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OCTOBER 2016

FRENCH NATIONAL CANCER INSTITUTE SCIENTIFIC REPORT / 2015-2016

RAPC

SAN

G16

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FREN

CH N

ATIO

NAL

CANC

ER IN

STIT

UTE

SCI

ENTI

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2016

52, avenue André Morizet92100 Boulogne-Billancourt

France




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 : 978-2-37219-242-2

ISBN net : 978-2-37219-243-9

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 2016. It is available at the following address:Institut National du Cancer (INCa)Direction de la recherche52, avenue André Morizet – 92100 Boulogne-Billancourte-cancer.fr© 2016. 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.

Cancer Plan2014-2019

FRENCH NATIONAL CANCER INSTITUTE 2015-2016 SCIENTIFIC REPORT

3

SCIENTIFIC REPORT 2015-2016


4

TABLE OF CONTENTS

PREAMBLE 6

Key figures 8Clinical trials indicators 11Molecular genetics centres: activity indicators 12International framework 14

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 2015-2016 cancer research activity 29

1. SUPPORT IN BIOLOGY AND BASIC SCIENCES FOR CANCER RESEARCH 31

1.1. Research programmes 31

1.2. The genomic and the epigenomic programmes 40

2. TRANSLATIONAL AND INTEGRATED RESEARCH 45

2.1. Research programmes aiming to accelerate cross‑disciplinarity and transfer of knowledge to clinical practice 45

2.2. The Translational and multisdisciplinary Research Training Programmes 50

2.3. Strengthening of organisation and infrastructures dedicated to translational/integrated research in integrated cancer research sites (SIRICs) 54

3. CLINICAL RESEARCH AND DEVELOPMENT OF EARLY‑PHASE TRIALS FOR INNOVATIVE DRUGS 56

3.1. Clinical cancer research programmes 56

3.2. Early‑phase clinical trials for innovative drugs 59

3.3. Personalised medicine tools and programmes 62

3.4. Organisation of clinical research and strengthening of structures, infrastructures and tools 68

4. RESEARCH IN HUMAN AND SOCIAL SCIENCES, EPIDEMIOLOGY AND PUBLIC HEALTH 72

4.1. The recurrent programme for Human and social Sciences (HSS), Epidemiology and Public Health (EPH) Research 72

4.2. Population Health Intervention research 75

4.3. Initiatives developed to support research on environmental risks 77

4.4. PhD Programme in HSS‑EPH 2016 in collaboration with academic partners 79

5. INTERNATIONAL COMMITMENTS 81

5.1. Strategic vision, mission and values 81

5.2. INCa’s European commitments 82

5.3. INCa’s global commitments 84

6. BIBLIOMETRIC STUDY, EVALUATION AND REVIEW OF RESEARCH INVESTMENT 90

6.1. Bibliometric study 90

6.2. Focus: Trends in the French funding stream of intervention research addressing all aspects of cancer control, a cross‑sectional analysis 2010‑2014 95

6.3. International evaluation 97

6.4. Review of research investments 98


5

Part 3. Focus on strategic topics for advancing cancer research 103

1. CHALLENGES ASSOCIATED WITH THE ARRIVAL OF IMMUNOTHERAPIES 106

1.1. Biological and clinical databases: a unique tool to assess and monitor immune checkpoint inhibitors efficacy 106

1.2. Resources and infrastructures integration to face the immunotherapy challenges 107

2. THE TRIPOD PROGRAMME: GENERATION, INTEGRATION AND SHARING OF BIOLOGICAL AND CLINICAL DATA WITHIN THE SCOPE OF PRECISION MEDICINE 109

2.1. Data collection and integration: development of decision‑making tools 109

2.2. Data sharing for coordinated targeted therapies assessment 110

3. STUDYING TO SET UP A SPECIFIC PROGRAMME SUPPORTING LATE‑PHASE CLINICAL TRIALS 111

3.1. Late clinical trials close to cancer care management to improve patients’ survival 111

3.2. Identifying the main challenges of current clinical practices 112

4. STRENGTHENING THE STRUCTURING OF CANCER PUBLIC HEALTH RESEARCH 113

4.1. Fostering the capabilities of human and social sciences, epidemiology and public health 113

4.2. Supporting the visibility of human and social sciences, epidemiology and public health research 113

5. NEW INTERNATIONAL COMMITMENTS 115

5.1. European initiative FLAG‑ERA on digital medicine for cancer 116

5.2. Joint Action on Rare Cancers 116

5.3. Global network on prostate cancer 117

Conclusion 118

Appendices 119

1. CLINICAL TRIALS REGISTRY 120

2. CSO‑COMMON SCIENTIFIC OUTLINE 122

3. 2014‑2019 CANCER CONTROL PLAN ACTIONS PROGRESS RELATED TO CANCER RESEARCH 123

6FRENCH NATIONAL CANCER INSTITUTE 2015-2016 SCIENTIFIC REPORT

The 2015‑2016 scientific report, prepared by INCa in collaboration with Aviesan Cancer Institute (ITMO Cancer‑Aviesan), summarises the activities carried out this year in the field of research and innovation supported by the National cancer control plan (NCCP). We would like to take the opportunity to thank the Scientific Advisory Board’s (SAB) members for advising and guiding the Institute during its structuring process and providing relevant recommendations for its initiatives.The present report highlights the input of INCa and ITMO Cancer‑Aviesan during this 12‑month period to pursue the task of providing strong support in basic science research, translational research and training, clinical research, and research in the fields of human and social sciences, epidemiology and public health through the coordination of research programmes with its partners and the support of infrastructures and networks. The critical analysis of each programme is provided herein.This period’s focus has been on tobacco prevention, management of children with cancer and access to personalised medicine. Through all these different programmes, INCa has had an instrumental role on a European and international scale. The Cancer control plan intends to develop and roll out targeted therapies and personalised medicine and to strengthen the links between care and research, and transversely, places an emphasis on support and access to innovation for the treatment of malignant diseases. INCa coordinates personalised medicine programmes based on the patient’s tumour molecular profile, the PAOLA clinical trial including European centres based on BRCA status and the AcSé programme. The latter was described in Nature Reviews Clinical Oncology and the results of the two first AcSé programmes presented at ASCO 2016 meeting. Additionally, spin‑off results from INCa’s participation in the International Cancer Genome Consortium (ICGC) were achieved in 2016 with major results from two studies of the Breast Cancer Project, launched in 2008, published in Nature and Nature Communications showing how whole exome sequencing will further allow better tumour definition and disease classification. The role of coordination and support in cancer research of INCa and ITMO Cancer‑Aviesan cannot be achieved without providing strong parallel support whether at the funding or management level of structures and infrastructures. By way of example, the above achievements in personalised medicine and

PREAMBLE

7FRENCH NATIONAL CANCER INSTITUTE

2015-2016 SCIENTIFIC REPORT

patient access to therapy could not be achieved without the molecular screening performed in the 28 molecular genetics centres throughout France, the collaborative clinical groups or the 16 early‑phase clinical trials centres (CLIP²) and the collaboration with its partners on a national and international level, in the academic or private sector. Multidisciplinary integrative cancer research is supported on a regional level by the Cancéropôles, Biological and clinical databases (BCBs) for specific tumours, and Integrated cancer research sites (SIRICs). In addition, the Institute is developing the TRIPOD platforms to improve clinical and translational research linked with the existing structures and infrastructures.On an international level, the translational programme from research to public health set up by INCa on cervical cancer control is gaining momentum, the President has had the privilege to be a member on the Strategic Advisory board of the Global Alliance for Genomic and Health (GA4GH), INCa serves as a member on the International Cancer Genome Consortium (ICGC) and the International Cancer Research Partnership (ICRP). On a European level, INCa is continuing its partnership in the ERA‑Net TRANSCAN‑2 network of research funding in translational research and has joined the FLAG‑ERA initiative to support the first transnational programme dedicated to Digital medicine for cancer.One of INCa and ITMO Cancer‑Aviesan goals is to promote research in fields where unmet needs have been identified and to provide the settings where those involved in various disciplinary approaches can exchange and work synergistically to develop future research projects and networks. Due to the increasing complexity of the discoveries in the tumour cell biology field, understanding and managing cancer will only be achieved through the training of young doctors, biologists, and researchers for the future challenges ahead. With support from the two supervising ministries, the International Scientific Advisory Board and Board of Directors, INCa will have provided continuous financial support for research projects (and maintained and increased this support despite budget restrictions) based on transparent methods, international Evaluation and participation of patient advocates in all the INCa’s calls for proposals and in every field of cancer research.All my thanks go to all colleagues at INCa, Aviesan and Inserm for their critical contributions to the programmes and this report.

Prof. Christine Chomienne

Director of INCa's Research and Innovation programmes

Director of the Inserm Cancer institute

Director of ITMO Cancer‑Aviesan


8

KEY FIGURES

53%53%

4%8%

18%

23%

3%

24%

20%

Investigator-driven calls

Strategic research initiatives/thematic programmes

Platforms/resources/infrastructures

Research training/ Young teams of excellence

HSS-EPH

Translational

Biology and basic sciences

Clinical

2007-2015 FUNDING ALLOCATION PER PROGRAMME TYPE

2016 PROGRAMMES FUNDED BY INCa, INSERM FOR ITMO CANCER-AVIESAN AND MINISTRY OF HEALTH (DGOS) - MULTI-YEAR FUNDING* Provisional

0

5

10

15

20

25

30

35

DGOSInsermINCa

Investigator-driven projectsStrategic research initiatives/thematic programmes

Research training and young teams of excellencePlatforms, resources, infrastructures

€ M

illio

n Clinician training in biologyFDV PhDATIP-Avenir (cancer field)Translationnal trainingHSS research chair*HSS PhD

IBiSA Platforms*Equipments*Cooprative intergoups

Heterogeneity*Tobacco programmeAnsesEnvironmentPhysics, mathematicsIntervention reseachTranscan

PRME-K*PHRC-K*PLSS-EPHPRT-K*PLBIO


9

TRENDS IN MULTI-YEAR FUNDING AWARDED TO INVESTIGATOR-DRIVEN CFPS MANAGED BY INCa*No translational research projects in 2008 - 2016 Clinical and translational results pending

TRENDS IN THE NUMBER OF PROJECTS SELECTED IN INVESTIGATOR-DRIVEN CFPS MANAGED BY INCa *No translational research projects in 2008 - 2016 Clinical and translational results pending

0

10

20

30

40

50

60

70

80

Clinical* Translational*Human and Social sciences, epidemiology, public healthBiology and basic sciences

Nb

of p

roje

cts

2016201520142013201220112010200920082007

0

50

100

150

200

250

300

350

400

Clinical Translational*Human and Social sciences, epidemiology, public healthBiology and basic sciences

Nb

of p

roje

cts

2016201520142013201220112010200920082007

0

5

10

15

20

25

Clinical* Translational*Human and Social sciences, epidemiology, public healthBiology and basic sciences

€ M

2016201520142013201220112010200920082007

TRENDS IN THE NUMBER OF PROJECTS SUBMITTED TO INVESTIGATOR-DRIVEN CFPS MANAGED BY INCa*No translational research projects in 2008


10

TRENDS IN THE MEDIAN VALUE OF THE 3 MOST FUNDED INVESTIGATOR-DRIVEN CFPS MANAGED BY INCa

0

100,000

200,000

300,000

400,000

500,000

600,000

0

100,000

200,000

300,000

400,000

500,000

600,000

Median value of projects submittedMedian value of projects selected

2014 20152013201220112010200920082007

2014 201520132012201120102009200820070

100,000

200,000

300,000

400,000

500,000

600,000

2014 20152013201220112010200920082007

Clinical research

Biology and basic sciences

Translational*

*No translational research projects in 2008


11

CLINICAL TRIALS INDICATORS

NUMBER OF CLINICAL TRIALS OPEN FOR PATIENT ENROLMENT PUBLISHED IN THE NATIONAL REGISTER (15 MAY 2016)

TRENDS IN PATIENT ENROLMENT IN CANCER CLINICAL TRIALS

0

10,000

20,000

30,000

40,000

50,000

201420132012201120102009200820072006200520042003

Nb o

f pat

ient

s en

rolle

d

24,037

26,00328,167

34,06742,803

48,246

37,49244,023

2015

0

100

200

300

400

500

600

700

800

108

233

417553 643

687

517602

528

Apr-0

7Ju

l-07

Dec-

07Ju

l-08

Dec-

08Ju

l-09

Dec-

09Ju

l-10

Dec-

10Ju

n-11

Dec-

11Ju

n-12

Dec-

12Ju

n-13

Dec-

13M

ay-1

4

592

Oct-1

4De

c-14

May

-15

Dec-

15Ap

r-16

May

-16


12

MOLECULAR GENETICS CENTRES: ACTIVITY INDICATORSPredictive molecular testing in France in 2015: Activity of the 28 molecular genetics centres

Amiens

Lille

Rouen

Caen

Brest

RennesAngers

Nantes

Poitiers

Bordeaux -La Réunion

Source: INCa, 2016Drafted by INCa’s Research Division, 2016

Toulouse

Montpellier - Nîmes

Marseille

Number of patients who benefited from predictive molecular testing in 2015

10,000

6,000

3,000

1,500

Nice

GrenobleSt-Etienne

LyonClermont-Ferrand

Limoges

Tours - Orléans

Dijon

Besançon

Strasbourg

Nancy

Reims

Gustave Roussy

CurieAP-HP

Paris

Paris


13

EXAMPLE: SCREENING FOR KRAS MUTATIONS IN PATIENTS WITH COLORECTAL CANCER

EXAMPLE: SCREENING FOR EGFR MUTATION IN PATIENTS WITH LUNG CANCER

0

5,000

10,000

15,000

Nb

of p

atie

nts

enro

lled

1,100

10,012

17,24616,581

19,34721,85517,003

18,568

20,000

25,00021,375

201520142013201220112010200920082007

0

10,000

20,000

30,000

Nb

of p

atie

nts

enro

lled

1,269 2,667

16,83420,750 24,558

26,614

21,995

23,336

20152014201320122011201020092008


14

INTERNATIONAL FRAMEWORK

JARC

Joint Action on RARE CANCERS

WP9 – Childhood cancers

Global Partnerships

Europe

Bilateral agreements

Regional Networks

CANCON

Quality improvement in cancer control

(WP8 – Survivorship & rehabilitation)

EUROMED

Screening & early diagnosis in Mediterranean

countries

JARC


WP5 – Quality of care

CANCON


(WP9 – Screening)

CCP Transversal objectives

IARC - GICR

Global initiative on cancer registry

COFAC COL

Collaborative network on cervical cancer

control

LAOS / THAILAND

Research & public health projects on

cervical cancer control

SENEGAL

Agreement on cancer control

WHO

Implementation of WHO guidelines on cervical cancer

control

Childhood, adolescents

and young adults cancers

Reducing inequities

Enabling earlier diagnosis

(Objective 1)

Public health

(Objective 15)


15

2016 INCa’s International portfolio according to the Cancer control plan objectives

CANCON


(WP6 – cancer care network)

CANCON



European Commission EXPERT

GROUP on cancer control

US NCI

US National Cancer Institute - Global

coordination

NCC – CHINA

National Cancer Center – cancer control

IARC

International Agency for Research on Cancer

– INCa sits at IARC Board of Directors

FRENCH POLYNESIA

Cancer control

ICGC

International Cancer Genomic Consortium

ICART

International Consortium for Action

and Research on Tobacco Control

FLAG ERA

Digital medicine for cancer

GA4GH

Global Alliance for Genomics and Health

TRANSCAN 2

Translational research

ICRP

International Cancer Research Partnership

ICGC


US NCI

National Cancer Institute - Early phase

clinical trials

IRCI

International Rare Cancers Initiative

JAPAN

Memorandum of Understanding with

Japan National Cancer Center on research

2014-2019 Cancer Control Plan objectives

Innovation & research

(Objectives 5 & 13)

Comprehensive and personalised

cancer care (Objective 7)

Personalized medicine

(Objective 6)

Tobacco control (Objective 10)

Global Partnership / Cancer Control (Objective 16)


16



This 10th report to INCa’s international Scientific Advisory Board (SAB) reviews actions both from INCa and Aviesan’s Multi‑Organisation Thematic Institute for Cancer (ITMO Cancer‑Aviesan). This report corresponds to the 3rd year of implementation of the 2014‑2019 Cancer control plan.Importantly, INCa’s scientific report is the key element for SAB members to review the actions undertaken and subsequently advise and guide the Institute during its structuring processes and its initiatives.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, 16 CLIP² centres, 28 molecular genetics centres, and 13 designated cooperative intergroups have made the base for cancer research excellence in France. In the last few years, INCa has established a highly proactive policy, recognised by European and American colleagues, to expand access to targeted therapies for patients identified as candidates through molecular tests.The 2015 and 2016 years have marked a turning point for all the structures supported by INCa, which aims to optimise the proposed infrastructures as well as to ensure nationwide coverage: SIRICs were the subject of a mid‑term evaluation, the designations of the CLIP² centres and the regional Cancéropôles have been renewed and the set‑up of the novel initiative, the TRIPOD platforms, to promote translational and clinical research, is underway. The Institute’s goal is to support the foreseeable development of medicine based on specific biological parameters of tumours and individual patients by providing research and treatment facilities with a greater capacity for more advanced testing.

The first part of this report is focused on the recommendations of INCa’s SAB, chaired by Prof. Daniel Louvard. The section summarises the previous recommendations and describes the actions conducted to implement novel initiatives and/or to reinforce the major existing programmes for the following topics: • Translational research and multidisciplinary training; • Molecular genetics, biology and sciences related to cancer research; • Evaluation and key performance indicators of clinical research; • Strategies for research in public health and human and social sciences; • Collaborations on national, European and international levels; • Institute’s profile and communication.

The second section of this report presents a detailed review of the research programmes carried out in 2015 and 2016, and takes into account the actions undertaken since 2007 in the following four main research areas, for which the total investments over the 2007‑2015 period are: • Biology and basic sciences: €323M; • Translational research: €184M; • Clinical research: €222M; • Research in Human and Social Sciences, Epidemiology and Public Health: €74M.

SUMMARY OF THE REPORT


As of July 2016, 922 proposals had been submitted and 198 research projects selected to all 2016 CFPs operated by INCa. The evaluation processes for the translational research and clinical trials programmes are pending. The total multi‑year investment for 2016 is estimated at €62M at the end of the year.

As of July 2016, ITMO Cancer‑Aviesan programmed 5 CFPs, more than 410 proposals were submitted, and 50 projects were selected. Final results are still pending for 2 programmes. The total investment of ITMO Cancer‑Aviesan for 2016 should be €27M, including the programmes operated by other agencies in the framework of the Cancer control plan budget. Further to the previous SAB meeting, ITMO Cancer‑Aviesan launched in February 2016 the CFP dedicated to functional Heterogeneity of Tumours in their Ecosystem (HTE programme). This programme aims to meet the increasing interest and dynamics in the tumour microenvironment and in multidisciplinary networks.

In addition, according to the 2014‑2019 Cancer control plan, the previous strategic orientations and SAB recommendations, the Institute and its partners launched a specific programme to reduce smoking and change the current prevalence of Tobacco‑related cancers (PRIORITE Tabac) through three calls for proposals (2015, 2016 and 2018). The latter are intended to cover a wide range of disciplines, from basic and clinical science to public health, via information and communication technologies, economics and political science, sociology, law, biology and epidemiology.In 2016, the Integrated Research Action Programme (PAIR programme) was renewed and specifically dedicated to paediatric tumours to further improve access to innovation and research for children, adolescents and young adults.

This part also presents an in‑depth bibliometric study on France’s position in cancer research, conducted by Inserm for ITMO Cancer‑Aviesan. This study is intended to support the impact assessments that the Institute aims to launch on national and international levels.

The third part of this report presents the definition of strategic research areas in line with previous SAB recommendations and with the 2014‑2019 Cancer control plan. INCa, in collaboration with ITMO Cancer‑Aviesan, and with SAB members’ contributions, proposes to continue its actions for 2016‑2017 and to encompass the following priority actions: • Integration of immunotherapy in the precision medicine programme; • Implementation of the TRIPOD programme to generate, share and integrate biological and clinical data; • Launch of a specific programme to promote large‑scale therapeutic clinical trials aiming to address pressing issues close to patient care; • Structuring of the HSS‑EPH research field; • Strengthening cancer control programmes at European and international levels.

This section presents, within each priority measure, a set of potential actions that could be implemented.



This section compiles the main recommendations (2007‑2015) under 6 broad areas, and summarises the main actions achieved by INCa: • Priority given to translational research and multidisciplinary training; • Molecular genetics, cancer biology and sciences; • Evaluation and key performance indicators of clinical research; • Strategies for research in public health and human and social sciences; • Collaboration at national, European and international levels; • Communication.

Part 1. SUMMARY OF PREVIOUS RECOMMENDATIONS OF THE MEMBERS OF THE INTERNATIONAL SCIENTIFIC ADVISORY BOARD AND CORRESPONDING ACHIEVEMENTS


20

Priority given to translational research and multidisciplinary training

2007

• The Board supports the investment plan prepared by INCa for training physicians/scientists and investigators in translational research. • Focus on a few high priority programmes. • Reduce the number of calls for proposals.

2009

• The Board gives priority to translational research, which must be a central mission for INCa. • It recommends establishing a specific evaluation process and developing an attractive career path. • Define the criteria for centres of excellence (comparable to the comprehensive cancer centres in Europe and North America), and establish a process before opening a national call. • Strong support for existing actions to simplify the life sciences landscape.

2011

• Strong support for the SIRIC initiative (Integrated Cancer Research Sites). The Board recommends an increase in the number of SIRICs and their budget, and the development of a system for networking the SIRICs. • The Board recommends that balance be maintained between support for the SIRICs, and for studies conducted by the cooperative intergroups and on the initiative of investigators. • INCa should play an active role in promoting training and career development for the next generation of investigators specialising in translational research.

2012

• The Board is very pleased with the implementation of the SIRIC programme and the number of eight centres of excellence for translational research is sufficient. We strongly recommend that the SIRIC sites develop joint activities and platforms. • The Board highly encourages INCa to continue its investment in training and education across all disciplines, including bioinformatics, basic, translational and clinical research, as well as behavioural science.

2013

• The Board is convinced by the critical importance of the training of the next generation of physician scientists, which will require a strong partnership with universities and hospitals. INCa should continue to be proactive in convening these partners. • The Board would like to suggest to further reinforce the roles and support of presently identified SIRICs and to clarify the role of Cancéropôles in territories with and without the presence of a SIRIC.

2014 • The Board acknowledges the potential of the Cancéropôles and the SIRICs, however, both programmes should undergo a regular international peer‑review and possibilities for interaction between these organisations should be implemented.

2015

• Investing in the next generation of young independent investigators and the training of clinicians, pharmacists and veterinarians will ensure the future of basic and translational cancer research. While the Board appreciates what INCa has achieved so far on this front, we recommend a strong increase in the number and the duration of grants awarded to young researchers. It will be also important to develop new actions for the continuous training of clinician scientists. • The Board welcomes the new initiative to set TRIPOD platforms that will foster better translational and clinical research. Moreover, it will be an excellent lever to facilitate collaborations between academic and industrial partners.


21

Actions achieved or in progress

Achieved2008: Recurrent support for translational research training since 2008.2009: Joint strategic research orientations published by INCa and ITMO Cancer‑Aviesan; Recurrent support for translational research.2011-2012: Creation and designation of integrated research sites (SIRICs): 2 in 2011, 6 in 2012. Participation in the European ERA‑Net initiative to support joint translational research

programmes.2012: First evaluation of training programme provided to medical students to perform translational

research. Inter‑SIRIC working groups creation on data sharing, immunotherapy, radiotherapy, etc.2013: Working group for coordination and planning of the methodology used to evaluate SIRICs.2015: Coordination between SIRICs and Cancéropôles officially included in Cancéropôle contracts

of objective and performance and as criteria in the SIRIC mid‑term evaluation. 16% increase in number of students funded.In Progress Ongoing discussions on partnership with French charities in order to set up TRIPOD platforms implementation.


22

Molecular genetics, cancer biology and sciences

2007

• The Board supports the expansion of a national tumour registry. Resource allocation would be more effective if it were based on more accurate data. • Genomics and epigenetics are priority areas for support. • Support for tumour banks at institutional level should be directed towards the collection of biological resources accompanied by high‑quality clinical annotation. • Focus on a few high‑priority programmes. • Reduce the number of calls for proposals.

2010

• The Board recommends that the number of molecular diagnostic platforms be reconsidered, and recommends improved interaction with basic/translational research, and a focus on information systems for platforms and clinical data. • The Board supports development of research in epigenomics and on the tumour microenvironment. • The Board supports training for clinicians and researchers in the new skills associated with the molecular diagnosis and prognosis of cancer.

2011 • The Board encourages the development of data processing systems for bioinformatics and medical data, and research on complex systems in collaboration with other research organisations.

2012

• The Board recommends that large scale NGS facilities be implemented at some of the SIRIC sites and services shared with the oncology community. Complementary bioinformatics expertise and clinical data management must be available at these centres. • The research programme for cancer biology is an important asset, and requires sustained funding.

2013

• The Board supports the agenda of INCa to bring mathematicians and physicists in close interaction with cancer biologists and clinicians. • The Board would like to suggest to further reinforce the roles and support of presently identified SIRICs and to clarify the role of Cancéropôles in territories with and without the presence of a SIRIC. • The Board applauds the agenda of the INCa in expanding the infrastructure of next generation sequencing (NGS) and implementing the results in clinical practice. This investment will likely pay off handsomely over the next five years in terms of improving clinical practice and personalised medicine.

2014

• 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 as this is a unique programme. We strongly endorse the proposal to establish a network linking the major established platforms. • 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. • The Board strongly supports the priority on basic understanding of the tumour ecosystem and looks forward to seeing specific implementation plans.


