Oncopôle / Institut Claudius Regaud
Source: INCa, 2015Drafted by INCa’s Research Division, 2015
Paris
Guadeloupe Guyane
Martinique
La Réunion Mayotte
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This new designation is to renew and strengthen the national network of expert centres for early phase clinical trials for adult and paediatric cancers, continuing the actions undertaken in 2010, when the early phase clinical trial centres were first designated. This structure aims at: • facilitating the availability of new drugs for patients, based on an organised network that can offer all patients in France access to early phase clinical trials;
• enhancing the visibility and attractiveness of French clinical research to industry in France and abroad;
• improving the quality of early phase trials in France and increase their number;
• developing academic clinical research for evaluating the drugs in indications not covered by the development plans of pharmaceutical companies;
• Increasing the visibility of paediatric sites for a broader access to innovative clinical trials.
Initial impacts • INCa is increasingly recognised as a pioneering institution in Europe, capable to setting up a coordinated programme for early clinical trials linked with molecular genetics platforms.
• An increase in the number of patients enrolled in early phase clinical trials.
• Leadership among clinical research investigators: increasing numbers of proposals for industry-sponsored phase I trials in the CLIP2 centres.
The designation of the 16 CLIP² and allocated funding should allow sites to recruit dedicated staff and optimise their operational structures. In addition, this designation has increased the visibility of the CLIP² and generated growing interest among the pharmaceutical companies.
These initiatives have contributed to increase the number of early phase clinical trials, particularly in phase I study (the most innovative) and the number of patients enrolled in these trials since 2010. These initiatives have also facilitated the access to innovative drugs for patients in France. Both the agreement between the US NCI and INCa, and the subsequent process implemented independently between INCa and pharmaceutical companies are unique in Europe. This type of public-private
partnership offers a model for coordination between European countries. Extending this model at European level has the potential to accelerate enrolment in these trials and improve their feasibility, particularly in rare and paediatric cancers.
3.2.2. DESIGNATION OF NEW COOPERATIVE INTERGROUPSSince 2012, INCa has conducted a competitive evaluation aimed at designating French Cancer Cooperative Intergroups with an international dimension. The goals of this action are described below.
Table 20. Objectives of the designation of French Cancer Cooperative Intergroups
Objectives
To promote the grouping and improve collaboration between cooperative groups at national level and to cover the different cancer pathologies.
To promote interaction between INCa and the cooperative groups for carrying out clinical trials and translational research, and contribute to enhancing the measures for invigoration of clinical research of the Cancer Control Plans.
To improve the international visibility and attractiveness of clinical research in France and to develop European and international cooperation in clinical and translational research in France.
Programming institution INCa
Operating institution INCa
Funding institution INCa
Funding (in €M) 1.3
Between 2012 and 2015, 13 cooperative intergroups were designated for 2 years after competitive evaluation via annual calls for applications. The applications were assessed by an international independent review committee.
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The missions of these intergroups are scientific, including carrying out large-scale projects and providing expert advice to INCa as well as contributing to research structuring, and related to organisation and governance challenges.
Six cooperative intergroups were designated in 2012: • the French Intergroup for Thoracic Oncology (IFCT); • the LYSA-LYSARC Lymphoma Research Intergroup; • the French Myeloma Intergroup (IFM); • the Head and Neck Intergroup (GORTEC-GETTEC-GERCOR); • the Digestive Tumours Intergroup (FFCD-GERCOR); • the ARCAGY-GINECO Intergroup for Gynaecological Tumours.
Two other cooperative intergroups were designated in 2013: • the INTERSARC Soft tissue Sarcoma Cooperative Intergroup; • the French Breast Cancer Intergroup (FBC).
In 2014, five cooperative intergroups were designated: • the Collaborative Intergroup for Acute Leukaemia (CIGAL); • the Society of Paediatric Oncology (SFCE); • the GERICO-UCOG Intergroup for Geriatric Oncology; • the French Urological Oncology Intergroup (ICFuro) for Non-Gynaecological Genitourinary Cancer;
• the Cooperative Intergroup for Neurological Oncology (IGCNO).
Their strong involvement in Action 5.2 of the 2014-2019 Cancer Control Plan is anticipated, particularly in clinical trials aimed at major therapeutic challenges, i.e. about increasing survival and reducing treatment side-effects and delayed effects, which target the enrolment of 50,000 patients per year in 2019.
3.2.3. CREATION OF A NETWORK OF CLINICAL RESEARCH TEAMS TO CONTRIBUTE TO RECRUITMENT OF CANCER PATIENTS FOR CLINICAL TRIALSSince 2006, INCa and the French Ministry of Health have established 26 Mobile Clinical Research Teams (French acronym EMRC). The objective is to create conditions that encourage researchers in community hospitals (public and private) to participate in clinical trials. Approximately 70 FTEs (Clinical research associate) have been recruited, based in over 160 different hospitals throughout France.
Table 21. Network of clinical teams designed to foster enrolment of patients in clinical trials
Objectives
To promote participation in clinical trials by hospital researchers.To ensure equal access to clinical trials for patients in all types of hospitals in France.To ensure the good quality of data collected during clinical trials.
Funding institution Ministry of Health (DGOS)
Funding (in €M) 3 / year
Results
Reliable quantitative indicators: number of patients enrolled in clinical trials by FTE. Qualitative assessment, performed by an ad hoc committee, based on comprehensive reports on the organisation and management of teams.
Initial impactsNumber of patients enrolled has continuously increased in community hospitals (non-university hospitals and non-cancer care centres) between 2008 and 2014, from 2,300 to 6,216 patients.
• 190 hospitals reported enrolment of patients through the network of clinical teams in 2014;
• Over 220 hospitals declared their interest in receiving assistance from one of these teams.
3.2.4. ENROLMENT OF PATIENTS IN CLINICAL TRIALS: A 97% INCREASE FROM 2008 TO 2014
INCa has conducted annual survey with healthcare organisations funded under the Cancer Control Plans, to evaluate clinical cancer research activities carried out in 2014. All of the organisations took part in the survey. The number of patients enrolled in clinical trials increased by 97% from 2008 (base year) to 2014, +122% for patients participating in academic trials and +22% for patients participating in industrial trials during the same period.
Figure 17 describes the progression of patient enrolment recorded in INCa’s annual survey, and Figure 18 shows the distribution of this enrolment among the different types of care facilities.
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Fig. 17. Enrolment of patients in cancer clinical trials in France in 2014 (INCa survey)
0
10,000
20,000
30,000
40,000
50,000
201420132012201120102009200820072006200520042003
Nb of patients enrolled - academic trialsNb of patients enrolled - industry-sponsored trialsAll
24,04326,003
28,167
37,492
42,803
Fig. 18. Enrolment of patients in cancer clinical trials in 2014, by type of care provider (INCa survey)
0%
10%
20%
30%
40%
50%
60%
2014201320122011201020092008
University HospitalsCancer Care CentresCommunity Centres (public)Community Centres (private)
In 2014, a slight decrease (2.3%) in enrolment rate was observed; this decrease was mainly observed in Paris university hospitals and community centres. The ratio of enrolment in academic vs. industrial trials remained stable over the years (83/17), but the number of patients enrolled in this type of trial decreased significantly (5.5%, from -1% for Cancer Care Centres to -10% for university hospitals).
3.2.5. INCA’S CANCER RESEARCH CLINICAL TRIALS REGISTER
Since 2007, INCa’s clinical trials cancer register has eased access to cancer clinical trials conducted in France. It is freely accessible on INCa’s website, and enables provision of quality and up-to-date information to patients, health professionals and the general public.
Table 22. The cancer clinical trials register
ObjectivesTo provide information on cancer clinical trials conducted in France.
Results
1,923 clinical trials advertised on INCa’s website in May 2015:602 ongoing recruiting trials, sponsored by more than 243 industrial and academic bodies.60% of trials registered are sponsored by academic bodies.
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Fig. 19. Number of clinical trials advertised on 15 May 2015
0
200
400
600
800
1,000
1,200
mai-15
déc-1
4
oct-1
4
mai-14
déc-1
3
juin-
13
déc-1
2
juin-
12
déc-1
1
juin-
11
déc-1
0
juil-1
0
déc-0
9
juil-0
9
déc-0
8
juil-0
8
déc-0
7
juil-0
7
avr-0
7
Academic trialsIndustrial trialsOpen Trials
The INCa cancer clinical trials register provides information accessible to the general public, and facilitates the search of clinical trials. Visitors to the clinical trials register can, with the help of a multi-criteria search engine, accurately target their search using selection criteria, as the sponsor or target organ, and can also apply the geographic criterion using the geolocation module included in the register.
In 2014, in line with the objectives of Actions 5.4 and 7.16 of the 2014-2019 Cancer Control Plan, INCa initiated a process for collecting the results of terminated clinical trials, in order to publish information in the register. Since the new Web portal was launched in 2012, including a new system for counting visits, between 20,000 and 30,000 visits/month have been recorded.
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4 RESEARCH IN HUMAN AND SOCIAL SCIENCES, EPIDEMIOLOGY AND PUBLIC HEALTH
10 years of structuring actions by INCa in human and social sciences, epidemiology and public healthThe year 2015 marks the 10th anniversary of the French National Cancer Institute (INCa). It is also an opportunity to take stock of 10 years of action to support the development of Human and social sciences, epidemiology and public health research in cancer in France. One of the INCa’s goals at its creation was to bring social sciences and public health research applied to oncology in France up to the best international standards. It was acknowledged at that time that social sciences have the potential to provide meaningful insights and tools that are relevant across the continuum of cancer control: prevention, early detection, diagnosis, treatment and supportive care. However, the contribution of social sciences to cancer research was relatively low in France, particularly when compared to English-speaking countries. And very few social science research teams were working on cancer-related issues, or had limited interactions with biomedical research. In order to achieve this goal, social sciences and public health research have been directly associated with the initiatives of the 2003-2007, 2009-2013 and 2014-2019 Cancer Control Plans, based on multiple levers: the launch of calls for proposals, the organisation of scientific events (workshops and seminars) and the support of research infrastructures.
NUMEROUS THEMATIC AND INVESTIGATOR-DRIVER CALLS FOR PROPOSALS TO INCREASE THE NUMBER OF SOCIAL SCIENCES, EPIDEMIOLOGY AND PUBLIC HEALTH RESEARCH PROJECTS FUNDED.
Since 2005, INCa has launched over 25 calls for proposals for research in the fields of social sciences, epidemiology and public health; some of them jointly with other official organisations. The objectives of these calls were to encourage researchers in these disciplines to focus on cancer-related issues in the longer term. In 2010, a new call for proposals in Population Health Intervention Research (PHIR) was introduced, primarily to reduce health inequalities in cancer. The same year, INCa also cooperated with other public funding bodies to increase research into pollutants and environmental and occupational determinants of cancer. During this decade, more than 350 research projects, covering all relevant disciplines, were funded for a total amount of €55 million. Numerous research topics were supported and included: Cancer patient mood – Burnout in cancer caregivers – Sexual life and cancer – Quality of life in cancer patients – Economic analysis of cancer drugs – Non-conventional medical care and alternative medicine in cancer patients – Patient autonomy and relationship with the health care system – Working trajectories of cancer patients – Social, territorial and cultural inequalities in cancer – Prospects in the development of clinical research – Behavioural, occupational and environmental risk factors for cancers – Risk and risk factor perceptions and interventions in prevention strategies.
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Alongside the funding provided following calls for proposals, INCa is also committed to supporting the next generation of researchers from these disciplines interested in cancer- related issues, and 59 doctoral students and post-doctoral researchers have been funded so far.
REGULAR SCIENTIFIC EVENTS OPEN TO THE SCIENTIFIC COMMUNITY AND THE PUBLIC
To strengthen the visibility of social sciences, epidemiology and public health research, but also to create a meeting ground for social sciences researchers, INCa has regularly organised national and international conferences and seminars. In total, more than 12 scientific events were organised over the period 2005-2015. For example, the “Cancer and Work” conference was an opportunity to present and promote the results of projects funded under the calls for proposals launched jointly by INCa and ARC Foundation in 2006 and 2007. The international symposium organised in 2010 on “Inequalities in cancer: search and intervene. Methodological and organisational issues of public health intervention research” was the first initiative on this topic in France. It allowed participants to review the typology of interventions for reducing health inequalities in cancer, methodological issues and opportunities, and barriers for the implementation of public health intervention research in France. The international conference organised in 2013 “Nutrition and Cancer: hot topics from biology to public health issues” helped to identify gaps in knowledge on the nutrition and cancer link. In 2014, INCa organised its first international scientific conference dedicated to population health intervention research, “Intervention research against cancer: bringing together researchers, policy-makers and practitioners,” in partnership with several French and foreign organisations. This conference, which brought together over 200 researchers, policy-makers and practitioners, was an opportunity to present and discuss achievements, challenges and opportunities of this type of research for the continuum of cancer control.
SUPPORT FOR RESEARCH INFRASTRUCTURES IN EPIDEMIOLOGY AND PUBLIC HEALTH: INVESTING FOR THE FUTURE
Recognising their importance in epidemiology and public health research in cancer and as a specific action of Measure 3.5 of the 2009-2013 Cancer Control Plan, regarding environmental and health-related behaviours, INCa decided to support large research cohorts. A partnership with the French Public Health Research Institute (IReSP) and the Public Health Institute (ITMO Public Health-Aviesan) of Aviesan was concluded. Both institutes are designated by the Ministry of Scientific Research to manage all cohorts supported under the call for “Investments for the Future” organised by the French government to stimulate research. Sixteen cohorts were supported for a total of €5 million (excluding investment from the Ministry of Scientific Research). In 2014, the decision to fund new cohorts (totally new or ancillary to the existing ones) was approved. The aim of this call was to promote the development of multidisciplinary approach through the integration of biological, clinical, environmental, behavioural and socioeconomic data, as well as other relevant characteristics of the participants of these cohorts. Four cohorts were funded for a total of €1.1 million.
PERSPECTIVES: STRENGTHENING AND SUSTAINING THE SUPPORT
A huge investment in social sciences, epidemiology, and public health research in cancer has been made over the past decade in France, with a strong increase in the number of projects over time. The fight against cancer poses new medical, scientific, ethical/legal and economic challenges. Research in social sciences, epidemiology and public health has an important role to play, and its role in cancer research has been confirmed and reinforced by the 2014-2019 Cancer Control Plan.
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based on letters of intent (December 2014-January 2015) and a final selection phase requiring full proposals (March-June 2015). Only coordinators of proposals shortlisted at the 1st stage were invited to submit full proposals.
4.1.3. RESULTSSixty-six letters of intent were received in early December 2014, broken down as follows by major discipline group.
Table 23. Distribution of the projects submitted and selected between HSS-PH and Epidemiology
Proposals submitted
Projects selected
Epidemiology / Biostatistics 27 10
Human and Social Sciences / Public Health 39 7
Thirty letters of intent were shortlisted in late January 2015 by the Committee. Coordinators involved were then invited to submit a full proposal, which was evaluated from March to June 2015 (2 external experts per project). The total amount requested for the 30 shortlisted projects was €7.7 million (average: €255,000).Seventeen projects were finally selected in June 2015, for a total budget of €4.27 million (average: €251,000).
Projects selected in epidemiology and biostatistics respectively aim at studying the risk factors (environmental and genetic) for cancer and statistical methods for early clinical trials, and their design will evolve because of current diagnostic and therapeutic innovations. The selected research projects in the human and social sciences and public health priority focus on the emotional and cognitive effects of cancer, and side-effects of treatments in cancer patients (elderly patients, young women, conjugal partners), as well as on the social and economic disparities affecting all aspects of management. Clinical and translational research is also the subject of studies in these disciplines (patient participation in clinical trials comparing innovation trajectories, industrial models dealing with rare cancers). Breast cancer is the most common cancer location concerned in all HSS-EPH projects.The following table and figure provide perspective on the current consecutive year, the process of submission and state of HSS-EPH research supported by INCa over ten years.
4.1. THE RECURRENT PROGRAMME FOR HUMAN AND SOCIAL SCIENCES (HSS), EPIDEMIOLOGY AND PUBLIC HEALTH (EPH) RESEARCH
4.1.1. CONTEXT AND SCOPE OF THE 2015 INVESTIGATOR-DRIVEN CALL FOR PROPOSALS IN HUMAN AND SOCIAL SCIENCES (HSS), EPIDEMIOLOGY AND PUBLIC HEALTH (EPH)The French National Cancer Institute continues to support research on HSS-EPH through the annual investigator-driven call for proposals. The 2015 CFP had the following general objectives: • Promote the emergence of original research and scientific
excellence in the various disciplines of HSS-EPH applied to cancers; • Increase and enhance multidisciplinary scientific research associating teams, disciplines and technological means to respond effectively to an issue or a precisely defined objective.
This call for proposals is open to all disciplines of social sciences, epidemiology and public health, and beyond, in cancer, and is particularly intended to encourage interaction between disciplines. Originality in the questions raised in these disciplines is a recommendation of the evaluation committee.
Beyond the choice of the investigators themselves, some aspects related to public health objectives were considered: • The determinants of inequalities in cancer and ways to reduce inequality;
• Changes in health behaviours and their individual and collective determinants;
• Human papillomavirus vaccine (HPV) coverage; • Biomedical innovations and the transformations they effect in cancer care pathways;
• Economy and cancer; • Questions of biostatistics and methodology in conducting projects.
4.1.2. SELECTION PROCEDUREEvaluation of research proposals by INCa is based on an international scientific evaluation committee whose members, recognised for their scientific and medical expertise in the field of research, review letters of intent and full proposals. The Evaluation Committee assesses the scientific quality of the projects, the synergy of the partnership between teams, technical and financial feasibility, and potential impact of the results. For the second selection of proposals included two phases: a preselection phase
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Table 24. Features of the investigator-driven call HSS-EPS since 2005
Objectives
Promote the emergence of original research and scientific excellence in the various disciplines of HSS-EPH applied to cancer.Increase and strengthen the focus of multidisciplinary scientific research around an issue or a clearly defined goal, enlisting teams, disciplines and technological means to effectively respond to it.
Programming institution INCa
Operating institution INCa
Funding institution INCa
Year 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Funding (in €M) 0.55 1.99 2.28 2.81 2.42 5.15 4.79 4.36 4.81 4.1 4.27
Proposals submittedProjects selectedSelection rate
169
56.6%
5922
37.3%
7924
30.4%
6413
20.3%
4416
36.4%
8427
32.1%
7222
30.6%
5019
38%
5420
37%
102 22
21.6%
6617
26%
Fig. 20. Trends in the number of proposals submitted and funded since 2006
2015201420132012201120102009200820072006
Proposals (LOI) submittedProjects selected
22 2413 16
59
7964
4427 22 19 20
84
22 17
102
6672
50 54
4.2. POPULATION HEALTH INTERVENTION RESEARCH
INCa has, since its creation, strongly supported human and social sciences research, extended in 2009 to epidemiology and public health. Since 2010, this trend has been completed by a dedicated call for proposals in population health intervention research. Fifteen projects have been funded since 2010, for a total of €7 million. The projects funded in 2014 and 2015 are presented in Table 25.