23

2015

• The Board is enthusiastic about the new programme on tumour heterogeneity and ecosystem. It is a timely topic presented in a comprehensive and integrated manner. This program nicely integrates and introduces an interesting model for data analysis and sharing across independently funded projects. • The Board is delighted that the Prime Minister is putting so much responsibilities in the hand of INCa for its momentous effort, the large scale sequencing of human genomes for clinical purposes. The INCa should embrace its responsibility to devise good policy for this effort. • The Board alerts INCa to the fact that investment in infrastructures and scientific equipment will be needed to accomplish the whole programme.


Achieved2011-2016: Calls for proposals (CFPs): ‑ creation of national clinical‑biological databases; ‑ research projects in mathematics, physics, engineering sciences and cancer; ‑ research projects based on systems biology; ‑ research projects based on epigenetics; ‑ research projects based on microenvironment and tumour heterogeneity.2011: Publication of institutional recommendations for the creation of tumour collections

for research programmes.2013-2015: Selection of molecular genetics centres where to implement NGS technology. New designation of Cancéropôles for 2015‑2017 with an obligation to formalise a partnership

with SIRICs located in their territories to implement common strategic areas.2016: Launch of the new programme on tumour heterogeneity. Launch of a specific call for proposals to fund equipment of research labs and centres. Launch of the 2025 Genomic Medicine France Plan.


24

Evaluation and key performance indicators in clinical research

2008

• The Board encourages the establishment of more key performance indicators (KPIs), especially for clinical trials (e.g. time taken to put the studies in place, number of patients, closure of databases, etc.), and clarification of clinical trial management (e.g. data centres, EMRCs [mobile clinical research teams] etc.). • In anticipation of a less favourable economic climate, the Scientific Advisory Board suggests continuing to provide full funding for the best projects.

2010 • The Board supports the implementation of key performance indicators (KPIs) and milestones to confirm the efficacy of scientific strategy.

2012 • The Board encourages the design of innovative clinical trials and methodology in assessing the value of NGS.

2013

• The Board has been very pleased and impressed by the objective measurements of key performance indicators such as CLIP², PPP and patients entry into clinical trials. The Board advises that INCa limits the number of cooperative groups to optimise the use of clinical trial resources in an integrated manner and minimise duplication of infrastructure.

2014

• The Board believes that validation of potential therapeutic targets emerging from academic/public research laboratories and their transition to early clinical trials should be facilitated. Further, it stresses the need to refocus the CLIP² initiative towards phase I trials. • The Board strongly supports the efforts of INCa to partner with the private sector in order to facilitate access of patients to innovative therapeutics. • The Board encourages INCa to leverage the on‑going precision medicine trials with tumour microenvironment and immune read‑outs.

2015 • The Board applauds the comprehensive approach to precision cancer medicine for paediatric patients across France.


Achieved • Annual review meetings to review successes and failures in clinical research. • Performance indicators for projects selected under the Hospital Clinical Research Programme (PHRC). • Performance indicators for public‑private partnerships in early‑phase clinical trials.

2012-2015: Designation of 13 cooperative intergroups.2013: Development of the Health Investments Observatory (HELIOS).2015: New designation of CLIP² centres.2011-2016: 12 CFPs, 21 molecules, 18 early‑phase clinical trials funded and conducted in CLIP² centres.2016: Launch of AcSé E‑Smart clinical trial for paediatric patients.In progressDesign of the AcSé immunotherapy clinical trial.


25

Research strategies in human and social sciences and public health

2007 • The Board supports the development of research on screening, early diagnosis and prevention strategies.

2010 • The Board recommends the development of a specific strategy for preventive research (including behavioural and social sciences, epidemiology, public health, statistics, economics, etc.).

2012

• The Board endorses the main recommendations on the excellent prevention strategy report. The key components are capacity building, coordination with other funders and development of measures of behaviour. • In light of the shocking increasing prevalence of smoking in France, the Board specifically recommends to dedicate programmes that aim to develop and evaluate interventions to reverse this trend.

2013

• The Board shares INCa’s determination to reverse the shockingly high and rising rates of smoking in France, particularly amongst the poorest. The board endorses two activities: (a) executing the planned multi‑disciplinary research programme and (b) calling to account French authorities for failing in their obligations as signatories to the WHO Framework Convention on Tobacco Control. • The Board encourages INCa to take leadership in developing partnerships with other agencies in fostering research in prevention, especially concerning tobacco and related products.

2014

• The Board acknowledges INCa’s efforts to build capacity in the area of prevention/intervention research implementation. However, it is concerned that this multidisciplinary domain still needs to be further developed in collaboration with other relevant agencies. The Board strongly suggests that the priority about tobacco control should be used to strengthen this field. • The Board strongly encourages INCa to continue to call to account French authorities to ensure they meet all their obligations as signatories to the WHO Framework Convention on Tobacco Control.

2015

• The Board applauds the creation of a Chair dedicated to cancer research prevention. It congratulates INCa for its leadership in developing the required partnerships with other French agencies and institutes. The Board encourages INCa to continue its work in capacity building for cancer prevention research in France. • The Board is pleased that tobacco control is a priority of the Cancer control plan. The Board continues to encourage INCa to call to account the French authorities to ensure that they meet their obligations as signatories to the WHO Framework Convention on Tobacco Control (Article 6). The Board urges INCa to better align its programme to the goal of reducing tobacco prevalence in France. • The Board supports the research programmes on inflammation and tobacco substitution.


Achieved2012: Strategic report on cancer prevention research: changing health behaviours and their individual

and collective determinants.2014: Primary prevention programme in collaboration with IReSP (French Public Health Research

Institute). 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.

Launch of the National Programme to Reduce Smoking (PRNT)2015: Launch of the first joint programme of actions in research/public health to combat tobacco‑related

cancers with LNCC and ARC Foundation (in collaboration with Inpes, MILDECA and DGS). Chair of excellence in prevention research (in collaboration with EHESP and IResP)2016: Announce by the French Minister of Health in May : several measures of the PRNT,

such as plain packaging; Launch of the 2nd Tobacco related cancer programme including areas focussed

on biology and inflammation and tobacco substitution.In progress • Creation of a university chair of excellence in HSS. • Publication of the CFP dedicated to prevention of risks of second cancer with ARC Foundation.


26

National, European and international Partnerships

2007

• The Board encourages an integrated approach within the European Union. • The Board encourages financial incentives for cooperative groups wishing to consolidate and study specific subjects.

2008

• Whenever possible, priority should be given to projects where European collaborations are ongoing or planned. This information should be contained in the application. • Need to continue our action through the use of effective methods to involve the pharmaceutical industry. One model that could be considered is the CRADA initiative in the US NCI.

2009

• The Board encourages INCa to work with patient associations to strengthen strategic research programmes. • The Board strongly recommends the implementation of actions to simplify the life sciences landscape. • The Board recommends that links be strengthened with the regulatory agencies and the existing large cooperative groups, and encourages the development of new large cooperative groups in order to improve the efficacy of clinical trials.

2010

• The Board encourages more interaction with the 2 main cancer charities and the development of optimum synergy. • The Board supports the efforts made to increase collaboration between the various cooperative groups at national and international levels.

2013 • The Board is pleased by INCa’s leadership into the planning of the preparation of Third Cancer Plan. INCa is encouraged to use this opportunity to refine its portfolio of projects to better reflect the strategic priorities of the Cancer Plan.

2015 • The Board acknowledges INCa participation to the ICART project and encourages INCa to engage in comparative and collaborative research on tobacco control.


Achieved • Since 2008, INCa has been a partner in 7 European projects aimed at coordinating research. • Exchange/collaboration with the pharmaceutical industry and biotechnology companies. • INCa is showing increased leadership through its international communications on personalised medicine.

2008: INCa has joined the ICGC Programme.2009 and 2015: Signature of agreements with NCI on early phase clinical trials.2009-2016: Recurrent CFPs with French charities: PAIR programme.2010-2015: Involvement in 4 European projects.2012-2013: Designation of cooperative intergroups.2014: Launch of the 2014‑2019 Cancer control plan: INCa appointed as pilot of the plan.2014-2019: Involvement in 4 European projects.2015: INCa has joined the signatories to the Melbourne Call launched by the International

Consortium for Action and Research on Tobacco (ICART).2016: INCa has joined the signatories to Global Alliance for Genomic and Health.


27

Communication

2008

• As an integral part of its responsibility as a leader in the fight against cancer, INCa should: –Sponsor international symposia; –Continue its leading role in providing information to the public; –Take a leading role in issues related to cancer survival.

2009 • The Board recommends organising more international symposia to increase INCa’s visibility.

2010 • The Board encourages INCa to promote international scientific events regularly, and to foster better communication with regard to scientific strategy.

2012 • The Board is very pleased with the quality and conciseness of the Scientific Report.

2013 • The Board would like to encourage INCa to continue to develop the communication tools, and dissemination of science towards the lay person, and the interactions with patients’ advocacy groups.

2015 • The Board compliments the INCa teams for the efforts introducing very useful, comprehensive and clear activity and scientific report documents.


Achieved2008-2016: Joint funding of the Integrated Research Action Programme workshops: PAIR (INCa/ARC

Foundation/National Cancer League). Clinical trial registry• Symposium on environment and cancer• Symposium on quality of life and cancer• International conference on the tumour microenvironment2012: Symposium on cancer and Inequalities International R&D Dating International forum on prospective in cancer research and treatment2012: Strategic report on a programme for cancer prevention research: Changing Health Behaviours

and their Individual and Collective Determinants2013: International symposium on nutrition and cancer; Participation of patient advocacy in evaluation committee; Web documentary on Cancer research for the general public in collaboration with ARC Foundation; Report on the main advances in the tumour microenvironment (programme co‑funded by INCa/ARC

Foundation).2014: International symposium on intervention research.2016: Online report on precision medicine.In progress• 2016: International symposium on nanomedicine in collaboration with NCI.• 2016: International symposium on intervention research.


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Part 2.REPORT ON 2015-2016 CANCER RESEARCH ACTIVITY

INCa has a pre‑eminent role in France with a national mandate encompassing all activity areas of value in the cancer control chain, from research to prevention and screening, to the organisation of cancer care and information for patients and their relatives.INCa and ITMO Cancer‑Aviesan involvement in cancer research is mainly based on the management of call for proposals (CFPs) and on the follow‑up of the selected projects. Every year, INCa issues to the scientific community investigator‑driven calls for proposals in the 4 main research areas: cancer biology, translational research, clinical research and research in human and social sciences, epidemiology and public health. In addition, INCa has renewed the call for proposals for health intervention research on reducing cancer‑related inequalities and manages a specific call on Integrated Research Action Programme (PAIR programme) for specific tumour types or major public health issues, such as tobacco‑related cancer.The Cancer control plans focus also on specific research priorities, in collaboration with institutional partners, which are mostly programmed by ITMO Cancer‑Aviesan through several CFPs: Systems biology, Epigenome and cancer, Physics, Mathematics and Cancer, Environmental Risks and Cancer, multidisciplinary training support, laboratories’ equipment and Heterogeneity of Tumours in their Ecosystem.In addition, the Institute promotes a novel vision of integrative cancer research through the designation and the support of SIRICs and biological and clinical databases (BCBs). Moreover, INCa aims to enhance personalised medicine through support for rapid and secured access to new treatments, the AcSé programme, the development of public‑private partnerships to support early‑phase clinical trials of innovative drugs in INCa‑designated CLIP² centres and implementation of novel tools in INCa‑molecular genetics centres.These integrative missions provide the Institute with a distinctive voice in the global cancer control arena that is valued by other agencies and professionals worldwide. INCa’s commitments in Europe and more globally in an international setting reflect the above vision, mission and values.


30

Table 1. Recurrent calls for proposals programmed by INCa and ITMO Cancer‑Aviesan

Call for proposals (funders) Number of proposals submitted

Number of projects selected (% selection) Funding (€M)

2015 2016 2015 2016 2015 2016

Biology and basic sciences (INCa) 267 281 34 (13%) 38 (14%) 17.21 20.30

PHRC‑K Programme for Hospital Clinical Cancer Research (DGOS)

186 192 37 (20%) pending 20.14 pending

PRME‑K Programme for Medico‑Economic Cancer Research (DGOS)

16 10 4 (25%) pending 1.46 pending

PRIORITE Tabac Programme on tobacco‑related cancers (INCa‑ARC Foundation‑LNCC)

NA 21 NA 7 (33%) NA 3.52

PRT‑K Programme for Translational Research (INCa‑DGOS)

162 153 21 (13%) pending 8.45 pending

Training in Translational Research (Inserm)

101 115 25 (25%) 29 (25%) 2.11 2.01

Human and Social Sciences, Epidemiology and Public Health (INCa)

66 86 17 (26%) 16 (18%) 4.27 3.51

Population Health Intervention Research (INCa)

29 22 7 (24%) pending 1.07 pending

Epigenomics (Inserm) 45 NA 10 (22%) NA 4.57 NA

Physics, Mathematics, Engineering Sciences and Cancer (Inserm)

79 67 15 (19%) 13 (19%) 4.94 5.02

Cancer and Environmental Risks (Inserm) 32 37 8 (25%) 8 (22%) 3.18 3.74

Systems Biology (Inserm) 35 NA 7 (20%) NA 4.40 NA

Table 2. Research infrastructures and tools, coordinated by INCa under the Cancer control plan

Name Number Research fields Objectives Selection year 2015 Funding (€M)

Cancéropôles* 7 MultidisciplinaryResearch

coordination2011 & 2015 7.35

Tumour biobanks** 58 Biology Research tools 2004 12.6

Biological and clinical databases 14 Translational Research tools 2011, 2012 & 2013 1.24

SIRIC* 8 MultidisciplinaryResearch

programmes2011 & 2012 15.23

Molecular genetics centres 28Clinical research &

CareInfrastructures 2006 24.51

Cooperative intergroups* 13 Clinical researchResearch

coordination2012, 2013 & 2014 0.69

CLIP²* 16 Clinical researchResearch

programmes2010 & 2015 2.73

EMRC (Mobile clinical research teams) 70 FTEs Clinical research Research tools 2007 6.64

Clinical trial registry 1 Clinical research Research tools 2007 N/A*Designated structures** Estimated amount allocated by Ministry of health under the global investment for preparing, conserving and sharing biological resources (€24.9M)


31

Research focused on cancer biology helps to increase the basic knowledge of oncogenesis, and of the development and progression of cancer. The understanding of biological mechanisms opens up new prospects for advances in treatment, inhibition of resistance mechanisms and the development of tools through the establishment of projects involving physics, mathematics or information technology.

In order to promote and support this progress in the long term, INCa launches a recurrent call for proposals, focussed on cancer biology and basic sciences, and completed by thematic CFPs programmed by ITMO Cancer‑Aviesan in order to strengthen the new areas of research.

Because of the evolution of cancer research trends and the growing number of multidisciplinary projects submitted to the ITMO Cancer‑Aviesan programmes, the Systems biology, Epigenome and Cancer (section 1.1.3 and 1.2.2, respectively) and Research in Physics, Mathematics and Engineering sciences related to cancer (section 1.1.2) CFPs were merged to launch a new call for proposals dedicated to functional tumour heterogeneity and the tumour microenvironment.

1.1. RESEARCH PROGRAMMES1.1.1. BIOLOGY AND BASIC SCIENCES FOR CANCER RESEARCH PROGRAMME (PLBIO)Since 2005, INCa has issued to the French scientific community an investigator‑driven call for proposals for the funding of original and promising projects in different areas and disciplines of cognitive research in oncology. This annual call for proposals represents approximately 30% of the total expenditure on investigator‑driven calls for proposals every year.

The programme in 2016In 2016, 38 projects were selected from the 281 proposals submitted. The selection rate is approximately 13.5%, which

tends to be consistent with the recommendations of the INCa’s SAB and international standards. In 2016, overall funding for the 38 selected projects is €20.30M.

Table 3. Features of the programme Biology and Basic Sciences for Cancer Research

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 2015 2016

Funding (in €M) 17.21 20.30

Proposals submitted 267 281

Projects selected 34 38

Selection rate 12.7% 13.5%

To comply with the objectives of the CFP, nearly 90% of the projects funded aim to study the biological mechanisms of cell transformation and disease progression, according to the international CSO classification1 (Figure 1).

1 1SUPPORT IN BIOLOGY AND BASIC SCIENCES FOR CANCER RESEARCH

1 – The detailed description of the CSO classification is presented in Appendix 2


32

Fig. 1. Distribution of selected projects for the Biology and Basic Sciences for Cancer Research programme in 2016 according to the CSO classification

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 28% of these study oncogenes, tumour suppressor genes and signalling pathways involved in cell proliferation and cell transformation (CSO 1.3), whereas 21% of the funded projects focus on processes linked with 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).

The second area of interest in the CSO classification deals with treatment. As such, 6.6% of projects study either molecular mechanisms of response and resistance to treatments, or identification of new therapeutic targets (CSO 5.3).

Finally, it is interesting to note that nearly 13% of the projects concern breast tumours, and 11% haematological diseases (this proportion has been relatively stable over the years). In accordance with the objectives of this CFP, nearly 36% of the projects are non‑specific to a tumour type, highlighting the fact that the projects are more focussed 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 funded projects for the Biology and Basic Sciences for Cancer Research programme in 2016

The programme over the 2007-2016 period Since 2007, 345 projects have been selected from the 2,268 proposals submitted to the cancer biology research programme, for a total budget of €165.18M (Table 4).

The number of letters of intent (LoI) submitted in 2016 remains very high (281). 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 a major funding agency for cancer‑related research programmes, alongside the French National Research Agency (ANR), which funds basic research (cancer excluded).

BiologyAetiologyPreventionEarly detection, diagnosis, and prognosisTreatmentCancer controlScientific models

BiologyAetiologyTreatment

4% 7%

89%

5.3 Systemic Therapies - Discovery and Development

2.1 Exogenous Factors in the Origin and Cause of Cancer

1.4 Cancer Progression and Metastasis

1.5 Resources and Infrastructure

1.3 Cancer Initiation: Oncogenes and Tumour Suppressor Genes

1.2 Cancer Initiation: Alterations in Chromosomes

1.1 Normal Functioning

Trea

tmen

tAe

tiolo

gyBi

olog

y

27.6%

21.1%

3.9%

34.2%

2.6%

3.9%

6.6%


33

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 2016 TOTAL

Funding (in €M) 14.46 13.52 13.56 20.79 14.44 15.88 15.06 19.96 17.21 20.30 165.18

Proposals submitted 106 145 342 241 203 191 208 284 267 281 2,268

Projects selected 40 30 27 43 30 32 33 38 34 38 345

Selection rate 37.70% 20.70% 7.90% 17.80% 14.78% 16.75% 15.80% 13.40% 12.73% 13.50% 15.21%

The analysis of the funded projects over the 2007‑2016 period according to the CSO classification shows that the projects mainly focus on tumour biology. This trend has been quite stable over the years (Figure 3).

Fig. 3. Distribution of the selected projects for the Biology and Basic Sciences programme over the 2007‑2016 period

0%

20%

40%

60%

80%

100%

CSO1Biology

CSO2Aetiology

CSO3Prevention

CSO4Early detection,

diagnosis and prognosis

CSO5Treatment

CSO6Cancer control

and Survivorship

CSO7Scientific

models

2007200820092010201120122013201420152016

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

2007200820092010201120122013201420152016


34

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 gene expression regulation. Indeed, it can be noted that the proportion of projects studying DNA repair mechanisms, epigenetic regulation and microRNA‑dependent regulation of transcription has increased over the years. This trend can be linked with 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.

An in‑depth analysis highlights that this increase is related to the projects focussing on chromatin stability (DNA repair mechanism, replication regulation, chromosomal translocation and remodelling, etc.) (Figure 4).

Fig. 4. Analyses of selected projects in CSO category 1.2 Cancer initiation: alterations in chromosomes

0

5

10

15

20

25

30

35

Gene expressionChromatin stability

Epigenetics

2016201520142013201220112010200920082007

3% 3%

5%

13%

6%

9%

5%

3%

8%

2007200820092010201120122013201420152016


35

The gene expression projects have been relatively stable over the years. Of these projects, the proposals that study epigenetics mechanisms present an interesting profile. Indeed, the number of projects has increased over the years. The launch of the dedicated programme for epigenetics (section 1.2.2) made it possible to address the needs within this research field, then the percentage of epigenetics projects decreased. In 2016, the increase observed in the framework of the PLBIO is most probably due to the discontinuation of this dedicated research programme.

Moreover, French epigenetic research is particularly strong, offering of a wealth of prospects, and many teams have been established in this field in recent years. With the United Kingdom, France ranks first in Europe for research in epigenetics.

Projects studying tumour suppressor genes, oncogenes and signalling pathways involved in cell transformation and cell proliferation have been relatively stable over the 2007‑2016 period (CSO 1.3).

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 profile seems relatively stable over the years but in‑depth analyses show that the study topics vary over time. Interestingly, a further analysis of these projects highlights that the projects focussing on invasive process and metastatic progression have increased over time (Figure 5).

In 2016, ITMO Cancer‑Aviesan launched a specific call for proposals addressing these issues (section 1.1.4) and this may explain the slight decrease observed this year.

These observations confirm the complementarity between the investigator‑driven PLBIO and the ITMO Cancer‑Aviesan thematic programmes in addressing the needs of cancer research.

Fig. 5. Analyses of the selected projects of CSO category 1.4 Cancer Progression and Metastasis

0%

5%

10%

15%

20%

25%

Invasive processStromal interactionAngiogenesisMetabolismImmune microenvironmentApoptosis

2007200820092010201120122013201420152016

Finally, the number of projects focussing 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 important to note that the projects in the CSO 5.3 section are specifically directed at understanding molecular mechanisms of action and resistance, the characterisation of molecular signatures of treatment response, and the identification of new druggable targets.

HighlightsIn 2016, 38 projects funded out of the 281 proposals submitted for a total budget of €20.30M.


36

1.1.2. PROGRAMME FOR RESEARCH IN PHYSICS, MATHEMATICS AND ENGINEERING SCIENCES RELATED TO CANCERInitiated in 2011, this programme aims to bolster multidisciplinary partnerships to provide a different point of view and a different way to tackle the understanding of cancer progression and to improve the detection, diagnosis and management of the disease.

Table 5. Features of the programme for Research in physics, mathematics and engineering sciences related to cancer

Objectives

To attract physicists, mathematicians and engineers to 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 2015 2016

Funding (in €M) 4.94 5.02



Selection rate 19% 19%

In 2016, the wording of the call for proposals was amended to promote radio‑physics and radiotherapy issues and to exclude studies addressing the tumour microenvironment, as they are covered by the new tumour heterogeneity and ecosystem programme (section 1.1.4). Finally, 67 proposals were submitted and 13 projects were selected for a total amount of €5.02M.

Several projects study nanoparticles to prevent cancer cell migration, to target cancer cells or to measure the absorbed dose and the biological effects of irradiated tissues.

Other projects address new physics‑based approaches: • To develop and to characterise non‑linear endomicroscope prototypes to minimise invasive oncology surgery;

• To improve hadron therapy protocols; • To reduce the number of images per patient without impairing the accuracy of dosimetry, to minimise constraints on patients receiving radioimmunotherapy;

• To develop preclinical imaging devices that simultaneously acquire positron emission tomography (PET) and ultrafast ultrasound images (UUI) or that allow retrieval of dynamic aspects (oxygen and blood saturation) in addition to localised images;

• To model numerically the effect of electroporation‑based therapies and their biological effect on tumours.

Over the 2011‑2016 period, 97 projects have been funded in the framework of this multidisciplinary programme for a total amount of €24.84M (Table 6).

Table 6. Trends in selection and funding of the programme for research in physics, mathematics and engineering sciences related to cancer

Year 2011 2012 2013 2014 2015 2016 TOTAL

Funding (in €M) 2.62 4.17 4.02 4.07 4.94 5.02 24.84

Proposals submitted 64 57 54 47 79 67 368

Projects selected 17 21 19 12 15 13 97

Selection rate 26% 37% 35% 25.5% 19% 19% 26%

In general, the proposals selected are ambitious and quite risky projects whose scientific outcomes would have major medical impact by improving the diagnosis and monitoring of anticancer therapy response. In addition, they help involve physicists and engineers in cancer research.

As confirmed by the analysis of the funded projects with the CSO classification, the studies mainly focus on the development of new tools dedicated to localised therapies and the development of technologies for cancer detection, staging, diagnosis, theranostics and/or prognosis.


37

Fig. 6. Distribution of the selected projects according to the CSO classification over the 2011‑2016 period

1.1.3. PROGRAMME FOR RESEARCH IN SYSTEMS BIOLOGY FOR CANCERSystems biology research is a priority set out in the 2009‑2013 Cancer control plan, and a first call for proposals was launched in 2012, programmed by ITMO Cancer‑Aviesan in close collaboration with INCa.

In 2016, this programme was not renewed since it was replaced by the call for proposals dedicated to the tumour heterogeneity and ecosystem that also addresses systems biology (section 1.1.4).

Table 7. Features of the systems biology programme in 2014 and 2015

Objectives

Support upstream multidisciplinary research (mathematics, physics, chemistry, information technology, biology etc.), in order to progress to the modelling of complex processes or integral biology in the area of cancer.




Year 2014 2015





15 %

47%

27%

1%10%

Biology

Aetiology

Early detection, diagnosis, prognosis

Treatment

Scientific models


38

Table 8. Trends in selection and funding of the Systems biology programme

Year 2012 2013 2014 2015 TOTAL

Funding (in €M) 2.77 1.47 2.95 4.41 11.60

Proposals submitted 21 22 24 35 102

Projects selected 4 4 6 7 21

Selection rate 19% 18% 25% 20% 21%

Over the 2012‑2015 period, 21 projects were selected among the 102 applications submitted to this multidisciplinary programme for a total amount of €11.60M.

The analysis of the projects according to the CSO classification shows that the funded projects mainly focus on biology and the development of specific scientific models, particularly on computational modelling of gene expression and signalling pathways involved in cancer initiation, deciphering the networks

involved in tumour dynamics, metabolic remodelling, cancer cells mobility and metastatic spread and the multilevel nature of the immune microenvironment.

The projects also address computer‑assisted modelling of the response of tumour cells to therapeutic strategies and the development of new technologies and the identification of novel biomarkers for early detection.

Fig. 7. Distribution of the selected projects according to CSO classification over the 2012‑2015 period

Highlights 2012-2015:21 projects selected for a total amount of €1.60M in the framework of the Systems biology programme.

17%

10%

9%

12%

5%

21

%

Normal Functioning

Cancer Initiation: Alterations in Chromosomes

Cancer Initiation: Oncogenes and Tumour Suppressor Genes

Cancer Progression and Metastasis

Resources and Infrastructure

53%

14

%

%12

BiologyEarly detection, diagnosis, prognosisTreatmentScientific models


39

1.1.4. TUMOUR HETEROGENEITY AND ECOSYSTEM PROGRAMMEThe 2014‑2019 Cancer control plan and INCa’s Scientific Advisory Board strongly supports the priority of basic understanding of the tumour ecosystem.

In this context, ITMO Cancer‑Aviesan, in collaboration with Aviesan’s Cell Biology, Development and Evolution Institute (ITMO BCDE) and Aviesan’s Health Technologies Institute (ITMO TS) launched, in 2016, a programme to fund research projects in the field of tumour cell heterogeneity and cell relationships in their ecosystem.

As mentioned previously, this CFP is intended to address the issues of the Epigenome and Cancer, Systems Biology programmes and the modelling and mechanobiology aspects of the Physics, Mathematics and Engineering sciences related to cancer CFP.

The objectives of the Tumour heterogeneity and ecosystem programme are to promote the implementation of a critical mass in terms of resources and skills to conduct research projects of an interdisciplinary nature which require cooperation between national teams from different thematic fields such as cell biology, mathematical modelling, genetics and (epi) genomics, and mechanobiology in an integrated way. It covers both fundamental and translational aspects, and takes into account that the developments of new therapeutic strategies are needed considering tumour heterogeneity to elaborate truly effective personalised or targeted medicine.

Prior to the launch of this programme, ITMO Cancer‑Aviesan determined the French strengths and the unmet needs in this field. This study shows that about 300 teams ranging from biology, mathematics, bioinformatics and clinicians express their interest in meeting for the programme. The structuring of the communities involved took place several months prior to the deadline for submission, to ensure that multidisciplinary networks could be set up to apply. For this purpose, ITMO Cancer‑Aviesan publicised the new programme and met the different teams at the regional level through the different Cancéropôles.

Table 9. Features of the tumour heterogeneity and ecosystem programme

Objectives

To promote the implementation of a critical mass in terms of resources and skills to conduct research projects of an interdisciplinary nature in an integrated way in the field of heterogeneity of tumour cells in their ecosystem, requiring cooperation between teams from the fields of cell biology, mathematical modelling, genetics and (epi) genomics, mechanobiology.



Funding institutions Inserm for ITMO Cancer‑Aviesan

Year 2016

Proposals submitted 73

Projects pre-selected 27

For the first edition, 73 letters of intent were submitted and 27 were pre‑selected, including proposals from 5 individual teams. The latter are specialised in developing multicontrast magnetic resonance image acquisition methods tailored to the accurate quantification of tumour heterogeneity with robust texture analysis, Magnetic Resonance Histology, or studying the deregulated mechanisms on the supportive signals emanating from the microenvironment of leukaemia‑initiating cells.

Following on from the scientific evaluation committee, a dedicated workshop was organised to promote the establishment of multidisciplinary networks, where the pre‑selected investigators met before the complete project submission, as per committee recommendations. Around 185 business‑to‑business meetings were held.

In addition, this programme integrates and provides an interesting model of sharing and analysing data between independently funded projects within 3 different work packages: internal communications within the programme, exchange biological resources, digital data and algorithms and overall coordination and management of the programme.


40

1.2. THE GENOMIC AND THE EPIGENOMIC PROGRAMMES1.2.1. THE ICGC PROGRAMME The International Cancer Genome Consortium (ICGC) was established in 2008 to bring together researchers worldwide to comprehensively analyse the genomic, transcriptomic and epigenomic changes in different tumour types or subtypes that

are of clinical and societal importance across the globe and make the data available to the entire research community as quickly as possible, and with minimal restrictions, to accelerate research into the causes and control of cancer. As of December 2015, the consortium had received commitments from funding organisations in Asia, Australia, Europe North and South America for 85 projects (Figure 8).

Fig. 8. ICGC cancer genome projects map, December 2015

INCa and ITMO Cancer‑Aviesan support the French involvement in the programme: • Liver project launched in 2008, directed by Prof Jessica Zucman‑Rossi;

• Breast cancer project launched in 2008, directed by Dr Alain Viari and Prof Gilles Thomas (†);

• Prostate Cancer project launched in 2011, directed by Prof Olivier Cussenot;

• Ewing Sarcoma project launched in 2012, directed by Prof Olivier Delattre;

• Retinoblastoma project launched in 2013, directed by Dr François Radvanyi;


41

• Gynaecological Carcinosarcoma project launched in 2013, directed by Prof Alain Puisieux;

• Leiomyosarcoma project launched in 2013, directed by Dr Frédéric Chibon;

• Prolymphocytic B‑cell leukaemia project launched in 2014, directed by Dr Olivier Bernard.

The retinoblastoma, gynaecological carcinosarcoma, leiomyosarcoma and prolymphocytic B‑cell leukaemia projects are part of the rare tumours programme.

Focus on Breast programme resultsThe first paper on the 560 breast cancer whole genomes generated and analysed under the auspices of the ICGC Breast Cancer Working Group has been published in Nature (May 2016), co‑signed by Gilles Thomas and Michael Stratton1.

This publication is the result of an international and intercontinental project and a substantial scientific and logistic achievement. It represents the clear fruition of the vision for cancer genomes articulated by the ICGC in Toronto in 2007 and illustrates perfectly all the benefits of international collaboration that genome projects have induced over the last 25 years. Indeed, it currently represents the largest number of whole genome sequences of any cancer type. The work will stand as a milestone in the somatic genetics of breast cancer, since essentially the whole genome has now been covered and all types of mutation have been analysed in a substantial number of cases, covering all subtypes, supported by expression and methylation studies and addressing the major questions that can be elucidated by genetics. The results will continue to be analysed for many years and will undoubtedly yield further insights.

The results show that 93 protein‑coding cancer genes carried likely driver mutations, including 5 new identified genes. Some non‑coding regions exhibited high mutation frequencies but most have distinctive structural features probably causing elevated mutation rates and do not carry driver mutations. Mutational

signature analysis was extended to genome rearrangements and revealed 12‑base substitution and six rearrangement signatures. Three rearrangement signatures, characterised by tandem duplications or deletions, appear to be associated with defective homologous recombination‑based DNA repair: one with deficient BRCA1 function; another with deficient BRCA1 or BRCA2 function; the cause of the third is still unknown.

This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes in operation, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.

There has been a major French contribution to this programme, fully funded by the INCa, focussed on HER2‑positive tumours. HER2‑positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, treatment resistances, associated with specific gene expressions or mutations, have been observed, revealing the underlying diversity of these cancers and understanding the full extent of HER2‑positive disease heterogeneity is still a challenge.

In the first French paper, published in Nature Communications2, an in‑depth genomic characterisation of 64 HER2‑positive breast tumour genomes was carried out that exhibited 4 subgroups with distinctive genomic features (in terms of somatic mutations, copy number changes or structural variations) and based on expression data. The figure 9 shows that, in addition to HER2 amplification, the tumours harbour different genetic characteristics leading to the 4 sub‑categories identified. This study suggests that, despite being clinically defined by a specific gene amplification, HER2‑positive tumours merge with the whole luminal‑basal breast cancer spectrum rather than standing apart. Moreover, these results lead to a refined ERBB2 amplicon of 106kb.

1 – Nik‑Zainal S. et al. (2016). Landscape of somatic mutations in 560 breast cancer whole‑genome sequences. Nature, 534, 47‑54. doi: 10.1038/nature176762 – Ferrari A. et al. (2016). A whole‑genome sequence and transcriptome perspective on HER2‑positive breast cancers. Nature Communications 7:12222. doi: 10.1038/ncomms12222


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Fig. 9. General summary: Multiple Correspondence Analysis (MCA) of biological and genomic variables

This map has a simple geometrical interpretation: a category is plotted at the centre of gravity of the patient points for those patients that choose that category (conversely, at a scaling factor, patient points are located at the centre of gravity of categories they choose).

By way of example, patient points have been linked with the RNA group that they belong to (grey ellipses). Therefore, the proximity of two categories suggests that they are chosen by a similar set of patients.

0.0 0.5 1.0 1.5

–0.5

0.0

0.5

1.0

Axis_1 74%

Axis

_2 1

2%

RNA.A

RNA.B

RNA.D

RNA.C

LST.L

LumB

RPS6KB1.A

CCND1.A

SV17.HTP53.WTFGA.L

SV17.LBasal

Her2

PR.POSER.POS

ER.NEGPR.NEG

pLum.LmLum.H pLum.H

LST.H

mLum.L

TP53.MFGA.H

–1.0

–1.0

–0.5


43

Focus on Retinoblastoma programme resultsRetinoblastoma is the most common intraocular paediatric cancer with an incidence of one case per 15,000–20,000 live births. Most patients are diagnosed before the age of five years. In high‑income countries, patients have an excellent prognosis. However, in the majority of cases, enucleation of the affected eye has to be performed. In middle and low‑income countries, retinoblastoma is still a deadly disease. 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. Using transcriptome data, the first results show that two different tumour subtypes exist in retinoblastoma, cone‑like tumours and bivalent tumours that present both cone‑like and ganglion‑like cell characteristics. Additionally, genomic alteration analysis and exome sequencing show that bivalent tumours present higher genomic instability and coding mutations than cone‑like tumours. Moreover, methylome analyses also allow the differentiation of cone‑like and bivalent‑type tumours since the latter are hypomethylated.

These f irst results demonstrate that retinoblastoma is a heterogeneous disease and have been submitted for publication.

1.2.2. EPIGENOME AND CANCER PROGRAMMELaunched in 2013 and managed by ITMO Cancer‑Aviesan in close collaboration with INCa, this programme aims to decipher the epigenetic mechanisms associated with cancer. As mentioned previously, this programme was not renewed in 2016 because it was merged with other programmes to form the tumour heterogeneity and ecosystem programme (section 1.1.4).

Table 10. Features of the Epigenome and cancer programme

Objectives

Promote the critical mass and skills to decipher the epigenetic mechanisms associated with cancer, based especially on developments of the production of high‑quality reference epigenome maps, to pave the way for innovative ideas to unravel the processes related to tumour development and recurrence.




Year 2013 2014 2015

Funding (in €M) 4.15 4.61 4.57

Proposals submitted 30 34 45

Projects selected 11 12 10

Selection rate 36% 35% 22%

Launch of the ICGCmed ProgrammeThe International Cancer Genome Consortium for Medicine (ICGCmed) aims to link the wealth of genomic data already

amassed, as well as new genomic data being generated, to clinical and health information, including lifestyle, patient history, cancer diagnostic data, and response to and survival following therapies, across the cancer spectrum. As a worldwide consortium, ICGCmed has the research and organisational expertise to implement the ambitious project of analysing the genomes of more than 200,000 patients by

the end of 2025 and linking this data to high-quality clinical information including treatment information and outcomes.

Using these large-scale integrated data, researchers, scientists, policy-makers and clinicians will be able to work with patients, healthcare providers and others to develop preventative strategies, markers for early detection of disease, more specific criteria and methods for diagnoses and prognoses, and interventions based on matching the patient’s disease molecular subtype with the most effective combinations of therapies.

More information available on ICGCmed website: http://icgcmed.org/

http://icgcmed.org/


44

Since 2013, 33 proposals have been selected for a total amount of €13.33M.

The projects mainly address the epigenetic mechanisms leading to oncogenesis and tumour progression in order to identify or to decipher cancer development mechanisms (78%). The analysis of the funded projects based on the CSO classification highlights that the projects also address the epigenetic mechanisms involved in cancer aetiology, mainly exogenous factors in the origin and cause of cancer, epigenetic regulation in response to treatment and with a view to opening up new opportunities for more effective and selective anticancer therapies targeting DNA methylation (Figure 10).

Moreover, it is interesting to note that the projects are technically innovative and present multidisciplinary approaches by combining high‑throughput epigenomic screening, bioinformatics, in vivo studies and in cellulo approaches. For example, the NGS approach is used to characterise the methylome landscape for different processes such as chromatin remodelling in the tumour microenvironment, cancer‑induced inflammation, or B and T‑cell differentiation in leukaemia.

Fig. 10. Distribution of the Epigenome projects according to the CSO classification over 2013‑2015 period

Highlights2013-2015: 33 projects selected for a total amount of €13.33M in the framework of the Epigenome and cancer programme.

2%

78%

7%6%

3%

Normal functioning

Cancer initiation: Alterations in Chromosomes

Cancer initiation: Oncogenes and Tumour Supressor Genes

Cancer progression and Metastasis


93%

4 %

BiologyAetiologyTreatment


45

2 2TRANSLATIONAL AND INTEGRATED RESEARCH

Translational research in oncology aims to bridge the gap between basic research and clinical research in order to translate scientific progresses into products and procedures that benefit patients.

In line with the previous Cancer control plans, translational research receives significant support through dedicated calls for proposals, programmes to strenghten training in this research field and a policy of designated multidisciplinary integrated research sites.

2.1. RESEARCH PROGRAMMES AIMING TO ACCELERATE CROSS-DISCIPLINARITY AND TRANSFER OF KNOWLEDGE TO CLINICAL PRACTICEAlongside the national investigator‑driven CFP operated by INCa, integrated and thematic programmes have been set up such as the programme dedicated to tobacco‑related cancers and the integrated actions programme dedicated to specific pathologies, in partnership with other agencies and charities. The support to translational research has also been extended since 2012, on a European level in the context of coordinated actions against cancer, particularly through the TRANSCAN network.

2.1.1. THE TRANSLATIONAL RESEARCH PROGRAMME (PRT-K)The objective of this call for proposals (PRT‑K), 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 promote the translation of scientific and medical discoveries into clinical advances for cancer patients.

In 2015, 21 projects were selected for funding representing a global budget of €8.45M (€5.6M INCa + €2.9M DGOS). In 2016, 153 letters of intent were received and 46 pre‑selected for the full proposal step.

Table 11. 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)


Funding institution INCa/Ministry of Health (DGOS)

Year 2015 2016

Funding (in €M)8.45

INCa: 5.58DGOS: 2.86

Pending


Projects selected 21 Pending

Selection rate 13% Pending

Unlike the 2014 selection which included a large spectrum of studied tumour types (including adrenal tumours and uveal melanoma, for example), the 2015 selection is more focussed on high‑incidence cancers (breast, ovarian, colorectal, lung, liver, prostate, leukaemia) and includes projects using innovative technologies such as proton minibeam radiation therapy, targeted drug delivery with ultrasound and microbubbles and immunotherapy using CAR‑T cells. One project focuses on medulloblastoma which is a tumour appearing predominantly in children. It is also noteworthy that 2 projects address survivorship issues, one on fertility preservation and the other on risk of second cancer.


46

Since 2007, 1,030 proposals have been submitted in response to this call for proposals, and 149 have been selected and funded for a total amount of €59.9M (2016 results not included, final selection in progress). The overall selection rate for this call for proposals is 14.5% (Figure 11).

Fig. 11. Trends in selection for the Translational Research Programme over the 2007‑2015 period

The CSO typology of the projects funded since 2007 corresponds to the characteristic profile for translational research (Figure 12), especially allocated to two main categories of research projects: • projects that involve the development of techniques for early detection, diagnosis, prognosis using biomarkers (genetic, biological, immunochemical, microbiological);

• projects based on the improvement of patient care thanks to the development of new therapeutic strategies and to the understanding of mechanisms of treatment resistance.

Fig. 12. Distribution of the selected projects to the Translational Research Programme since 2007

Highlights2015: 21 projects funded for a total amount of €8.45M2016: 153 proposals submitted

2.1.2. THE EUROPEAN TRANSLATIONAL CANCER RESEARCH PROGRAMMEThe ERA‑Net TRANSCAN‑2 is pursuing its now well‑established coordination mandate of translational cancer research funding across Europe, with the involvement of 29 funding agencies and ministries from 15 Member States, 3 Associated Countries, and a third country (Taiwan). With the support of the European Commission, the purpose of this research funder’s network is to fund high‑impact collaborative research projects, involving research teams from the participating TRANSCAN‑2 countries, through joint transnational calls for research proposals.

The 2014 TRANSCAN‑2 call for research proposals was dedicated to translational research on human tumour heterogeneity to overcome recurrence and resistance to therapy. The table below shows the results of this CFP. The funding decision was completed in February 2016.

0

2

4

6

8

10

12

20152014201320122011201020092007

Fund

ing

in €

M

Funding in €M Nb of projects

Nb

of p

roje

cts

0

5

10

15

20

25

30 BiologyAetiologyPreventionEarly detection, diagnosis, and prognosisTreatmentCancer controlScienti�c models


26%

10%

47 %

2% 2%13%


47

Table 12. Features of the first TRANSCAN‑2 call for proposals (JTC2014)

Call steps Global for TRANSCAN-2 Outcomes for France

Eligibility 117 LoI 93 French research teams involved in 73 LoI19 LoI with French coordination

1st step: LoI selection 33 LoI selected26 French research teams involved in 20 LoI6 LoI with French coordination

2nd step: full proposals selection 16 full proposals selected, including 85 research teams

13 French teams in 11 projects2 projects with French coordination

Selection rate 13.7% 15.1%

Funding€17.2M (Global Budget, including €4M of co‑funding from the European Commission)

€3.08M shared as follows: • €2.1M (INCa’s budget including €0.58M of co‑funding from the European Commission) • €0.97M (ARC Foundation budget including €0.12M of co‑funding from the European Commission)

The 2015 TRANSCAN‑2 joint call for proposals focuses on immunology and immunotherapy of cancer: strengthening the translational aspects. The selection process is ongoing. Fourteen letters of intent have been selected out of the 33 submitted. The next and final selection step will proceed in September 2016.

2.1.3. RESEARCH AND ACTION PROGRAMME TO REDUCE SMOKING AND CHANGE CURRENT PREVALENCE OF TOBACCO-RELATED CANCERS (PRIORITE 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. Tobacco is the primary causal factor for 80% of deaths from lung cancer, and is associated with an increased risk in 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.

In this context, INCa, in collaboration with other agencies, ministries and research teams, has set up a multidisciplinary

partnership programme in order to establish research and actions priorities on tobacco and tobacco‑related cancers. This programme is part of the 2014‑2019 Cancer control plan and is linked with the “French National Programme to Reduce Smoking” (PNRT).

Three CFPs, focussing on cancers related to tobacco and its components, are scheduled during the Cancer control plan (2015, 2016 and 2018). The objective of the CFPs is to cover a wide range of disciplines, from basic and clinical science to public health, via information and communication technologies, economics and political science, sociology, law, biology and epidemiology.

The CFPs are also intended to promote intervention research projects on this topic, and welcome studies on specif ic populations including women, teenagers and young adults and vulnerable populations. Social, economic, cultural and spatial inequalities should also be considered as cross‑cutting topics for all research areas.

For each edition, the areas will be updated based on projects that have been supported, advanced research in this field and to address the research gaps identified.

The first edition, launched in 2015, presents 5 areas: • Area 1: Determinants and trajectories of smoking; • Area 2: Consumer and stakeholder behaviours;


48

• Area 3: Electronic nicotine delivery systems (electronic cigarettes);

• Area 4: Smoking cessation in cancer patients; • Area 5: Screening for tobacco‑related cancers and innovative research on new screening methods.

This first session led to the selection of 7 projects for funding among the 21 proposals submitted and the selection rate is 33%. The total amount of funding is €3.52M, including €1M allocated by the charities ARC Foundation for Cancer Research (ARC Foundation) and the National Cancer League (LNCC).

Fig. 13. Distribution of the selected projects according to the CSO classification

The analysis the projects selected according to the CSO typology shows that the projects mainly study cancer control, early detection and prevention.

Indeed, two projects focus on the development of new screening methods for tobacco‑related cancers. The first aims to assess the combined effect of the scanner and circulating tumour cell research on screening for tobacco‑related cancers, helping patients to stop smoking and addressing the psychological impact of this approach.

The other project hypothesises that it is possible to identify a limited panel of risk biomarkers and develop a lung cancer risk prediction model that substantially improves existing models in identifying those subjects that are most likely to benefit from screening.

A translational approach on rodents was also selected by the committee. Indeed, this study assumes that in the context of the study of chains of causes and trajectories of smoking (i.e. factors related to starting and stopping smoking, and the role of inequalities, including social inequalities and social determinants), animal models can help in understanding the mechanisms that underlie vulnerability to addiction. This project will generate new knowledge for understanding the neurobiological processes associated with addiction symptoms and thus pave the way for new approaches to fight against smoking and tobacco‑related cancers.

Two projects focus on electronic cigarettes (e‑cig). The first aims to describe the e‑cig and smoking trajectories in the Constances cohort. The second project addresses the nature and impact of e‑cig messages on youth during the formative teenage years (13‑17).

Two integrated smoking cessation programmes for patients with HNSCC may start in the next months. These patients represent a priority in smoking cessation programmes. Patients with HNSCC face unique challenges due to the level of tobacco addiction, frequently underserved population, and low caregiver illness perceptions. This population is at high risk of a second primary tumour, the incidence of which may decrease with an efficient tobacco cessation programme. The proposed interventions are also intended to help reduce the side effects of surgery and/or radiotherapy.


Biology

Prevention


Cancer control43 %

7%

21%

29%


49

Table 13. Distribution of the projects submitted and selected by area

Submitted projects

Selected projects

Area 1: Determinants and trajectories of smoking

5 2

Area 2: Consumer and stakeholder behaviours

2 0

Area 3: Electronic nicotine delivery systems (electronic cigarettes);

3 1

Area 4: Smoking cessation in cancer patients

5 2

Area 5: Screening for tobacco‑related cancers and innovative research on new screening methods

6 2

The 2016 edition includes a new area focused on biology of tobacco‑related cancers. As for the other areas, the priority issues were identified during a workshop gathering several experts in this field.

Overall, few projects with public health orientations were submitted in this first edition. The Institute continues, with these partners, to mobilise researchers in this field.

2.1.4. THE INTEGRATED RESEARCH ACTION PROGRAMME: PAEDIATRIC PAIRSince 2007, INCa has launched an annual thematic programme dedicated to a specific pathology, the Integrated Research Action Programme (PAIR).

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 and young adults, several actions have been drawn up by INCa, since 2014.

Among these actions, INCa, ARC Foundation and LNCC propose a PAIR dedicated to childhood, adolescent and young adult cancer, scheduled for 2016.

This programme intends to elucidate childhood cancers and improve their care based on fundamental and translational research integrating all fields, including biology, epidemiology, and human and social sciences. This programme should also offer an opportunity to bolster integrated paediatric research and to develop and to strengthen research in emerging areas.

The writing of the call for proposals has involved a multidisciplinary committee, in close partnership with parents and patient representatives.

Focus in the fight against smokingAfter Australia in 2012, plain packaging on cigarette packs arrived in France in May 2016. The Institute has played a key role in the genesis of this government decision, endorsed in January 2015. The Institute has funded in recent years, in collaboration with the Directorate General of health, various scientific studies on the possible impact of plain packaging in France, and actively participated in disseminating this information especially to parliamentarians.

The Institute continues its efforts in combating smoking by funding the evaluation of the implementation of plain packaging on cigarettes. This study is one of the major milestones of the PNRT.

The Paediatric PAIR workshopOrganised in April 2016 in collaboration with ARC Foundation and LNCC, this national workshop promoted discussions around 5 areas:

• Predisposition and susceptibility;

• From cancer biology to therapeutic innovations, example of acute lymphoid leukaemia;

• New concepts in immunotherapies;

• Post-cancer: a research topic;

• Expectations of patient associations.


50

2.2. THE TRANSLATIONAL AND MULTISDISCIPLINARY RESEARCH TRAINING PROGRAMMESSupport to translational research is completed by an investment plan to promote training and career development for the next generation of investigators.

Training support in translational research and in interdisciplinary research is pursued, even increased, in compliance with the SAB recommendations. These initiatives are supported by dedicated calls for applications in translational research training, in biology training for clinicians and in multidisciplinary training through a specific PhD programme.

2.2.1. THE TRANSLATIONAL RESEARCH TRAINING PROGRAMMEInitiated by INCa in 2007 and continued by ITMO cancer‑Aviesan in 2012, this programme aims to facilitate complementary translational research training of graduates of medicine, pharmacy, dentistry and veterinary science.

Table 14. Features of the 2015‑2016 translational research training programme

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.




Year 2015 2016





In 2016, 29 candidates were selected for a total amount of €2.01M: 18 for a master’s degree, 10 for a PhD thesis, and one post‑doctoral fellowship. In compliance with INCa’s SAB recommendations, the number of training grants has increased.

From 2008 to 2016, 206 training grants have been awarded for translational research, including 17 post‑doctoral candidates, 78 PhD students and 111 master’s students. The figure 14 presents the distribution of grants according to the degrees since 2008.


51

Fig. 14. Distribution of the selected applications according to the degrees over the 2008‑2016 period

Since 2014, the number of proposals submitted has significantly increased and highlights the increased interest of students or

young clinicians, pharmacists and veterinarians in a cancer research career (Table 15).