In 2014, the call for proposals in “primary prevention” was launched in the context of a partnership with the Institute of Research in Public Health (IReSP), and other partners. The aim of this call for proposals was to support the emergence of research projects on social determinants of health, and on changes in individual and collective health-related behaviours. In 2014, INCa, together with other French and international organisations, also organised an international conference dedicated to intervention research: Recherche interventionnelle contre le cancer: réunir chercheurs, décideurs et acteurs de terrain (Intervention research on cancer, bringing together researchers, decision makers, and practitioners decision- and policy-makers, community representatives and in organisations (200 participants), to demonstrate and discuss intervention research can enhance the evidence base for cancer control decisions and interventions.
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Conference material is available at: http://www.e-cancer.fr/Professionnels-de-la-recherche/Colloques-et-symposiums/RISP-2014 and at http://fr.slideshare.net/Institut_national_du_cancer/presentations. The speakers presented projects stemming from France, Europe and the North America.
In 2015, INCa has programmed the new edition of the call for proposals in intervention research, with three main modifications. First, the scope of the call has been extended, and now includes all dimensions of cancer control: ranging from primary prevention to secondary prevention, tertiary prevention, healthcare organisation, and survivorship and rehabilitation issues. Second, this call also encourages research in methodological issues. Third, two types of proposals are expected: full research proposals
(advanced research protocols, with a strong methodological approach and successful partnerships, to be funded for 24 to 48 months), and emerging research projects (to encourage the development of intervention research on a topic relevant to the 2014-2019 Cancer Control Plan, to be funded for 12 months for a maximum of €30,000). The goal is to allow young researchers or those interested in intervention research to develop and pilot an intervention designed to be submitted to the next edition of the call for proposals as a full research project. Finally, the administrative guidelines strongly recommend the establishment of partnerships between researchers and stakeholders. The scientific committee for the selection of the project will meet in October 2015.
Table 25. Features of intervention research programme in 2014 and 2015
Objectives Focus on primary prevention to support the emergence of research projects on social determinants of health, and on changes in individual and collective health-related behaviours.
To support full research projects (advanced research protocols, with strong methodology.
To support emerging research projects (for young researchers or those interested in intervention research to develop and pilot an intervention designed to be submitted to the next edition of the call for proposals as a full research project).
Programming institution INCa – IreSP INCa
Operating institution INCa INCa
Funding institution INCa, IReSP, and other partners INCa
Year 2014 2015
Proposals submitted Projects selected Selection rate
5819 (4 cancer)
33%
PendingPendingPending
Cancer intervention research projects selected and funded by INCa and ARC Foundation (in €M)
Financial incentive for smoking cessation in pregnancy. A randomised,
multi-centre study.
0.4
PendingEvaluating efficacy of a smoking cessation intervention incorporating a “social
support” component in a population of vocational trainees.
0.4
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2014-2015 HighlightsKey issues of the international conference (November 2014):• Perimeter of the intervention research in behaviour,
and in social and territorial determinants of health;• Methodological issues in intervention research;• Knowledge transfer and decision making; • Support for intervention research in the context
of developing countries.
4.3. INITIATIVES DEVELOPED TO SUPPORT RESEARCH ON ENVIRONMENTAL RISKS
4.3.1. SUPPORT FOR RESEARCH ON ENVIRONMENTAL RISK FACTORSSince 2012, a dedicated call has been launched by ITMO Cancer - Aviesan to strengthen support for research in the area of environmental risk factors: 104 proposals have been submitted and a total amount of €8.4 million allocated to 30 projects over a four-year period. The majority of the projects (50%) address aspects related to the development of models for analysing the effects of the environment or the study of interactions and transmission of toxic effects (mutational and epigenetic alterations). They also address important public health and social issues as well as major gaps in environmental epidemiology of cancer. They potentially open new scientific and technical perspectives in the field, and may have potential applications for policy-makers, such as generating new standards in environmental toxicology. They combine epidemiology, molecular biology/genomics, and bioinformatics methods, and use concentrations of contaminants that are typically encountered in real life, corresponding to people’s actual exposure.
Table 26. Effects of exposure to environmental risk factors for cancer 2012-2015
ObjectivesTo improve the knowledge of delayed effects of exposure of individuals to risk factors associated with the environment, in terms of analysing the risks of cancer occurrence and progression.
Programming institution ITMO Cancer- Aviesan
Operating institution Inserm
Funding institution Inserm for ITMO Cancer - Aviesan
Year 2012 2013 2014 2015
Funding (in €M) 2.4 2.8 3.2 3.4
Proposals submittedProjects selectedSelection rate
239
39%
227
32%
247
29.1%
327
21%
In 2015, 32 projects have been submitted. Ten of them were resubmissions of previous years. Seven projects of a major interest
to the scientific community have been selected. They include studies on mechanisms of cancer progression and aetiology after
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exposure to viral infection (HPV co-infections: mathematical modelling and newly generated epidemiologic data; HCV: role of viral infection and mutational fingerprint in the mechanisms of hepatocellular carcinoma) or to different health hazards such as pesticides (human cellular aging and carcinogenesis for mesenchymal derived tumours such as osteosarcoma), chemical pollutants (the relationships between environmental exposures in utero and disease outcome during pregnancy, methylome profile at birth, identification of new replication stress-induced factors as novel biomarkers for the early stages of transformation by carcinogens), dioxins (block lung tumour cell proliferation and induce tumour cell death via specific kinase modulators) or plastic additives (evaluation of risks in female reproductive tissues, specifically mammary gland tumour promotion).
4.3.2. INITIATIVE DEVELOPED IN COLLABORATION WITH THE FRENCH NATIONAL AGENCY FOR FOOD, ENVIRONMENTAL AND OCCUPATIONAL HEALTH AND SAFETY (ANSES) TO SUPPORT RESEARCH ON ENVIRONMENTAL RISKS In the 2013 call for proposals for the National Research Programme in Employment-Health- Environment launched by the French National Agency for Food, Environmental and Occupational Health and Safety (Anses), a 2-fold increase in the number of proposals submitted in the area of assessment and analysis of environmental risks for cancer has been observed, while in 2014 and 2015 this figure was similar with those of 2011 and 2012.
Table 27. Main characteristics of the Research Programme in Employment-Health-Environment in the field of cancer
ObjectivesTo evaluate and analyse environmental risks for human health in the general population or at work. From emerging risks to known risks, which can generate complex scientific polemics, and for which a single approach can include concepts, methods and tools from different disciplines.
Programming institution Anses
Operating institution Anses
Funding institution Inserm for ITMO Cancer – Aviesan
Year 2011 2012 2013 2014 2015
Funding (in €M) 1.26 1.2 0.85 0.89 0.79
Proposals submittedProjects selectedSelection rate
319
29%
207
35%
446
13%
295
14%
255
20%
A total of 32 cancer-related projects from this call were supported by the Cancer Control Plan in 2011-2015. Other remaining cancer-related projects were supported by the Ministry of Labour and ADEME (French Environment and Energy Management Agency).
Projects funded by Inserm for ITMO Cancer - Aviesan include 4 studies of environmental risk factors related to the development of childhood cancers. They address the role of UV exposure in the occurrence of malignant haemopathies, the role of in utero and postnatal pesticide exposure on the occurrence of acute childhood leukaemia, and the risk of predisposition to
some childhood cancers following exposure of older fathers to xenobiotics, through the transmission of an “environmental epigenetic fingerprint”.
The majority of the other studies included the impact of multiple occupational and environmental exposures to pollutants (known or suspected to be carcinogens), and the identification of exposure-related biomarkers, relationship between risk factors and genetic predispositions, and the genotoxic and carcinogenic properties of several PAH, alone and in a mixture, for primary human lymphocytes.
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In addition, 3 projects included a link with social sciences, and study 1) The development of tools to monitor the health of populations living near an industrial waste, 2) A socioeconomic evaluation of health damage related to chemicals, 3) The impact of previous exposure to one or more known occupational (asbestos, PAHs, silica, diesel) or environmental (radon, air pollution) lung carcinogens on the perception of the disease and quality of life in lung cancer patients.
2014-2015 HighlightsLAUNCH OF A NEW UNIVERSITY CHAIR IN CANCER RESEARCH PREVENTIONThe report on the strategy for cancer prevention research based on health-related behaviours changes, presented to the SAB in October 2012, stressed the need to develop basic and applied research in this field. The experts had proposed several initiatives (17) to implement this strategy. One of them was the creation of cancer research chairs.To meet this recommendation, INCa, in partnership with IReSP and EHESP (French School of Public Health), is to create a new University chair dedicated to cancer research prevention.This chair will focus on population health intervention research and transferability. This research (both methodological and interventional) is a priority worldwide, but it is non- existent in France. The chair holder will have to develop an academic degree for students, researchers, stakeholders and decision-makers.The budget for this chair is €0.18 million (€0.15 million from INCa), and will allow the chair holder to build a research team. The chair holder was selected by an international committee and will hold that position for the next three years, with the possibility of renewal after a mid-term evaluation. A scientific committee will help the funders to validate scientific guidelines. The chair will be established at EHESP before the end of the year.
4.4. PHD PROGRAMME IN HSS-EPH 2015 IN COLLABORATION WITH ACADEMIC PARTNERS
Following the call for applications launched in March 2015, 29 applications for a doctoral scholarship in the disciplines of HSS, epidemiology and public health were submitted early May (12 in epidemiology and 17 in HSS).
The multidisciplinary evaluation committee, composed of nine experts, preselected 14 candidates, who were then interviewed by the same committee in late June 2015.Six thesis projects have ultimately been funded for three years: three in epidemiology/biostatistics (on environmental, occupational, behavioural and genetic risk factors, and on the evaluation of treatments directed at genetic abnormalities), one project in psycho-oncology (on determinants of participation in immunochemical colorectal cancer screening), one sociology project (on reporting and recognition systems for occupational cancers), and one project in information and communication sciences (on reception of cancer screening campaigns by disadvantaged groups).
The results of the 2015 session bring to 17 the number of doctoral students funded since 2011 through this programme, in partnership with the School of Advanced Studies in the Social Sciences (EHESS) first, and then with the School of Public Health (EHESP).
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5.1. A NEW DESIGNATION FOR THE 2015-2017 PERIOD
In 2014, INCa launched a call for applications to renew the designation of the Canceropoles, based on: • seven common missions set for all the Canceropoles; • one specific mission related to the regional or interregional environment. This allows adaptation of the Canceropoles to the local political and strategic priorities, given their positioning as regional representatives of those involved in cancer research actors (Table 28).
Table 28. Common missions of the 7 Canceropoles
Mission 1To federate scientists of different disciplines under scientific leadership
Mission 2To promote detection and increase the visibility of innovative projects
Mission 3To participate in the development of clinical trials with regional/interregional partners
Mission 4To support research teams in the development of their projects
Mission 5To increase the detection of innovation and subsequent technology transfer
Mission 6To encourage the emergence of new technologies
Mission 7To allow the implementation of new structuring actions at regional and interregional levels
The creation of the Canceropoles was one of the organisational measures undertaken under the 2003-2007 Cancer Control Plan, and represented a major action for strengthening the national research dynamic, mobilising stakeholders at regional and interregional level. After 11 years, the Canceropoles have acquired a geographical and institutional base for oncology research support which is recognised by local stakeholders (government, industries, etc.). They have been able to establish close relationships with political and economic stakeholders in their region, for whom they facilitate the link between regional and national policies.In 2011, after assessment by the French Evaluation Agency for Research and Higher Education (AERES), INCa granted designation to the 7 Canceropoles for a 3-year period. While extending the dynamic initiated under the previous Plans, the 2014-2019 Cancer Control Plan issues new priorities including the development of personalised medicine and links between care and research, and transversely, emphasises support and access to innovation for the treatment of malignant diseases. The 16th operational objective of the 2014-2019 Cancer Control Plan, “Consolidate the structuring of research in the regions” specifies the need to “Refocus the roles of the Canceropoles in areas that are not covered by other organisations (emerging projects in innovative themes and technologies, and from young teams, and regional or interregional research priorities, including technology transfer)”. In addition, Action 16.8 specifies the need to “coordinate the actions of the SIRICs and Canceropoles in order to strengthen research in a given territory” (if applicable).
5 THE CANCEROPOLES(“CANCER HUB”)
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Through Mission 1, which impinges on all the other missions, the Canceropoles will provide scientific leadership via unifying scientific priorities at regional and interregional level. The targeted priorities are linked to the particular research strengths of the Canceropoles’ territory, but a special emphasis was placed on multidisciplinary, innovation, and research in human and social sciences, epidemiology and public health (HSS-EPH).
Through Mission 2, Canceropoles have to spur the detection and emergence of innovative projects, through investigator-driven regional or interregional calls for proposals, specifically dedicated to the consolidation of preliminary results.
The 2014-2019 Cancer Control Plan establishes as a priority the connection between care and research structures. The development of shared actions with the objective of strengthening the “research/management” continuum is the main objective of Mission 3.
Canceropoles will also contribute to the emergence of initiatives at this level in relation to the local and regional coordination structures (e.g. Interregional Group for Clinical Research and Innovation - GIRCI and Regional Oncology Networks – RCC). The development of clinical research and the emergence of research projects within the Interregional Programme for Hospital Clinical Cancer Research Programme (PHRC-I) are part of this framework, with the purpose of increasing patient enrolment in therapeutic clinical trials.
By setting up a support service for the design and management of projects, through their 4th mission, the Canceropoles enhance the chances of success for research projects. This service is intended for young researchers and young teams in particular, but also aims at promoting European projects.
The orientation of researchers by Canceropoles towards appropriate structures and programmes such as national development structures will help increasing the valorisation potential of the outputs of funded research projects. This 5th mission consists to allow the detection and/or maturation of innovative projects.
As part of Mission 6, the Canceropoles promote regional technological development through the emergence of new platforms, as well as the development of innovative technologies on existing platforms. This support will be in the form of fund sourcing, and contribution to startup of operations in terms of staff and equipment. Finally, through the 7th mission, the Canceropoles have been tasked with the implementation of local structuring actions, which could be extended to a region- interregion- or nation-wide scale, after a positive proof of concept.
Each Canceropole will formalise a partnership with SIRIC, if one is present on its territory. The goal is a concerted action for the implementation of common strategic axes, pooling of related resources, and scientific leadership for joint actions when possible.
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Table 29. Examples of actions to be led by Canceropoles for the 2015-2017 period
Mission 1 Île-de-FranceTo federate scientists of different disciplines under scientific leadership: Theoretical and practical bioinformatics training; Digital communication on civil society and the world of industry.
Mission 2Grand Sud-Ouest
To promote detection and increase the visibility of innovative projects: Annual “Pre-Emergence” call for HSS-EPH research projects to encourage meetings and exchanges between researchers from different disciplines and optimise the writing of submitted proposals.
Mission 3 Nord-Ouest
To participate in the development of clinical trials with regional/interregional players: 1) Equity with GIRCI: ERNU clinical trial for the recruitment of patients in 40 non-university hospitals; Joint evaluation of PHRC-I Cancer; Creation of a functional platform dedicated to the processing of research data; Call for proposals for emerging clinical or translational research; 2) Actions with RRC: Location of the centres for the ERNU trial, and creation of annual training in clinical research.
Mission 4 Grand-EstTo support research teams in the development of their projects: Help for young researchers in the writing of proposals; Specific training in setting up projects implemented by the Clinicians Committee (COCLIN).
Mission 5Lyon Auvergne Rhône-Alpes
To increase the detection of innovation and subsequent technology transfer: “Proof of Concept” call for proposals with academics, clinicians and entrepreneurs.
Mission 6 Grand-Ouest
To encourage the emergence of new technologies: Emergence and support of the new epigenetic platform; Emergence of a platform for bioinformatics, biostatistics analysis and management of medical information; Emergence of a platform for radionuclides and ionising radiation; Help with fundraising and transfers for recruitment of staff to the platforms; Annual training activity related to the disciplines of the platforms.
Mission 7Provence Alpes-Côte d’Azur
To favour the implementation of new structuring actions at regional and interregional levels: Enlargement of existing thematic networks and dynamic (LEA Cohort – Virtual Microscopy and Experimental Histopathology – Bioinformatics); Acquisition of skills and additional expertise (Single Cell); Networking (Sunrise).
Moreover, the Canceropoles have been organised into thematic areas (Figure 21), and each has specific missions, which constitute their 8th mission in accordance with the 2015-2017 designation period.
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Fig.21. Specific themes and missions
Therapeutic InnovationsCancer diversityScreening and preventionResearch in Bioinformatics (Cross functional axis)Structuring regional Oncogeriatry researchRare CancersFrom development and validation
of prognostic and predictive biomarkers to therapeutic innovationClinical and Biological aspects of B-cell malignanciesMolecular imaging and treatment adaptationCancer and NeurosciencesCancers, individual and societyInterventional research to develop evidence based public policy for reducing social inequalities
Cell-signaling and therapeutic targetsGenome Dynamics and CancerInnovative Therapies and Clinical ResearchCancers: individual and collective issuesHealth TechnologiesExpanding of actions to the French Overseas Departments
Clinical ResearchSingle CellBioinformaticsVirtual Microscopy and Experimental HistopathologyLEA CohortQuality of Life PlatformBiobanksStrengthening structuration of oncology players in PACA and around Mediterranean sea
Tumour progression and Resistance, Innovative therapiesInfections, immunity and cancerNanomedecine, Innovative technologies and CancerBioinformatics, Modeling and CancerPrevention, individuals, society and cancerEnvironment, Nutrition, Epidemiology and CancerHead and neck cancersProstate cancerOccupational cancers in wine-making areaTargeted cancer prevention in schools
Health indicators-Epidemiology-Human and Social SciencesTranslational Research-Biomarkers, imaging technologies and early phase trialsViral infection and CancerImmunity and CancerPancreas cancersCross-frontier cooperation
Targeting and RadiotherapiesImmunotherapiesUse of products from the sea in cancerTumour niche microenvironmentIntegrative Biology of Cancer networkHumanities and social sciences in CancerMulti-parametric characterisation of oesophageal cancerComparative biology: pets/human
Source: INCa, 2015Drafted by INCa’s Research Division, 2015
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5.2. CONTRACTING AND MANAGING THE CANCEROPOLES
Following evaluation by an international board, the 7 Canceropoles were granted designation and received a total funding of €21 million. The scientific programme of each of them was defined with INCa. The Contract of Objectives and Performances (COP) resulted from these agreements thus includes shared goals, a methodology to reach them, and a set of quantitative and qualitative monitoring indicators.
To strengthen the management of the actions of each Canceropole, INCa also created 2 committees: • A Strategy Committee (COSTRAT), the mission of which is to discuss the implementation of the COP and monitor concerted or specific actions performed in each Canceropole on an annual basis;
• A Steering Committee (COPIL), which is in charge of the operational implementation of the COP.
2014-2015 Highlights• New designation by INCa of 7 Canceropoles for
2015-2017.• 26 June 2015, first INCa-Canceropoles “COSTRAT”
meeting in INCa headquarters, in the presence of the Presidents of each organisation.
Canceropoles were able to show the uptake of the new Cancer Control Plan within regional research, built on past achievements and already a dynamics hold on to the actions of period 2015-2017.INCa confirmed the crucial role of Canceropoles in innovation, their contribution to the emergence of projects, teams and technologies, and the structuring of initiatives in regions, at proof of concept level and prior to a national deployment, if appropriate.