Table 15. Trends of the 2011‑2016 translational research training programme

Year 2011 2012 2013 2014 2015 2016

Funding (in €M) 1.49 2.11 1.35 2.35 2.11 2.01

Proposals submitted 35 39 51 103 101 115

Projects selected 19 25 22 30 25 29

Selection rate 54% 64% 43% 29% 25% 25%

The analysis of the projects funded over the 2007‑2015 period according to the CSO typology shows that the training consists mostly of cancer biology‑related projects (Figure 15).

0

4

8

12

16

20

201620152014201320122011201020092008

Master PhD Post-doc Total

0

7

14

21

28

35

22

1717 19

2522

30

25

29

Num

ber o

f pro

ject

s ac

cord

ing

to th

e de

gree

s

Nb

of p

roje

cts


52

Fig. 15. Distribution of the selected applications according to the CSO classification over the 2007‑2015 period

The analysis of the trajectories of the recipients indicates that they continue working in translational research after their training, suggesting that the programme is meeting its objectives.

2.2.2. SUPPORT FOR TRAINING IN INTERDISCIPLINARY RESEARCH FRONTIERS IN LIFE SCIENCES (FdV)The FdV graduate school recruits students trained in various disciplines (e.g. biology, physics, mathematics, medicine, economy, linguistics, etc.) from around the world. This programme is hosted by PRES Sorbonne Paris Cité under the guidance of Paris‑Descartes and Paris‑Diderot Universities.

This training is also supported by the Bettencourt‑Schueller Foundation.

The support to this programme aims to promote multidisciplinary training to adapt and to meet the needs of cancer research.

Table 16. Features of the PhD programme Frontiers in Life Sciences in the field of cancer

Objective

The PhD programme aims at promoting ambitious research projects using a broad range of academic disciplines in order to understand living systems.

Programming institution Frontiers in Life Sciences graduate school

Operating institution Frontiers in Life Sciences graduate school


Year 2015 2016




According to the INCa's SAB recommendations, ITMO Cancer‑Aviesan increased in 2016 its support to this programme. Four cancer thesis projects were selected out of the 5 proposals submitted.

The projects address complex tumour microenvironment constraints during tumour initiation and progression combining biological, mathematical and physical approaches to model cytoskeleton dynamics, generate new scientific models or to improve immunotherapy targeting and effectiveness.

Table 17. Trends in selection and funding for Training in interdisciplinary research

Year 2010 2011 2012 2013 2014 2015 2016 TOTAL

Funding (in €M) 0.21 0.21 0.21 0.21 0.21 0.31 0.42 1.78

Proposals submitted 4 7 5 6 4 4 5 35

Projects selected 2 2 2 2 2 3 4 17

Biology

Aetiology


Treatment

Scientific models

23 %

3%

42%

5%

27%


53

Since 2010, 17 PhD candidates have received funding, for a total amount of €1.78M.

The analysis of the thesis projects based on the CSO typology shows that the studies are intended to unravel the fundamental mechanisms of cancer cell invasion, decipher complex tumour constraints or to identify new cancer biomarkers responsible for

the emergence of resistance to specific therapies (Figure 16). These studies are in line with the scientific evaluation committe recommendations by addressing, for example, the mechanical properties changes of the extracellular matrix leading to invasion and how physical forces involved in basal membrane removal contribute to the invasive process.

Fig. 16. Distribution of the selected thesis projects according to the CSO classification over the 2010‑2016 period

HighlightsJune 2015: Workshop on the scientific outcomes of the theses funded over the 2010-2012 period. The PhD candidates presented their main results, highlighting the importance and the added value of such multidisciplinary training.

12%

17%

44%

6%

Normal functioning

Cancer initiation: Alterations in Chromosomes

Cancer progression and Metastasis

Resources and Infrastructure

82%

12%

Biology


Scientific models

9%


54

2.3. STRENGTHENING OF ORGANISATION AND INFRASTRUCTURES DEDICATED TO TRANSLATIONAL/INTEGRATED RESEARCH IN INTEGRATED CANCER RESEARCH SITES (SIRICS)In 2011 and 2012, 8 French cancer research sites were designated as a SIRIC (Integrated Cancer Research Site) for a five‑year period, and have thus become national reference centres for cancer research. The budget allocated to this programme is €64M, funded jointly by INCa, Inserm for ITMO Cancer‑Aviesan and the French Ministry of Health (DGOS). The SIRIC programme aims to strengthen the relationship between the various aspects of research (fundamental, clinical, public health, epidemiology, and human and social sciences), by combining a critical mass of stakeholders (physicians, researchers, engineers, caregivers and patients) committed to working according to the specificities and constraints of translational research. Thus, this programme intends to optimise and speed up the generation of new knowledge and foster the distribution and application of this knowledge in standard practice. Each SIRIC has its own

integrated research programmes, strategically deployed thanks to the strengths and expertise present.

Within the framework of the coordination of this SIRIC programme, over the 2015‑2016 period, INCa organised a seminar with SIRIC directors, offering some valuable time for discussions and sharing of experience. In addition to presenting the progress in each SIRIC’s activities, the day was also an opportunity, as it is the case every year, to address specific topics or issues. More operational, but equally important, meetings were also arranged with managers to promote further progress in the programmes.

Furthermore, during the 2015‑2016 period, many SIRIC teams continued to invest in collaboration initiatives between sites with a view to speeding up progress in the research conducted (Figure 17). For example, the OSIRIS group (Inter‑SIRIC Group for sharing and integration of clinical, biological and genomic data) aims to publish the work conducted on the definition of clinical, biological and genomic items by the end of 2016.

Fig. 17. Inter‑SIRIC working groups

In 2015, within the framework of its evaluation role, INCa organised the mid‑term assessment of the 8 designated SIRICs,

in conjunction with the financial partners ITMO Cancer‑Aviesan and DGOS.

January 2014 January 2015 January 2016

OSIRIS (Sharing and integration of clinical, biological and genomic data)

Drug design & development

Human and social sciences – Public health

Immunology & immunotherapy

Clinical trials & precision medicine

Resistance to treatments

Radiotherapy


55

The international scientific committee in charge of this review congratulated the SIRIC sites for all the research done and recognised the structuring work implemented and the impact of the activities carried out on the quality of the research produced and the dissemination of its findings. The committee encouraged them to continue their work and initiatives during the second period, placing particular emphasis on: • Strong focus on multidisciplinary approaches in research projects;

• Development of high‑quality projects in human and social sciences and public health initiated on the basis of a clear and ambitious strategy; research in health economics being of particular interest in the context of the development of precision medicine;

• Reinforcement of dissemination actions (not only in terms of communication of findings but also with a view to transfer to clinical practice);

• Continuation and reinforcement of collaboration projects between SIRICs.

The committee also made the following recommendations to SIRICs: • To simplify governance structure with the SIRIC management having a strong role;

• To simplify SIRIC programme, platform and activity organisation;

• To schedule regular meetings of their respective international scientific board;

• To involve patient representatives in disseminating actions and in SIRIC governance and/or the integrated research programmes;

• To highlight the added value of SIRIC sites with a view to raising their national and international profile (and more specif ically though publications having benefited from contributions from SIRIC sites);

• To promote gender equality for senior positions, wherever possible.

A new call for applications is scheduled for December 2016. Both currently designated sites and new sites will have the opportunity to submit an application.

2016 HighlightsQualitative analysisIn parallel with this evaluation, the Centre de Sociologie des Organisations research institute conducted a qualitative analysis. The purpose of this study was to shed light on the organisational mechanisms that facilitate or restrict cooperation within the SIRIC sites and, in particular, links and exchanges between research and clinical activity. The results of this analysis were reported in September with the SIRICs staff who took part. The report is summarised below:SIRICs act as catalysts of local dynamics, and also international dynamics. Although they share some common features, such as a strong involvement in internationally hot topics, they vary from one another, as regards how stakeholders use them

(SIRIC as structuring processes, as a cognitive map of ocal, scientific assets and/or as a label) and according to their local anchoring.SIRIC management depends strongly on their relationships with some key stakeholders, among them the local leading scientists and hospital top management. Facing strong constraints, their steering teams promote the creation or reinforcement of platforms, the creation of new organisational entities devoted to translational research or the recruitment of new profiles, specialised in translational research. Two activities appear to be key factors to be integrated for SIRIC stakeholders: pathology and bioinformatics. However, this integration is far from self-evident.


56

3 3CLINICAL RESEARCH AND DEVELOPMENT OF EARLY-PHASE TRIALS FOR INNOVATIVE DRUGS

Within the framework of the successive Cancer control plans, INCa has implemented several actions to support clinical research through CFPs, specific programmes to roll out targeted therapies and personalised medicine and the setting up of specific infrastructures. In addition, the support to clinical research has been extended through international collaborations, the establishment of public‑private partnerships and the support to access to innovation.

3.1. CLINICAL CANCER RESEARCH PROGRAMMESNationwide funding of academic clinical research is organised through 2 annual calls for research proposals operated by INCa, and funded by Ministry of Health (DGOS).

3.1.1. THE NATIONAL PROGRAMME FOR HOSPITAL CLINICAL RESEARCH ON CANCER (PHRC-K)PHRC‑K funds cancer clinical research projects with the following objectives: • Evaluation of the safety, tolerance or feasibility of the use of health technologies in humans;

• Assessment of the efficacy of health technologies. To meet this objective, priority is given to funding research that, using controlled comparative methods, randomised or not, should help achieve recommendations with strong scientific evidence.

In accordance with the 2014‑2019 Cancer control plan, the orientations of the PHRC‑K programme particularly concern: • Areas pertaining to advanced forms of tumour diseases, oncogeriatrics and paediatric oncology;

• Research projects addressing individual or collective behavioural modif ications, or exploring drug‑based approaches in the prevention of cancer risks;

• Projects that include assessment of patients’ quality of life (during and/or after illness);

• Combination of several targeted drugs, or combinations of targeted drugs with chemotherapy or radiotherapy;

• Clinical validation of the eff icacy of innovative health technologies for treatment or diagnosis;

• Increase of survival; • Reduction in the medium and long term toxicity of treatments, and its assessment, especially for children and young adults;

• Palliative care; • Meta‑analyses addressing controversial issues in treatment efficacy.

In addition, strong involvement of cooperative intergroups is warranted, particularly with regard to proposing and conducting clinical trials aimed at responding to the major therapeutic questions of increasing survival, reducing the side‑effects and delaying effects of treatments.

To this end, up to 50% of the budget could be devoted to large‑scale projects conducted by cooperative intergroups.

Table 18. Features of PHRC‑K programme

Objectives

Evaluate safety, tolerance or feasibility of the use of health technologies in humans;Assess the efficacy of health technologies.



Funding institution Ministry of Health (DGOS)

Year 2015 2016

Funding (in €M) 20.14 21*



Selection rate 19.9% Pending

* Provisional


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In November 2015, of 186 letters of intent submitted to PHRC‑K, 37 projects were finally selected for funding for a total amount of €20.14M.

Table 19. Types of projects selected through PHRC‑K 2015

Number of projects selected1

Drug therapy 20

Immunotherapy 3

Surgery or other innovative techniques 4

Radiotherapy 8

Imaging (including PET) 1

Nuclear medicine (excluding PET) 2

Biomarkers (diagnosis, prognosis) 5

Management strategy 3

Prevention 1

In the framework of the 2015 CFP, 12 paediatric and 5 geriatric proposals were submitted. Of these, 3 paediatric projects (therapeutic studies) and 1 project on adolescents and young adults were selected, but none of the geriatrics projects were funded.

One is an international study on Classical Hodgkin’s lymphoma in children, adolescents and young adults, another one is a phase I study of a propranolol and oral metronomic vinorelbine combination for children and teenagers with refractory/relapsing solid tumours. The 3rd project is an international prospective randomised study in children younger than 5 years with medulloblastoma (MB) that aims to stratify paediatric brain tumours by differentiating low and high‑risk MB in two arms, mainly based on tumour genomic characteristics. The last project aims to evaluate long‑term health status and quality of life in adult survivors with Philadelphia‑negative acute lymphoblastic leukaemia treated with an intensive paediatric‑inspired protocol (GRAALL2003/05). One prevention study and one meta‑analysis aiming to ascertain treatments for head and neck cancer were also selected.

Since 2007, 1,979 proposals have been submitted to the PHRC‑K programme and 479 projects have been selected for an overall amount of €166.54M (results for 2016 are not included as the selection process is in progress). The overall selection rate for this call for proposals is 24.2%.

Fig. 18. Trends in selection and funding for PHRC‑K over the 2007‑2015 period

In compliance with the objectives of the CFPs, the CSO analysis of the projects funded shows that this programme is intended to support clinical applications of localised and systemic therapies, early‑phase clinical trials and studies related to cancer control and prevention (Figure 19).

1 – As the same project may fall under more than one category, the total value is over 37.

0

5

10

15

20

25

201520142013201220112010200920082007

Fund

ing

in €

M

Funding in €M Nb of projects

Nb

of p

roje

cts

0

10

20

30

40

50

60

70

80


58


3.1.2. THE NATIONAL PROGRAMME FOR MEDICO-ECONOMIC CANCER RESEARCH (PRME-K)The PRME‑K comprises two main areas: • Innovation in cancer care, aiming to validate the effectiveness of

innovative health technologies for cancer care in anticipation of their evaluation by the French National Authority for Health (HAS);

• Cancer care management pathways aiming to compare in real life the effectiveness of alternative care strategies involving health technologies in order to optimise cancer care.

Table 20. Features of the PRME‑K programme

Objectives

Validate the effectiveness of innovative technologies for cancer care;Compare in real life the effectiveness of alternative care strategies involving health technologies in order to optimise cancer care.



Funding institution Ministry of Health (DGOS)

Year 2015 2016

Funding (in €M) 1.46 2*




* Provisional

In 2015, 16 proposals were submitted and 4 projects were selected (25%). Two of them were aimed at evaluating the cost/effectiveness and cost/benefit ratios of different surgical approaches: • two approaches for the resection of small rectal tumours; • two strategies of perineal reconstruction after abdomino‑perineal resection for anorectal carcinoma.

A third will assess the budgetary impact of tyrosine kinase inhibitor discontinuation in chronic myeloid leukaemia patients with deep molecular response and the final one will evaluate prospectively, in a randomised way, the cost‑benefit, safety and feasibility of ambulatory surgery versus traditional pathways in the management of endometrial cancer.

Highlights• 2015: 41 projects funded in the framework of the

clinical research programmes for an overall budget of €21.6M.

• 2016: 192 and 10 proposals submitted to the PHRC-K and PRME-K programmes, respectively.

65%

17%

2%

34%

10%1%1%

11%

23%

1%

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 Recurrence

TreatmentPreventionEarly detection, diagnosis, prognosisCancer control


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3.2. EARLY-PHASE CLINICAL TRIALS FOR INNOVATIVE DRUGS

3.2.1. COOPERATION BETWEEN US-NCI AND INCa FOR EARLY-PHASE CLINICAL TRIALSSince 2009, INCa has collaborated with the US National Cancer Institute (NCI)‑Cancer Therapy Evaluation Program (CTEP) and a new Consortium Agreement was signed on October 2015. This agreement is the result of the willingness of INCa and the NCI to enhance the discovery and development of novel anti‑cancer agents and to facilitate joint development of research projects.

This collaboration includes investigational agents provided to CTEP from NCI collaborators1. This partnership should enable the CLIP² structures to develop innovative projects based on the proposed CTEP molecules, especially for rare diseases. As such, CLIP² investigators have the opportunity to network with those of the NCI, prior to the submission of a proposal.

The first collaboration allowed to set‑up 4 clinical trials with CTEP molecules in INCa’s designated CLIP² centres, and 2 are still recruiting (Table 21).

Table 21. Collaboration between INCa and NCI

Agent Title Details Status

Hedgehog inhibitor (vismodegib)

A Phase II study of GDC‑0449 in patients with advanced chondrosarcomas ‑ CHONDROG study

Institut Bergonié, Bordeaux

45 enrolled patients2 patients still on treatmentClosed to accrual (Open 12/2010)

AKT inhibitor (MK-2206)

A Phase II study of MK‑2206 in patients with relapsed or refractory diffuse large‑B cell lymphoma ‑ AKTIL study

Centre Léon Bérard, Lyon

22 enrolled patients Enrolment was stopped following the interim analysis of first stage of Simon two‑stage designComplete (Open 12/2011)

Met and VEGFR2 inhibitor (cabozantinib)

A Phase II study of XL184 (Cabozantinib) in treating patients with relapsed osteosarcomas and ewing sarcomas ‑ CABONE study

Institut Bergonié, BordeauxActive (12/2014)50/90 enrolled patients

Anti-CD30 Antibody-Drug Conjugate (brentuximab-vedotin)

A pilot trial of AVD and Brentuximab Vedotin (SGN‑35) in the treatment of stage II‑IV HIV‑associated Hodgkin lymphoma ‑ AMC‑085 study

LYSARC‑AMC joint protocolActive (5/2015 in France)9/20 enrolled patients

1 – See investigational agents at the link: http://ctep.cancer.gov/protocolDevelopment/docs/ctep_active_agreements.xlsx


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3.2.2. FRENCH PUBLIC-PRIVATE PARTNERSHIPS FOR EARLY-PHASE CLINICAL TRIALSSince 2011, INCa has promoted public‑private partnerships with pharmaceutical companies in order to propose new therapies being evaluated by the CLIP² centres. The goal is to select academic clinical trials to assess drugs in indications or conditions other than those included in pharmaceutical firms’ development plans. Thus, this programme is intended to give early access for patients and investigators to these molecules, albeit with the risk of premature discontinuation of certain molecules.

In total, INCa launched 12 specific CFPs to propose 21 molecules in development and 18 projects were selected to evaluate these molecules. Among the 18 selected projects, 15 have actually started, 12 were co‑funded by the ARC Foundation. The characteristics and the statuses of these projects are summarised in Table 22. Figure 20 presents the different cancer sites covered in this programme.

Table 22. Projects funded by INCa


PI3K inhibitor (Buparlisib)

A Phase II, multicentre trial aiming to evaluate BKM120 in monotherapy in patients with recurrent or progressive metastatic head and neck cancer under platin and cetuximab‑based chemotherapy – PIK‑ORL Study

Léon Bérard centreActive (12/2012) 53/70 enrolled patients

CDK4/6 inhibitor (Palbociclib)

An open‑label multicentre, phase I‑II study with tumour molecular pharmacodynamic evaluation and pharmacokinetics of PD‑0332991 combined with vemurafenib in patients suffering from metastatic melanoma with BRAFV600 mutated and CDKN2A loss defined by either low CDKN2A mRNA expression, or mutation or loss of CDKN2A gene and expression of Rb – Optimum Study

AP‑HP St LouisActive (04/2014) 16/40 enrolled patients

CDK4/6 inhibitor (Palbociclib)

Efficacy and safety of PD‑0332991 in patients with advanced gastrointestinal stromal tumours refractory to Imatinib and Sunitinib: A Phase II study – CYCLIGIST Study

Bergonié InstituteActive (01/2014) 26/63 enrolled patients

PI3K/mTor inhibitor (PF-5212384)

Phase II clinical trial evaluating the efficacy of the dual inhibition of PIK/Akt/mTor signalling pathway by PF‑05212384 (PKI‑587) for patients with myeloid neoplasm secondary to chemo‑radiotherapy (t‑AML/MDS) or de novo relapsed or refractory AML – LAM‑PIK Study

Curie InstituteActive (06/2015) 11/39 enrolled patients

P70/AKT inhibitor LY2780301

A Phase Ib, open‑label, dose escalation study of the safety, tolerability and efficacy of LY2780301 (a p70/Akt inhibitor) in combination with Gemcitabine in patients with advanced or metastatic cancer – INPAKT Study

Gustave Roussy52 enrolled patientsClosed to Accrual (Opened 09/2013)


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P70/AKT inhibitor LY2780301

A prospective, multicentre, uncontrolled, phase Ib/II study of LY2780301 in combination with weekly paclitaxel in HER2‑negative metastatic or locally advanced breast cancer in patients with and without PI3/AKT/S6 pathway activation ‑ TAKTIC Study

Paoli‑Calmettes Institute

Active (01/2014) Phase I complete10/50 enrolled patients, phase II

P38/MAPK inhibitor LY2228820

Phase I/II study of LY2228820 with radiotherapy plus concomitant TMZ in the treatment of newly diagnosed glioblastoma – GLYRad Study

Jean Perrin centreActive (01/2015) 9/50 enrolled patients

P38/MAPK inhibitor LY2228820

A randomised open‑label phase II multicentre trial assessing the efficacy and safety of Tamoxifen plus LY2228820 in advanced or metastatic breast cancer progressing on aromatase inhibitors – OLYMPE Study

François Baclesse centreActive (01/2015) 4/114 enrolled patients

Oncolytic virus JX-594

A phase Ib/II study of metronomic cyclophosphamide and the oncolytic poxvirus JX‑594 in patients with advanced breast cancer and soft tissue sarcoma – METROmaJX Study

Bergonié InstituteActive (09/2015) 7/30 enrolled patients in phase I

Tasquinimod

Multicentre phase I‑IIa trial of tasquinimod in combination with megestrol acetate in advanced hormonosensitive endometrial adenocarcinoma – TASQUENDO Study

François Baclesse centre Closed

PARP inhibitor Olaparib

A phase Ib study of olaparib with concomitant radiotherapy in locally advanced/unresectable soft‑tissue sarcoma – RADIOSARP Study

Bergonié InstituteActive (06/2016) 0/42 enrolled patients

Anti-PD-L1 Antibody (Durvalumab)

A dose escalation Phase I study with an extension part evaluating the safety and activity of an anti‑PDL1 antibody (DURVALUMAB) combined with a small molecule CSF‑1R tyrosine kinase inhibitor (PEXIDARTINIB) in patients with metastatic/advanced pancreatic or colorectal cancers – MEDIPLEX Study

Léon Bérard centreActive (06/2016)2/58 enrolled patients

Dual mTORC1/mTORC2 inhibitor AZD2014

A multicentre, randomised, non‑comparative, open‑label Phase I/II evaluating AZD2014 (dual mTORC1/mTORC2 inhibitor) in combination with anastrozole versus anastrozole alone in the treatment of metastatic hormone receptor‑positive endometrial adenocarcinoma – VICTORIA Study

Léon Bérard centre Active (04/2016) 1/72 enrolled patients

PARP inhibitor Olaparib

A phase I/II trial to assess the safety and efficacy of metronomic cyclophosphamide, metformin and olaparib in recurrent advanced/metastatic endometrial cancer patients – ENDOLA Study

Hospices Civils de LyonActive (04/2016)0/33 enrolled patients

Anti-PD-L1 Antibody (Durvalumab)

Phase I trial evaluating the safety of MEDI4736 in combination with Docetaxel, Cisplatin and 5 FU in induction for locally advanced head and neck squamous cell carcinoma – MEDINDUCTION Study

Gustave Roussy Pending approval


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Fig. 20. Innovative molecules: funding distribution by organ

3.3. PERSONALISED MEDICINE TOOLS AND PROGRAMMES

3.3.1. NEXT GENERATION SEQUENCING FOR CLINICAL APPLICATIONSSince 2013, INCa has supported the development of targeted NGS for diagnostic purposes in the 25 oncogenetics laboratories and in the 28 molecular genetics centres. In 2013, INCa launched a specific CFP and selected 11 pilot teams in order to carry out an implementation phase for NGS. As of the end of 2015, 20 oncogenetics laboratories and 13 molecular genetics centres had started to use NGS for clinical diagnostics for some of their patients (Figures 21 and 22). Based on experience gained during this pilot phase, this technology is being rolled out in 2015 in all the molecular genetics centres and oncogenetics laboratories. Funding from INCa supported the technical validation phase for NGS and the recruitment of bioinformatics engineers in the laboratories.

Fig. 21. Implementation of NGS in clinical diagnostics in molecular genetics centres

Fig. 22. Implementation of NGS in clinical diagnostics in oncogenetics laboratories


HaematologyGastrointestinal cancersColorectal / AnusMelanomaLung / Upper aerodigestive tractBreastUrinary and genital systemsCentral nervous systemSarcoma and connective tissues Other locationsNon-specific

13%

4%

11%

14%4%

23%

5%7% 12%

3%

4%


Number of centres where NGS is in routine practice since 2014

Number of centres where NGS is in routine practice since 2015

Number of centres where NGS is in validation stage

6

7

15


Number of lab where NGS is in routine practice since 2014

Number of lab where NGS is in routine practice since 2015

Number of lab where NGS is in validation stage

5

8

12


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Accreditation of NGS analysis according to the ISO15189 standard is the next milestone to ensure the quality of the tests performed for clinical purposes. None of the somatic genetics laboratories and only 3 oncogenetics laboratories were accredited for NGS technology in 2015. Accreditation is a challenge because NGS requires new skills, especially for data analyses and interpretation, and because few CE‑IVD diagnostic kits are commercially available. To support this, a monitoring group led by INCa was created to improve feedback and the definition of good practices. A guide for validating NGS has been issued in 2015, and serves as a reference for the accreditation of laboratories. This work is still ongoing to complete these recommendations for informatics and bioinformatics processes.

In 2013, INCa also selected 5 reference teams in bioinformatics. Their role is to provide their expertise to clinical laboratories, to develop, validate and release analytical solutions and to facilitate networking between bioinformatics engineers. Since 2013, the 5 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 those most suitable for the information systems of the facilities to which the laboratories belong. The “test” data sets compiled to evaluate the pipelines could also become a reference data set that all laboratories could use to evaluate their protocol locally. The work undertaken by the bioinformatics reference teams since 2013 must be maintained in order to continue the ongoing work and to support the roll‑out of NGS throughout all the laboratories. A special effort will be focussed on technology transfer of the pipelines and the expertise from the reference team to the clinical laboratories.

The medical interpretation of results is another issue that needs to be addressed, in order to make the best use of NGS results to improve patient outcome on a national scale. This requires improving the assessment of the biological and clinical significance of the rare mutations identified with NGS techniques. Clinical follow‑up of patients with some mutations in their tumour will also be essential to improve the knowledge base on these mutations. This applies to INCa’s participation in Global Alliance, and can be supported by the inter‑SIRIC working group on data integration which aims to improve data sharing.