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6.1. STRATEGIC VISION, MISSION AND VALUES
Fighting cancer requires a global endeavour and it is in the furtherance of INCa’s mission to promote partnership with institutions worldwide in order to support high-quality cancer control initiatives. INCa’s favoured routes for implementing global cancer control are collaborative projects, transnational in design, that have proven to be of equal benefit to all participating members. In taking this approach and as shown in Section 2 below, INCa also synergises with and enhances France’s current National Cancer Control Plan (NCCP) for the benefit of French patients as well as for cancer patients worldwide. INCa’s international activities acknowledge the WHO-led Global NCD Action Plan 2013-2020, which recognises cancer as a major
health priority for all world regions, and endeavours to contribute to global efforts to reach the 2025 target to reduce premature NCD mortality by 25%. INCa’s global agenda also echoes France’s efforts to address the glaring disparities in the way cancer affects rich and poor within and across countries worldwide.
6.2. SYNERGY BETWEEN THE OBJECTIVES OF THE FRENCH NCCP AND INCa’S PORTFOLIO OF EUROPEAN AND INTERNATIONAL PARTNERSHIPS
The framework below shows INCa’s portfolio of international partnerships and projects, and how they relate to the National Cancer Control Plan objectives.
6 INTERNATIONAL DEVELOPMENTS
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Fig. 22. INCa’s international partnership portfolio
US NCI
US National Cancer Institute - Early phase
clinical research
Global Partnerships
Europe
National Agreements
Regional Networks
CANCON
Joint Action on Quality improvement in cancer
control
(WP8 - Survivorship and Rehabilitation)
EUROMED
Screening & early diagnosis in the mediterranean
countries
(WHO collaborative centre)
CANCON
Joint Action on Quality improvement in cancer
control
(WP6 - Research in comprehensive cancer
control network)
CANCON
Joint Action on Quality improvement in cancer
control
(WP8 - Survivorship and Rehabilitation)
European Commission EXPERT
GROUP on cancer control
US NCI
US National Cancer Institute - Global
coordination
International cancer research funders group
WHO
World Health Organisation –
Technical coordination
IARC
International Agency for Research on Cancer
– INCa sits at IARC Board of Directors
ICGC
International Cancer Genome Consortium
ICART
International Consortium for Action
and Research on Tobacco Control
CSA PerMed
Concerted and support action in personalised
medicine Eranet TRANSCAN 2
Coordination of national funding programmes in
translational research
ICRP
International Cancer Research Partnership
ICGC
International Cancer Genome Consortium
US NCI
US National Cancer Institute - Early phase
clinical research
IRCI
International Rare Cancers Initiative
JAPAN
Memorandum of Understanding with
Japan National Cancer Center on research
ICART
International Consortium for Action
and Research on Tobacco Control
CANCON
Joint Action on Quality improvement in cancer
control
(WP9 – Screening)
NCCP cross-cutting goals National Cancer Control Plan (NCCP) objectives
IARC - GICR
International Agency for Research on Cancer – Global Initiative for
Cancer Registry
COFAC COL
Collaborative Network on Cervical
cancer Control in Francophone Africa
LAOS /THAILAND
Research and Public Health project on cervical cancer
SENEGAL
Cooperation agreement on Cancer control (research &
public health)
Meet the needs of children, adolescents
and young adults
Reduce inequalities
Early diagnosis & screening
(Objective 1)
Innovation & Research
(Objectives 5 & 13)
Comprehensive and personalised
cancer care (Objective 7)
Personalised Medicine
(Objective 6)
Reduce smoking (Objective 10)
Global Partnership / Cancer Control (Objective 16)
Collect data / support Public
Health (Objective 15)
6.3. INCa’S EUROPEAN AND INTERNATIONAL PORTFOLIO
6.3.1. EUROPE
INCa has contributed to BASIS (“Breast Cancer Somatic Genetics Study”), a research project funded by the European Commission from July 2010 to December 2014. BASIS was aimed at generating comprehensive catalogues of somatic mutations in a minimum of 400 ER+ve, HER2-ve ductal-type breast cancers (both PR+ and PR-), which constitute the largest subgroup in this classification scheme and account for ~40% breast cancer cases. BASIS worked under the ICGC (International Cancer Genome Consortium) model through high coverage, shotgun genome sequencing of both tumour and normal DNA.
Complementary catalogues of transcriptomic changes (mRNA and miRNA profiles) and epigenomic changes (genome-wide DNA methylation) were generated to produce a comprehensive biological examination of ER+ breast cancer. Integrated analyses of these data sets were completed and the results compared to parallel data sets from other classes of breast cancer as well as other types of cancer.
See pages 14 and 15
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CANCON is a Joint Action co-funded by DG Santé, the aim of which is to support Member States’ cancer control policies, by advancing cancer care and population-based screening programmes, addressing survivorship and rehabilitation issues, and improving coordination between primary and secondary care. Recommendations in these 3 areas will be compiled into a European Guide on Quality Improvement in Comprehensive Cancer Control.
INCa leads CANCON’s work-package 8 (WP 8) on survivorship and rehabilitation, and contributes to WP 6 (development of the concept of comprehensive cancer care network) and WP 9 on screening.
With regard to WP 8, INCa has convened its partners twice to assess, with the assistance of experts, the evidence selected from the literature review. A first draft of recommendations has been prepared, which addresses the monitoring of late and long-term effects, comorbidities and surveillance for recurrence and secondary malignancies, psychological aspects of survivorship and supportive care, self-management, back-to-work issues and palliative care.
WP 6 considers a new model of care provision, as championed through the concept of a comprehensive cancer care network. INCa contributes to the topic of cancer research, namely with French examples of integrated cancer research sites (SIRIC), and other similar European examples in the United Kingdom, Germany and Italy.
The overall purpose of WP 9 is to provide guidance to Member States, based on the best available evidence, in order to support or improve the implementation of population-based cancer screening programmes. INCa brings to WP 9 its expertise in the implementation of national screening programmes, especially for breast and colorectal cancers.
The results of the BASIS study provide a near definitive overview of the somatic genetics of breast cancer, a landmark milestone in understanding the disease. BASIS was able to construct comprehensive genomic profiles for each of the 560 cancer cases, demonstrating the full breadth of inter-tumour variation in breast cancer. The BASIS study has defined a set of 119 mutated cancer genes, some commonly active and some rare, as well as mutational signatures that are operative in breast cancer. These findings are currently being woven together to produce a journal article that will be submitted for peer review by 2015.
All of the data from this project will be deposited in the ICGC Breast Cancer DCC and in the European Genome-Phenome Archive, and as such will be freely available to bona fide researchers so that they can continue to mine this information for future therapeutic value.
INCa is a member of PerMed, a Coordination and Support Action financed by the European Commission. This consortium of 27 partners representing key decision makers in research and research policy, industry, health care and patient organisations was tasked with developing a Strategic Research and Innovation Agenda (SRIA) to spur the implementation of Personalised Medicine (PM) in Europe.
The SRIA was off icially presented on 2 June 2015 to the European Commission and Parliament. It is based on a thorough literature review as well as interviews and consultations with experts and representatives from all relevant PM sectors. It contains 35 recommendations clustered into five challenges (Developing Awareness and Empowerment, Integrating Big Data and ICT Solutions, Translating Basic to Clinical Research and Beyond, Bringing Innovation to the Market, and Shaping Sustainable Health Care). The SRIA also presents 9 prioritised recommendations, which have the highest potential impact for the patients, citizens and the society as a whole. PerMed SRIA is available on http://www.permed2020.eu/_media/PH7_PerMed_Brochure_2015-06_Interaktiv.pdf.
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6.3.2. INTERNATIONAL PROJECTSInternational Consortium for Action and Research on Tobacco (ICART) One of the key outcomes of the meeting convened by the International Cancer Research Funders Group in January 2014 at the INCa premises was a proposal to establish an International Consortium for Action and Research on Tobacco (ICART). The main objective of ICART is to increase investment in the evidence base for tobacco control, through maximising the impact of the partner’s own investment by joining with others, and by mobilising new commitments to support international research activities for tobacco control. This effort intends to place special emphasis on increasing research capacity and involving cancer organisations in Low- and Medium-Income Countries (LMICs) where the burden of tobacco use is increasing.
INCa has joined the signatories to the Melbourne Call launched by ICART during the World Cancer Congress 2014, and met with other tobacco control leaders at the World Conference on Tobacco or Health in Abu Dhabi in March 2015, to discuss ICART priorities. The ICART plan will be implemented in 2015/16.
WHO Strategic and Technical Meeting on Management of Cancer, Geneva 2015
INCa attended WHO’s Strategic Technical Meeting on Management of Cancer in Geneva in April 2015. This meeting was aimed at identifying priority areas for WHO’s work in cancer control, from the disease management perspective, excluding primary prevention and palliative, and within the boundaries of WHO’s current mandate of setting norms and standards and providing technical support to government.
The 2011 United Nations Political Declaration on Non-Communicable Diseases (NCDs) highlighted the urgency of addressing the four major NCDs and their shared risk factors. The WHO Member States subsequently committed, at the 2013 World Health Assembly, to a 25% relative reduction in premature mortality from NCDs by 2025. This target – spelled out in the WHO Global NCD Action Plan 2013-2020 – cannot be achieved without substantial reduction in cancer mortality.
The ERA-NET Cofund TRANSCAN-2 – which builds on the preceding TRANSCAN ERANET – links research funding agencies and ministries in 15 Member States, 3 Associated Countries, and a third country. By pooling resources to support translational cancer research, TRANSCAN-2 offers opportunities for scientists and clinicians across the participating countries to collaborate. TRANSCAN-2 launched its first call for research proposal (JTC) on “human tumour heterogeneity to overcome recurrence and resistance to therapy” in early 2015. The joint funding mechanism put in place by the European Commission for this call allows the Commission to contribute additional funding up to 33% of the aggregate national budget spent on the selected research projects. Three additional JTCs are expected to follow. The partners also intend to connect with other European initiatives so as to expand coordination.
EUROPEAN COMMISSION EXPERT GROUP ON CANCER CONTROL
INCa has been appointed by the Health Authorities to represent France in the expert group on cancer control established by the European Commission in furtherance of the Decision of June 2014 (2014/C 167/05). The expert group mandate is to assist the Commission, at its request, with drawing up policy documents, guidelines and recommendations on cancer control. Members of the expert group include representatives of EU, EEA and EFTA countries, as well as representatives of patients’ organisations, European and international organisations active in cancer prevention, and European professional or scientific associations. The second meeting of the group was convened in Luxembourg in March 2015. Representatives were asked to review new developments in the field of EU action on cancer and advice on the upcoming cancer registry data call coordinated by the JRC and the European Network of Cancer Registries, the European Commission Initiative on Breast Cancer, prevention activities at EU level, including dissemination of the European Code against Cancer, the CANCON Joint Action and the future joint action on rare cancers.
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The study is a collaboration between Institut de recherche pour le Développement (IRD), Thailand Ministry of Public Health, the Faculty of Associated Medical Sciences of Chiang Mai University, the Centre National de Référence des Papillomavirus Humains, Pasteur Institute, and the Institut National d’Etudes Démographiques (INED) of France. It receives funding from INCa, Fondation de France and the Global Fund to Fight AIDS, Tuberculosis and Malaria.
Collaborative network on cervical cancer control in Africa – COFAC-Col: definition of a first joint challengeCervical cancer kills more than 288,000 women each year worldwide and disproportionately affects the poorest regions of the world. Cervical cancer remains an avoidable cause of death and its control is a priority of the WHO-led Global NCD Action Plan 2013-2020.
The African Consortium on Cervical Cancer Control Research (COFAC-Col) was created during AORTIC 2013 by 5 Francophone African countries (Senegal, Cote d’Ivoire, Cameroon, Gabon and Madagascar). It is coordinated by the Director of the Cancer Institute of Dakar. INCa acted as an initiator and a catalyst for establishing this collaborative network, and currently supports its research projects. With a focus on high quality research relevant to public health and based on shared knowledge, the primary goal of COFAC-Col is to provide a working model to implement standardised research protocols across the 5 countries. The current focus is on identifying the nature of the HPV genotypes associated with high-grade intraepithelial neoplasia lesions and invasive cancers in a series of significant cases coming from the countries. Conducted through an inter-disciplinary approach involving pathologists, oncologists, virologists and epidemiologists in each of the countries, COFAC-Col will produce robust local scientific evidence enabling public health decisions to be made. Furthermore, its cross-disciplinary nature will result in a unique contribution to capacity building for cancer control, with training, transfer of methodologies and expertise taking place across countries.
The second COFAC-Col meeting convened in January 2015 in Dakar was successful in creating an atmosphere conducive to exchanging information among participants and overcoming the challenges faced at the onset of a research project.
THAILAND –the research program “PapilloV - HPV infections and associated cervical lesions in HIV+ Thai women” come to a closeThe main objective of the ‘PapilloV’ study was to palliate the lack of information concerning HPV ecology and the risk factors of cervical cancer in HIV-infected women in Thailand, by assessing the prevalence, incidence, and clearance rate of HPV cervical infections and associated cervical lesions. The study was also to provide the distribution of the HPV genotypes involved and assess the other risk factors of cervical lesions. The study public health goal is to help design screening algorithms for early detection of cervical cancer based on the identification of HPV-HR and to allow the assessment of a HPV vaccine policy in this specific population.
This study was conducted within a cohort of HIV-infected women receiving antiretroviral treatment in Thailand, the PHPT cohort (PHPT is an International Research Unit of the Institut de Recherche pour le Développement (IRD) in France and the Faculty of Associated Medical Sciences at Chiang Mai University in Thailand). The follow-up of these women includes Pap-smear and HPV testing every year, with treatment and more intensive follow-up for women with cervical lesions or HR-HPV infection.
Between February 2012 and June 2013, 829 HIV-infected women were enrolled in 24 public hospitals throughout Thailand. At inclusion, a gynaecological exam, a cervical sample for HPV genotyping and a pap-smear for screening of cervical lesions were performed. These exams are repeated every year for 3 years.
At baseline, 26% of the women had HPV-infection including 18% high-risk HPV (HR-HPV). HPV52, HPV39, HPV51, HPV16 and HPV18 genotypes were respectively identified in 20%, 14%, 14%, 12% and 5% of HR-HPV cases.
The follow-up appears excellent with, on 1 July 2015, 89% of the women having at least 2 visits, and 71% having at least 3 visits.
These results will be presented as an oral communication in the HPV 2015 Papillomavirus Conference, in Lisbon, 17-21 September 2015 (and a publication is under preparation).
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Strategic bilateral partnershipsSignature of a Memorandum of Understanding between INCa and the National Cancer Center of Japan, a leading cancer centre in Japan
INCa and NCC Japan intend by this MoU to promote high-quality research and strengthen the evidence base that underpins cancer prevention and control, with a particular emphasis on innovative technologies and their assessment through clinical research, and a cancer registry.
Renewal of the partnership agreement between INCa and the Senegalese health authority
This agreement strengthens the long term privileged collaboration between INCa and the Senegalese Ministry of Health in the
area of cancer control. It puts a particular emphasis on the implementation of collaborative and multidisciplinary research and public health projects.
Innovation in Cancer Clinical Trials – sharing international experience
INCa took part in an International Symposium on Cancer Clinical Trials in Tokyo (May 2015).The event is a partnership with the Japanese National Cancer Center, with whom INCa has signed an MoU (see above), US
NCI, and Embassies of the USA, France, UK and the Republic of Korea. The symposium brought together experts from 5 countries to promote exchange of knowledge and good practices. By coordinating research with international partners, the participants hope to make faster progress in cancer research, building on the investments in cancer research made around the world.
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Table 30. Position of France in world cancer research
Publication rate (%) Year 2005 Year 2009 Year 2014
US 37.5 33.9 32.0
Japan 10.5 8.4 14.0
China <5.0 <5.0 7.5
Germany 9.0 8.1 7.3
England 6.9 6.4 6.0
Italy 6.2 6.2 6.0
France 5.4 5.3 <5.0
However, in terms of excellence of publications through “Top 1% Highly Cited papers”, France takes the 4th place (with a contribution of 10.5%) after the US (60%), England (15%) and Germany (13.6%). Highly cited papers co-signed with pharmaceutical companies are very important in France (almost 20% of these papers).
France co-signed 46% of its cancer-related papers with international partners. The leading partners are the US, with 16.6% of total co-signed papers, and Australia, with 15.2% of co-signed “Top 1% Highly Cited papers”.
Cancer research in France relates mostly to the following two specialities: Clinical Medicine (63% of the papers), Basic Research (i.e. Molecular Biology-Genetics and Biology-Biochemistry) (16.3%). The other fields represent fewer than 5% of cancer papers. However, it is interesting to note among them some papers in the Top 1% Highly Cited Papers: • 13 papers in Mathematics and Computer sciences; • 19 papers in Material Sciences and Engineering, e.g. nanoparticles;
INCa defined an evaluation methodology, identified tools and initiated new partnerships or continued participation in national/international networks as part of the evaluation of research projects funded by the Institute.
The evaluation takes place at several levels during the life of research projects, and for each project subject to funding, a number of ex-ante and ex-post indicators are used to define and thus to meet the objective of the evaluation.
7.1. CANCER RESEARCH IN FRANCE – A BIBLIOMETRIC OVERVIEW WITH AN IN-DEPTH ANALYSIS OF THE 2010-2014 PERIOD
In 2015, Inserm conducted a bibliometric study of Cancer Research in France on behalf of ITMO Cancer - Aviesan. Preliminary results of this study are summarised below.
Position of the French scientific research in the world Over the 2010-2014 period, researchers worldwide have published 7,513,750 articles, letters and reviews, referenced in the Web of Science database. France is ranked at the 5th place in the world in terms of number of citations of scientific publications, all scientific areas combined. The impact of France in the biomedical field is greater than the world standard, and France is also at the 5th rank in terms of number of citations.
Position of France in world cancer researchIn the field of cancer research, the number of publication has increased from 500,557 articles, letters and reviews during the 2005-2009 period to 781,320 during the 2010-2014 period. The sharp increase in the number of Chinese publications has led France’s ranking to the 7th position (Table 30) compared to 2005-2009.
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• 24 papers in Agricultural Sciences, focused on nutrition.In Clinical Medicine, the most represented sub-area is Oncology (42.2% of publications). Moreover, Oncology, Gastrohepatology, Haematology and Rheumatology/Orthopaedics/Sport account each more than 5% of the “Top 1% Highly Cited papers”.
7.2. STRENGTHENING OF EX-ANTE ASSESSMENT TO DRAW UP FUTURE GUIDELINES
Ex-ante assessment is mainly performed to help decision-makers, to allow the selection of projects to be funded, the prospective detection of innovation and the definition of strategic research priorities.
Ex-ante data may come from projects submitted by researchers on one hand and from evaluations of committee experts of CFPs on the other hand. The experts base their opinion on defined criteria and on bibliometric data.
To do so, optimisation of relationships between INCa and ITMO Cancer in their working processes, as well as the contribution of Canceropoles through their detailed knowledge of research at regional activity at regional level, should allow detecting emerging topics.
7.3. A PILOT STUDY FOR EX-POST ASSESSMENT OF TRANSLATIONAL FUNDED PROJECTS
In 2014, in order to establish the ex-post evaluation of research funding at INCa, a pilot evaluation of the 2007 call for translational research projects was conducted.
The aim was to measure the impact of funded projects two years after the end of INCa’s grant and 7 years after the beginning of the projects. The evaluation method used in this pilot study will serve as the basis for future evaluations. However, it will also be adapted according to the results of a benchmark study on the evaluation tools, which is conducted within the framework of the Action 17.13 of the 2014-2019 Cancer Control Plan, “Develop shared tools for evaluating cancer research projects”.
This pilot study was mainly based on data analysis of final reports of projects and a questionnaire survey to principal investigators (PI).The methods often used are desk analysis, peer review, questionnaire surveys fulfilled by PI stakeholders, and interviews. These methods allow to highlight projects impacts through in-depth case studies. In most systematic reviews and primary studies, research impact is assessed along several dimensions, which can be grouped into 5 categories: • advancing knowledge; • capacity building; • informing decision-making; • health benefits; • socioeconomic benefits.
Each category split into subcategories has a set of indicators and metrics capable of estimating the impact size. The more frequently quoted and accessible dimensions of impact in the pilot study were advancing knowledge (using bibliometric approaches), capacity building (mainly using a desk analysis approach), and informing decision-making (i.e. how and to what extent research findings are included in decision processes).
Several interesting aspects have been highlighted within the different thematic chapters of the questionnaire, and other aspect included in the case studies.
Translational research impact on practicesIn 37% of projects, an improvement of protocols or practices, was observed, e.g. “The possibility of offering a new biopsy in a metastatic progression” in a neuroblastoma project, “The identification of biomarkers associated with angio-immunoblastic T (T-LAI) (CXCL13, ICOS, etc.) lymphomas was introduced as part of the diagnostic routine by immunohistochemical techniques and/or flow cytometry.”
Scientific impactIn terms of knowledge production, 64.3% of projects have resulted in additional scientific f indings after the writing of the final activity report. PI declared 4.8 publications on average issued from the projects funded. Furthermore, 64% of PI reported to have developed collaborations in order to conduct the project and 78% of these collaborations have been developed with international structures.
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Economic impactThe leverage effect of INCa funding has been reported in half of the projects. Although no commercial product has been identified at the time of the evaluation, 43% of projects led to the filing of a patent and/or licence. Job creation or sustainability was reported in 28% of projects.These projects have significantly contributed to structuring research and capacity building, for example, the creation of a new team and several large-scale international consortia.
Dissemination of research resultsApart from scientific productions, this point has to be improved significantly.
7.4. INCREASING INVOLVEMENT OF INCa IN INTERNATIONAL NETWORKS OF ASSESSMENT OF RESEARCH IMPACT
As a member of the International Cancer Research Partnership (ICRP), since 2009, INCa uses the Common Scientific Outline (CSO) classification to encode the funded research projects according to their type. Moreover, based on this system shared internationally by many research institutions and funding bodies, each year INCa updates data of its funded projects in the ICRP data base. This database is accessible online (www.icrpartnership.org/). It is thus possible for each ICRP member to perform international comparisons on funding data and results on cancer research.
Moreover, as part of Action 17.13 of the 2014-2019 Cancer Control Plan “Develop shared tools for evaluating cancer research projects”, INCa plans to implement a tool to gather more ex-post evaluation data.
Hence, local initiatives tools, as well as tools already in widespread use, are currently being considered.
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PART 3.FOCUS ON STRATEGIC TOPICS FOR ADVANCING CANCER RESEARCH
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The Action Plan for the organisation of health research planning, prepared by several public research agencies, including INCa, and government bodies, was released on 15 July 2015. It is aimed at better using available structures, timing of calls for proposals (CFPs) and funding of clinical and translational research in 2015. In order to facilitate the national and international visibility of health research planning and to simplify the task for researchers, the Action plan proposes to redefine research planning principles in terms of sharing logistical procedures for CFPs, harmonisation of the norms for evaluating projects and coordination of the definition of national priorities in the framework of the National Health Strategy and the National Research Strategy, which should concern all health research fields, except research in biology. The Action Plan will be implemented in 2015 and proposes to continue to address these issues in the coming years. In the matter of scientific planning, A steering committee will be set up, including public research agencies, INCa, government bodies and charities, and will be responsible for the definition of scientific priorities based on proposals from the scientific committee. The scientific committee will include national and international academics, especially the Director of ITMO Cancer - Aviesan and the Director of research programmes at INCa. Nine scientific planning groups, corresponding to the fields of the current Aviesan institutes and chaired by their respective directors, and including researchers and non-academics, have been proposed and each asked to define three to five primary foci for 2015 and operational procedures in subsequent years.
1.1. CONTEXT
In France, most public cancer research programmes have been set up as parts of the National Cancer Control Plans.
The current 2014-2019 Cancer Control Plan was launched on the 4 February 2014. The National Health Strategy, launched by the Ministry of Health on the 8 February 2013 on the one hand, and the National Research Strategy — France Europe 2020 – included in the July 2013 Act regarding higher education and research on the other hand, inspired the writing of the Cancer Control Plan. The National Research Strategy, released on March 2015, has the ambition to both maintain France among the top worldwide research nation and allow France’s research to address the scientific, technological, environmental and societal challenges of the 21st century. Along with the 2014-2019 Cancer Control Plan, these National Strategies include broad recommendations for research planning.
To palliate the insufficient collaboration across areas in planning health research, lack of participation by researchers in identifying scientific priorities in some fields, and redundancy between research programmes and a general lack of visibility, both the Minister of Health and the Minister of Research have in 2014 requested the CEO of the French National Alliance for Life Sciences and Health (Aviesan), set up in April 2009 and bringing together the main stakeholders of life and health sciences research in France, to coordinate the preparation of an Action Plan.
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1.2. INCa’S OPERATIONAL PROCEDURES AND PROPOSALS REGARDING RESEARCH
1.2.1. SIMPLIFYING THE PROCEDURES FOR SCIENTIFIC PRIORITISATIONOne of INCa’s main missions is to coordinate cancer actions and stakeholders in France, particularly cancer research. INCa has been using specific procedures for prioritising its programmes research for years: i.e., recommendations of its Scientific Advisory Board, and proposals from expert groups and scientific partnerships. The implementation of procedures proposed by the Action Plan will have to take into account INCa’s established operating and dedicated procedures, with the objective of reinforcing simplicity.
Scientific Advisory Board (SAB)INCa’s SAB members are jointly appointed by the French Minister of Health and Minister of Research. Their mission is to ensure that INCa’s scientific and medical policy is consistent, to issue an opinion on INCa’s annual report and make recommendations and to provide opinions on INCa’s strategy and its implementation. The SAB’s recommendations and opinions also concern scientific planning or priorities. Given its composition and missions, INCa’s SAB should play the role of the scientific committee foreseen by the Action Plan for the organisation of health research planning, or at least strongly contribute to the determination of cancer-related scientific priorities by this scientific committee.
Scientific expert groupsWorking groups from INCa’s SAB can be set up specifically to discuss any relevant national issues. Hence, INCa’s SAB members have chaired specific working groups on INCa’s strategic report on, for example, cancer prevention research and on the increasing prevalence of smoking in France. Moreover, specific, multidisciplinary, scientific expert groups, including both researchers and patients’ advocates, have been frequently set up by INCa to contribute to research programmes dedicated to specific cancer diseases or issues, with the mission of proposing scientific priorities.
Scientific partnershipsINCa manages research programmes with public and private partners, such as public health agencies, research agencies, industrial companies, and charities funding research. For example, environmental or infectious issues are jointly managed by INCa and other public health and research agencies. Since 2007, INCa, ARC Foundation and the French National Cancer League have jointly prioritised specific disease cancers as targets for the Integrated Research Actions Programme, called PAIR. In the PAIR programme, specific expert groups are set up to propose scientific priorities to INCa and its partners. In the coming years, these charities and INCa might wish to give higher priority to shared scientific areas of interest and research programmes in their respective agendas. INCa has also developed European and international partnerships in cancer research. In 2009, INCa and US NCI signed a collaboration agreement that they have implemented, for example in promoting a programme of early phase clinical trials for innovative drugs. In Europe, INCa and public agencies and charities in more than 20 European countries have prioritised and implemented a common cancer translational research programme since 2010. The above collaborative trend should increase, within the Action Plan.
Simplifying the task of researchers is a core objective of the Action Plan. So as facilitating collaborations between national and international cancer research funders although, each research funder, being accountable to taxpayers or donors or crowdfunders, needs to ensure that its strategic scientific priorities are implemented. Preserving the diversity of cancer research fields and of medical specialities among clinical researchers is important too. Mobilising contributions from these research communities in order to propose scientific priorities should guarantee that all research fields and issues are considered. It is well known that in clinical research, patients and academic investigators’ priorities sometimes disagree, and academic investigators’ priorities are not always priorities for industry. Guaranteeing that the priorities of each of them will be welcomed and implemented in a unique frame would not be an easy task. Diversity among cancer research funders, fields and disciplines contributing to defining cancer
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scientific priorities seems essential. Therefore, accounting for cancer-related scientific priorities proposed by INCa and partners’ scientific expert groups should be formalised once the conformity of operational research procedures used with the principles of the Action Plan is established. Moreover, that would allow every stakeholder to comply with the proposals of the Action Plan.
Thus, according to its missions, INCa will continue to develop national and international collaborations and partnerships, and remain open to discussion of scientific priorities in cancer research. INCa will also continue to mobilise expert groups in research matters and consider their proposals in terms of priorities, at least in a context of partnership in fighting cancers.
These actions are in line with the Action Plan. INCa will take part in the discussion of scientific priorities in the framework proposed by the Action Plan for the organisation of health research planning with the other stakeholders.
1.2.2. PRIORITISING BY EVALUATING INCa’S CFPSResearch actions conducted as part of the 2014-2019 Cancer Control Plan with public funding are currently implemented by INCa and ITMO Cancer - Aviesan, mainly through CFPs. Most of INCa’s main CFPs for research are fully investigator-driven. Even if scientific priorities are defined prior to launching such CFPs, research proposals submitted may fail to include these priorities. Moreover, even if proposals include the priorities defined, they may not be selected through the process of scientific competition. Setting up scientific priorities is not enough to guarantee that proposals submitted in response to CFPs will comply with them. Therefore, INCa and ITMO Cancer - Aviesan will strengthen the evaluation of their CFPs in order to check that scientific priorities are adequately taken into account. Scientific priorities not considered by projects funded under investigator-driven CFP will be subsequently considered by INCa and ITMO Cancer - Aviesan for specific priority-driven CFPs.
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2.1. STATE OF THE ART OF NEXT GENERATION SEQUENCING IN ONCOLOGY IN FRANCE
Since 2013, INCa has supported the development of targeted NGS for diagnostic purposes in the 25 oncogenetics laboratories and the 28 molecular genetics platforms.
In 2013, via a call for proposals, INCa selected 11 pilot teams to carry out an implementation phase for NGS. A monitoring group led by INCa was created to improve experiences sharing and the definition of good practices. A guide for validating NGS has been issued, and serves as a reference for the accreditation of laboratories. Based on experience accumulated during this pilot phase, this new technology is being deployed in 2015 in the molecular genetics platforms and oncogenetics laboratories. Funding from INCa will support the technical validation phase for NGS and the recruitment of bioinformaticians into teams that have not participated in the pilot phase.
In 2013, INCa also selected 4 referral teams in bioinformatics. The role of these teams is to bring their expertise to clinical laboratories, to validate or develop analytical solutions and facilitate networking between bioinformaticians. Since 2013, the selected teams have developed dedicated analytical pipelines for each type of activity, and have validated these pipelines on data generated locally by the different laboratories using NGS. Several solutions are being studied in order to make these pipelines available to the community (virtualisation, direct access on a remote server, etc.), and are being tested to determine the most appropriate for the information systems of the structures from
which the laboratories belong. The “test” data sets constituted to evaluate the pipelines can also become a reference data set that all laboratories can use to evaluate their protocol locally. The efforts made by the bioinformatics referral teams since 2013 must be maintained in order to continue the ongoing work and to support the deployment of NGS throughout all the laboratories.
Meanwhile, the development of ultrahigh-rate sequencing and appropriate solutions for data analysis and storage renders it possible to consider the sequencing of tumour genomes in clinical practice. Whole exome sequencing (WES), combined with tumour RNA sequencing (RNAseq) seems to be a realistic approach for routine clinical use.
The required capacity to meet the very rapid growth expected in the next five years needs to be anticipated in the context of a pilot phase. More specifically, quality assurance, cost effectiveness and the constraints of French regulations need to be taken into consideration for the organisation of high-throughput sequencing, and for data storage and analysis. The medical interpretation of results is another key question that needs to be addressed immediately, in order to make the best use of clinical tumour genome sequencing at national level. Precision medicine requires close interdisciplinary collaboration between several stakeholders with a wide range of skills, and makes the integration and sharing of data critical, both for therapeutic decision-making and knowledge building. This relates to INCa’s participation in Global Alliance, and can rely on the inter-SIRIC working group on data integration.
2 PRECISION MEDICINE IN ONCOLOGY PRACTICE AT NATIONAL LEVEL: DATA AND INFORMATION TECHNOLOGY
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WES and RNAseq will be implemented as part of clinical trials in order to meet the following two main objectives: • Demonstrate that treatments guided by tumour biology improve patient survival;
• Take on the challenges of implementing tumour genome sequencing in routine clinical practice for a large number of patients.
Two clinical trials, on colorectal cancer (Acompli) and sarcoma (Multisarc) will begin in 2016, and will directly recruit patients based on WES and RNAseq data. Fifteen hundred pairs of exomes will be sequenced under this programme. This programme should confirm the feasibility of the approach, and should also respond to any ethical, economic or industrial issues raised.
2.2. PROPOSALS FOR A NATIONAL ORGANISATION FOR THE ANALYSIS AND STORAGE OF DATA GENERATED
A working group1 has been established by ITMO Cancer - Aviesan to estimate what NGS-based cancer analysis in routine medicine will require in terms of bioinformatics infrastructure and organisation in the future. A horizon of ten years was considered, and the plan limited to France, although it is clear that this organisation should be coordinated with other European or international initiatives. See an extract of the report produced by the working group in annex 1.
1 – Participants of the working group in alphabetical order: Fabrice André (Gustave Roussy), Emmanuel Barillot (Institut Curie, Inserm, Coordinator), Nora Benhabiles (CEA), Anita Burgun (APHP), Laurent Castera (Centre François Baclesse), Jean Charlet (UPMC), Olivier Delattre (Institut Curie, Inserm), Jean-François Deleuze (CEA), Patrice Denèfle (Roche Institute), Sophie Gomez (ITMO Cancer), Raphaël Guérois (CEA), Philippe Hupé (Institut Curie, CNRS), Pierre Laurent-Puig (APHP), Franck Lethimonnier (ITMO Technologies pour la santé, CEA), Carlo Lucchesi (Institut Bergonié), Nicolas Sevenet (Institut Bergonié), François Sigaux (INCa, ITMO Cancer), Eric Solary (Gustave Roussy), Alain Viari (INRIA, Fondation Synergie Lyon).
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was convened to discuss the framework of this new programme, which will replace and complete the previous “Epigenetics and Cancer”, “Systems Biology and Modelling” and some research fields of the “Physics, Mathematics and Engineering Sciences related to Cancer” programmes.
In the context of the 2014-2019 Cancer Control Plan and following the 10th recommendation of the INCa’s Scientific Advisory Board, which strongly supports the priority of basic understanding of the tumour ecosystem, ITMO Cancer - Aviesan has proposed to launch a programme to fund research projects in in their ecosystem. An operational working group1 meeting
3 NEW PROGRAMME: FUNCTIONAL HETEROGENEITY OF TUMOUR CELL RELATIONSHIPS IN THEIR ECOSYSTEM
1 – Participants in alphabetical order: Thierry Galli (Institut Jacques Monod, Inserm), Daniel Louvard (Institut Curie, CNRS, Coordinator), Sylvie Robine (Institut Curie, Inserm), François Sigaux (INCa, ITMO Cancer), Jean-Philippe Vert (Institut Curie, Mines Paris Tech), Laurence Zitvogel (Gustave Roussy, Inserm).
Microenvironment: a bibliometric study The rank of the French cancer research in microenvironment of tumour cells is 7th in terms of number of publication, such as the cancer research in general. However, the excellence of papers is at the top level. France is 2nd, behind United Kingdom and before the USA in the Top 1% Highly Cited Papers ranking.
Detailed bibliometric data in cancer research: Microenvironment
Microenvironment Rank (Nb of publications)
World share of papers (%)
Documents in Top 1% Highly Cited papers (%)
International Collaborations (%)
Industry Collaborations (%)
US 1 47.4 3.92 32.78 2.79China 2 13.1 1.27 32.06 0.69Italy 3 7.2 2.78 39.83 1.93Germany 4 7.1 3.04 54.01 5.42Japan 5 6.2 2.96 34.32 2.22United Kingdom 6 5.4 4.52 63.28 6.78FRANCE 7 4.3 3.94 45.52 5.38Canada 8 3.6 2.16 82.81 3.90South Korea 9 2.9 0.53 26.60 3.72Australia 10 2.6 3.53 62.35 2.94
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development of truly efficient personalised or targeted medicine. Oncology has been focused on the development of personalised medicine through the active search for new biomarkers derived from tumour cells and the design of targeted therapies. However, such treatment strategies are unlikely to make a significant difference if they do not take tumour heterogeneity and ecosystem into consideration.
New therapeutic strategies are needed that take tumour heterogeneity into account. Indeed, whole genome sequencing, while still being very expensive for large-scale use, is seen as a central tool for defining targeted therapies. Is this strategy appropriate when several tumour cell clones with different genotype and phenotype may be hiding? What is the precise relationship between genotype and phenotype? The genotype-phenotype map needs to be defined in a dynamic manner so as to anticipate the effect of targeting a particular clone, and this aim certainly requires both in vivo and in vitro approaches as well as mathematical modelling. Also of interest is the use of circulating tumour DNA found in the blood an easy source of material for sequencing? How can this material be of interest in defining tumour heterogeneity? The development of new therapies also needs to take epigenetic modifications into account. These changes are generally of two kinds, either DNA methylation or histone deacetylation. The use of such inhibitors has already been
3.1. SCIENTIFIC CONTEXT
In the last years, the notions of tumour heterogeneity and tumour micro-environment or ecosystem were introduced.
Several models of tumour evolution have been proposed, and in each case it is clear that several clones of tumour cells arise and compete at different time points of tumour development. This heterogeneity of tumour cells is a particular problem when therapy fails because of resistant clones. In contrast, tumour micro-environment refers to the recent concept that tumour-associated cells (fibroblasts, macrophages, lymphocytes, adipocytes, etc.) interact bidirectionally with tumour cells within and at the periphery of a tumour at its different stages. Cellular and molecular crosstalk between cancer and non-cancer tumour-associated cells strongly influences tumour growth and metastatic spread. The role of the educated stroma and immune cells in controlling or favouring tumour growth, invasion and metastasis needs to be thoroughly investigated so as to identify the positive and negative factors to efficiently target. In essence, the sequential acquisition of mutations, the longitudinal evolution and selection of clones in response to environmental cues and the design of new therapeutic drugs all need to be integrated into a comprehensive view of tumours in order to define future therapies. This knowledge appears even more crucial to the
Despite a moderate world share of Pharmacology and Pharmacy papers for Microenvironment in cancer research, it is noteworthy that the level of the documents in the Top 1% Highly Cited Papers is the highest for this speciality. It is also interesting to note the high percentage of industry collaborations in Haematology (18.18%).