2015 HighlightsNGS clinical diagnostics used in 20 oncogenetics laboratories and in 13 molecular genetics centres.

3.3.2. THE AcSé PROGRAMMEINCa developed the AcSé Programme in 2013 (Secured Access to innovative therapies) to provide a secured access to targeted therapies for patients in treatment failure situations, and the programme has been open recently to paediatric tumours.

The AcSé programme is managed by a scientif ic steering committee1, whose main tasks are the choice of eligible drugs, the definition of the programme guidelines, communications with patients and oncologists.

AcSé addresses the safety issues in patients with administered drugs that are not authorised for these indications, based on the patients’ molecular profile defined in the 28 INCa molecular genetics centres. In this context, all patients in France with advanced malignancies carrying the drug biomarker are eligible for inclusion, if there is no other clinical trial in which they could be enrolled. Moreover, AcSé trials may also include patients <18 years if safe dosing data are available.

The achievements of the first two clinical trials, sponsored by UNICANCERProof of concept is currently being demonstrated through two ongoing trials: • AcSé-crizotinib was implemented in 2013 and is funded by INCa and ARC Foundation. Currently, prescription of crizotinib is allowed only to adult patients with lung cancer with a specific molecular alteration, ALK gene translocation. However, crizotinib targets different molecular alterations that may be found in other cancers. To date, the AcSé‑Crizotinib trial allowed treating 180 patients in France who presented the specific mutation in 20 cohorts. In order to identify the potential genetic alterations ‑ ALK, MET and ROS1 ‑ targeted by crizotinib, more than 8,000 patients benefited from a biomarker analysis performed in INCa molecular genetics centres.

1 ‑ The steering committee is made up of various members of other organisations (e.g. UNICANCER, the sponsor of these first protocols conducted under the AcSé programme ‑ AcSé‑crizotinib & AcSé‑vemurafenib ‑ or the ARC Foundation as a co‑funder of the programme).


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Fig. 23. AcSé‑crizotinib: Description of recruitment by cohort (May 2016)

Fig. 24. AcSé‑crizotinib: Description of recruitment by age (May 2016)

0 5 10 15 20 25 30 35 40Miscellaneous adults malignancies

21. Rare paediatric malignancies

20. Thyroid cancer (follicular + medullary + papillary) - adults - MET mutated

19. Anaplastic thyroid cancer - adults - ALK mutated or ALK translocated

18. Glioblastoma - adults - MET amplified

17. Rhabdomyosarcoma - children and adults - ALK amplified

16. Inflammatory Myofibroblastic Tumour - children and adults - ALK translocated

15. Neuroblastoma - children and adults - ALK amplified or ALK mutated

14. Hepatocarcinoma - adults - MET amplified

13. Papillary renal cell carcinoma - adults - MET mutated or MET amplified

12. Clear cell renal carcinoma - adults - ALK amplified

11. Clear cell renal carcinoma - adults - ALK translocated

10. Ovarian cancer - adults - MET amplified

9. Cholangiocarcinoma - adults - ROS1 translocated

8. Gastric and gastroesphageal junction cancer - adults - MET amplified

7. Breast cancer - adults - ALK translocated

6. NSCLC - adults - ROS1 translocated

5. NSCLC - adults - MET amplified

4. Colorectal cancer - adults - MET mutated

3. Colorectal cancer - adults - MET amplified

2. Colorectal cancer - adults - ALK translocated

1. ALCL - children and adults - ALK translocated

0 10 20 30 40 5091-100

81-90

71-80

61-70

51-60

41-50

31-40

18-30

11-17

0-10

By age


65

• AcSé-vemurafenib, launched in October 2014, is intended to evaluate the efficacy and the safety of vemurafenib treatment in 500 patients with various types of cancer, all carrying the BRAF V600 specific genetic abnormality, targeted by this treatment.

Vemurafenib is exclusively prescribed for patient‑specific BRAF‑V600E‑mutated melanomas, the objective of the AcSé‑vemurafenib trial is to determine whether patients with a cancer other than melanoma and carrying this mutation could receive vemurafenib. To date, 86 patients have received vemurafenib treatment, and more than 10 other malignancies known to present BRAF mutations have been included.

Fig. 25. AcSé‑vemurafenib: Description of recruitment by cohort (May 2016)

Fig. 26. AcSé‑vemurafenib: Description of recruitment by age (May 2016)

2016 highlights• 1 international publication in Nature Reviews Clinical

Oncology “Equal Access to innovative therapies and precision cancer care”1;

• 2 presentations at international conference: – Oral communication in ASCO 2016 “Crizotinib in children and adolescents with advanced ROS1, MET or ALK-rearranged cancer: result of the AcSé phase II trial”;

– Poster presentation in ASCO 2016: “Biomarker-driven access to vemurafenib in BRAF-positive cancers: Second study of the French National AcSé Programme”.

0 5 10 15 20 25 30 3581 - 90

71 - 80

61 - 70

51 - 60

41 - 50

31 - 40

18 - 30

By age

0 1020

30 40 50 60Miscellaneous malignancies

10. Hairy Cell Leukaemia - mutation V600

9. Chronic lymphocytic leukaemia - mutation V600

8. Multiple myeloma - mutation V600

7. Sarcoma / Gastrointestinal stromal tumours GIST - mutation V600

6. Bladder cancer - mutation V600

5. Prostate cancer - mutation V600

4. Thyroid cancer - mutation V600

3. Cholangiocarcinoma - mutation V600

2. Ovarian cancer - mutation V600

1. Non-small cell lung cancer - mutation V600

20

Buzyn A. et al. (2016). Equal access to innovative therapies and precision cancer care. Nature Reviews Clinical Oncology 13, 385‑393. doi: 10.1038/nrclinonc.2016.31


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The new AcSé clinical trialsIn recent years, the AcSé steering committee has worked on the next AcSé projects including the development of paediatric components: • Two clinical trials in immunotherapy, AcSé-nivolumab & AcSé-pembrolizumab, that are intended to evaluate two anti‑PD‑1 agents in rare cancer cohorts (one trial per molecule) should be launched by the end of the year or in the first half of 2017, and will include paediatric cohorts;

• The eSMART trial, as part of the AcSé programme dedicated to paediatrics, was launched in June 2016, and is funded by INCa and the association Imagine for Margo. This study should address the specific needs of children and teenagers with relapsed life‑threatening malignancy, and their access to investigational drugs based on their molecular profile. AcSé‑eSMART will include 260 children in therapeutic failure situations and is intended to test 10 innovative molecules (targeted therapies, immunotherapies, alone or in combination) in a single clinical trial, and expects to double the number of new drugs proposed for treating children over the next 3 years.

2016 highlightsMassive impact in the French press following the launch of the eSMART trial in paediatric cancers.

3.3.3. THE PAOLA CLINICAL TRIALOlaparib, a PARP inhibitor, was granted European market approval in late 2014 for maintenance treatment of high‑grade ovarian cancer patients, fallopian tube and primitive peritoneal cancer patients, carrying a BRCA mutation (germline and/or somatic). In this context, the patient’s BRCA status, both somatic and germline genetics, will need to be acquired, within timelines consistent with the patient’s therapeutic management. The introduction of a somatic component will require the development of NGS on tumour samples. In this way, setting up a pilot phase was essential, building on the oncogenetics laboratories (germline genetics) and INCa molecular cancer genetics centres (somatic genetics).

Fig. 27. Schematic presentation of the design for BRCA status analysis

Set up of the BRCA genes analysis with the NGS technic on tumour samples

France selection to identify BRCA status in patients eligible to PAOLA1 clinical trial

Support to NGS development at the national level

• 5 French partners selected• 1 May 2015 – 30 April 2017• INCa funding: €560,000• ARCAGY-GINECO funding: €250,000• Expected recruitment: 636 patients• 307 patients tested in 1 year

• 10 French teams supported • 1 September 2015 – 31 August 2016• INCa funding: €400,000• 1st mid-year activity report: June 2016


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PAOLA1 is a comparative clinical trial of olaparib‑bevacizumab versus bevacizumab in maintenance treatment (following first‑line chemotherapy). This clinical trial aims to include 612 European patients presenting with BRCA mutation or not. Hence, all patients should be tested for the BRCA status and 5 French centres have been selected for testing: • both somatic and germline BRCA statuses for French patients; • only somatic BRCA status for other European patients (Germany, Italy, Spain, Sweden, Denmark, Finland, Belgium, Austria).

The analyses started in May 2015.

During the first year, 392 samples were received by the 5 centres: • 218 from French patients; • 174 from European patients.

Of the 147 French patients who were tested for germline and somatic genetics, 29 had both germline BRCA and tumour BRCA mutations (19.7%) while 11 had a tumour BRCA mutation of somatic origin without a germline BRCA mutation reported (7.5%).

Moreover, 48 tumours BRCA‑mutated were detected in 160 patients tested for somatic genetics only (30%, 27 French patients and 133 European patients). Hence, a BRCA mutation was identified for 88 patients of the 307 tested (28.7%).

To date, 151 tested patients have been included in PAOLA1: 100 French patients and 51 European patients.

Table 23. BRCA status follow‑up in PAOLA1, 1 May 2015 to 30 April 2016

French patients received by the five French testing centres 218

European patients received by the five French testing centres 174

French patients tested for somatic and germline genetics 147

French patients with germline and somatic BRCA mutations 29 (19.7%)

French patients with somatic BRCA mutations without a germline BRCA mutation reported 11 (7.5%)

French patients tested for somatic genetics only (pending test for germline genetics) 27

European patients tested for somatic genetics 133

French and European patients with somatic BRCA mutations 48 (30.0%)

Total patients tested 307

Total patients with BRCA mutations (germline and somatic BRCA mutations or somatic BRCA mutations)

88 (28.7%)

French patients tested and included in PAOLA1 100

European patients tested and included in PAOLA1 51

Highlights100 French and 51 European tested patients included in the PAOLA1 clinical trial over the first year.


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3.4. ORGANISATION OF CLINICAL RESEARCH AND STRENGTHENING OF STRUCTURES, INFRASTRUCTURES AND TOOLS

3.4.1. EARLY-PHASE CLINICAL TRIALS CENTRES (CLIP² CENTRES)Promoted by the 2009‑2013 Cancer control plan, the initiative to structure clinical and translational research is supported by INCa through a specific designation: early‑phase clinical trials centres.

This objective is being pursued in the 2014‑2019 Cancer control plan by undertaking a new designation of these structures. These new centres, most of which have been renewed, have seen their scope of activity somewhat extended. Particularly, this designation allowed the collaboration of CLCC centres and University hospitals, locally closed, to apply for a common early‑phase clinical trials centre, and for 6 of them to integrate paediatric activities (Figure 28).

Fig. 28. The 16 early‑phase clinical trials centres (CLIP² centres)

This initiative has contributed to the overall increase in the number of clinical trials launched (+86%) in each designated centre and in the number of patients (+136%), especially in phase I (Figure 29).

CLIP² designation for the 2015‑2019 period was initiated in 2014, for designation of centres effective at the end of April 2015. Therefore, 2014 is considered to be a transition year for the CLIP² network and the activity data cannot be taken into consideration.

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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Fig. 29. CLIP² activity

3.4.2. ENROLMENT OF PATIENTS IN CLINICAL TRIALSSince 2006, INCa and the French Ministry of Health have funded 26 Mobile Clinical Research Teams (EMRC) for a total amount

of €3M. Furthermore, since 2004, additional funding of €3M is annually allocated to University Hospitals and Cancer Care Centres by the Ministry of Health. The objective of this support is to create conditions to promote the involvement of public and private researchers in clinical trials. Approximately 140 FTE positions, mainly research nurses, have been hired, based in over 160 different hospitals throughout France. Another aim is to ensure equal access to clinical trials for patients in all types of hospitals in France and the best quality of data collected during clinical trials. In 2015, INCa carried out an annual survey of clinical cancer research activities in these hospitals. The results show that the number of patients in the clinical trials increased significantly over the 2008‑2015 period: • +122% increase in total; • +148% for patients participating in academic trials; • +50% for patients participating in industrial trials during the same period.

The ratio of enrolment in academic vs. industrial trials is stable over the years (82/18). A substantial increase in 2015 versus 2014 can be observed that could be explained by an increase of recruitment in University hospitals, mainly those in the Paris area.

Figures 30 and 31 present the progression of recruitment of patients recorded in INCa’s annual survey, and the distribution of this recruitment among the different types of care facilities, respectively.

Fig. 30. Enrolment of patients in cancer clinical trials in France 2003‑2015 (INCa survey)

0

1000

2000

3000

4000

5000

201520142013201220112010

Nb

of p

atie

nts

enro

lled

Nb of patients enrolledAverage nb of new trials per CLIP²

CLIP² 2010-2014 CLIP²2015-2019

Aver

age

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er C

LIP²

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2015201420132012201120102009200820072006200520042003

Nb patients enrolled - academic trialsNb patients enrolled - industry-sponsored trialsAll


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Fig. 31. Enrolment of patients in clinical cancer‑related trials according to the type of care provider 2008‑2015 (INCa survey)

3.4.3. INCa’S CANCER RESEARCH CLINICAL TRIALS REGISTRY The clinical trials registry in cancer research managed by INCa provides easy access to information on clinical trials using a multicriteria search engine, making it possible to search for clinical trials, using various criteria such as the sponsor or the organ under study, as well as the geographical location of recruiting centres using a geolocation module.

From 2007 onwards, the registry of clinical trials in cancer research has allowed easy access to relevant information on trials performed in France. Available in open access on INCa’s website, it provides a wealth of high‑quality data and regular updates for patients, healthcare professionals and the general public.

Table 24. Registry of Clinical Trials in Cancer Research

ObjectivesTo provide information relevant to clinical trials in the field of cancer open to inclusion in France.

Results

2,098 clinical trials published through the registry on INCa’s website in May 2016: • 592 trials opened to patient recruitment, proposed by more than 250 industrial or academic/public sponsors; • 62% of the clinical trials have an academic sponsor.

0%

10%

20%

30%

40%

50%

20152014201320122011201020092008

University HospitalsCancer Care CentresCommunity Centres (public)Community Centres (private)


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Fig. 32. Number of clinical trials published up to 15 May 2016

In 2014, in accordance with actions 5.4 and 7.16 of the 2014‑2019 Cancer control plan, INCa initiated a process aiming to collect the results of clinical trials, in order to publish them

through the registry. Since the launch of the new internet portal in 2012, between 20,000 and 30,000 visits/month have been recorded.

0

200

400

600

800

1,000

1,200

1,400

Academic TrialsIndustry Sponsored TrialsOpen Trials

Apr

-07

Jul

y-07

Dec

-07

Jul

y-08

Dec-

08

Jul

y-09

Dec

-09

July

-10

Dec

-10

Jun

-11

Dec

-11

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-12

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-12

Jun-

13

Dec

-13

May

-14

Oct-1

4

Dec-

14

May

-15

Dec-

15

Apr-1

6

May

-16


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4 4RESEARCH IN HUMAN AND SOCIAL SCIENCES, EPIDEMIOLOGY AND PUBLIC HEALTH

One of INCa’s goals is to bring social sciences and public health research applied to oncology in France up to the best international standards. In line with the Cancer control plan, particular efforts are being devoted to increasing basic and health intervention research in order to reduce social inequalities related to cancer, and increase the impact of cancer prevention measures, participation in screening and access to care.

To achieve this goal, INCa has established links with other national organisations in order to combine experience and know‑how in deciding how to modify the approach to environmental and behavioural risk factors.

4.1. THE RECURRENT PROGRAMME FOR HUMAN AND SOCIAL SCIENCES (HSS), EPIDEMIOLOGY AND PUBLIC HEALTH (EPH) RESEARCH

4.1.1. BACKGROUND AND OBJECTIVES OF THE CALL FOR PROPOSALSThe role of human and social sciences, epidemiology and public health (HSS‑EPH) in cancer research is confirmed by the 2014‑2019 Cancer control plan. The objectives of several strategic measures presented in the Plan are based on the progress that could be made through HSS‑EPH research. Research conducted in these areas should facilitate and build multidisciplinary collaboration between researchers from the HSS‑EPH disciplines: psychology, sociology, economics, anthropology, political science, epidemiology, biostatistics, public health — prevention and screening — as well as history of science, communications theory, geography and law, especially labour law. It is also crucial to encourage interactions with researchers from other disciplines such as biology, genetics, environmental sciences, immunology, toxicology and clinical research.

The general objectives of the present call for proposals are as follows: • To encourage the emergence of original research proposals of scientific excellence in the different HSS‑E‑PH disciplines applied to cancers;

• To develop and to strengthen multidisciplinary scientific research that unites teams, disciplines and technological resources around one specific research issue or objective.

4.1.2. INDICATIVE TOPICS FOR RESEARCHERS’ ATTENTIONAlthough the present CFPs is an investigator‑driven programme, some aspects related to the public health objectives of the 2014‑2019 Cancer control plan were proposed as indicative research topics. The researchers were free to use these topics as a basis, but it was not a condition for the scientific evaluation of the projects. Tentative topics for the year 2016 were as follows: • Modelling the costs of caring for patients with cancer; • Palliative care/end of life care (Action 7.6); • Comorbidity and cancer (Action 2.16); • Improved knowledge of the experience of patients and their families (Actions 9.17.1; 9.17.3; 9.18.1).

The analysis of the projects submitted shows that about 23% of the proposals meet the proposed indicative topics, suggesting that they might influence the investigators’ choices.

4.1.3. 2016 RESULTSIn 2016, 86 proposals were submitted and 16 projects were selected for funding for a total amount of €3.51M. The table 25 presents the features of the HSS‑EPH programme in 2015 and 2016.


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Table 25. Features of the programme for Human and social Sciences (HSS), Epidemiology and Public Health (EPH) research

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 identified goal, enlisting teams, disciplines and technological means to effectively respond to it.




Year 2015 2016




Selection rate 26% 18.6%

The distribution of submitted proposals by major discipline categories is presented in table 26.

Table 26. Distribution of LoIs submitted and selected, projects selected and amounts funded by major disciplines

LoIs submitted

LoIs selected

Projects selected

Funding (€M)

Epidemiology/biostatistics 44 23 11 2.47

Social and human sciences/public health

42 14 5 1.04

TOTAL 86 37 16 3.51

It should be noted that the number of projects submitted is relatively balanced between the major disciplines of the CFPs (epidemiology/biostatistics versus HSS/public health).

It is important to highlight the differences in success rates between the 2 phases by disciplinary categories. They were 52% for the Epidemiology/biostatistics category and 33% for the HSS/public health category for the pre‑selection of the LoIs. The corresponding figures were 48% versus 36% during the second phase based on full projects.

Finally, the selection rate at the end of these 2 phases was 25% for the Epidemiology/Biostatistics category and 12% for the HSS/public health category. At least two reasons might explain this observation. First, research in HSS and public health applied to cancer is relatively new in France, compared to research in epidemiology and biostatistics. Based on the comments of referees and external reviewers, there seem to be more methodological difficulties and weaknesses in the social and human sciences and public health research projects submitted. Additional initiatives from INCa might be needed in order to reduce the gap. Some directions are given in the strategic topics section of this report (See Part 3 chapter 4).

The projects selected for funding in epidemiology are aimed at studying environmental, nutritional and genetic risk factors for cancer, even though there is a strong trend towards molecular epidemiology. For example, two of the three projects aim to study: 1. Biomarkers of dietary fatty acids, lipid metabolism, and risk

of ovarian cancer; 2. Immunity, inflammation and breast cancer risk.

Projects in biostatistics aim at testing the existence of statistical cure and modelling the time to cure in population‑based cancer survival, but also at identifying minimal clinically significant differences in health‑related quality‑of‑life scores integrating the occurrence of the response shift effect. Selected projects in human and social sciences and public health focus on geographical inequalities in access to oncology expertise, quality of life for minor siblings of childhood and adolescent survivors of acute leukaemia, medium‑ and long‑term after diagnosis, but also the impact of mediation on chemotherapy‑induced pain neuropathy and on cooperation between institutions, adults, parents, clinicians and researchers to improve access to information after childhood, adolescent or young adult cancer. Breast cancer and sarcomas are the main cancer sites studied in all projects and represent 20% and 12%, respectively.


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4.1.4. THE HSS-EPH PROGRAMME OVER THE 2007-2016 PERIODSince 2007, 177 projects have been selected to the investigator‑driven HSS‑EPH programme for a total amount of €36.56M.

Fig. 33. Trends in selection and funding

The figure 34 presents the distribution of the funded projects over the 2007‑2016 period according to the CSO classification.

Fig. 34. Distribution of the selected projects according to the CSO classification

0

2016201520142013201220112010200920082007

Fund

ing

in €

M

Funding in €MNb of projects

1

2

3

4

5

6

Nb

of p

roje

cts

0

5

10

15

20

25

30

5%7%

16%

8%

Aetiology Prevention Early detection, diagnosis, prognosis Treatment Scientific modelsCancer control

14%

59%

%21

%3 %7

%8 7%0,8%1,1%

End-of-Life CareEthics and ConfidentialityResources and InfrastructuresEducation and CommunicationCost Analyses and Health Care DeliveryBehaviourSurveillance Patient care and Survivorship Issues

2 %

1,1%Ethics and Confidentia-lity 0,8%


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In compliance with the objectives of the call, 59% of the funded projects relate to cancer control and survivorship issues, with particular emphasis on behavioural factors, patient care and survivorships issues that represent 16% and 14%, respectively. Moreover, surveillance methodologies represent 8% and cost analyses and health care delivery 7%.

Aetiology category encompasses the epidemiology studies and represents 21% of the funded projects whereas social sciences related to treatment and early detection represent 8% and 7%, respectively.

4.2. POPULATION HEALTH INTERVENTION RESEARCH In 2010, the support for human and social science research was strengthened and completed by a dedicated CFPs in population health intervention research to reduce the inequalities. In 2011, the SAB recommended the set‑up of a specific strategy for preventive research that should include behavioural and social sciences, public health, etc. Based on these recommendations and on the 2012 strategic report on cancer prevention research, the scope of the programme was extended to include interventions for promoting behaviour changes and for reducing the inequalities in 2013.

In 2015, the CFPs scope included all aspects of cancer control: ranging from primary prevention, to secondary prevention, tertiary prevention, healthcare organisation, and survivorship and rehabilitation issues. This call also encourages research in methodological issues.

Secondly, two types of proposals are expected: • full research proposals presenting advanced research protocols, with a strong methodological approach and established partnerships, to be funded for 24 to 48 months;

• 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.

Finally, the administrative guidelines strongly recommend the establishment of partnerships between researchers, stakeholders in the field and decision‑makers.

Table 27. Features of the population health intervention research programme

Objectives

Promote the emergence of projects in intervention research applied to cancers, that are original and of scientific excellence, and likely to produce knowledge that is scientifically valid and socially useful. Encourage original partnerships between research teams in different disciplines (human and social sciences, public health [prevention/health promotion], epidemiology, biostatistics, etc.) and practitioners in the field (medical, allied health, and social services personnel, non‑profit organisations, etc.), in order to facilitate the implementation and transferability of the findings in different contexts.




Year 2015 2016

Funding (in €M) 1.07 Pending




In 2015, 7 projects were selected, including 4 emerging research projects, among the 29 submitted proposals, for a total amount of €1.07M.

In 2016, two modalities were added: a transversal area based on the explicit integration of the issue of health inequalities in research plans and an emphasis on justifying and evaluating the efficiency of the proposed interventions in the research projects.

In 2016, 22 projects were submitted including 8 emerging projects. The evaluation process is ongoing.

Since 2010, 24 projects have been funded for a total of €7.24M (Table 28).


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Table 28. Trends in selection and funding of Intervention research programme over the 2010‑2015 period

Year 2010 2011 2012 2013 2014* 2015 TOTAL

Funding (in €M) 0.61 1.51 2.18 0.71 1.15 1.07 7.23

Proposals submitted 8 37 20 10 59 29 163

Projects selected 2 3 5 3 4 7 24

Selection rate 25% 8% 25% 33% 7% 24% 14%

* In 2014, partnership INCa, IReSP, ARC Foundation, ANRS, MILDT.

Figure 35 highlights that the projects address 4 CSO categories: aetiology, prevention, early detection and diagnosis, cancer control, survivorship and outcome research. A clear trend

is emerging amongst the projects towards prevention and survivorship/outcome research. Health behaviour, cost analyses and health care delivery are the most studied topics.

Fig. 35. Distribution of the selected projects according to the CSO typology over the 2010‑2015 period

Highlights2015: 7 projects selected for a total amount of €1.07M, including 4 emerging research projects.2016: 22 projects submitted.

3%

23%

13%

3

4

%

44%

4

%

AetiologyPreventionEarly detection, diagnosis, prognosisCancer control

%

48%

6%

Resources and InfrastructuresEducation and CommunicationCost Analyses and Health Care DeliveryBehaviourPatient care and Survivorship Issues


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4.3. INITIATIVES DEVELOPED TO SUPPORT RESEARCH ON ENVIRONMENTAL RISKS

4.3.1. SUPPORT FOR RESEARCH ON ENVIRONMENTAL RISK FACTORS, CANCER AND ENVIRONMENT PROGRAMME Since 2012, a dedicated CFP has been launched by ITMO Cancer‑Aviesan to strengthen support for research in the area of environmental risk factors.

Table 29. Features of the Cancer and environment programme

Objectives

To 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.



Funding institutions Inserm for ITMO Cancer‑Aviesan

Year 2015 2016





Table 30. Trends in selection and funding of the Cancer and environment programme over the 2012‑2016 period

Year 2012 2013 2014 2015 2016 TOTAL

Funding (in €M) 2.52 2.91 3.25 3.18 3.74 15.6

Proposals submitted 23 22 24 32 37 138

Projects selected 9 7 7 8 8 39

Selection rate 39% 32% 29% 25% 22% 28%

In 2016, 8 projects of major interest to the scientific community were selected for a total funding of €3.74M. They address important issues on exposure to endocrine disrupting chemicals (EDCs) such as, the targets of low‑dose effects of xenoestrogen exposure, the occurrence of testicular germ cell tumours and changes in methylation due to exposure to EDCs, the identification of exposure, diagnostic and prognostic markers of prostate cancer and related to EDC exposure.