Indicators of publications on Microenvironment for French cancer research
Microenvironment Rank (Nb of publications)
World share of papers (%)
Documents in Top 1% Highly Cited papers
(%)International
Collaborations (%) Industry
Collaborations (%)
Oncology 1 48.4 5.19 48.15 5.19Cell Biology 2 15.4 2.33 55.81 9.30Immunology 3 13.6 2.63 34.21 2.63Biochemistry & Molecular Biology 4 11.8 3.03 39.39 6.06
Medicine Research & Experimental 5 11.8 3.03 33.33 6.06
Haematology 6 3.9 0 36.36 18.18Pharmacology & Pharmacy 7 3.6 10 30 10
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3.2. THE NEW PROGRAMME FRAMEWORK
Based on these considerations, ITMO Cancer - Aviesan has proposed to launch a programme to fund research projects in the field of functional heterogeneity of tumour cell relationships in their ecosystem. In the context of the 2014-2019 Cancer Control Plan, ITMO Cancer in collaboration with the Aviesan’s Cell Biology, Development and Evolution Institute (ITMO BCDE) will open this call for proposals by the end of 2015, with the aim of constituting a critical mass in terms of resources and skills to conduct research projects of interdisciplinary nature that require cooperation between national teams from different fields such as cell biology, mathematical modelling, genetics and (epi-) genomics and mechanobiology, in an integrated way. An international collaboration may be considered, subject to specific funding of teams in the countries concerned.
Eligible research questions will be as follows: • Exploring how the two-way interactions of tumour cells and their tumour microenvironment may hamper or promote tumour progression;
• The reprogramming of the tumour microenvironment, especially mesenchymal cells, endothelial and immune cells;
• The influence of microbiota on tumour stroma architecture; • The built-in mechanisms leading to the epithelial-mesenchymal transition (EMT-like) and reverse mesenchyme-epithelial transition (MET-like) leading to metastasis;
• The modelling of signalling pathways involved in bidirectional exchange between tumour cells and the microenvironment;
• The modelling of tumour heterogeneity from in vivo data or 3D models, within the constraint of the microenvironment of the primary tumour and/or metastasis;
• The development of methods predicting the efficacy, resistance to treatment or recurrence of the tumour, according to the degree of interaction within the tumour microenvironment;
• The evaluation of treatments (combinations, new strategies, administration schedule) targeting subclonal somatic events of the tumour or its microenvironment.
The following will be considered outside the scope: • Genetic and epigenetic approaches based only on getting high-quality reference genome maps of the epigenome or tumour cells;
• Clinical trials.
shown in a phase I/II trial. As such, epigenetic modifications also need to be integrated into the dynamic genotype-phenotype map of tumour heterogeneity.
Considering tumour heterogeneity as an ecosystem, in each defined step of tumour development, interactions between the transformed cells and their microenvironment direct the evolution of this process. During carcinoma development, tumour cells secrete signalling molecules that influence the surrounding non-cancer cells, which, in return, favour tumour cell growth, survival, migration and metastasis. A number of partners in the microenvironment of the tumour have been identified and are the subject of active research. These partners are in part composed of the carcinoma-associated fibroblasts (CAF), the endothelial cells, and/or the complex host immune system. Carcinoma-associated fibroblasts (CAF) are the most abundant population of non-cancer cells found in tumours, and their presence is often associated with poor clinical prognosis. CAF cells exert pro-carcinogenic roles during carcinogenesis, and are able to drive cancer cell-dependent pro-invasive extracellular matrix remodelling. For instance, it has been shown that exosomes released by activated tumour-associated fibroblasts are able to induce in cancer cells a key signalling pathway in the acquisition of motility, and hence metastatic property. In addition, recent studies have highlighted the existence of active crosstalk between endothelial cells and the tumour mass, resulting in tumour angiogenesis. Indeed, cancer stem-like cells have been identified and found in the vicinity of blood vessels, and the latter has been proposed to act as a feeding ground for tumours, especially governing the fate of cancer stem-like cells. The involvement of oxidative stress in promoting tumour angiogenesis, mediated by the NOX (NADPH oxidase-dependent) enzymes in endothelial cells, has been recently investigated. The natural course of cancer involves interactions between the tumour and the host immune system. A French team headed has provided evidence that the type, density and location of immune cells within the tumour strongly influence the prognosis, independently of TNM classification. Recently, research on tumour microenvironment (and immune response in particular) has provided much evidence to support a leading role in the assessment of cancer prognosis, and open new avenues in treatment of cancer patients via immune-modulators, such as anti-PD1/PD1 ligand or anti-CTLA4 antibodies.
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In particular, annual funding of €3.7 million is allocated by the Ministry of Health (DGOS) to tumour banks responsible for the cryopreservation of specimens for medical purposes on behalf of regional facilities that do not have facilities for freezing. In this context, the tumour banks ensure cryopreservation of samples where this is found to be an essential prerequisite for conducting molecular testing to enable the improved diagnostic and therapeutic care of patients. In 2011, INCa updated the indications for storage and cryopreservation for medical purposes published in 2006, which list tumours for which cryopreservation is indispensable for patient care.
Furthermore, annual funding of €5.2 million has been allocated by DGOS since 2005 to support the role of the tumour banks in contributing to science. Since 2012, a new formula for distributing this budget has been in place, based on indicators of volume and quality. In 2005, INCa prepared its first activity report on the tumour banks, and has continued to prepare an annual report since then. Monitoring has made it possible to evaluate the organisation of services and the quality of their scientific contributions.
4.1. 10-YEAR REVIEW AND ACHIEVEMENTS
4.1.1. The tumour banksFollowing the establishment of 58 hospital-based tumour banks in France some twelve years ago, INCa was commissioned with monitoring, evaluating and strengthening their development so that they would set up a quality system in order to fulfil their roles in health and contributing to science. The tumour banks are structures located in health facilities, in which biological samples are catalogued, cryopreserved, and then made available to physicians and scientists for clinical tests or research studies, according to specific, legally defined conditions. The tumour banks have been structured by INCa, under the supervision of DGOS, through the allocation of financial support, annual monitoring of activities, and the development of recommendations regarding roles in health and scientific contribution.
Since 2005, the tumour banks have received dedicated, targeted financial support.
4 EVOLUTION OF BIOLOGICAL RESOURCES: TUMOUR BANKS AND CLINICAL-BIOLOGICAL DATABASES
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research purposes), to allow scientific exploitation of biological resources by organising the collections into thematic networks.
Furthermore, the tumour banks have undertaken a quality certification procedure according to French Quality Standard NFS 96-900, “Quality of Biological Resource Centres (BRCs) - Management System of a BRC and Quality of Biological Resources,” published in 2008. Since 2014, financial support for scientific contributions is subject to quality certification of the tumour bank.
Fig. 23. Tumour biobanks activity in 2013
Paris
Source: INCa, 2015Drafted by INCa’s Research Division, 2015
Cumulated number of patients(end of 2013)
Nb of new patients(within the year)
Contributions to project research(nb patients)
Contributions to publications(nb patients)
1,000
1,000
1,000
1,000
INCa has also drawn up and published several recommendations to better structure the organisation of the tumour banks. The “Ethics Charter for the Tumour Banks” contains recommendations for the collection, preservation and use of human tumour samples in relation to medical care and oncology research. Its objective is to help those involved in various aspects of oncology to establish research partnerships and protect the rights of patients. INCa also published “Étude des coûts de fonctionnement” (A study of funding operating costs) and “Recommandations pour la mise à disposition de ressources biologiques à des fins de recherche” (Recommendations for making biological resources available for
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A clinical-biological database is a tool for collecting and managing data concerning individuals, patients and/or subjects involved in research protocols. The data include clinical information, scientific and medical analyses carried out on biological samples from specimens, epidemiological information and administrative data collected using surveys or questionnaires. A BCB should make it possible to optimise the collection of all this information at national level, and its exploitation across various research disciplines (epidemiological, basic, translational and clinical). It should make it possible to study, for a large number of cases, the relationships between: • clinical and biological data (results of biomedical analyses); • disease history (medical and treatment history) and case history;
• data – social, demographic, environmental and behavioural, individual and collective;
• national and/or international epidemiological data (cohorts, registers, etc.);
• administrative (geographical and occupational) and socio-economic data.
Since 2011, INCa has funded the structuring of 14 BCBs, with an overall budget of €8 million.
Table 31. Features of the BCB programme
Year Projects selected
BCB selectedFunding (in
€M)
2011 5
Lynch syndromeKidney cancerLiver cancerMelanomaMesothelioma
2.8
2012 4
Pancreatic cancerGliomaSarcomaGastroesophageal carcinoma
2.6
2013 5
Marrow Transplantation and Cellular TherapyMyeloproliferative disordersLymphomaPeritoneal carcinomatosis of gastrointestinal originPredisposition to breast and ovarian cancer
2.4
For the last decade, the support policy conducted by DGOS and INCa has made it possible to make advances in the organisation of medical and scientific activities of the tumour banks, and their overall activity has developed considerably (Figure 24). Currently, all CHU (University Hospitals) and CLCC (Care Cancer Centres) have access to a tumour bank with a local organisation that enables them to fulfil all their roles.
Fig. 24. Activity of tumour banks since 2001
0
20,000
40,000
60,000
80,000
100,000
120,000
140,000
160,000
2013201220112010200920082007200620052004200320022001
Nb of samples used in health careNb of samples used in research
Each tumour bank, or biobank, must have a level of organisation that includes: • collection according to a research strategy and a high level of biological and anatomopathological expertise;
• standardised procedures to guarantee the biological quality of samples;
• the ability to collect and provide appropriate high-quality clinical and biological data;
• the ability to respond rapidly to requests for collaboration at national level.
4.1.2. THE CLINICAL-BIOLOGICAL DATABASES (BCB)In 2011, and subsequently in 2012 and 2013, INCa implemented a CFP for “Clinical-Biological Databases” (BCBs), with the aim of stimulating, in accordance with recommendations made to the tumour banks, the coming together of different players to create, around a common pathology, clinical-biological databases linked to biological samples.
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Different specimens from a patient will be the subject of specific biological analyses needed for his/her care, e.g. -omic analyses as well as immunomonitoring. These biological data must be collected and integrated with the other types of data already linked to the specimen. They must also be linked to clinical data related to monitoring this patient, i.e. treatments administered and the response to treatment. Thus different types of specimens linked to a set of data of a different nature (clinical, histopathological and biological features, and nature of treatment and of the response to treatment) will be collected throughout the patient care pathway. This implies a tighter multidisciplinary coordination between surgeons, clinicians, anatomopathologists and biologists. It will thereby be possible to monitor patients longitudinally, with access to specimens from key points in the progression of the disease. The grouping of these different types of data is being organised, either by reconstructing links and interlinking data from one database to another, or by direct collection of the data in a data warehouse. The interlinking of data is constrained by current regulations, which do not allow use of a unique patient identifier.
The biobanks must become part of this dynamic. It will no longer be a matter of entering data to provide a basic description of patient and sample profiles, but to have the ability to create links between specimen and patient data, whether these are clinical, biological, genomic or epidemiological data.
The establishment of an organisation to allow the collection of data generated in the course of care, linked to longitudinal storage of specimens, allows to plan the creation of cohorts of patients that have features in common – the same tumour location or a similar molecular profile of their primary tumour, for example. This represents a tool with very high added value for carrying out research projects and generating new knowledge. It may involve analyses of data already collected, or the generation of new data based on stored specimens. For this reason, the distinction between storage of specimens for medical reasons and for research reasons will tend to narrow down, or even disappear altogether.
This action strengthens the structuring of the thematic networks, in order to develop as fully as possible an organisation that encourages the sharing of data and biological resources for projects conducted on a national scale. In this sense, the BCB foreshadows future organisational developments needed by the development of precision medicine.
4.2. DEVELOPMENT OF THE COLLECTIONS IN THE CONTEXT OF PRECISION MEDICINE
The development of precision medicine will have impacts on the organisation of biological collections, which will have to meet new challenges: logistical and technical challenges, ethical and regulatory challenges, and challenges related to data sharing.
For solid tumours, the tumour banks have been structured for cryopreservation of tumour specimens taken from the primary tumour. The techniques used for biological analysis of tumours allow to use fixed specimens for research projects, constituting a first development in the tumour banks’ scope of activity. These fixed specimens are often stored in anatamopathology laboratories, and not in a centralised manner. Moreover, the development of techniques for the analysis of circulating tumour DNA has led to the development of liquid biopsies, allowing tumour progression to be monitored at the molecular level throughout the course of the disease. These liquid biopsies, stored in a biobank, will have to be linked to up to date patient follow-up data, and interlinked with previous specimens that have already been stored and annotated. Thus the operation of tumour banks for solid tumours is going to converge with that of tumour banks for liquid tumours, providing “longitudinal” storage for patient specimens.
Ultimately, the activity of the tumour banks will expand and become more complex: these biobanks will have to be able to handle diversity in types of specimens, in the methods for preserving them, and in the locations where they are stored, together with the interlinking of patient specimens taken throughout the course of their illness.
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asset that should be used to its best advantage. To date, there are two models in use: – Biobanks hand over the samples they store for research projects according to procedures that are specific for each of them;
– The BCBs have established a national networked organisation centred on a specific pathology. Each BCB gives access to the data it has collected, and hands over specimens in its charge according to rules for governance that have been previously established. This point is especially crucial for rare pathologies, for which specimens are few, and sometimes small in size.
The model put in place by the BCBs foreshadows that for the new generation of biological resource collections which will be established in the context of developing precision medicine. Experience has shown that structuring a BCB is complex, and that every eventuality cannot be defined. Where there is no BCB, governance procedures must be defined to optimise the scientific use of the collections thereby created, and allocate the biological resources according to a collegial and multidisciplinary decision-making procedure.
Thus the need to share data and specimens at national level will become major, and require several challenges to be met: • To share data, it is necessary to standardise and structure them. Scientific teams must develop their repositories of clinical, epidemiological, biological and genomic data for each disease category by jointly defining the semantics, ontology and formats for each variable. This work must first integrate the national repositories, such as the minimum data set for characterising tumour specimens, and data provided for collection in the Cancer Communication File. This process has already been initiated under the inter-SIRIC working group “Osiris.” In addition to designing data repositories, standardisation and structuring of medical records will be decisive. The obligation for all medical managers (including those in the private sector) to complete patient files via standardised electronic documents will make it possible to constitute high-quality data in data warehouses.
• From a computational point of view, it will mean implementing IT solutions for assembling all the data for one patient, and all the data for a patient cohort, in order to enable in-depth exploitation of data, depending on the access rights given to health professionals and researchers. The question will be to define how to integrate all the data for a patient or patient cohort where data are produced in multiple centres.
• From an ethical and regulatory point of view, the unavoidable need for large-scale sharing of biological resources and data for both research and care should to lead to fundamental changes. The procedures for informing patients and obtaining consent will have to be considered differently. Given the wide range of potential uses for data and biological resources, it seems difficult to both precisely define or foresee all uses, and to provide information that is clear and comprehensible to all. The purpose is all the more complex to define and to convey consistently when most of the projects are organised in a multi-centre and retrospective manner. There will be a need for reflection on the notion of “purpose and broad consent,” or on the notion of “dynamic consent” or “variable scope.”
• The final major challenge is that of governance, in defining conditions for access to this new generation of biological resource collections. The latter are by nature limited in quantity, and therefore constitute a national-scale scientific
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Marseille (AP-HM), Lyon (iHOPE) and Lille (CHU and COL) and part from the European network Innovative therapies for children with cancer (ITCC). They all have had previously enrolled pediatric patients in early phase trials. They are designated for a 4 year-period and with a funding from INCa and the French national cancer league. Each has set up dedicated structure and staff for trials. Theirs facilities are adjacent to the adult CLIP² facilities, reinforcing bridges between them to improve the sharing of expertise.
Both solid tumors and hematology are considered and a focus is made on precision medicine in these CLIP2. In line with this, the 6 sites will participate to genomic driven programs called MAPPYACTS and eSMART trials, described below. Another objective of these CLIP² is to reinforce links with pharmaceutical companies. The designation and the funding will be incentive for pharmaceutical companies to collaborate with these CLIP² on trials with innovative agents. These CLIP² will promote academic early phase trials with new anti-cancer therapies and propose new methods for drug development.
The 2014-2019 Cancer Control Plan also sets the objective of providing children, adolescents and young adults with appropriate care in relation to their cancer types. Too few drugs have been developed for children with cancer, because childhood cancers are rare diseases and affect a fragile population. With respect to access to innovative drugs, the 2014-2019 Cancer Control Plan encourages a general policy of setting priorities for drug development, which includes the development of drugs for paediatric oncology and appropriate methodologies for clinical trials involving these patients.
Moreover, to enhance the knowledge of mechanisms underlying cancers that affect children and to develop specific drugs, several childhood tumours will be included for complete genome sequencing. INCa and the Ministry of Health (DGOS), supports
Childhood cancer is a rare disease, constituting 1-2% of all cancers. There are approximately 2,500 new cases each year in France among children and teenagers. The 2014-2019 Cancer Control Plan has made paediatrics one of its cross-cutting priorities. In order to further improve access to innovation and research for children, adolescents, teenagers and young adults, several actions have been drawn up by INCa, since 2014. In late 2014, INCa has designated a cooperative intergroup dedicated to paediatric oncology with the following general aims: • developing and conducting therapeutic trials, especially to optimise treatments and de-escalate treatment to reduce side-effects;
• accelerating and increasing recruitment of children and young adults in clinical trials;
• participating in INCa efforts to develop multi-organ clinical trials, personalised and precision medicine;
• developing and submitting translational research projects in INCa research call for proposals;
• contributing to research structuring initiated and managed by INCa, especially in helping to mobilise researchers in paediatric cancers in INCa multidisciplinary research programmes such as the next PAIR programme.
Since 2007, INCa launched an annual thematic programme devoted to a specific pathology. The programme, entitled, “Integrated Research Action Programme” (PAIR) will be dedicated to childhood cancers in 2016. It is aimed at covering all areas of research, funding projects in basic sciences (biology and epidemiology), human and social sciences, translational and clinical research.
In 2015, 6 of the 16 designated CLIP2 have also been designated for paediatric expertise. They are located in Villejuif (Gustave Roussy and its partners: Trousseau Hospital-Robert Debré Hospital), Paris (Curie Institute), Nantes (CHU and ICO),
5 KEY SCIENTIFIC ISSUE IN PAEDIATRIC ONCOLOGY: CURING MORE CHILDREN MORE EFFECTIVELY
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also since 2014 an international project (MAPPYACTS), aiming at determining the molecular profile of tumours in order to propose a targeted therapy.
MAPPYACTS for Molecular Profiling for Paediatric and Young Adult Cancer Treatment Stratification will use whole exome sequencing and RNA sequencing of tumors for an increased detection of targetable genomic alterations. Then, patients may be addressed to ESMART (European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors in children) and be assigned to a treatment arm based on molecular alterations in their tumor profile.
ESMART is one of the AcSé programme dedicated to children and young adults. AcSé programme was implemented in 2013 to provide a secured access to targeted therapies to patients in situations of treatment failure. The programme has been open recently to children.
Finally, it is important to emphasise the contribution of groups and charities for patients and relatives, which are very involved and active members. INCa undertakes to meet them frequently and discuss the achievements of paediatric actions of the 2014-2019 Cancer Control Plan.
Paediatric research in oncology: a bibliometric studyThe paediatric oncology represents 6% of French cancer publication with a visibility greater than the norm and is distinguished by the level of excellence of its publications (2.12% in the Top 1% Highly Cited papers). Almost 1% of papers are published in scientific or medical journals with a high impact factor. Moreover, France is leader in terms of collaboration with industry in this area.
Paediatrics Rank (Nb of publications)
World share of papers (%)
Documents in Top 1% Highly Cited papers (%)
International Collaborations (%)
Industry Collaborations (%)
US 1 35.25 1.81 27.64 1.90Germany 2 7.35 2.25 50.09 2.13England 3 7.15 2.53 52.68 2.31Italy 4 6.21 1.72 39.28 1.51China 5 5.95 0.52 20.40 0.64Canada 6 5.61 2.78 53.86 2.03Japan 7 5.32 0.84 16.72 0.88FRANCE 8 5.26 2.12 45.74 3.94Turkey 9 3.70 0.36 10.25 0.18Netherlands 10 3.41 2.94 57.48 3.14
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INCa enlarged its Scientific Advisory Board to include users’ representatives as prescribed by Action 14.1 of the 2014-2019 Cancer Control Plan. The President of the Association for Research on Brain Tumours (ARTC-Sud), and the President of the Associations Info-Sarcomes and Together Against Gastrointestinal Sarcoma Tumours (Ensemble contre le GIST), were appointed as members of the SAB in March 2015, by both the Ministries of Health and Research, for a five-year term.
6.2. … AND AN OBLIGATION OF THE INCa INSTITUTIONAL PROJECT
INCa’s commitment on health democracy was formalised within the framework of its Institutional Project. Involving all cancer control stakeholders –patients, relatives and professionals– increased the relevance and the efficiency of the Institute. INCa drafted a Charter governing its relations with the stakeholders and established, in February 2013, a “Users and Professionals Committee” (COMUP), which serves as a permanent consultative body, under the aegis of the INCa Chairperson. Following a call for applications, 28 members were selected: Fourteen representatives of patients, relatives and users from the health care system (users’ panel) and 14 health, research or social sector professionals (the professionals’ panel), for a three-year term. Thus, COMUP sits every three months, in plenary sessions or in workshops. The COMUP Chairperson sits at INCa’s Board, and is also a member of the Steering Committee of the AcSé programme.
Plenary meetings allow INCa to present critical actions for which the opinion and the experience of the members of the COMUP are sought.
6.1. AN OBJECTIVE OF THE 2014-2019 CANCER CONTROL PLAN…
To enhance the capacities of every individual for self-determination on health issues, the 2014-2019 Cancer Control Plan strengthens the collective involvement of patients and users of the health system in the development and implementation of policies for action on cancers, in both the disease management and scientific areas. One of the objectives of the Cancer Control Plan concerns the deployment of health democracy (“Objective 14: Breathe life into health democracy”), and responds to one of the three main components of the National Health Strategy, aimed at “assessing the rights of patients and users, and involving them in bodies involved in organising and developing our health care system.”
INCa started several years ago, in the area of research in particular, to introduce the participation of users’ representatives in evaluation committees for calls for proposals. One or two patient representatives sit at the selection committees, participate in discussions and decision-making. In 2012 the Institute signed a partnership agreement with the French National Cancer League to enable the League patients’ committee for clinical research to review the protocols launched by academic and industrial sponsors. Through this agreement, 97 protocols were reviewed in 2014, including five concerning the design of protocols (2 pre-proposals for PHRC-K and 3 draft protocols or advanced synopsis). Thirty sponsors contributed with protocols, including 11 cancer care centres, 7 university hospitals, 5 cooperative intergroups and 6 pharmaceutical companies. Work is underway with the sponsors to involve the patients’ committee in dissemination of results of clinical trials to the general public.
6 SCIENTIFIC AND HEALTH DEMOCRACY IN THE 2014-2019 CANCER CONTROL PLAN
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Various research themes were thus discussed with COMUP, such as: • patient perception and measures to support clinical cancer research;
• research programme and actions to reduce smoking and reduce the prevalence of tobacco-related cancers (PRIORITY Cancers Tobacco).
Other work was able to reveal research questions, for example: • end of life and cancer research; • publication of economic research outcomes on the economic impact of the disease on the financial resources of patients and their families.
6.3. BREATHING LIFE INTO HEALTH DEMOCRACY WITH INCA’S PARTNERS
INCa also developed an in-depth dialogue with its partners and Board members, with regards collaboration with users of the health system, so as to clarify how “users of health care” may be involved, in particular, with regards the designation of cooperative intergroups and Canceropoles in 2014.
The Institute also encourages charities representing cancer patients to get closer of the research organisations. A meeting organised by the Institute on 31 March 2015 demonstrated the usefulness of collaboration between charities and research stakeholders, and pointed both incentives and obstacles to these types of collaborations.
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APPENDICES
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(fewer biases), but also has drawbacks: it is still more expensive (about twice as many for a standard coverage), it produces a huge volume of data (but we could keep only calls, or even only gene regions, or use compressed format with some acceptable loss of information), and might not be useful in full-length form for medical purposes before long. On the other hand, the absence of capture (unlike WES) seems to make it more reliable both for copy number estimation and variant calling (http://biorxiv.org/content/early/2014/10/14/010363.article-info). It has to be noted that coverage will have to be adapted to cover biopsy cellularity and tumour heterogeneity.
Another strategy could be not to sequence deeply, but only 3-4X to assess translocations and copy number, while simultaneously doing deep targeted sequencing (>200X) to find mutations (at least until deep WGS (>200X) is in place). This would reduce the genome raw data volumes 10-fold, but tumour heterogeneity and low clonality might compromise this strategy. In the future, liquid biopsy analysis (ctDNA, circulating tumour cells) should be included as well.
SAMPLE SCREENING STRATEGY (HOW MANY SAMPLES PER PATIENT? HOW MANY READS?)It was assumed that both normal and tumour genomes will be sequenced (this is highly preferable for efficient variant identification). In the long term it was also assumed that tumour heterogeneity will have to be assessed and that to do so, several samples per tumour could be profiled. The group considered that either one (low option) or five (high option) samples per patient will be analysed, both in genome and transcriptome. This amounts to 1.2 to 4.4 million profiles (800,000–2,400,000 genomes and 400,000–2,000,000 transcriptomes) per year. Note that several sequences per year and per patient might also become necessary at some point to provide longitudinal monitoring of tumours.
This report is an attempt to estimate what the NGS-based cancer analysis in routine medicine will require in terms of bioinformatics infrastructure and organisation in the future. A horizon of ten years is envisaged and the plan is limited to France although it is clear that this organisation should be coordinated with other European or international initatives. There remain many uncertainties, rendering this exercise difficult and probably limited to better evaluate the order of magnitude, and propose one scenario. Nevertheless, the figures in the group’s report, and more importantly the list of dimensions to consider, are aimed at providing a framework to guide decision-makers. They will have to be adjusted depending on the strategic options chosen, as well as the constraints imposed by the situation, in particular by their partners (policy maker, technical limitations, ethical and legal issues, etc.). These parameters are also examined below.
1.1. SCREENING STRATEGY
PATIENTS SCREENEDIn the following the group assumed that within a few years all new cancer cases as well as relapses will be screened by NGS in the future. It estimated 350,000 new cases per year and ~50,000 relapses, or a combined 400,000 tests per year. The hypothesis was that both will undergo the same type of screening. Note that in short term one can imagine that only tumours of a subset of patients will be sequenced (e.g. patients with refractory metastasis), reducing the dimension of the problem by one or two orders of magnitude.
TYPES OF SCREENINGThe group assumed that both genome and transcriptome will be screened. RNAseq will be the technique of choice for the transcriptome, whereas either targeted-seq, whole exome-seq (WES) or whole-genome sequencing (WGS) will be used for the genome. WGS is simpler to implement, easier to analyse
1 PROPOSALS FOR A NATIONAL ORGANISATION FOR THE ANALYSIS AND STORAGE OF DATA GENERATED
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1.2. VOLUMES
STORAGE POLICYA central question for evaluating volumes is the policy of data conservation: which data will be stored? How long will they be kept? How will they be made available, and to whom?
The table below summarises the volumes produced per year using standard Illumina solutions, for one sample (raw data or calls), or for one patient and 400,000 patients (in the case where five or one samples are profiled) (Table 32).
Table 32. Volumes of data produced per year
Sequencingdata volumes
Raw data1 sample
Calls (VCF)1 sample
5 tumour samples + 1 normal sample | 400,000
(calls-raw)
1 tumour sample + 1 normal sample | 400,000
(calls-raw)
WGS 200X 1,000 GB 1.00 GB 6-6,000 GB 2.4-2,400 PB 2-2,000 GB 0.8-800 PB
Exome-seq100M pairs 30 GB 0.25 GB 1.5-180 GB 0.6-72 PB 0.5-60 GB 0.2-24 PB
Targeted 1000X 100s genes 1 GB 10.00 MB 0.06-6 GB 0.024-2.4 PB 0.02-2 GB 8TB-0.8 PB
RNAseq 80M pairs 12 GB 0.20 GB 1-60 GB 0.4-24 PB 0.2-12 GB 0.08-4.8 PB
For example with the first scenario (5 samples per patient), the total volumes would be 2,424 PB per year for raw data in case of WGS 200X and RNAseq 80M pairs. If only 1 sample is analysed per patient (scenario 2), it is still about 804.8 PB. Even with this more economical strategy, about one Exabyte of data (1,000 PB) will be produced yearly.
With scenario 2, storing raw data for 5 years would require a 4,024 PB storage capacity (> 4 Exabytes). If only calls were kept (and not raw data), 0.88 PB per year would be required, or even less (0.28) if exome-seq is used instead of WGS. Of course reducing coverage (e.g. RNAseq 40M pairs) would reduce raw data volumes accordingly. Conversely increasing the number of samples per patient to 5 (in particular to assess heterogeneity) would lead us to more than 12 Exabytes produced if WGS is used.Again, it should be stressed that these numbers are only orders of magnitude and estimated for data without loss of information. A volume reduction of at least one order of magnitude could also be anticipated by using lossy data compression techniques. This would require ad hoc preliminary study.
Long term storage of all raw data doesn’t seem realistic today, being orders of magnitude above the present capacity of the Investissements d’Avenir-funded France Génomique, for example (or other large scale storage facilities such as TGCC (CEA HPC) or IDRIS (CNRS)). To our knowledge, no hospital in France has a storage capacity of more than 2 PB, and most have less than a few hundred Tb. Nevertheless, one can imagine that it will be technically more easily achievable in 2020-2025, but since storage density doubling time has increased to about 5 years now, the cost of such storage volume is likely to remain unacceptable (although it is decreasing).
But the first question is whether it is justified. On the one hand one can expect that the performance of sequencing analysis will reach some plateau, and quality of results will be reliable enough not to keep raw data. On the other hand, it is not easy to predict when this technological stabilisation will happen.The question of medical record regulations must also be examined to establish which data must be kept and which could be discarded. Note that the host centre must also comply with the regulations for biomedical data storage. This legal context is likely to evolve in the future with the more widespread use of NGS screening and its potential for biomedical research and improved medicine.
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DATA MANAGEMENTIt should be pointed out that beside the data storage per se, a robust and efficient data management system will also be required, not for the sequence data itself (which are mere files), but for the associated metadata (production centre, patient inclusion id, etc.), in order to achieve perfect traceability and retrieval of data.
Some clinical records (the medical electronic file of each cancer patient) also have to be integrated in order to provide a comprehensive corpus of information that physicians will be able to query and use as a reference when treating a given patient. This raises the question of the local organisation of electronic medical records and of data gathering and structuring, using adequate ontologies. This question deserves a dedicated study and is not covered in this document.
ORGANISATION OF DATA PROCESSINGIndependently of data storage, the question of bioinformatics data processing has been raised. In particular, should it be done locally or centralised in a high-performance computing centre? Although centralisation would avoid duplication, it has many drawbacks that make it impractical: it requires transfers of massive raw data, and it makes all platforms dependent on a centralised facility and network bandwidth, which might cause delay in the event of problems with one of these critical components. Of course local computation should be done in a fully traceable way, and all local computing facilities should be configured and administered similarly. Coordinated management of computational nodes and of software should be ensured at national level.
Bioinformatics data processing will have to be standardised both in terms of: 1) quality control procedures (e.g. raw data quality control, correct tumour/normal pairing, data integrity) and 2) high level analysis (variant calling, copy number, etc.).
Here again the cost of data processing will vary greatly depending on the options: WGS, exome or targeted. The difference in terms of CPU time requirement may reach two orders of magnitude.
ORGANISATION OF DATA STORAGEThree options have been considrered for data organisation. In the first option, all data are processed locally on each sequencing platform. In the second, all data are transmitted from the high throughput sequencing platforms disseminated across the national territory to ~10 regional nodes (e.g. SIRICs or other comprehensive cancer centres), where they are stored. In the third option, data are centralised in one national centre (the regional layer can still exist), which integrates all results (it can integrate all data, or only a reduced version such as calls). This option provides a duplication which will help to ensure data durability. It also facilitates the exploitation of the data in the context of scientific research or public health. Note that an adequate network should be available, probably for regulatory reasons, but also for performance, especially if the time delay for returning results to the clinicians needs to be kept short (days or so). This advocates for more local (regional) solutions. As a comparison, a network similar to RENATER would ensure a bandwidth of 10 Gbit/s, which is around 40 PB/year, something compatible with the volume anticipated, at least for some of the options of sequencing and storage policy exposed in the table above.
1.3. SEQUENCING AND DATA ORGANISATION
ORGANISATION OF DATA PRODUCTION (SEQUENCING)Data production is a matter of many constraints that limit the mode of organisation. The first one is linked to the life cycle of samples, which must be compatible with the medical handling of patients. Another aspect is the requirement of addressing the needs of the entire population of cancer patients across the national territory. On the other hand, excessive dissemination of platforms should be avoided as it would require excessive duplication of resources and complicate their coordination. These elements favour a compromise as a distributed organisation in a series of platforms covering the country, centralised regionally around a few SIRIC or similar structures, and interconnected together to exchange experience and provide backup options in case of temporary failure. This organisation would maintain efficiency, while covering the territory nicely and linking the project to regional and other subnational medico-economical structures.
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1.5. TRAINING ISSUESOne key aspect of this project is the training of adequate personnel: NGS platform engineers, bioinformaticians, and physicians. The group anticipated a situation similar to what happened when MRI was developed: all physicians (primarily oncologists) will have to be able to understand NGS-based diagnostic and theranostic reports; these reports will be established by NGS-specialist physicians, who will master the ins and outs of the technique and its consequences for patient care. Both specialists and non-specialists will have to receive adequate training.
1.6. CONCLUSIONAnticipating the computational infrastructure required for NGS-based cancer analysis in routine medicine in the future is an uncertain exercise. At many steps there will be alternative choices, for which the group did not currently have enough elements to figure out where the optimum will be. Each option might affect the scale of the solution required, in some cases by two orders of magnitude. Moreover, compromises will probably have to be made between the future costs of biotechnologies and computational infrastructure (which we do not know), and the ideal situation where full traceability of results and unrestricted availability of scientific data for research are ensured (while preserving confidentiality of course).
Among the main parameters influencing the dimension of the infrastructure are:
1. the number of analyses per sample;2. the sequencing strategy (e.g. WGS vs exome vs targeted and the respective coverage);3. the evolution of the biotechnologies (cost, performance, and strategic policy of the providers);4. the storage policy (calls, lossy compressed data, or raw data? how long to keep data?). Note that it seems doubtful that we can expect to keep all raw data in the case of WGS.
Despite these uncertainties, the group anticipated that genomics will lead to the generation of hundreds of Petabytes per year, if not Exabytes of data. Not all these data will have to be stored, but after analysis and compression we will have to store Petabytes yearly.
Note that it might be difficult to install and maintain on all sequencing platforms the computational infrastructure required if WGS is chosen, in which case this infrastructure might be shared at the regional level (e.g. in SIRICs).
1.4. DATA SHARING FOR IMPROVED TREATMENT DECISION-MAKING AND FOR RESEARCH
Obviously the extensive data produced in the medical context will be of huge of interest for clinical and biological cancer research, provided informed consent is obtained and/or any appropriate legal and ethical requirements are met: epidemiological studies, clinical retrospective studies, and more fundamental research. One central question is whether research use would require and justify access to raw data, or if calls would suffice. Today, many projects make use of raw data and could not be conducted without them. Nevertheless it is anticipated that these requirements will diminish in the future (although it is hazardous to say when), and that the difference in cost between the two options (storing raw data vs only calls) will be so high that it will be difficult to fund for a limited number of research projects. As an indication, the cost of 1 PB storage is currently estimated at ~€1.5 million for 5 years in our hands.
One key interest in data sharing is of course the improvement of treatment decision-making. It is anticipated that the compilation of genomic profiles, treatments and clinical records will constitute a powerful reference resource for the medical oncologist. This database will be accessed either directly by oncologists, or through algorithms which would mine them to extract the most promising treatment for each patient according to accumulated clinical experience, and help the physician to make an informed decision on personalised treatment. This alone justifies enabling easy access to all profiles and clinical records, which supposes some degree of centralisation and highly reliable services. Continuous submission of profile and clinical data to this database must be organised to achieve the goal of making incremental improvements in the decision-making algorithm, based on genetic alterations of tumour cells.
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Note that both a centralised solution hosting data from all French patients and a star-like organisation can be envisaged at this stage. The group proposed two scenarios as examples among other possibilities: • In a first scenario, exome-seq or targeted-seq, and RNAseq are done on 5 samples per patient and only calls are stored. A national centralised tumour sequence databank service is set up, and requires an infrastructure with a few PB of storage and 10K cores for computation to start with. Every year a few more PB will have to be added to accumulate the growing amount of data, and of course equipment should be updated and replaced after 5 years.All of this, including bandwidth requirement, is compatible with today’s technology. Centres like Institut Curie have facilities which are only one order of magnitude below this number, making it realistic to scale up in the next 5 years.
• In a second scenario, WGS is chosen in addition to RNAseq, and again only calls (but all calls) are stored. Computations are done locally and centralised afterwards. In such a case 8 regional centres with around PB level storage and 3K cores are required, plus one central node with 10X higher capacity.
Finally, one cannot exclude an intermediary scenario where, during an interim period – at least until procedures and software are stabilised – all raw data should be stored as well.
Whatever the scenario, today the development and organisation of computer facilities must be anticipated that are one to three orders of magnitude higher in capacity than the ones we commonly have today in the field of cancer clinics and medicine. Quality and certification issues will have to be addressed at all levels of the organisation, including sequencing, computer infrastructure and software solutions. Data durability will also require that data be duplicated or triplicated, with a proportionate impact on the storage volumes (or the cost) presented above.
One remaining key question is about the involvement of private partners in the setup and running of such facilities, both for sequencing and for data analysis and storage. Given the rapid evolution of the technology, on both the biotechnological side, and informatics and bioinformatics side, outsourcing might enable the greatest flexibility. This would also come with constraints like some fragility, a high level of dependence, and higher cost.
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Milestones in managing the INCa research clinical trials registry
2007-2008 2009-2010 2011-2012 2013 2014 2015
National collaborations
• Initiation of dialogue with ANSM (French Medicine Agency, formerly AFSSAPS).
• 2009: Agreement concluded between INCa and ANSM for relaying of information on clinical trials of drugs authorised by ANSM.
• 2010: operational collaboration with ANSM.
• Several meetings with ASIP santé (French Shared Health Information Systems Agency) to develop access to the registry for physicians during multidisciplinary patient consultations.
• A total of 325 trials were relayed by ANSM (From September 2010); 174 trials were registered in the INCa registry.