Other studies address issues on the skin adaptation to UV radiation at the transcriptional level, the effects of exposure to air pollution, throughout one’s lifetime, the risks and the associated mechanisms of carcinogenic effects of different exogenous ligands or the impact of nanoparticles in food, by using original mouse models.

They should result in the development of suitable skin protection solutions or serve as experimental models to study the adverse effects of other food additives.

Since 2012, 39 projects have been selected among the 138 proposals submitted for an overall amount of €15.6M.

Half of the projects (50%) address the lines of the CFP in the development of models for analysing the effects of the environment or study interactions and transmission of toxic effects (mutational and epigenetic alterations). They address important issues in terms of public health and social concerns as well as major gaps in environmental epidemiology of cancer research. They combine epidemiology, molecular biology/genomics, physics and bioinformatics methods to address issues


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on everyday‑life contaminant concentrations, corresponding to real exposure (i.e. pesticides, UV, radiation, chemical and metal pollutants, etc.).

They potentially open up new scientific and technical prospects to identify high risk subgroups and may have scope for policy‑makers such as generating new standards in environmental toxicology.

4.3.2. PROGRAMME OF THE FRENCH NATIONAL AGENCY FOR FOOD, ENVIRONMENTAL AND OCCUPATIONAL HEALTH AND SAFETY (ANSES) TO SUPPORT RESEARCH ON ENVIRONMENTAL RISKS

This multi‑agency programme addresses various public health issues related to the environment and employment. Cancer‑related projects were covered by INCa in 2010 and ITMO Cancer‑Aviesan for the 2011‑2016 period.

Table 31. Features of the 2015‑2016 Research Programme in Employment‑Health‑Environment in the field of cancer

Objectives

To evaluate and analyse environmental risks for human health in the general population or at work.To address emerging and known risks, which can generate complex scientific debates, and for which a single approach can include concepts, methods and tools from different disciplines.

Programming institution Anses

Operating institution Anses


Year 2015 2016





In 2016, 35 cancer‑related proposals were submitted and 6 projects were selected for funding for a total amount of €1.01M. Among these funded projects, it is interesting to note that some projects address environmental risk factors for childhood cancers, such as leukaemia, brain tumours or embryonic tumours. These projects are novel studies on farming pesticides, traffic and air pollution, high voltage power lines and ionising radiation from natural sources.

Importantly, these projects are multidisciplinary by combining social sciences, epidemiology, molecular biology studies and other different experimental methods to address exposure to different compounds (i.e. polycyclic aromatic hydrocarbons, PAHs, metals) in order to identify biomarkers to improve early detection and/or to open up new prevention strategies or to set up new behavioural tests.

Since 2010, 46 cancer‑related projects were funded in the framework of this programme for a total budget of €6.79M. In addition, the Ministry of Labour (DGT) and the French Environment and Energy Management Agency (ADEME) also funded cancer‑related projects.

The analysis of the projects funded by INCa and Inserm for ITMO Cancer‑Aviesan over the 2010‑2016 period according to the CSO classification shows that the studies mainly focus on environmental and occupational exposures and on the interactions of exogenous factors with genes and genetic polymorphisms in order to decipher the causes and origins of cancers (Figure 36).


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4.4. PHD PROGRAMME IN HSS-EPH 2016 IN COLLABORATION WITH ACADEMIC PARTNERS

For the 6th consecutive year, INCa, in partnership with the School for Advanced Studies in Social Sciences (EHESS) and the Public Health PhD Network of the School of Advanced Studies in Public Health (EHESP), launched a call for applications for doctoral fellowships to promote research in HSS‑EPH applied to cancer. Among the 28 applications submitted, 11 candidates were from the HSS/public health disciplines and 15 from the epidemiology/biostatistics category. Two projects were classified as out of the scope.

The multidisciplinary evaluation committee pre‑selected 14 candidates, who were then interviewed by the same committee at the end of June 2016.

To strengthen its support to the training of the next generation of young researchers in HSS‑EPH, working in the cancer field, INCa decided to award in 2016, 7 doctoral fellowships, with a funding of €90,000 during three years. Like the PL HSS‑EPH programme, the distribution of the applications received is relatively balanced between disciplinary categories, with regard to the associated research potential. However, here again, it is noted that the majority of the projects selected relates to the epidemiology/biostatistics category, with a total of 5 projects. The 2 projects in the HSS/public health group are in psychology and health economics.

The results of the 2016 session bring the number of doctoral students funded since 2011 through this programme to 24. A review process will be set up by INCa to ensure that this programme has met its objectives.

33%Exogenous factors in the originand cause of cancer

BiologyAetiologyEarly detection, diagnosis, prognosisCancer control Scientific models

27% Interaction of genes and/or genetic polymorphism with exogenous and/or endogenous factors

Resources and infrastructures related to aetiology

77%

4%

5%

7%

7%

17%


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Table 32. List of doctoral fellowships funded in 2016.

Title Discipline

Discovering new predictive biomarkers of risk of breast cancer and prostate cancer: new horizons opened by metabolomics applied to nutritional epidemiology.

Epidemiology

Interpolating between different populations in early‑phase clinical trials in oncology.

Biostatistics

Oral cancer drugs and their social representations: psychosocial study of the process of appropriation of oral cancer drugs by patients and health professionals.

Health Psychology

Medico‑economic evaluation of patients with metastatic melanoma in the MELBASE cohort in real life.

Economics

Nutrition, biomarkers of exposure to fatty acids and risk of ovarian cancer and endometrial cancer in the European EPIC cohort.

Epidemiology

Exploitation of genetic and epigenetic signatures detected in tumour DNA to make inferences about the aetiology of cancer in the context of epidemiological studies.

Epidemiology

Environmental risk factors for childhood brain tumours. Epidemiology


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5 5INTERNATIONAL COMMITMENTS

5.1. STRATEGIC VISION, MISSION AND VALUES INCa has a pre‑eminent role in France with a national mandate encompassing all activity areas of value in the cancer control chain, from research to prevention and screening, to the organisation of cancer care and information for patients and their relatives. The specific nature of INCa’s integrative mission provides our Institute with a distinctive voice in the global cancer control arena that is valued by other agencies and professionals worldwide. Figure 37 shows how INCa’s global portfolio acts synergistically with national cancer control objectives in France, and how the connections between national and network capabilities have a decisive impact on global health.

A dear principle driving INCa’s global endeavour is its attachment to multilateralism with an empowering vision grounded on solidarity.

Support for the French‑speaking countries has become an obvious and heartfelt choice for INCa as well. INCa’s support goes preferentially to initiatives that promote collaboration across regions of the world, advancing research towards community priorities to build bases of evidence. Global networks are emerging as a shared response to the challenge of coordinating cancer control more efficiently. They make it possible to spread excellence and concentrate resources, with clear advantages in terms of

clinical benefits. Networks also represent a shift from competition to cooperation.

INCa’s commitments in Europe and more globally on the international setting reflect the above vision, mission and values.

At the European level, INCa is involved in 4 European projects and joint actions on cancer control: CANCON, TRANSCAN‑2, FLAG‑ERA, the Joint Action on Rare Cancers and is representing France on the Expert Group on Cancer Control established by the European Commission. INCa is also committed in the following initiatives: the Global Alliance for Genomics and Health (GA4GH), the International Cancer Genome Consortium (ICGC), the International Cancer Research Partnership (ICRP), the Global Initiative on Cancer Registry (IARC‑GICR), the International Rare Cancers Initiative (IRCI) and the International Consortium for Action and Research on Tobacco Control (ICART).

INCa is actively involved in French‑speaking Africa and in Asia, where its international programme on HPV and cervical cancer control has been implemented. The Institute has also established privileged bilateral agreements aiming at improving cooperation in cancer control with the US‑National Cancer Institute, the Senegalese Health Authority, the Chinese National Cancer Center, the Japanese National Cancer Center and the Brazilian National Cancer Institute.

Key actions The International programme on cervical cancer control set up by INCa is gaining momentum, with the active involvement of 5 Sub-Saharan African countries, 2 Asian countries and WHO to help the global network transition from research to public health.

INCa’s President has had the privilege to be a member on the Strategic Advisory board of the Global Alliance for Genomic and Health.

In Europe, the CANCON Joint Action will soon enact its final set of recommendations for quality improvement in cancer control. TRANSCAN-2 is pursuing its now well-established European mandate in translational research with the launch of its second call for research proposals. The European Commission Expert Group on Cancer Control is preparing the next phases of concerted new efforts to be delivered by the Health Programme in cancer control.


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Fig. 37. Synergy between national cancer control plan objectives and INCa’s global portfolio

5.2. INCa’S EUROPEAN COMMITMENTS

The CANCON Joint Action will soon enact its final set of recommendations for quality improvement in cancer control. CANCON is a Joint Action co‑funded by DG SANTE which aims at supporting Member States’ cancer control policies, in the areas of cancer care coordination and population‑based screening, survivorship and rehabilitation. Recommendations in these areas will be compiled into a European guide on quality Improvement in comprehensive cancer control, to be published in 2017.

INCa leads CANCON’s work on survivorship and rehabilitation (WP8), and is actively involved in 2 other work‑packages, on comprehensive cancer care network (WP6) and on cancer screening (WP9).

INCa has actively contributed to the def inition and recommendations pertaining to a new model of care provision, as championed through the concept of comprehensive cancer care network (CCCN) under WP6. The CCCN model aims to reconcile the expertise of specialised centres with greater accessibility of general hospitals and other healthcare institutions (imaging centres, community care centres, etc.) as well as primary care providers (general practitioner, home nurses, etc.). Literature review shows that CCCNs are emerging as a shared response to the challenge of coordinating cancer care among existing services, with a patient‑centred approach. The CCCN model promotes equity of access to high‑quality care, optimised use of facilities and improvements in cost‑effectiveness. Besides, CCCNs offer optimal conditions to conduct translational, clinical and outcome research. The Regional Cancer Networks established in France under the Legal act of 25 September 2007 are in line with the CCCN model promoted by CANCON; the same is true for the French SIRICs with regards to research integration into CCCNs.

JARC


WP9 – Childhood cancers

Global Partnerships

Europe

Bilateral agreements

Regional Networks

CANCON



EUROMED

Screening & early diagnosis in Mediterranean

countries

CANCON


(WP6 – cancer care network)

CANCON



European Commission EXPERT

GROUP on cancer control

US NCI

US National Cancer Institute - Global

coordination

NCC – CHINA

National Cancer Center – cancer control

IARC

International Agency for Research on Cancer

– INCa sits at IARC Board of Directors

FRENCH POLYNESIA

Cancer control

ICGC


ICART

International Consortium for Action

and Research on Tobacco Control

FLAG ERA

Digital medicine for cancer

GA4GH

Global Alliance for Genomics and Health

TRANSCAN 2

Translational research

ICRP

International Cancer Research Partnership

ICGC


US NCI

National Cancer Institute - Early phase

clinical trials

IRCI

International Rare Cancers Initiative

JAPAN

Memorandum of Understanding with

Japan National Cancer Center on research

JARC


WP5 – Quality of care

CANCON


(WP9 – Screening)

CCP Transversal objectives 2014-2019 Cancer Control Plan objectives

IARC - GICR

Global initiative on cancer registry

COFAC COL

Collaborative network on cervical cancer

control

LAOS / THAILAND

Research & public health projects on

cervical cancer control

SENEGAL

Agreement on cancer control

WHO

Implementation of WHO guidelines on cervical cancer

control

Childhood, adolescents

and young adults cancers

Reducing inequities

Enabling earlier diagnosis

(Objective 1)

Innovation & research

(Objectives 5 & 13)

Comprehensive and personalised

cancer care (Objective 7)

Personalized medicine

(Objective 6)

Tobacco control (Objective 10)

Global Partnership / Cancer Control (Objective 16)

Public health

(Objective 15)

See pages 14 and 15


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Concerning survivorship (WP8), INCa has coordinated the drafting of the 38 recommendations which address the monitoring of late and long‑term effects, comorbidities and monitoring for recurrence and secondary malignancies, psychological aspects of survivorship and supportive care, self‑management, back‑to‑work issues and palliative care. These evidence‑based recommendations reflect best practices in Europe and beyond, and current literature knowledge. WP8 proposes a European organisational survivorship care model, embedding survivorship and rehabilitation throughout the continuum of care to improve survivors’ quality of life. Key messages (pending final review) include: • Cancer survivor follow‑up, late effect management and tertiary prevention needs to be anticipated, personalised and implemented into care pathways, with the active involvement of survivors and their relatives;

• Early detection of patient needs and access to rehabilitation, psychosocial and palliative care services should be improved;

• An integrated and multi‑professional care approach coordinated with community care providers is needed to implement the survivorship care plan;

• For children, adolescent and young adult survivor, late health and psychosocial effects of cancer and treatments should be anticipated and addressed;

• More research in the area of survivorship is needed to provide data on late effects, as well as the impact and cost‑effectiveness of supportive care, rehabilitation, palliative and psychosocial care interventions.

INCa is also involved in WP9, the purpose of which is to produce further advice and guidance for accurate implementation of cancer screening in the EU Member States, in accordance with current European quality assurance guidelines for cancer screening. Challenges in screening implementation, addressed in WP9, are related to issues in planning and gradual well‑steered introduction of currently recommended programmes in regions or settings where effective and cost‑effective programmes are not yet available; modifying or reorganising currently running programmes with new tests, treatments, policies or organisational models; and developing key strategic tools on evaluations needed for policy‑making on possible new cancer screening programmes (other than for breast, cervical or colorectal cancer). The current chapter includes 8 policy recommendations on governance (structure, quality assurance procedures, and legal framework), organisation (implementation in multiple phases, mandate and resources) and evaluation (linkage and indicators for quality and

effectiveness, health‑economy and harm‑benefit monitoring) of cancer screening.

TRANSCAN-2 is pursuing its now well-established European mandate in translational research with the launch of its second call for research proposals.The ERA‑Net TRANSCAN‑2 project is a unique European network of research funding agencies and ministries from 15 Member States, 3 Associated Countries, and a third country (Taiwan) actively involved since 2011, with the support of the European Commission, in financing high‑impact translational cancer research projects. The overarching aim of TRANSCAN‑2 is to achieve sustained coordination in the area of translational cancer research beyond national boundaries or interests (see section 2.1.2).

TRANSCAN‑2 works as a hub for European research funding agencies and ministries to coordinate their funding strategy through joint calls for proposals, offering their respective country’s scientists a unique opportunity to collaborate across Europe, with funding allocated under the known rules of their own country. To ensure research excellence, project selection is carried out by an international independent high‑level scientific evaluation committee. Five joint transnational calls have already been launched under TRANSCAN 1 & 2, with 46 collaborative research projects currently funded, while the results of the 5th call are expected by the end of this year.

TRANSCAN‑2 has placed a particular emphasis on close collaboration with its Scientific Advisory Board, which includes eminent scientists. Their opinions serve as the basis to steer the strategic decisions of TRANSCAN‑2.

INCa is the leading party of the TRANSCAN‑2 work‑package that defines the network’s strategy and scientific research priorities. Under WP4, INCa coordinates in particular the development of links with other European and international initiatives, keeping track of their endeavours to provide the network with topical inputs. INCa also has been renewed as chair of the TRANSCAN‑2 network board.


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European Commission expert group on Cancer ControlMember State and stakeholder representatives brought together in the European Commission Expert Group are preparing the next phases of concerted new efforts to be delivered by the Health Programme in cancer control.INCa has been appointed by the Health Authorities to sit on France’s behalf on the Expert Group on Cancer Control established by the European Commission pursuant to the Decision of June 2014 (2014/C 167/05). The mandate of the expert group 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 patient organisations, European and international organisations active in cancer prevention, and European professional or scientific associations. The last meeting of the group was convened in Luxembourg on February 2016. In line with the roadmap of items established for the group, this session included a review of the state of play of various cancer initiatives, so as to provide advice on the need to reinforce the ongoing European framework on cancer control and the different options for doing so through the Health Programme.

5.3. INCa’S GLOBAL COMMITMENTS

Immediate past President of INCa invited to serve on the Strategic Advisory board of the Global Alliance for Genomics & Health.Immediate past President of INCa has had the privilege of serving on the Strategic Advisory Board of the Global Alliance for Genomics and Health (GA4GH; http://genomicsandhealth.org/) which includes the Directors of the Host Institutions, Directors of major funders of the Alliance (NIH, Wellcome Trust) and a number of independent global leaders from various fields. In accepting this task, INCa wanted to acknowledge the momentum created by GA4GH and the challenges ahead to advance the implementation phase of data sharing. INCa is committed to moving forward and being an active member of this global endeavour.

GA4GH was formed to help accelerate the potential of genomic medicine to advance human health. It brings together over 300 leading institutions working in healthcare, research, disease advocacy, life science, and information technology. The partners in GA4GH work together to create a common framework of harmonised approaches to enable the responsible, voluntary, and secure sharing of genomic and clinical data. GA4GH currently has 371 organisational members from 35 countries.

INCa’s global programme for cervical cancer control.The international programme set up by INCa on cervical cancer control is gaining momentum, with the active involvement of 5 Sub-Saharan African countries, 2 Asian countries and WHO to help the global network transition from research to public health.

Cervical cancer remains an avoidable cause of death and its control is a priority of the WHO‑led Global NCD Action Plan 2013‑2020. Cervical cancer continues to kill about 300,000 women each year worldwide and disproportionately affects the poorest regions of the world.

To tackle this challenge, INCa has developed various initiatives in Asia and Africa, with local professionals over the years. The figure 38 provides an overview of the whole scheme.

http://genomicsandhealth.org/


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Fig. 38. INCa’s global programme for cervical cancer control

AsiaTwo studies have been funded/co‑funded by INCa in Asia, targeting HIV+ women in Thailand and Laos, with a view to collecting evidence and building capabilities for cervical cancer control in these countries. The results of the studies are reported below. Their principal investigators cooperated and convened an international meeting in June 2016 to discuss the outcomes of the studies and the implementation of their public health goals with the health authorities.

Thailand: the “PapilloV-HPV infections and associated cervical lesions in HIV+ Thai women” research programme comes to a close.The 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 public health goal of the study 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 an 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 the 24 participating public hospitals throughout Thailand. At inclusion, a gynaecological

COFAC Col Collaborative Research &

Public Health Network on cervical cancer control

in Francophone Africa Pays : Gabon, Senegal,

Cameroon, Cote d’Ivoire, Madagascar

LAOS/THAILAND Research & Public

Health project on cervical cancer

in HIV+ women

Study scope: identification of HPV genotypes associated with

high-grade intraepithelial neoplasia lesions and invasive cancers/

Monitoring of HPV 16/18 prevalence to assess the potential benefits

of a vaccination programme

LaoCol VP: Multicenter cross-disciplinary study analysing the efficacy and cost/effectiveness

of cervical lesion screening by HPV detection vs Pap smear in HIV infected women in Laos.

PapilloV: Research study analysing the HPV infection and cervical

lesions in HIV+ women receiving antiretroviral therapy in Thailand

Senegal Cooperation agreement on Cancer control

(research & public health)

WHO Cooperation agreement to help with guidelines' implementation

in cervical cancer control

Union for the Mediterranean EUROMED

Mediterranean countries

Feasibility study using liquid biopsy for HPV detection

Focus on Screening


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exam, a cervical sample for HPV genotyping and a Pap smear for screening of cervical lesions were performed. These exams were 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.

Laos: the LaoCol-VP research programme delivers preliminary results.LaoCol‑VP is a collaborative study between the Centre of Infectiology Christophe Mérieux located in Vientiane and the Lao National HIV/AIDS Control Programme (CHAS) on the efficacy and cost‑effectiveness of HPV‑based screening methods vs Pap smears for the detection of cervical cancer among HIV+ women living in Laos. The study is also to compare the performance of careHPV™ versus Pap smear for the detection of CIN2+ lesions and evaluate the prevalence of the different types of oncogenic HPV among HIV+ women living in Laos. It is a multicentre transversal study involving 4 principal hospitals in Laos. The purpose is to raise awareness and capacity of professionals across the country. 644 women have been enrolled to date. After informed consent, careHPV™ testing, Pap smear, colposcopy, with biopsy if necessary and genotyping with PapilloCheck™, were performed and results analysed separately. Preliminary results show 35% positive careHPV™ tests; 19% abnormal colposcopy results. Of these, 52 (41%) are CIN1, 43 (34%) are CIN2+ and 5 present invasive carcinoma. CareHPV™ showed a better sensitivity and a lower specificity compared to Pap smear for the detection of CIN2+. HPV16, HPV52, HPV68, HPV51 and HPV18 genotypes were respectively identified in 18%, 18%, 16%, 14% and 8% of HR‑HPV cases.

The study is co‑sponsored by INCa and the Mérieux Foundation.

AfricaCOFAC-Col: the African Consortium for Cervical Cancer control is spurring connections between national & network capacities.

In 2013, INCa launched during the annual meeting of AORTIC, the African Consortium on Cervical Cancer Control (COFAC‑Col) with 5 African countries (Senegal, Gabon, Cote d’Ivoire, Cameroon and Madagascar). The current focus of the network 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 these countries. Under COFAC‑Col, INCa funds the following research projects:

• In Gabon: Molecular epidemiology and HPV prevalence in premalignant lesions and cervical cancers in the female population of the River Congo Basin;

• In Senegal: Prevalence of oncogenic HPV in CIN2+ lesions; • In Cote d’Ivoire: Genotyping of HPV‑DNA associated with cervical neoplasia;

• In Cameroon: Prevalence and genetic diversity of oncogenic HPV types in precancerous lesions and invasive cervical cancers in Cameroon;

• In Madagascar: Genotyping and prevalence study of HPV associated with cervical neoplasia in Madagascar.

These research projects are implemented as a collaborative effort of the network, with standard protocols and implementation issues being discussed during regular teleconferences organised by INCa. The network is co‑coordinated by the Lorraine Institute of Oncology. A shared online database has been developed by the coordinator (Institut Joliot‑Curie of Dakar, Senegal) to collect the data of all participating countries. Each country’s team involves pathologists, oncologists, virologists and epidemiologists. COFAC‑Col is achieving its primary goals as its preliminary results have been obtained. • In Gabon, 93 patients have been enrolled to date, with among them 57 carcinomas and 20 CIN3. The preliminary results indicate the presence of HPV16 & 18 in 19 samples.

• In Senegal, 168 patients have been enrolled and pathology testing performed on 120 samples. 101 carcinomas, 3 adenocarcinomas and 3 CIN3 have been found. 44 samples have been analysed for HPV, 23 of which were found to be HPV+. The preliminary results indicate the presence of HPV16 (14 samples), HPV45 (3 samples), HPV18 (2 samples) and HPV31, 33, 35 and 39 in 1 sample respectively.

• In Cameroon, 40 patients have been enrolled, 22 samples analysed and result show HPV16 in 4 samples.

• In Cote d’Ivoire, the teams are ready to start with a retrospective analysis of 50 samples.

• In Madagascar, the retrospective study will concern 448 samples. To date, 160 samples have been amplified by PCR, including 122 squamous cell carcinoma and 14 CIS 2&3. The preliminary results indicate the presence of HPV9 in 10 samples, HPV16 in 10 samples, HPV18 in 1 sample and HPV45 in 11 samples.

A letter to the editor entitled “COFAC‑Col: a cervical cancer control networking initiative in 5 French‑speaking African countries” was published in the May 2016 issue of Cancer Epidemiology, Biomarkers & Prevention1.

1 – Berthet N. et al. (2016). COFAC‑Col: a cervical cancer control networking initiative in five French‑speaking Afican countries. Cancer Epidemiology Biomarkers & Prevention, 25, 1004‑1005. doi: 10.1158/1055‑9965.EPI‑15‑1248


87

Next steps of the programme • Feasibility study using liquid biopsy for HPV detection to be launched in Senegal.

• WHO to help the global programme transition from research to public health.

• INCa is funding the first stages of an ambitious Union for the Mediterranean (UfM) project in health, conducted by the WHO collaborating centre for cancer early detection and screening.

Feasibility study using liquid biopsy for HPV detection to be launched in Senegal.A joint study between the Lorraine Institute of Oncology and Institut Joliot‑Curie of Dakar will be launched using a liquid biopsy test, CaptHPV, to detect circulating HPV DNA. This study is based on recent publications showing that circulating HPV DNA can be detected in the serum of patients at each stage of HPV‑associated carcinoma using droplet PCR (Journal of Pathology, 2016, Nature Partner Journal Genomic Medicine, 2016). As the promise of liquid biopsy as a potential screening tool continues to grow, the Senegalese study should demonstrate that the test is also capable of detecting the HPV genotypes present in the Senegalese patient population. This innovative study is

built as a specific sub‑study of an ongoing study in France the purpose of which is to evaluate the specificity and sensitivity of the test under real conditions.

WHO to help the global programme transition from research to public health.INCa has entered into an agreement with the World Health Organization (WHO) ‑ Department of reproductive health & research. The main purpose of the agreement is to promote implementation of WHO guidelines on cervical cancer control by French‑speaking low and medium‑income countries. The agreement comprises 3 complementary objectives: • The translation and publication of a French version of WHO “Comprehensive cervical cancer control: a guide to essential practice”, to improve ownership of the cervical cancer control issue among French‑speaking countries;

• The development of recommendations regarding a screening algorithm: “HPV testing followed by Pap smear”, which is relevant for those countries which have set up cytology capacities and started Pap smear‑based screening programmes;

• Technical assistance for the implementation of WHO cervical cancer control recommendations in the COFAC‑Col countries. The methodology and tools developed for English‑speaking countries will be adapted to the context of the COFAC‑Col countries, to help upgrade their current cervical cancer control programmes, with a coherent and homogeneous approach.