• Discussion with ANSM with regard to relaying information on non-drug trials.
• Collaboration with the 3 main national public health insurers: posting the link to the INCa registry on their websites.
• Initiation of reflection with the Santor and Springer companies for the development of a mobile application, “Clinical Trials Registry,” available to practising oncologists.
• Initiation of a collaboration with the National Cancer League to make the patient committees aware of clinical research and how to use the clinical trials registry.
• Modification of the agreement beetween INCa and ANSM: all authorised trials in cancer are transmited to INCa.
• Initiation of the clinical trials results retrieving process in order to publish them on the INCa’s website, with the collaboration of patient committees.
• Initiation of a reflection in order to develop a web portal to register clinical trials data directly by sponsors.
International collaborations
• Collaboration with the US NCI: direct relaying of data from French clinical trials for entry into the NCI PDQ registry.
• Due to modifications made by NCI to the trials registration process, end of direct INCa submissions to the NCI PDQ registry.
Figures • 100 trials advertised from 50 academic sponsors.
• 2008: advertisement of clinical trials conducted by industry.
• Over 1,000 clinical trials advertised in the registry.
• Most visited INCa’s web page: over 200,000 visits in May 2011
• Over 1,500 clinical trials advertised in the registry.
• Over 1,780 clinical trials advertised in the registry.
• Over 1,920 clinical trials advertised in the registry.
2 CLINICAL TRIALS REGISTRY
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Distribution of clinical trials registered according to several criteria on 15 May 2015
Total OpenTotal 1,923 602
Academic 1,177 427Industrial 746 175
ANATOMICAL CLASSIFICATION* Total OpenBreast 272 80Prostate 106 35Respiratory system 196 52Colon and rectum 155 54Upper aerodigestive tract (UADT) and ENT
90 27
Liver and bile ducts 78 26Urinary system 66 16Female genital organs 104 40Digestive system (other than colon or rectum)
101 29
Skin – Melanomas 67 16Blood – Haematology 375 98Nervous system 94 32Sarcomas 56 21Male genital organs 7 1Endocrine system 27 9Metastases 73 21Others 180 58
*The sum may be greater than the total, since some trials belong to several categories**Also includes vaccines***Only for non-industry-sponsored trials
TYPE OF FUNDING*** Total OpenPublic 330 156Industrial 303 82Mixed 79 20Not specified 394 132
INTERVENTION* Total OpenDrug** 1,323 348Radiotherapy 190 75Imaging 112 40Surgery 117 67Transplant 57 15Pharmacology – Translational Research
142 38
PHASE Total OpenI 160 52I-II 129 43II 619 154II-III 26 6III 484 123IV 30 4None 341 135
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The Common Scientific Outline, or CSO, is a classification system organised around seven broad areas of scientific interest in cancer research. The development of the CSO is laying a framework to improve coordination among research organisations, making it possible to compare and contrast the research portfolios of public, non-profit, and governmental research agencies. This classification is subdivided in 7 categories: • Biology • Aetiology (causes of cancer) • Prevention • Early Detection, Diagnosis, and Prognosis • Treatment • Cancer Control, Survivorship, and Outcomes Research • Scientific Model Systems
As a member of the ICRP consortium (International Cancer Research Partnership), INCa and its partners use this classification to code the granted projects.
For example, figure 25 presents the overview of the French investments in cancer research of INCa, Ministry of Health (DGOS) and Inserm for ITMO Cancer – Aviesan according to this CSO classification.
Fig. 25. 2007-2014 French cancer research funding by CSO Category
25%
3%
12%
30%
19%
3%
8%
BiologyAetiologyPreventionEarly detection, diagnosis, and prognosisTreatmentCancer controlScientific models
We can notice that the repartition of investments is quite homogenous among the clinical trials and innovative molecules testing (CSO 5 Treatment) and cancer biology research (CSO1 Biology). These fields are covered by the most important call for proposals of INCa and the Ministry of Health (DGOS).
3 CANCER RESEARCH FUNDING AND CSO CLASSIFICATION
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Moreover, development of novel technologies for cancer diagnosis and prognosis (CSO4 Early detection, diagnosis and prognosis) and patient care issues (CSO6 Cancer control) represents 19% and 12%, respectively. These funding are in accordance with France priorities and the Cancer Control Plans.
Research into Aetiology (CSO2) and Prevention (CSO3) are less represented and this is why the 2014-2019 Cancer Control Plan aims to strengthen these topics. To fulfil these objectives, INCa has launched since 2012 specific call for proposals and a new university chair in cancer research prevention in 2015.
Interestingly, scientific models (CSO7) are minor among granted research projects. This trend is also observed in the other international agencies using the CSO classification. Indeed, it has been noted that researchers among the world develop new scientific models according to their specific needs to achieve their projects. Thus, they are not the main topic of the research project but tools.
These observations lead to the update of the CSO codes in order to respect research trends according the projects submitted and awarded by the different partners. Hence, the CSO 7 have been supressed and directly incorporated into the different sections. Sub-categories have also been enriched, (e.g. addition of research related to cancer stem cells), and clarified.
The 6 new different categories CSO now include:
CSO 1 BIOLOGY • Normal Functioning • Cancer Initiation: Alterations in Chromosomes • Cancer Initiation: Oncogenes and Tumour Suppressor Genes • Cancer Progression and Metastasis • Resources and Infrastructure
CSO 2 AETIOLOGY • Exogenous Factors in the Origin and Cause of Cancer • Endogenous Factors in the Origin and Cause of Cancer • Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors
• Resources and Infrastructure Related to Aetiology
CSO 3 PREVENTION • Interventions to Prevent Cancer: Personal Behaviours (Non-Dietary) that Affect Cancer Risk
• Dietary Interventions to Reduce Cancer Risk and Nutritional Science in Cancer Prevention
• Chemoprevention • Vaccines • Complementary and Alternative Prevention Approaches • Resources and Infrastructure Related to Prevention
CSO 4 EARLY DETECTION, DIAGNOSIS, AND PROGNOSIS • Technology Development and/or Marker Discovery • Technology and/or Marker Evaluation with Respect to Fundamental Parameters of Method
• Technology and/or Marker Testing in a Clinical Setting • Resources and Infrastructure Related to Detection, Diagnosis, or Prognosis
CSO 5 TREATMENT • Localised Therapies - Discovery and Development • Localised Therapies - Clinical Applications • Systemic Therapies - Discovery and Development • Systemic Therapies - Clinical Applications • Combinations of Localised and Systemic Therapies • Complementary and Alternative Treatment Approaches • Resources and Infrastructure Related to Treatment and the Prevention of the Recurrence
CSO 6 CANCER CONTROL, SURVIVORSHIP, AND OUTCOMES RESEARCH • Patient Care and Survivorship Issues • Surveillance • Population-based Behavioural Factors • Health Services, Economic and Health Policy Analyses • Education and Communication Research • End-of-Life Care • Research on Ethics and Confidentiality • Resources and Infrastructure Related to Cancer Control, Survivorship, and Outcomes Research
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GUARANTEEING THE CREATIVITY AND COMPETITIVENESS OF BASIC RESEARCH TO INCREASE OUR KNOWLEDGE OF THE DETERMINANTS OF CANCERBasic research, which helps to advance understanding of the mechanisms of cancer development, is the source of all advances in prevention, diagnosis and treatment. The Cancer control plan guarantees funding for excellent and creative basic research: over 50% of research monies will be devoted to basic research, via calls for proposals set up by the French National Cancer Institute and ITMO Cancer- Aviesan. Interdisciplinary approaches that combine biology, mathematics, bioinformatics, physics, chemistry and
human and social sciences will be encouraged through these calls for proposals. Actions aimed at reducing the impact of cancer determinants require effort and investment in technological fields (biotechnologies for health, technologies related to all aspects of genomics, imaging, robotics, instrumentation, information technology, etc.), and in the area of public health (epidemiology, screening and prevention).
Research into the environmental and social determinants of cancer will be intensified and will involve toxicology, epigenetics, molecular and analytical epidemiology, and the disciplines involved in human and social sciences and health economics.
4 2014-2019 CANCER CONTROL PLAN ACTIONS PROGRESS RELATED TO CANCER RESEARCH
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Action 12.5: Developing observation and surveillance, and improve the knowledge of cancers associated with environmental exposures among the general population
Head and associates: INVS ANSES; INCa; IReSP; ITMO cancer
MILESTONES DATE STATUS
Published by ANSES of a special report taking stock of ongoing research projects on Environment-Cancer
01-12-2014 Done
Projects selected for funding through the 2014 Environment Health and Work call for projects. New Environment Health and Work call for projects launched in 2015 with a special topic ‘Cancer and Environment’ 2015 (Anses)
01-12-2014 Done
Study of Health impact of exposure to drinking-water clorination by-products on the cancer of bladder (InVS/E1).
30-06-2015 Pending
Projects selected for funding through the 2015 Environment Health and Work call for projects. New Environment Health and Work call for projects launched in 2015 with a special topic ‘Cancer and Environment’ 2016 (Anses)
01-10-2015 Pending
Statistical analysis of the levels of biomarkers exposure and their determinants. Final report of the perinatal component of the national programme (InVS)
31-12-2015 Pending
Feasibility study for the multi-sites surveillance multi-sites of the cancers incidence around nuclear power plants (InVS/E3)
31-12-2015 Pending
Pilot study on the evaluation of the environmental exposures on collected mesothelioma within the framework of DO (InVS/E2)
31-12-2015 Pending
PROGRESS
Special report published and disseminated at the scientific meeting on 28 November 2014. See https://www.anses.fr/fr/content/les-cahiers-de-la-recherche.Selected projects for funding through the 2014 Environment Health and Work call for projects published on 9 December 2014: 33 projects submitted and 5 projects funded by ITMO Cancer - Aviesan (€0.89 M). See https://www.anses.fr/fr/content/programme-national-recherche-%C2%AB-environnement-sant%C3%A9-travail-%C2%BB-33-projets-s%C3%A9lectionn%C3%A9s-57.Results of the call for projects dedicated to impacts of an exposure to cancer environmental risks factors published: 32 projects submitted, 8 projects funded for a global amount of €3.16M.
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Action 13.1: Guaranteeing the independence and creativity of research by providing a rate of funding for basic cancer research over 50% of the total value of calls for proposals from INCa and ITMO Cancer - Aviesan
Head and associates: INCa; ITMO cancer
MILESTONES DATE STATUS
Investigator-driven call for projects in biology and basic sciences -PLBIO2014 31-12-2014 Done
Thematic call for projects dedicated to basic research-2014 31-12-2014 Done
Investigator-driven call for projects in biology and basic science -PLBIO2015 31-12-2015 PendingThematic call for projects dedicated to basic research--2015 31-12-2015 PendingPROGRESS
The global multi-year amount allocated to basic research is €44.18M and represented 53% of the global funding of call for projects managed by INCa and ITMO Cancer- Aviesan. Results of the Physics, mathematics and engineering sciences related to Cancer 2015 call for projects published: 13 projects selected (€5M). The calls for projects Biology and basic sciences 2015, Systems Biology for Cancer 2015 and Epigenetic and Cancer 2015 currently pending.
Action 17.11: Maintaining the principle of investigator-driven and competitive calls as the main method for selecting cancer research projects
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REDUCING THE INCIDENCE, MORTALITY AND SOCIAL IMPACT OF CANCER THROUGH TRANSLATIONAL AND CLINICAL RESEARCHTranslational and clinical researches transform the discoveries made through basic research into progress in public health and advances in diagnosis and treatment. Research projects aimed at identifying new opportunities for early diagnosis and improving patient survival or that enable a reduction in secondary effects and sequelae – with the help of less toxic treatments or processes of treatment de-escalation – will receive strong support. The most vulnerable populations, especially children and older people, and people with the rarest and most serious forms of cancer must be at the core of this research.
The Cancer Control Plan provides for a doubling of patient numbers included in therapeutic trials, i.e. inclusion of 50,000 patients per year in 2019, while correcting geographic inequalities in access to clinical research: research centres should be opened in the overseas departments; mobile clinical research teams must be better distributed on the territory and territorial coverage of early phase clinical trial centres (CLIP2) improved, including the designation of dedicated centres for children. In
addition, increased information will be provided to patients on ongoing and upcoming research.
In order to support tobacco control, the Cancer Control Plan provides for development of a multi-year programme of integrated research and intervention regarding issues related to tobacco, the results of which will contribute to the development of more effective strategies to combat smoking. Apart from tobacco, intervention research in cancer prevention and screening will be stimulated to promote behavioural change and to correct inequalities of access to and uptake of public policy.
Understanding the social consequences of cancer and its repercussions on the lives of patients and those close to them relies on a variety of sources (observatories, barometers, cohorts and ad hoc studies). Schemes for observation and research will be consolidated, and research in human and social sciences and public health will be encouraged in order to develop and update the knowledge of patient trajectories and living conditions for several years after their initial cancer diagnosis. Further upstream, prevention policies, including vaccination, need to be better understood and supported through population-based studies.
Action 5.1: Optimising the organisation of translational research by combining institutional funding (DGOS/ITMO Cancer/INCa via the budget from ANR) for INCa
Head and associates: Aviesan DGOS; INCa; DGRI
MILESTONES DATE STATUS
Annual launch of the recurring call for projects for translational research (PRTK 2014) 31-03-2014 Done
Selected projects for funding by evaluation committee (Results PRTK 2014) 31-03-2014 Done
Annual launch of the recurring call for projects for translational research (PRTK 2015) 31-03-2015 DonePROGRESS
Annual call for projects for translational research co-funded by DGOS and INCa. 138 pre-proposals submitted, 47 pre-proposals selected, and finally, 16 projects selected for funding (€8.5M)
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Action 5.2: Including 50,000 patients per year in therapeutic trials by 2019
Head and associates: INCa; ITMO cancer DGOS
MILESTONES (NONE FOR 2014-2015) DATE STATUS
PROGRESS
The levels of recruitments of patients to cancer clinical trials were published in the previous 2013-2014 scientific report for the year 2013. The number of patients recruited for 2013 is 44,000
Action 5.3: Pursuing the development effort of early-phase clinical trial centres (CLIP2) to provide better territorial coverage and promote the creation of dedicated centres for children
Head and associates: INCa; ITMO cancer
MILESTONES DATE STATUS
Launch of a CLIP² call for projects 28-04-2014 Done
Launch of a call for designation of new CLIP² 08-07-2014 Done
Results of designation of new CLIP² 31-03-2015 Done
2 new clinical trials authorised 31-12-2015 PendingPROGRESS
2 call for projects for early phase clinical trials launched in 2014: the first one with 5 innovative molecules from Novartis and the second one with 6 molecules from Astra Zeneca.Call for a new designation of early phase clinical trials centres launched in July 2014: 16 new CLIP² designated, 6 among them have an early phase clinical trials skill for children. June 2015: 1 project selected among the Novartis molecules and 6 projects selected among the Astra Zeneca molecules
Action 8.3: Paying closer attention to the physical sequelae of cancer treatments
Head and associates: INCa
MILESTONES DATE STATUS
Organised INCa transverse group dedicated to SELT (Long term sequelae) 30-06-2014 Done
First synthesis document from SELT group (Long term sequelae) 31-12-2014 Done
Launch of the PHRC call for projects to improve knowledge and support clinical research projects about the mechanisms underlying the development of lesions as a complication of cancer treatment.
30-06-2015 Pending
Communication on sequelae among health professionals through dissemination of path guides
31-12-2015 Pending
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Action 8.7: Promoting observation and research devoted to preventing the risk of second cancer
Head and associates: ARC Foundation INCa; IReSP
MILESTONES DATE STATUS
Validation of the calendar for actions to be led on the duration of the Cancer Control Plan, identification of potential partners
31-12-2014 Done
Identification of researchers/actors to be requested and discussion 30-06-2015 Done
Publication of the Inca’s report on smoking of the cancer patients 30-06-2015 PendingWorkshop/Special day gathering the actors interesting in call for projects which will be launched
31-12-2015 Pending
Kick-off of the multidisciplinary network’s works on the “healthcare professionals” topic 31-12-2015 Not startedPublication of INCa’s report on physical activity and cancer 31-12-2015 Not startedPROGRESS
Publication on the INCa’s report on smoking of the cancer patients reported to December 2015.
Action 9.17: Consolidating and coordinating the schemes for observation and research related to life during and after cancer
Head and associates: INCa INPES; LNCC; IReSP; ITMO cancer
MILESTONES DATE STATUS
Launch of a study on brakes for the breast reconstruction after a breast cancer (League) 30-06-2014 Done
Support of research projects (IReSP) 23-09-2014 Done
Renewal of the cancer barometer 31-10-2014 Done
Publication of the 2014 Cancer Observatory (LNCC) 23-04-2015 Done
Survey for the cancer barometer 31-05-2015 Done
Feasibility study for life 5 years after a cancer diagnosis VICAN 5 01-09-2015 PendingData collection and survey for VICAN 5 01-09-2015 PendingDefinition of a theme for the 2016 Cancer Observatory (LNCC) 31-12-2015 Not started
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Action 11.13: Improving the knowledge of cancers risk factors perceptions and behaviours
Head and associates: INCa INPES; IReSP
MILESTONES DATE STATUS
Survey for the cancer barometer 31-05-2015 Done
Meeting with partners to estimate needs to make investigation according to the progress of the cancer barometer
30-06-2015 Not started
Meeting with partners to estimate needs to make investigation according to the progress of the cancer barometer
31-12-2015 Not started
Action 11.14: Making intervention research a genuine tool for prevention and behavioural change
Head and associates: INCa ARC Foundation, IReSP
MILESTONES DATE STATUS
Workshop on interventional research in Cancer Control 31-12-2014 Done
Launch of the recurrent call for proposals in intervention research 30-06-2015 Done
Launch of the recurrent call for proposals of the tobacco Programme 29-08-2015 Pending
Action 17.9: Promoting, by monitoring the quality of clinical practices, and with the help of exacting accreditation criteria and recommendations for good practice, appropriateness in procedures and focusing of resources on care measures that comply with standards
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CONSOLIDATING FRANCE’S LEAD IN DEPLOYING TARGETED THERAPIES AND PERSONALISED MEDICINEDuring the first two Cancer Control Plans, France acquired a system of organisation that enabled a patient to be treated according to the genetic and biological features of his/her tumour, while considering the patient’s own unique features affecting his/her sensitivity to the process of carcinogenesis and to treatments. This system, which is unique in the world, relies on the oncogenetics scheme on the one hand, and the molecular genetics platforms on the other. The new sequencing technologies should help all patients at genetic risk to benefit from individualised diagnosis within times that are compatible with effective treatment. Territorial coverage of genetic counselling services will also be improved.Funding for the molecular genetics platforms will be placed on a permanent footing, and the times taken to carry out testing
will be shortened. Conditions for complete genome analysis of tumours by new sequencing technologies should be in place by the end of the Plan, since the feasibility and usefulness of this approach have been demonstrated. The target for tumour sequencing has been set at 50,000 tumours per year by 2019.The exponential development of targeted therapies predicts a profound change in clinical practice, a revolution in the treatment of many cancers, and economic impacts that call for a comprehensive policy on technologies and drugs in cancer care so that all at once innovation will be stimulated, its access will be guaranteed to the greatest possible number of people, and its costs will be controlled. This policy will rely on new processes for evaluation, and a change to faster and more versatile pricing methods for innovative treatments.