Fig. 39. The 3 complementary objectives of WHO – INCa agreement

French version of WHO "Comprehensive cervical cancer control: a guide to essential practice"

Recommendations regarding a screening algorithm "HPV testing

followed by Pap smear"

Implementation of WHO cervical cancer

control recommendations in the COFAC-Col

countries with adapted methodologies and tools

developed for English-speaking

countries


88

A workshop will be organised jointly by INCa and WHO, with the COFAC‑Col teams and country health representatives, as well as eminent experts. Technical assistance tailored to each country’s needs will be provided by WHO to facilitate the implementation of the guidelines (drafting of national strategy papers, training plans for health professionals, etc.).

INCa is funding the first steps of an ambitious Union for the Mediterranean (UfM) project in health, conducted by the WHO collaborating centre for cancer early detection and screening.As part of INCa’s global strategy for cervical cancer control, INCa has entered into an agreement with the WHO collaborating centre for cancer early detection and screening, to conduct a study entitled “Development of a strategy to enrol women in breast and cervical cancer screening programmes, in 3 Mediterranean countries, members of the Euromed Network”.

This study represents the first steps of an ambitious project called “WoRTH”, which is the f irst health project to be granted designation by Union for the Mediterranean. It will be implemented in the framework of the EUROMED network, which promotes the screening and early detection of cancers in non‑EU Mediterranean countries. The study will be rolled out in 2 Mediterranean regions (Balkans & Maghreb) and 3 countries (Albania, Montenegro and Morocco).

Its main objective is to design the enrolment protocol in each country, taking into account the urban and rural context, local resources and societal acceptance. The strategy will be developed in line with national public policies and plans and in close coordination with national health authorities and healthcare practitioners.

INCa and China National Cancer Center sign a Memorandum of Understanding.A bilateral Memorandum of Understanding was signed in June 2016 where INCa and China National Cancer Center intend to enhance and expand cooperative efforts in the field of cancer control, through mutual exchanges. The focus is on implementation of the Cancer control plan on a national and regional/provincial level, including governance and impact assessment. Personalised medicine has also been discussed during a visit by an NCC delegation to INCa.

© Institut National du Cancer, 2016


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INCa has received delegates from the Brazilian National Cancer Institute.As part of the frame agreement signed between the Health Authorities of France and Brazil, INCa has received delegates from the Brazilian National Cancer Institute, headed by its Deputy General Director.

The INCa has had the privilege to welcome delegates from the National Cancer Institute of Brazil, in June 2016, as part of

the implementation of the frame agreement signed between the Health Authorities of both countries. Discussions have focused on the strategic research programmes implemented by both Institutes, as well as on the rolling out of personalised medicine in France. The visit of the molecular diagnostic centre of HEGP allowed the delegates to grasp the organisational framework developed by INCa. Areas of collaboration have been addressed, in particular the setting up of a molecular diagnostic collaborative network.

© Institut National du Cancer, 2016

Global investments in international programmesINCa’s support for the international programmes amounts to €1.41M. The CSO classification shows that support was primarily dedicated to aetiology (HPV genotyping) and early detection, including dedicated equipment and training for diagnosis (Figure 40).

Fig. 40. Distribution of the projects allocated to the international programmes according to the CSO classification

AetiologyPreventionEarly detection, diagnosis, and prognosisCancer control

14 %

38%

5%43 %


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6 6BIBLIOMETRIC STUDY, EVALUATION AND REVIEW OF RESEARCH INVESTMENT

Inserm has conducted a bibliometric study for ITMO Cancer‑Aviesan in order to assess France’s position in the cancer research field1.

This study is also a major component of the evaluation process that INCa proposes to measure the outcomes and the impact of cancer research funding, detection of innovation and emerging research trends and the definition of research priorities. This information is also shared with the ICRP consortium in order to discuss and implement appropriate survey tools and methodological approaches for impact assessment.

6.1. BIBLIOMETRIC STUDY

6.1.1. FRANCE IN WORLDWIDE RESEARCHOver the 2011‑2015 period, 7,287,402 articles, letters and reviews published worldwide were indexed in the Web of Science core collection. Of these publications, 2,898,196 belong to biomedical research.

When using the citation criterion, France is ranked 5th and 6th in scientific research and biomedical research, respectively (Tables 33 and 34).

Table 33. Indicators of the 8 most cited countries in the world in all research fields (2011‑2015)

Country Nb of articles Times cited Rank% international collaborations

% industry collaborations

% highly cited papers*

USA 1,950,126 16,857,823 1 35.0 2.4 1.78

China 1,087,509 6,177,386 2 23.9 0.8 1.06

United Kingdom 554,916 4,862,800 3 54.1 2.9 2.04

Germany 516,943 4,478,616 4 52.3 3.2 1.75

France 360,290 2,960,932 5 55.0 3.3 1.65

Canada 321,593 2,642,480 6 50.6 2.0 1.79

Japan 399,570 2,509,770 7 28.6 2.2 0.84

Italy 319,739 2,475,465 8 46.2 1.9 1.47

World 7,287,402 43,989,737 22.7 1.4 0.96

(*) Corresponds to the 1st percentile of the most cited publications of a domain according to ESI domains.

1 – Thomson‑Reuters provides several thematic rankings and 2 are used in this study: ‑ Web of Science (WOS Categories), which includes 250 categories: each journal can be assigned to several categories. Publications positioning in the 1st percentile of the most cited

publications of a category are called "Documents in Top 1%"; ‑ Essential Science Indicators (ESI domains), which includes 22 main domains: a journal is assigned to only one domain. Publications positioning in the 1st percentile of the most cited

publications of a domain are called "Highly Cited Papers".


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Table 34. Indicators of the 8 most cited countries in the world in biomedical research (2011‑2015)

Country Nb of articles Times cited Rank% international collaborations


% highly cited papers*

USA 959,255 9,527,928 1 31.8 2.6 1.79

United Kingdom 253,003 2,625,041 2 52.1 3.7 2.25

Germany 220,218 2,124,819 3 48.0 4.1 1.88

China 289,208 1,571,103 4 24.4 3.7 0.53

Canada 143,417 1,426,538 5 50.3 2.6 2.08

France 136,979 1,356,002 6 47.4 4.0 2.04

Italy 149,753 1,313,466 7 41.3 2.3 1.67

Japan 176,453 1,167,750 8 23.1 1.8 0.70

World 2,898,196 20,286,663 21,1 1.5 0.93

(*) Corresponds to the 1st percentile of the most cited publications of a domain according to ESI domains.

The number of publications among the 1% and 10% most cited publications worldwide correspond to the visibility indicators and position France above the world standard (3rd rank).

Importantly, France shows high rates of collaboration with international and industrial partners.

55% of French general publications are co‑signed with another country and 3.3% involve an industrial partner. In the biomedical field, 47% of French publications are international collaborations and 4% with industry.

6.1.2. FRENCH CANCER RESEARCHOver the 2011‑2015 period, cancer research publications represent 12% of global scientific publications.

Table 35. Indicators of the 8 most publishing countries on cancer over the period 2011‑2015

CountryNb total

of publicationsNb

Cancer publicationsRank

% in the cancer publications corpus

USA 1,950,126 268,034 1 31.52

China 1,087,509 136,000 2 15.99

Japan 399,570 60,616 3 7.13

Germany 516,943 59,700 4 7.02

United Kingdom 554,916 56,606 5 6.66

Italy 319,739 50,298 6 5.92

France 360,290 40,196 7 4.73

Canada 321,593 35,174 8 4.14

World 7,287,402 850,283


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France is ranked 7th with 40,196 publications on cancer, representing 4.7% of the overall cancer publications.

International profile of French cancer researchIn the most highly cited papers corpus, France represents 11% and is ranked 4th, highlighting the French contribution to the

cancer research field. Moreover, the internationalisation of cancer research publications in this corpus is important for the majority of countries, except for USA and China that have less than 50% of publications with an international partner.

Table 36. Indicators of excellence publications (Top 1% Highly Cited Papers*) in the field of Cancer (2011‑2015)

CountryNb

publicationsPart

in the corpus (%)Rank

% international collaborations


USA 6,302 59.7 1 47.8 9.5

United Kingdom 1,764 16.7 2 78.2 15.25

Germany 1,455 13.8 3 83.3 18.08

France 1,162 11.0 4 84.0 19.10

Italy 1,131 10.7 5 85.7 17.06

China 1,084 10.3 6 45.9 6.73

Canada 1,015 9.6 7 84.1 15.37

Netherlands 829 7.9 8 84.2 12.55

World 10,550 100 40.8 6.91

(*) Corresponds to the 1st percentile of the most cited publications of a category according to WoS categories.

French researchers collaborate with more than 160 different countries. In general, international partnerships raise the profile of French publications. Indeed, the percentages of publications in the highly cited corpus are greater compared to the world standards or to France alone.

The USA is the leading partner of France in terms of number of publications with more than 6,800 publications co‑signed during the 2011‑2015 period, while with fewer publications, articles co‑signed with Australia and the Netherlands have the highest profile.


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Fig. 41. The 10 first partners of France in the field of cancer in number of publications (left panel) and in part of publications in the Top 10% Highly Cited Papers corpus* (right panel)

Clinical medicine in Cancer researchAmong the worldwide publications, the main research categories published are Clinical Medicine, Molecular Biology & Genetics and Biology & Biochemistry. In total, these publications represent 78.8% of the total publications.

In clinical medicine in the cancer corpus, the Oncology subcategory represents 45% of publications.

The major medical specialties of the cancer corpus that are highly cited are Oncology, Medicine, research and experimental (including general journals such as Nature Medicine, J Exp Med, EMBO, etc.) and Urology & Nephrology.

Moreover, the Oncology, Haematology and Medicine, research and experimental specialties show the highest rates of collaboration with international and industrial partners.

France

United Kingdom4,577

United Kingdom35.72%

Italy4,294

Italy35.47%

Germany4,407

Germany36.53%

Canada2,222

Canada35.87%

Netherlands2,663 Netherlands

38.04%

Belgium2,307

Belgium35.85%

Spain2,867

Spain36.69%

USA6,860

USA33.91%

Switzerland2,007

Switzerland34.28%

Australia1,375

Australia40.07%

France

(*) Corresponds to the 10st percentile of the most cited publications of a category according to WoS categories.


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Table 37. Publications indicators by medical specialty (WoS categories)

Medical specialties (WoS categories)

Nb publications

Part Clinical

medicine

Times cited

Category normalised

citation impact

% documents in Top 1%

% documents

in Top 10%

% Highly cited

papers

% international

collaborations

% industry

collaborations

Oncology 11,333 45.0 168,485 1.9 3.2 15.3 4.4 48.5 8.00

Haematology 2,556 10.2 32,963 1.8 2.7 18.4 3.6 53.7 6.22Radiology, nuclear medicine 2,537 10.1 16,591 1.2 1.9 11.7 1.0 34.2 2.88

Surgery 2,189 8.7 13,977 1.4 2.5 15.1 0.9 30.2 1.23

Gastroenterology & Hepatology 1,443 5.7 21,693 1.9 3.6 20.8 5.5 41.3 2.49

Urology & nephrology 1,332 5.3 14,557 1.9 3.4 17.0 3.7 38.9 3.83

Medicine, research & experimental 1,261 5.0 14,057 1.5 2.5 17.3 2.9 49.1 5.55

Pathology 1,167 4.6 7,719 1.1 1.9 12.9 1.2 41.1 2.23

Endocrinology & metabolism 1,116 4.4 12,694 1.3 2.2 14.5 2.2 45.5 3.76

Clinical neurology 1,035 4.1 8,355 1.3 1.9 13.9 1.5 38.1 2.71Source: Data adapted from InCites indicators Medicine, research & experimental includes general medical journals (e.g. Nature Medicine, J Exp Med, J Clin invest, EMBO Molecular medicine or Exp Hematol).

Focus on Human and social sciences, Public HealthIn the cancer corpus, France is ranked sixth with 5.9% of total publications on human and social sciences related to cancer. French publications show the highest rate of highly cited papers.

Interestingly, for human and social sciences related to cancer in journals dedicated to social sciences, in oncology and in clinical trials, France is ranked first for publications with industry.

The visibility indicators show that the French publications are ranked first in the highly cited papers category in journals dedicated to social sciences, clinical trials and biology, and second in oncology journals.

Thus, France exhibits major advantages in human and social sciences related to cancer.


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6.2. FOCUS: TRENDS IN THE FRENCH FUNDING STREAM OF INTERVENTION RESEARCH ADDRESSING ALL ASPECTS OF CANCER CONTROL, A CROSS-SECTIONAL ANALYSIS 2010-2014

Since 2010, INCa has supported population health intervention research1, in the 2009‑2013 and 2014‑2019 National Cancer control plans, and through the national and competitive dedicated programme2. This call for proposals is based on WHO recommendations3: • to improve daily living conditions; • to tackle the inequitable distribution of power, money, and resources;

• to measure and understand the problem and assess the impact of action.

At the present time in France, the development of intervention research is a major concern, supported in the National Health Strategy as well as in the National Research Strategy. Between 2010 and 2014, 15 projects were funded by INCa, for a total of €7.3 M.

After five years of funding, a specific analysis was needed on the proposals submitted for funding and/or funded (n=63) in descriptive and analytical perspectives (types of scientific engagement of the investigators, methodological and sociological trends).

Findings showed that the principal investigator gender population between 2010 and 2014 was balanced (26 woman and 37 men). All possible academic diplomas were represented. The majority of the investigators held a PhD degree and half of them a French HDR (French diploma mandatory to supervise PhD students). This suggests that it is mainly advanced researchers who were submitting projects.

Of the 7 French Cancéropôles, the “Ile de France” (Paris and its suburbs) was over‑represented (one‑thirds, 20 out of 63 projects) as well as “Sud‑Ouest” (21 projects). The proposed duration of the projects was: 36 months (46 projects), 24 months (22 projects) and 48 months (10 projects). Ten out of 15 of the funded projects were planned for 36 months.

These descriptive elements showed diversity amongst the targeted populations and in the types of partnerships involved (Figure 42). Different disciplines were used in the research proposals: public health and epidemiology, but also a wide range of human and social sciences. Methodological diversity emerged in the projects: quantitative designs (38 projects, 3 funded), qualitative designs (4 projects, one funded) and mixed‑methods studies (33 projects, 11 funded) (missing data for 4 projects), as well as a commitment to prevention research.

It was difficult to identify the logic models of several research proposals. In some cases, several theoretical frameworks were used, from different levels of abstraction: conceptual models (e.g. patient navigators, Fiscella, 20114), or middle‑range theories (e.g. Theory of planned behaviour, Ajzen, 19915).

Between 2010 and 2014, the funded projects were predominantly quantitative. Regarding actions tackling health inequities, the interventions mostly addressed individual factors6.

In 2015, the administrative guidelines strongly encouraged original partnerships between research teams in various disciplines (human and social sciences, public health [prevention/health promotion], epidemiology, biostatistics, etc.) and practitioners in the field (medical, allied health, and social services personnel, non‑profit organisations, etc.).

Based on the findings of this analysis, in 2016, the call for proposal stresses that research proposals need to justify the theoretical framework of the intervention and evaluate the effectiveness7 of the proposed intervention, and now contains a transversal axis based on the explicit integration of the issue of health inequalities in research plans.

1 – Hawe P., & Potvin L. (2009). What Is Population Health Intervention Research?. Canadian Journal of Public Health. Jan‑Feb;100, I8‑I14.2 – Call for proposals “Recherche Interventionnelle en Santé des Populations”. Paris, France: Institut national du cancer; 20153 – Combler le fossé en une génération : instaurer l’équité en santé en agissant sur les déterminants sociaux de la santé : rapport final de la Commission des Déterminants Sociaux de la Santé.

Organisation Mondiale de la Santé Commission des Déterminants Sociaux de la Santé 20104 – Fiscella K. et al. (2011). Patient‑reported outcome measures suitable to assessment of patient navigation. Cancer, 117, 3603‑3617. doi: 10.1002/cncr.262605 – Ajzen, I. (1991). The theory of planned behavior. Organizational Behavior and Human Decision Processes, 50, 179‑211.6 – Whitehead M. (2007). A typology of actions to tackle social inequalities in health. Journal of Epidemiology & Community Health, 61, 473‑478. doi: 10.1136/jech.2005.0372427 – Glasgow R.E. et al. (2013). Comparative Comparative effectiveness research in cancer: what has been funded and what knowledge gaps remain?. Journal of the National Cancer Institute,

105, 766‑773. doi: 10.1093/jnci/djt066


96

Fig. 42. Methodological analysis of the submitted proposals to the Intervention research CFPs over the 2010‑2014 period according to the targeted populations, the disciplines involved and partnerships

Not fundedFunded

2924

1512

830

54

96

11

33111

95

55

43

22

11

11

SexologyEnvironmental sciences

VirologyPhysical activity sciences

Medical InformationWork health

Political SciencesGeriatrics

BiostatisticsEducational sciences

AddictologyMedical oncology

NutritionMental Health-oncopsychology-neuropsychology

EconomyHuman and social sciences

Public health

239

75

33221

11

11111

1

22

4

1

1

11111

MigrantsPregnant women

SupportersFarmers

Population- communityDecision makers

TeachersProjects - methodological

Disabled peopleWorkersSmokers

Elderly peoplePhysicians, health professional, social workers

SurvivorsChildren/ teenagers/ Family

People in precarious- poor situationPatients

Disciplines

Populations

Partnerships General practitionners (GP)Occupationnal health

Prevention project managerFrench Cancer Registries

Legal sectorHealthcare profesionnals

Local authorityHealthcare insurrance (CPAM)/ Pension fund

University hospital (CHU)Local Institutes for health promotion/education (IRESP/CRES)

International collaborationAssociations

Industrial collaborationHealth economy

Unemployment office (Pôle Emploi)National education sector

ARC FoundationFrench National Cancer League

Health Regional Observatory (ORS)Multidisciplinary collaboration 28

246

219

325

45

303

614

52

3

151

2

15

37

35

11

21

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%


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6.3. INTERNATIONAL EVALUATION

Established in 2000, the International Cancer Research Partnership (ICRP) is a unique alliance of cancer organisations, working together to enhance global collaboration and strategic

coordination of cancer research. It includes 110 worldwide organisations from Australia, Canada, France, Japan, the Netherlands, United Kingdom, and the United States. INCa joined this partnership in 2009.

This consortium aims to improve access to information about cancer research being conducted, explore opportunities for cooperation between funding agencies and enable our members to maximise the impact of their independent efforts.

Fig. 43. Cancer organisations worldwide involved in the ICRP consortium

ICRP organisations share funding information in a common format (known as the Common Scientific Outline or CSO) to facilitate pooling data and evaluating data across organisations.

The ICRP database contains information on 76,777 grants, totalling over $50 billion in cancer research since 2000.

• Canadian Cancer Research Alliance (representing 42 organisations)

• National Cancer Center

• National Breast Cancer Foundation

• Cancer Australia• Cancer Institute New South Wales

• NCRI (Representing 27 organisations)

• KWF Dutch Cancer Society

• INCa

• Avon Foundation for Women• Coallition Against Childhood Cancer (representing 77 organisations)

• US Army Medical Research• NIH (25 institutes)• American Institute for cancer Research• American Cancer Society• Susan G. Komen for the Cure• Pancreatic Cancer Action Network• California Breast Cancer Research Program• Oncology Nursing Society Foundation• National Pancreas Foundation

https://www.icrpartnership.org/CSO.cfm

https://www.icrpartnership.org/database.cfm


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Detailed analysis of the international cancer research portfolio provides contextual data for cancer research organisations. The data allows funders to see the impact of their own investments, track national and global trends relevant to their own areas of investment and identify gaps in the funding landscape. Given the pressure on research funding budgets, it is important that organisations can track whether strategic investment delivers shifts in the cancer research portfolio and ultimately, benefits patients.

Thanks to this partnership, INCa enjoys the following benefits: • Access to senior representatives from an active, international network of cancer research funding organisations;

• Ability to share data/information on research evaluation and outputs;

• Disseminate the projects funded in France by INCa and its partners (Ministry of Health, ARC Foundation, LNCC);

• Access to the online research portfolio on the ICRP website, providing a cost‑effective way to display the current and ongoing cancer research data on an internationally recognised website;

• Unrestricted use of partner‑only analytical tools to conduct (pooled) data analyses to identify areas of strengths and gaps in cancer research, avoiding duplication and enhancing the organisation’s ability to fund strategically;

• Access to a forum for identifying scientif ic areas for multidisciplinary research and collaborations;

• Obtain assistance for the development of databases for its own research portfolio;

• Identify referees for the evaluation process of INCa’s calls for proposals.

In this way, ICRP provides a network and forum for cancer organisations to discuss investment trends and strategies; and identify collaborative opportunities to address gap areas, where appropriate. Moreover, the consortium publishes periodic reports on topic areas of interest: • Trends in global cancer research funding 2005‑2012: an analysis from the International Cancer Research Partnership;

• Translational research methodology report; • Obesity in Cancer report; • Environmental influences in Breast cancer report; • Landscape analysis chapter in Metastatic Breast Cancer Alliance report.

Further work is ongoing both within ICRP and in partnership with other international initiatives to link investment in cancer research to research outputs (such as publications, patents) and patient impact.

HighlightICRP hosted a panel entitled “ICRP: A Global Collaboration Enabling Analyses of Sponsor-Funded Cancer Research” at the prestigious American Evaluation Association meeting in Chicago on 11 November 2015. The topics covered were: • Translational research: monitoring trends in the

international cancer portfolio;• Prevention research: identifying and acting on trends in

research funding;• Global assessment of funding trends across a diverse

spectrum of breast cancer research;• Assessment of the International Cancer Research

Partnership’s lung cancer portfolio.

6.4. REVIEW OF RESEARCH INVESTMENTS

6.4.1. TOTAL CANCER RESEARCH FUNDING IN 2015 In 2015, INCa, Ministry of health and ITMO Cancer‑Aviesan have allocated a multi‑year total amount of €95.5M to research projects selected through competitive calls for research proposals and grants for designation. In addition ITMO Cancer‑Aviesan supported in 2015 research lab equipment that amounted approximately €4.9M and not included in the analyses presented below.

Figure 44 shows the funding allocation according to the CSO classification. Research projects in cancer biology and treatment have represented the most significant investments with 29% and 41%, respectively. On the other end, cancer prevention represents a mere 2% of the budget.


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Fig.44. 2015 multi‑year cancer research funding (INCa, Ministry of Health, ITMO Cancer‑Aviesan) according to the CSO classification

The budget managed by INCa amounted €73.9M, including Minstry of Health funding, while about €21.6M relates to the programmes managed by ITMO Cancer‑Aviesan.

Figure 45 shows the budget allocation of the programmes operated by INCa and ITMO Cancer‑Aviesan according to the CSO classification.

Cancer biology represents the highest investment with 53% of the ITMO Cancer‑Aviesan budget, aetiology comes second with 18%, then treatment 17% and early detection 12%.

ITMO Cancer‑Aviesan programmes are essentially thematic calls for proposals, addressing a specific topic like systems biology or epigenetics, and multidisciplinary research training that are mainly cancer biology related. Aetiology is covered by the programmes dedicated to the study of environmental risks.

Fig.45. Multi‑year 2015 research funding of the programmes operated by INCa and ITMO Cancer‑Aviesan according to the CSO classification

The breakdown of 2015 funding is different for INCa programmes.

The area of treatment represents 49% and biology 22% of the 2015 allocated funding. These areas are at the core of the main investigator‑driven CFPs managed by the INCa and funded by INCa and Ministry of Health (DGOS).

Importantly, various programmes and CFPs contribute to the treatment area: the programme for clinical research (PHRC‑K), specific early‑phase clinical trials programmes, molecular driven

Biology = €27.7MAetiology = €7MPrevention = €2.2MEarly detection, diagnosis, and prognosis = €13.1MTreatment = €39.3MCancer control = €6.2M

41%

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€ 35.7M49%

€ 10.6M14%

€ 16.1M22%

€ 2.2M / 3%€ 3.1M / 4%

€ 3.9M / 18%€ 2.5M / 12%€ 3.6M / 17%

Cancer control TreatmentEarly Detection, diagnosis, prognosis PreventionAetiologyBiology


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trial of innovative molecules and targeted therapies. This is in line with the precision medicine plan supported and rollout by INCa, in compliance with the objectives of the 2014‑2019 Cancer control plan.

Early detection, diagnosis and prognosis support have represented 14% and aetiology 4% of the programmes operated by INCa, respectively. Finally, cancer control, survivorship and outcomes research, and prevention research represented a total of 8% of the budget allocated to research.

This budget allocation reflects INCa’s cross‑functional support to cancer research and the complementarity between the programmes managed by INCa and ITMO Cancer‑Aviesan.

Figure 46 presents the distribution of 2015 multi‑year funding according to the different classes of programmes: • Investigator‑driven projects that concern the 4 large research areas (biology, translational, clinical, human and social sciences, epidemiology and public health);

• Strategic research initiatives and thematic projects that encompass INCa’s actions to support precision medicine and the targeted research programmes managed by ITMO Cancer‑Aviesan and the projects targeting a tumour type through the integrated research programme supported by INCa and the charities ARC Foundation and LNCC;

• Platforms, resources and infrastructures; • Research training and young teams of excellence that covers especially ATIP‑Avenir and the translational research training programmes.

This figure shows that 54% of the allocated budget was dedicated to the competitive investigator‑driven CFPs, managed by INCa whereas the thematic calls for proposals launched by ITMO Cancer‑Aviesan and the strategic clinical research initiatives supported by INCa represented 27% of the overall 2015 multi‑year funding.