Action 5.5: Defining the priorities regarding the development of cancer drugs
Head and associates: ANSM DGOS; DGS; INCa; DGRI
MILESTONES DATE STATUS
Meeting of the partners for this action: definition of the objectives, validation of the actions plan 01-11-2014 Done
Definition of criteria for drugs development 01-12-2015 PendingPROGRESS
Constitution of a group of experts currently on-going
Action 5.6: Adapting clinical trials to reflect the conceptual advances brought about by the arrival of targeted therapies
Head and associates: INCa DGOS; ANSM; DGRI
MILESTONES DATE STATUS
Launch of the ACSé-Vemurafenib clinical trial 26-12-2014 Done
Authorisation request of at least one genomics-guided clinical trial either transpathology or assessing the combination of innovative drugs
31-12-2015 Not started
PROGRESS
The clinical trial AcSé-vemurafenib started on July 2014, recruited 23 patients on June 2015. As a conclusion of the last partners meeting, which held on April 2015, an inventory of the adaptative trials led in France or at an international level appeared to be necessary.
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Action 6.1: Developing the oncogenetics scheme, and improve access to it
Head and associates: INCa DGOS
MILESTONES DATE STATUS
Publication of the synthesis of the 2013 oncogenetics activity 19-12-2014 Done
Publication of the dashboard of the 2014 oncogenetics activity 18-12-2015 Not startedPublication of the 2013-2014 assessment of the follow-up for cancer predisposed people 18-12-2015 Not startedLynch syndrome and MSI screening: Finalisation of the actions concerning the improvement to access to oncogenetics scheme
18-12-2015 Not started
Action 6.2: Consolidating access to molecular testing
Head and associates: INCa DGOS
MILESTONES DATE STATUS
Survey on the lead times of the molecular testing in the oncogenetics platforms of 5 Health Regional Agencies (ARS)
31-08-2014 Done
Survey on the access to the molecular testing with the oncologists giving chemotherapy treatments 31-12-2014 Done
Results of the study on economic impact of the use of targeted NGS techniques 31-12-2015 Not startedPROGRESS
Analysis of the second survey realised with oncologists will allow characterising practices to have a molecular testing more precisely depending in the type of care structure.
Action 6.3: Implementing, from 2014, clinical trials that include tumour exome analysis for 3,000 patients with breast cancers, colon cancers, lung cancers and sarcomas, in order to demonstrate the large-scale feasibility of these approaches and their utility in patient care
Head and associates: INCa Aviesan
MILESTONES DATE STATUS
Opening of the recruitment of patients for the breast and lung clinical trials SAFIR02 (Targeted sequencing)
31-12-2014 Done
Authorisation of new genomic-guided trials including exome sequencing 31-12-2015 PendingPROGRESS
Implementation of guided by exome sequencing clinical trials are in the course of implementation in the colorectal cancers and the sarcomas.
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Action 6.4: Supporting the implementation and performance of high-throughput sequencing for all cancers by the end of the Plan
Head and associates: INCa DGOS; ITMO cancer
MILESTONES DATE STATUS
Monitoring group for next generation-sequencing implementation in clinical routine 30-06-2014 Done
Elaboration of a guide of best practices for analyses realised by NGS technologies 30-06-2015 PendingTechnical validation of projects concerning tumoral exome sequencing in the clinical trials
31-12-2015 Not started
PROGRESS
2014: 9 pilot projects funded for the implementation of the targeted NGS for a diagnosis aim into oncogenetics laboratories and molecule genetics platforms. At the end of 2014, use of NGS for a part of their activity in clinical routine in 10 oncogenetics laboratories and 2 molecular genetic platforms.4 referring teams selected. Their mission: To develop bioinformatics NGS-data analysis tools and set up plans in order to disseminate these tools to all the platforms. A working group set up by INCa to publish recommendations at the autumn 2015 and to obtain the ISO 15189 accreditation of laboratories.
Action 6.5: Generating and understanding big data
Head and associates: Aviesan INCa; DGRI
MILESTONES DATE STATUS
Start of the activities of the Working group 22-12-2014 Done
Proposals on the management, storage and interpretation of the data 31-05-2015 Done
Programming of the action 30-09-2015 Not started
Action 6.6: Developing new experimental models to validate genomic data, develop new markers derived from proteomics, test the screening of new drugs, and commercialise these programmes
Head and associates: INCa; ITMO cancer
MILESTONES DATE STATUS
Symposium on results of the ICGC France-2015 projects 31-12-2015 Not startedPROGRESS
December 2014: ITMO Cancer funded a new international ICGC project on B prolymphocytic leukaemia. A set up plan for functional validation of genomic data generated by national and international projects currently on-going.
Action 6.7: Developing algorithms for identifying molecular abnormalities that cause cancer and prioritising projects aimed at developing tools to assist with treatment decisions as part of the Research Programme on the Performance of the Care System
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DEVELOPING THE STRUCTURES FOR CANCER RESEARCH AND CAREER PATHSIn the research area, the strong interaction between the INCa and ITMO Cancer - Aviesan will be renewed, via a new framework agreement between the two institutions. The scientific management of research monies from the Cancer control plan will be entrusted to INCa under this framework.
The continuum between basic research, translational research and clinical research, together with collaboration between disciplines, will be consolidated within the integrated cancer research sites (SIRICs). The latter will be regularly evaluated, particularly at the time of the new designation procedure following their first five years of existence.
The roles of the interregional canceropoles will be redefined, to provide better interaction with the SIRICs and with the regional
health structures, the most important of which are the Regional Health Agencies (ARSs) and regional oncology networks (RRCs), with which they will interact to provide easier access of patients to clinical research.
Interactions between users’ representatives, patients and researchers will be encouraged, so that issues raised by patients may be translated into research questions.
Developments in biomedical research also require modifications to career pathways, particularly the decompartmentalisation of the disciplines involved, from biology to human and social sciences, and including epidemiology and engineering sciences. Specific assistance will be granted to universities that establish dual education programmes, for example combinations of biology and mathematics, health and statistics.
Action 5.4: Involving patients and their representatives in clinical trials and in the pathway enabling access to this research
Head and associates: LNCC INCa
MILESTONES DATE STATUS
Integration of patients and their representatives in the design and the review pf clinical trials protocols 31-12-2014 Done
Participation of biomedical research patients’ committees in disseminating of clinical trials results
31-12-2015 Not started
Publication of results of clinical trials when ended in the INCa’s Cancer research clinical trials registry
31-12-2015 Not started
PROGRESS
Integration of patients and their representatives in the design and the review and proofreading of clinical trials protocols currently on-going, through an INCa-League’s agreement to be signed in order to allocate appropriated resources. INCa will support 50% of the global amount allocated.85 proofreaders included in patients’ committee – 97 protocols reviewed in 201491 proofreaders included in patients’ committee in 2015- 37 protocols reviewed on 26-05-2015.The French League led an anonymous investigation to know why a patient accepts or refuses to participate in a clinical trial. The survey was broadcast at the end of February 2015 and the analysis of the 262 exploitable answers is currently on-going.
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Action 5.11: Clarifying the process of identifying and evaluating technological
Head and associates: DGOS INCa; DGRI; ITMO cancer; ITMO Health Technologies
MILESTONES DATE STATUS
Technology Developments Committee (Comité de Veille Techologique CVT) and definition of the scope of the technology development
31-12-2014 Pending
Evaluation of expensive consumables 30-05-2015 PendingInnovation package 30-06-2015 Done
Based on international recommendations, papers and communications, establishments of terms of Technology Developments
30-06-2015 Not started
Continuation of the PREPS programme allowing the evaluation of innovative organisational typologies 30-06-2015 Done
Deployment of defined terms of Technology Developments to all the actors 31-12-2015 Not startedPROGRESS
An innovation design step currently on-going: Organisation of the national and local piloting, definition of the process to obtain the data, the scope of the eligible technologies, identification of local actors to be mobilised. Aim to identify and prioritise the technologies at their early stage of emergence and to prepare, most upstream possible, the research related to these technologies, their evaluation and funding.
Action 13.2: Supporting the continuum between basic research of excellence and clinical research in the Integrated cancer research sites (SIRICs)
Head and associates: INCa; ITMO cancer DGOS; DGRI
MILESTONES DATE STATUS
Validation of the 2011-2012 SIRIC mid-term assessment 31-10-2014 Done
Establishment of the international Assessment Committee 30-06-2015 Done
Hearing of SIRICS with the international Assessment Committee 31-12-2015 Not startedPROGRESS
Planning and process validated by the partners of the programme (DGOS and Inserm for ITMO Cancer). Information send to SIRICs.
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Action 13.3: Developing initial training to meet the needs of cancer research
Head and associates: DGESIP INCa; DGRI; ITMO cancer
MILESTONES DATE STATUS
A joint DGESIP, INCa and ITMO Cancer work to identify the appropriate doctoral school able to welcome students from other disciplines
31-12-2015 Not started
PROGRESS
2011-2014: Funding of PhD school “Frontiers in Life Sciences” by ITMO Cancer. 2014: 2 students working in the cancer area funded by ITMO Cancer.
Action 13.4: Increasing the attractiveness of careers in cancer-related research
Head and associates: Aviesan DGRI
PROGRESS
Results of the ITMO Cancer’s call for projects dedicated to Training in Translational Research published. Success of this call among doctors, pharmacists and veterinarians.
Action 14.1: Expanding In the area of cancer, the participation of users in steering, managing or delivering cancer care or research bodies
Head and associates: INCa; ITMO cancer DGOS; DGRI
MILESTONES DATE STATUS
Involvement of users’ representatives of our health system into the Cancer Control Plan Steering Committee
30-06-2014 Done
Appointment of user’ representatives into the INCa’s Scientific Advisory Board and into the Deontology and Ethics Committee
31-12-2014 Done
Involvement of users’ representatives of our health system in the establishment of technical permanent groups and especially, dedicated to screening of cancers
30-06-2015 Done
PROGRESS
3 users’ representatives appointed into the Cancer Control Plan Steering Committee: The President of the French League against Cancer, the President of the inter-associative Health Collective and the President of the National Union of patients affected with cancer or leukaemia. Participation of users’ and patients’ representatives extended to the whole consultative bodies at INCa: 1 users’ representative into the Deontology and ethics Committee and 2 into the Scientific Advisory Board. March 2015: INCa’s meeting with charities for cancer-affected people to discuss the relationships between charities and structures and actors involved in the field of cancerApril 2015: Call for designation for technical groups on cancer screening.The users’ representatives of the Scientific Advisory Board participated to the monitoring of the SIRIC programme. Next meeting on September 2015: Discussion on the partnership between SIRIC and users’ representatives.
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Action 16.6: Refocusing the roles of the Canceropoles in areas that are not covered by other organisations (emerging projects in innovative themes and technologies, and from young teams, and regional or interregional research priorities, including technology transfer)
Head and associates: INCa DGOS; DGRI
MILESTONES DATE STATUS
Publication of call for designation 2015-2017 19-03-2014 Done
Results of the call for designation 2015-2017 30-09-2014 Done
Signing of Objectives and Performance Contract (Contrat d’Objectif et de Performance COP) 29-05-2015 Done
Monitoring of canceropoles’ missions according to the COP 30-12-2015 Not started
Action 16.7: Organising in 2016, after five years of existence of the 8 SIRICs, a new call for applications open to both previously funded structures and new proposals
Head and associates: INCa DGOS; DGRI
MILESTONES DATE STATUS
Validation of call for designation planning 31-12-2014 Done
Validation of the process of the call for applications with the partners (Inserm and DGOS)
31-12-2015 Not started
PROGRESS
The planning takes into account the needs to have only one call as well for the renewal of the 2011-2012 SIRIC but also for new submitted proposals for designation.
Action 16.8: Coordinating the actions of the SIRICs and Canceropoles in order to strengthen research in a given territory
Head and associates: INCa DGOS; DGRI
MILESTONES DATE STATUS
Specific recommendations following the new designation of canceropoles included in the mi-term assessment report of SIRIC
31-12-2014 Done
Specific assessment criteria in the mid-term assessment of SIRIC ( reports and hearings) 30-06-2015 PendingPROGRESS
The importance of coordination between SIRIC and Canceropoles is a specific article in the COP and in the mid-term assessment of SIRIC.
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Action 16.9: Bringing support to the development of cancer control programmes led by international agencies, especially those targeting French-speaking countries in Sub-Saharan Africa and the southern Mediterranean
Head and associates: INCa Aviesan Sud; ITMO cancer
MILESTONES DATE STATUS
Overview of the situation of the registries of cancers in Senegal and Cote d’Ivoire 31-07-2014 Done
Support to the annual meeting of the Mediterranean network EUROMED (December 2014) 25-12-2014 Done
Renewal of the agreement with Senegal Health Authority 29-01-2015 Done
Strategic meeting of the World Health Organisation 27-04-2015 Done
Collaborative Centre OMS – feasibility of the cervical cancer screening through HPV screening in the Maghreb countries
15-10-2015 Pending
Preparation of the 2015 AORTIC group dedicated to prostate 03-12-2015 PendingSupport to the Global Initiative for Cancer registries from IARC 31-12-2015 PendingPROGRESS
INCa attended to the technical meeting of WHO in order to define the priorities in terms of Cancer Control – Through its financial support to the Global Initiative for Cancer Registries, INCa contributed to the establishment of 2 registries in francophone Africa.The collaboration with AORTIC consisted in developing new research and public health networks focused on cervical and prostate cancers.
Action 16.10: Developing collaborative networks between France and the southern countries in the areas of research and public health, based on infrastructures developed by Aviesan Sud partners (IRD, Pasteur Institutes, Mérieux Foundation, etc.) in the target countries
Head and associates: INCa Aviesan Sud; ITMO cancer
MILESTONES DATE STATUS
Africa/AORTIC HPV Research/ Public Health Multilateral cooperation: Meeting of the HPV network
27-01-2015 Done
Laos Merieux Foundation Research cooperation: HPV – HIV project 10-09-2015 PendingPROGRESS
INCa strengthened its partnerships with Aviesan Sud by supporting research projects in Asia (Laos, Thaïland,) and Africa (Gabon, Madagascar, Cameroon, Côte d’Ivoire, Senegal). The renewal of the agreement with IRD belongs to this strategic coordination. Through its support to research projects dedicated to infections, INCa aimed at defining a strategic prevention and assessing the predictive value of the different screening methods INCa started the development of a collaborative network with 5 African francophone countries (Senegal, Gabon, Côte d’Ivoire, Cameroon, et Madagascar) with the aim of cervical cancer control, one the priorities of the 2013-2020 WHO’s actions plan for non-infectious diseasesINCa organised a prefiguration meeting with representatives of 9 African countries in order to set up a francophone network for prostate cancer research including French teams from France, Antilles, and sub-Saharan Africa.
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Action 16.11: Participating actively in coordination actions of the international cancer research funders group and extend these with the European countries, the United States and with emerging countries
Head and associates: INCa Aviesan international
MILESTONES DATE STATUS
Tobacco: Signing Melbourne Call for international action and research on Tobacco control and cancer 05-12-2014 Done
Tobacco: International Consortium for Action and Research on Tobacco (ICART) meeting 19-03-2015 DonePROGRESS
March 2015: Participation to the CRUK and NCI’s meeting according to INCa’s engagement to the Melbourne Call on December 2014. Submitted proposals for visibility improvement of the network, clarification of the role of funders, actions on the most appropriated lever. Agreement of INCa to support the consortium.
Action 17.12: Strengthening the scientific monitoring of funded projects
Head and associates: INCa; ITMO cancer DGOS
MILESTONES DATE STATUS
Aviesan Mission for programming research in Health 31-12-2015 PendingPROGRESS
In 2014, Health and Research Ministries entrusted to Aviesan the mission to prepare an action plan and to organise Programming of Research in Health. The objective was an implementation in 2015. A Steering committee gathered and three working groups designed: Logistic and organisation, assessment, and scientific programming. The analysis of these groups highlighted a globally common methodology about assessment, scientific committees, and strategic piloting. Nevertheless, it seems desirable to converge on common and coherent procedures for each steps of call for projects. The Steering Committee has to determine the priorities for these subjects.
Action 17.13: Developing shared tools for evaluating cancer research projects
Head and associates: INCa; ITMO cancer DGOS
MILESTONES DATE STATUS
Starting the reflection 15-10-2014 Done
Overview of existing assessment tools at an international level 31-12-2015 PendingPROGRESS
In 2014, Working group with different partners of the cancer Control Plan or potential partners which funded research at a national level: Shared interest to set-up a methodology for assessment of research impacts (ex-post evaluation) of the funded projects and to have appropriated tools for ex-ante (See action 17.12) but also ex-post assessment of research.
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SHARING AND DISSEMINATION OF RESEARCH RESULTSRaw data and results of research must be shared within the scientific community at national, European and international level, especially under the Global Alliance for Genomics and Health, in order to spur medical progress. All citizens will be regularly informed of scientific advances, in an effort to report on the Nation’s efforts regarding cancer research.
Action 7.16: Improving information on clinical cancer trials
Head and associates: INCa; ITMO cancer LNCC
MILESTONES DATE STATUS
Teams brainstorming on the process of the collaboration. Design of a survey 30-09-2014 Done
Final validation of the process 30-12-2015 PendingPROGRESS
The validation of the results and their publication need to be defined, inducing a delay in the realisation of this action.
Action 13.5: Sharing information and data between professionals and the general public at national and international levels
Head and associates: INCa; ITMO cancer
MILESTONES DATE STATUS
GLOBAL ALLIANCE: Signing the adhesion agreement 30-12-2014 PendingThird GLOBAL ALLIANCE meeting 11-06-2015 DonePROGRESS
Signing of the agreement currently on strategic and juridical analysis. Due to its coordination role, research and innovation funding, INCa promote a common strategy aligned with other French organisations concerning clinical and genetics data, before its engagement. Open-access free of charge for some journals and with counterparts for others. In order to incite the researchers to ask an open-access for their publications, INCa and ITMO Cancer plan to have a dedicated part of the requested budget in the next calls for proposals.
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NOTES
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FRENCH NATIONAL CANCER INSTITUTE SCIENTIFIC REPORT / 2014-2015
FRENCH NATIONAL CANCER INSTITUTE SCIENTIFIC REPORT / 2014-2015
The French National Cancer Institute is the health and science agency in charge of cancer control.
Published by the French National Cancer InstituteAll rights reserved – Siren 185 512 777
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ISSN 2276-5751ISBN: 978-2-37219-150-0
ISBN net: 978-2-37219-151-7
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This document was published in October 2015. It is available at the following address:Institut National du Cancer (INCa)Direction de la recherche52, avenue André Morizet – 92100 Boulogne-Billancourte-cancer.fr© 2015. Institut National du Cancer (INCa)
Since 2003, the fight against cancer in France has been structured around national plans to mobilise all stakeholders on prevention, screening, care, research and support for patients and their friends and families. The 2003-2007 Cancer Control Plan set up the first comprehensive strategy to fight cancer; the second Cancer Control Plan (2009-2013) introduced the notion of personalised care.The 2014-2019 Cancer Control Plan intends to give each and every person, all over France, the
same chances for recovery and implement innovation even faster for patient benefit. This plan includes 17 objectives, all gathered around four major health priorities:l Cure more patientsl Preserve continuity and quality of lifel Invest in prevention and researchl Optimise management and the organisations efficiencyThe Cancer Control Plan falls within the implementation of a national health strategy and the “France-Europe 2020” Strategic Agenda for research, technology transfer and innovation.
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