Fig. 46. Distribution of 2015 multi‑year cancer funding per programme type: €95.5M investment

6.4.2. CANCER RESEARCH FUNDING FOR THE 2007-2015 PERIOD Since 2007, a total of 2,071 projects and applications have been funded through the different competitive calls for research proposals and grants for designation for a global amount of €803.40M.

The figure below presents the distribution of the funded projects and infrastructures according to CSO research categories and highlights the importance of Treatment and Biology areas in cancer research investments with 28% and 24%, respectively.

Projects addressing Cancer control and survivorship issues represented 20% of the overall funding during this period

Investigator-driven calls = €51.5MStrategic research initiatives/thematic programmes = €25.9MPlatforms/resources/infrastructures = €13.5MResearch training/young teams of excellence = €4.6M

5%

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27%

54%

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HSS-EPH = €4.3MTranslational = €8.4MBiology and basic sciences = €17.2MClinical = €21.6M

€ 6.2M8%


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that included the renewal of the Canceropôles designation in 2014 with special emphasis on social sciences.

Early detection, diagnosis and prognosis category represented 16% and encompassed mainly translational research, the support to the molecular genetics centres and next generation sequencing implementation.

Fig. 47. Distribution of 2007‑2015 multi‑year cancer research funding (INCa, Ministry of Health, ITMO Cancer‑Aviesan) according to the CSO classification: €803M investment

Figure 48 presents the distribution of the 2007‑2015 funding per programme.

The investigator‑driven calls for proposals of the four main research areas (biology, translational, clinical and social sciences, epidemiology and public health) represented a total of 53% of the 2007‑2015 investments, approximately €422M.

Importantly, the support to resources and infrastructures represented one fourth of the total funding, i.e. about €195M, highlighting the willingness to reinforce the organisational framework and the coordination of cancer research activities.

The support of cancer research training and the support to young researchers represented 3% of the total allocated budget for the period 2007‑2015, i.e. approximately €26M.

Fig. 48. Distribution of 2007‑2015 multi‑year cancer funding per programme type (INCa, Ministry of Health, ITMO Cancer‑Aviesan)


Biology = €196MAetiology = €65MPrevention = €21MEarly detection, diagnosis, and prognosis = €128MTreatment = €223MCancer control = €153MScientific models = €17M

2%

24%

8%

3%

16%28%

19%

Investigator-driven calls = €422MStrategic research initiatives/thematic programmes = €160MPlatforms/resources/infrastructures = €195MResearch training/young teams of excellence = €26M

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HSS-EPH = €33MTranslational = €60MBiology and basic sciences = €145MClinical = €184M


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INCa’s research funding strategy, in line with the 2014‑2019 Cancer control plan, is based on investigator‑driven calls for proposals, to ensure excellence, independence and creativity. Besides, the analyses of the areas covered by the investigator‑driven calls for proposals allow identifying the emerging research fields and the unmet needs, and serve to establish the basis for the strategic programming, including the initiatives dedicated to a specific type of cancer, such as the French support to ICGC programme.

Besides the investigator‑driven, the integrated research programmes (PAIR) targets cross‑cutting research issues in one pathology or cancer spectrum of clinical relevance. The next 2016 PAIR programme will focus on paediatric cancers.

The thematic programmes support emerging research fields, such as Epigenetics, Systems biology, multidisciplinary research for the development of news tools or techniques, Research in Physics, Mathematics and Engineering Sciences related to Cancer. This latter programme also provides different entry points and routes to confront cancer progression and improve the detection, the diagnosis and the management of the disease.

Strategic research initiatives and thematic programmes represented nearly 20% of the total investments over the period 2007‑2015, approximately €160M.

The figure 49 shows the trends of the different programmes funding over the period 2009‑2015 and highlights the significant increase of the support to strategic initiatives and thematic programmes that include the initiatives to strengthen strategic clinical research supported by INCa, such as innovative molecules testing or AcSé programme.

Fig. 49. 2009‑2015 trends in investment per programme (multi‑year grants)

The support to investigator‑driven projects, to research training and young researchers has been sustained over the years.

Investments for resources and infrastructures have decreased the two past years. INCa has designated, initiated and implemented several research infrastructures in the frame the successive national Cancer control plans and has been now coordinating, maintaining and reinforcing them to ensure an integrated and coordinated cancer research nationwide.

Investigator-driven calls Platforms/resources/infrastucturesStrategic research initiatives/thematic programmesResearch training/youngs teams of excelence

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PART 3.FOCUS ON STRATEGIC TOPICS FOR ADVANCING CANCER RESEARCH

The defined research workplan for 2017 remains in compliance with the objectives of 2014‑2019 Cancer control plan and the National research strategy and will pursue the actions initiated in 2015 and 2016. INCa and ITMO Cancer‑Aviesan will continue to support the structuring of research implemented over the last years. In doing so, the Institutes will guide the development of research projects of excellence with international scope in all fields, whether fundamental, translational, clinical or population‑based.

A few strategic topics have been identified, that will be related to INCa and ITMO Cancer‑Aviesan strengths and goals to support cancer research.

Coordinating the research structuringThe research programme of INCa has been instrumental in providing a favourable framework for initiating, fostering and sustaining research at the highest international level. The Institute has established, following competitive international selection, a number of structures to fulfil specific goals to answer scientific questions in the field of biological, translational, clinical, human and social science in the field of cancer. These structures have delivered significant multidisciplinary synergistic interactions for research funding and drug access to patients and have provided a basis for the coordination of clinical, fundamental and human and social science research at the regional level in France.

Thus in 2017, INCa aims to seek for an appropriate and ad hoc evaluation procedure that will enable a better assessment of the impact that these structures have provided for cancer research in France. These evaluations would also provide indicators for further improvement. A successful ad hoc assessment was performed in 2015 for the mid‑term assessment of the SIRICs and could be adapted for the next Cancéropôles designation.


Similarly, the renewed support to biological and clinical databases (BCBs) in 2017 will be based on an adapted definition of their missions to the current needs of cancer research. An adapted business plan will be shared amongst the BCBs in order to enhance their input in the context of biomedical cancer research.

Moreover, the drive to support research structuring should be extended to other fields, such as in public health and/or health technologies. It would be noteworthy to discuss in a dedicated task force whether similar structures in this field may be a challenging opportunity. Furthermore, the analysis of the structuring of the radiotherapy research, initiated in 2016 with experts in the field, should lead to INCa proposing concrete terms of support in 2017.

INCa will lean on these dedicated and selected structures to prepare the French research teams to the future challenges of fundamental research in cell biology as well as physics, chemistry and mathematics and support their involvement in targeted therapies, immunotherapy and digital medicine. Actions supporting and guiding the development of precision medicine will be pursued in 2017. This will generate large amounts of data of different kinds. We now need the tools to integrate and process these data with a view to their optimal conversion into clinical applications. We also need to adapt the existing organisation to the arrival of immunotherapy treatments for a large number of cancers and to facilitate research on predictive biomarkers.

The INCa’s SAB approved the development of an initiative that will link the genomic data of the molecular centres to that of the research clinical trials on innovative molecules, all performed within the INCa’s structures, including the BCBs and the inter SIRIC programmes on data integration and sharing, the OSIRIS programme. This programme will take advantage of INCa’s collaborations with its partners (French Ministry of Health, Aviesan) and its international collaborations within the European commission (FLAG‑ERA – Digital Medicine for Cancer). This latter aims to develop computer simulations to set up new tools and to support therapeutic decision. The Institute will also take part to the ICGCmed programme, which extends the ICGC programme and which will be based on tumour collections with detailed clinical annotations. With the recent breakthrough of checkpoint targeted therapies, the INCa’s structures will endeavour in 2017 to incorporate immunological data with that of genomics to facilitate fundamental and translational research i.e. on predictive biomarkers of efficacy or resistance.

Programming framework of Cancer research INCa and ITMO Cancer‑Aviesan have over the past years provided funding for research projects in different fields of cancer research, as reported and summarised in the previous chapters. This support for research projects will be pursued in compliance with the previously defined international selection procedure.



INCa and ITMO Cancer‑Aviesan missions are to identify the unmet needs in their research agenda through working groups, which could eventually recommend to launch a specific call for proposals. For example, the PAIR programmes aim to address cross‑cutting issues of a pathology: epidemiology, prevention, early diagnosis and management of patients and social sciences, and clinical research issues, cognitive and translational. The next programme should dwell on pancreatic cancer which represents a major cancer research and therapeutic challenge since it presents poor prognosis even if diagnosed early.

INCa will also launch, in collaboration with INCa‑designated cooperating intergroups, a programme targeted at fostering large therapeutic clinical trials to address pressing issues close to patients care, i.e. issues raised by the positive or negative short or long term results of the current cancer therapies. The selected therapeutic trials would contribute to the targets of 50,000 enrolments a year in therapeutic trials by 2019.

Strengthening international commitmentsIn 2017, INCa will continue its international programme for the promotion of cervical cancer control with French‑speaking countries in Sub‑Saharan Africa, and, with WHO support, will assist in its transition from research to targeted public health actions.

In this capacity, INCa will support the launch of a feasibility study on the use of fluid biopsies for HPV detection in Senegal, within the framework of the COFAC‑Col consortium, in conjunction with the Lorraine Institute of Oncology and Institut Joliot‑Curie in Dakar. This study will assess the use of a reliable, innovative method, the CaptHPV test, for detecting the presence of HPV DNA in blood samples.

In 2017, INCa should implement the agreement signed with WHO–Department of Reproductive Health and Research to promote the use of WHO guidelines in Southern French‑speaking countries, notably those of the COFAC‑Col consortium, with a view to improving prevention and control of cervical cancer.

Setting up a cancer research observatoryIn 2017, INCa will also making research results visible and accessible for the benefit of patients, the general public, researchers and supervisory bodies. These data will enable research analyses likely to modify practices significantly, and inform public decisions, notably in terms of public health or on medical‑economic aspects of technological, therapeutic and organisational innovations. Studies will be conducted to identify the best tools to provide accessible data to enable research studies to provide basis to further strengthen INCa’s support of cancer research. Interaction with Aviesan partners and charities, in cancer research in France and abroad, will allow to share tools and research projects.


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1 1CHALLENGES ASSOCIATED WITH THE ARRIVAL OF IMMUNOTHERAPIES

After decades of disappointing results, the promising results obtained with immune checkpoint inhibitors for the treatment of metastatic melanomas and adoptive modified autologous T cell (CAR‑T) transfer therapeutics in leukaemia and B‑cell lymphomas have re‑established immunotherapy as a major tool in the cancer treatment arsenal. This therapeutic approach raises high expectations on the part of clinicians and patients alike, and has already prompted extensive changes in the cancer care sector.

A number of immune checkpoint inhibitors have demonstrated remarkable clinical efficacy associated with long‑term responses in a large number of cancer sites. The two classes of this type of inhibitors, which are the most advanced in terms of clinical development, are anti‑CTLA‑4 and anti‑PD‑1/PD‑L1. A number of molecules have already been granted a European marketing authorisation, for melanoma, lung cancer, and more recently cancer of the kidney. A lot of clinical trials are in progress on other tumour sites and should lead to Marketing Authorisations in the coming months. Moreover, further checkpoint inhibitors classes are currently under development.

Nevertheless, only certain patient subgroups respond to these treatments, which may also cause major toxicity in some patients. For this reason, the identification of biomarkers predicting the efficacy or toxicity of these treatments, which are also very costly, is a major research challenge. The identification of specific biomarkers needs to be based on clinical trials or specific patient cohorts. At this stage, the clinical trials are mostly industrial and not very open to ancillary academic research projects. For this reason, patient cohorts treated by immunotherapy under marketing authorisations or temporary authorisations for use currently constitute a vital alternative for academic research.

1.1. BIOLOGICAL AND CLINICAL DATABASES: A UNIQUE TOOL TO ASSESS AND MONITOR IMMUNE CHECKPOINT INHIBITORS EFFICACY

Since 2014, INCa has been providing support for 14 BCBs that are intended to act as prospective cohorts on a national level

focusing on a specific disease (Table 38). This involves conducting clinical and biological monitoring of a representative cohort of the patient population concerned that is suffering from a specific disease. Throughout these patient care pathways, a set of different types of data (clinical, histopathological and biological characteristics, monitoring data (treatments, responses to treatments), quality‑of‑life and human and social sciences data) is documented in a shared database and various types of samples are collected at key stages of the progression of the disease. The aim is to promote collaborative and multidisciplinary research projects through the provision of biological resources and data analysis.

Table 38. Specificities of the BCBs implemented

BCBs Disease

MELBASE Melanoma

UroCCR Kidney cancer

FR3LyS Lynch syndrome/colon rectum

CRB Foie network Liver

Sarcoma CBDB Sarcomas and connective tissues

Glioblastomas Glioblastomas/Central nervous system

BIG-RENAPE Peritoneal carcinosis of digestive origin

Breast and ovarian cancer predisposition CBDB

Breast and ovarian cancer predispositions

BCBLYM Lymphomas

CRYOSTEM Bone marrow transplant and cellular therapy

BACAP Pancreas

FIMBANK Myeloproliferative syndromes

MESOBANK Mesotheliomas

FREGAT Oesophago‑gastric carcinomas


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Checkpoint inhibitors are available or under clinical development in a number of indications for which biological and clinical databases have been developed (cancers of the kidney, melanomas, mesotheliomas, sarcomas, pancreatic cancers, oesophago‑gastric cancers and glioblastomas). In fact, these BCBs are becoming unique tools for identifying new predictive biomarkers, new therapeutic targets, validating promising biomarkers or assessing patient care practices and in compliance with existing guidelines. INCa's support for building and consolidating these BCBs needs to be maintained, so that the databases can attain the critical mass and degree of maturity required to meet researchers’ needs as soon as possible.

A large number of molecules are currently under clinical development in various lung cancer subtypes with very promising results. Due to its incidence and mortality rate, which remain very high, lung cancer represents a major public health challenge. For this reason, building a BCB for this disease, based on the model developed by INCa in tandem with the existing BCBs, is now a key priority. Commitment from all stakeholders should allow it to become operational without delay.

Moreover, in the coming months, INCa is set to initiate two AcSé clinical trials assessing nivolumab and pembrolizumab in rare cancers and non‑colorectal cancers with an MSI phenotype. Blood samples will be collected at various stages of the treatment within the framework of these clinical trials. The collection compiled will subsequently be made available to the research community.

1.2. RESOURCES AND INFRASTRUCTURES INTEGRATION TO FACE THE IMMUNOTHERAPY CHALLENGES

At the present time, a number of potential biomarkers have been identified, such as tumour immunogenicity, pre‑existence of an immune response and PD‑L1 ligand expression, but their relevance to clinical practice is still unclear and needs to be elucidated in prospective studies. Immunohistochemical evaluation of PD‑L1 expression needs to be immediately implemented on a national scale in order to become part of routine clinical practice, as the marketing authorisation of some checkpoint inhibitors has been restricted to patients with a tumour expressing this ligand, but it is more complex. Indeed, the anti‑PD‑1/PD‑L1 response is independent of PD‑L1 expression in some cancers. Furthermore, certain patients with tumours not expressing PD‑L1 nonetheless respond to these treatments.

On a methodological level, it is essential to harmonise detection and scoring methods, compare the various antibodies available and define a positivity threshold for PD‑L1 expression before the routine clinical use of PD‑L1 expression as a predictive marker. Moreover, PD‑L1 expression is heterogeneous in the same tumour and varies over time under the effect of treatments, meaning that evaluating PD‑L1 expression at a given time or in a single region of the tumour may be insufficient. A specific research project was initiated in 2015 with pathologists from molecular genetics centres and AFAQAP (French Association for Quality Assurance in Pathological Anatomy) in order to address these questions, and should be continued. More broadly, besides PD‑L1 expression in routine clinical practice, it is essential to anticipate the transfer to routine clinical practice of new biomarkers of response to immunotherapies that need to be validated within the scope of translational research. This should involve close upstream cooperation between the teams of researchers developing and validating these biomarkers and the molecular genetics centres. As such, the current organisation of molecular genetics centres needs to evolve in order to incorporate predictive biomarkers for immunotherapy treatments, as it already the case for constitutional genetics. This involves bringing together the expertise required, implementing new technologies in routine clinical practice and adapting specimen and result circuits.


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Fig. 50. Layout of the integration of cooperating structures for immunotherapy

Moreover, immune checkpoint inhibitors are currently undergoing clinical evaluation in combination with a large number of different types of treatments, such as anti‑angiogenic agents, targeted therapies, standard chemotherapy and radiotherapy. It is necessary to base research on improving our understanding of the action mechanism of immunotherapies and improving the characterisation of the effect of combination partners on the immune system in order to build a foundation of scientific reasoning and sound preclinical data with a view to optimising strategies for developing treatments in conjunction with immunotherapy. This should involve close cooperation between immunology research teams and CLIP² centres, in order to devise early‑phase clinical trials assessing combinations of molecules made available within the framework of public‑private partnerships, which in turn will make it possible to conduct ancillary research projects.

The immunology research community is the focal point for addressing the different challenges associated with immunotherapy development. It has been united within the framework of the inter‑SIRIC “Immunology & immunotherapy” working group that brings together French experts in this field on the SIRICs and elsewhere. This provides an opportunity to facilitate the mobilisation of stakeholders and create synergistic actions nationwide.

Research projects on patients cohorts treated with immunotherapy

Implementation of new biomarkers in routine clinical practice

Inter-SIRIC working group Immunology &

Immunotherapy

BCB

CLIP²

Molecular genetics centres

Early-phases clinical trials of combinations

Ancillary research projects


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Precision medicine is based on increasingly precise tumour characterisation with a view to guiding patient treatment. To this end, several types of tests are performed in parallel on tumour samples taken at the time of diagnosis or at key stages of the disease. Histological tests (immunohistochemistry and in situ hybridisation) and mutations screening using targeted NGS have been conducted in an integrated manner in molecular genetics centres since their creation in 2006. They have required the establishment of a specific organisation incorporating anatomopathology and molecular biology. The arrival of PARP inhibitors in ovarian cancer during 2015, and in breast cancer in the near future, has led to the constitutional ongogenetics activity being merged with the existing system. Moreover, the arrival of new immunotherapy molecules will require research to identify new types of biomarkers for clinical practice. For this reason, molecular genetics centres will be required to incorporate this new skill. Therefore, in the short term, we will see the emergence of integrated centres that will allow for the coordination all of the tests required for the characterisation of a tumour sample (tumour or fluid biopsy).

Fig. 51. Aims of the TRIPOD programme

2.1. DATA COLLECTION AND INTEGRATION: DEVELOPMENT OF DECISION-MAKING TOOLS

The choice of treatment should be made through an integrated analysis of the molecular characteristics of the tumour, carried out within a collegial discussion involving the biologists and pathologists responsible for each of the tests conducted, bioinformatics engineers involved in the analysis of results, referring clinicians and the patient’s attending clinician. This practice is currently being rolled out through the establishment of Molecular Tumour Boards (MTB) within the molecular genetics platform, in the context of implementing targeted NGS as part of routine clinical practice.

At the present time, there are very limited resources for interpreting sequencing results and choosing the most suitable treatment. Therefore, it is essential to provide tools to support decision‑making and facilitate the interpretation of results in order to optimise the collegial decisions made in the MTB.

A first step consists of setting up a reference database of the variants identified by targeted NGS in the molecular genetics centres in 2017. This database will contain the variants of known clinical significance and the platforms will continuously populate the database with variants of unknown significance and information about the clinical context in which they have been identified. It will also contain a tool kit for predicting the deleterious nature of variants. This database will thus help to facilitate variant annotation, harmonise result reports and identify the variants to be prioritised for functional validation research.

However, this database is merely the first stage, as therapeutic monitoring of patients data (treatment administered according to the molecular characteristics of the tumour and response to this treatment) are an essential component of variant annotation. Indeed, a patient’s data needs to be interpreted in a context of

22THE TRIPOD PROGRAMME: GENERATION, INTEGRATION AND SHARING OF BIOLOGICAL AND CLINICAL DATA WITHIN THE SCOPE OF PRECISION MEDICINE

Collecting clinical and biological/imaging data in a format useful for a given patient and for all other patients,

wherever they live or are treated

Defining a synthetic sharable digital view

of the tumour and the patient

Offering flexibility and expertise for innovative

combined therapies

TRIPOD Programme


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arrival of new types of treatments, such as immunotherapy, and the combined use of multiple therapeutic approaches (targeted therapies, immunotherapy, standard chemotherapy and radiotherapy). As most of these treatments have yet to be granted a marketing authorisation, access to these innovative treatments in the next years will essentially be provided within the scope of clinical trials.

Clinical investigation centres, and more particularly early‑phase clinical trials centres such as CLIP², are set to play a major role in the patient care system. They will need to incorporate the evaluation of new therapeutic approaches and new treatment combination methods in their fields of expertise. As an example, the use of the abscopal effect of radiotherapy in conjunction with checkpoint inhibitors opens up new perspectives and represents a research pathway that is worth examining on the CLIP² sites. Moreover, clinical investigation centres take on a central role in the sharing of the data for patients with access to innovative treatments, which must imperatively be used as the basis for developing specific actions, particularly during the DCA implementation and DCC roll‑out phases.

As such, research conducted by the OSIRIS inter‑SIRIC working group (the inter‑SIRIC working roup for the sharing and integration of data) will provide an initial basic tool kit. The objective of this group is to share clinical and “OMIC” data generated within the scope of genomics‑driven clinical trials conducted by the SIRICs (e.g. the SHIVA, MOSCATO, PROFILER and SAFIR trials). In this context, a minimum set of some one hundred clinical items and some one hundred “OMIC” items is currently being finalised and will be used as a common base for sharing this type of data. Each item will be associated with a set of values defined according to the national and international guidelines in force. The next stage will consist of conducting a proof of concept on a restricted set of patients in order to evaluate the various technical procedures available and the feasibility of the project. The OSIRIS working group also offers the possibility of addressing the ethical and regulatory constraints associated with data sharing.

Beyond the national initiatives, INCa’s involvement in the ICGCmed international consortium, which aims to conduct a complete analysis of the tumour genome of 200,000 patients by the end of 2025 in relation to their clinical data, will help to address these challenges in a broader context.

overall knowledge, assisted by algorithms comparing the data with those of other patients.

For this reason, the establishment of a national database that, for each patient, compiles the molecular characteristics of the tumour at different stages of the disease, associated with data generated throughout the patient’s care pathway, is a prerequisite for the development of such decision‑making tools.

Compiling and integrating these multiple data, generated at different times and by different stakeholders, implies the use of interoperable healthcare information systems by the healthcare facilities responsible for inputting the data. In the context of the rollout of NGS – firstly targeted and then whole genome – in clinical practice to a very large number of patients, re‑entering all of the required data is not conceivable. Also, solutions capable of interfacing the numerous professional tools currently available for the purpose of sharing data are essential and a key success factor.

This challenge is at the core of the Genomic Medicine France 2025 Plan, which includes a measure dedicated to the creation of a data collector/analyser (DCA). This consists of a national data storage centre, associated with an intensive computing infrastructure designed to provide tools that will help the healthcare professionals to interpret results. In the field of oncology, interfacing with the Cancer Communication File (DCC) is envisaged. This digital file, aimed at improving care coordination, should provide healthcare professionals with the information contained in the key documents produced at each stage of the care pathway: anatomo‑cytopathological reports, surgical reports, the file produced by Multidisciplinary Consultative Meetings, the personalised care plan and the personalised monitoring and surveillance, or “post‑cancer”, plan. These documents are structured in accordance with the national guidelines1. In line with this approach, work is currently being finalised at INCa on the definition of a standardised report template for molecular tests performed using targeted NGS, in consultation with the healthcare professionals involved.

2.2. DATA SHARING FOR COORDINATED TARGETED THERAPIES ASSESSMENT

The development of precision medicine enables each patient to receive the most suitable treatment in terms of the molecular characteristics of his/her tumour. This is made possible by the

1 – Instruction SG/DSSIS/INCa no 2016‑109 dated 05 April 2016 on the update by 2017 of the target of the cancer communication file (DCC) target information system


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3 3STUDYING TO SET UP A SPECIFIC PROGRAMME SUPPORTING LATE-PHASE CLINICAL TRIALS

In previous years, INCa has launched several specific programmes to support early‑phase clinical trials, mainly through the 2009‑2013 Cancer control plan, especially CLIP², public‑private partnerships and AcSé programme.

INCa is considering to set up a specific programme aimed at supporting the emergence and funding of late‑phase clinical trials to address issues identified by the 2014‑2019 Cancer control plan.

3.1. LATE CLINICAL TRIALS CLOSE TO CANCER CARE MANAGEMENT TO IMPROVE PATIENTS’ SURVIVAL

Indeed, following the noteworthy achievements of the 2009‑2013 Cancer control plan in terms of structuring clinical research in the field of cancer, the Action 5.2 of the 2014‑2019 Cancer control plan has raised the bar to 50,000 per year the number of patients to be included in France in therapeutic clinical trials by the end of the plan. This has been identified as an important means toward to boost the pace of clinical progress, favour the earliest access to innovative treatments, as well as provide the best possible healthcare framework for patients included in clinical trials. As of now, this objective mostly relies on the nationwide PHRC‑K call for proposals that provides each year €20M to fund the most promising clinical research projects, competitively selected by an international scientific evaluation committee.

As these projects often aim to assess recent innovations in groups of patients with a relatively modest sample size, it is necessary to pursue further improvements on issues close to clinical care. For example, the optimisation of treatment results in terms of survival and the reduction of the burden of adverse effects that often severely hamper the quality of life of patients treated for cancer should be addressed, especially in the most vulnerable groups such as children and elderly patients.

The 2014‑2019 Cancer control plan sets out to consider issues of patient survival and reduction of treatment toxicity in therapeutic trials. In this purpose, an emphasis should be placed on the studies addressing issues close to routine healthcare, such as reducing the length of treatments, whether and when to stop treatment, or evaluating observance of oral chemotherapy drugs.

Although such issues are supposed to be studied thoroughly before transfer to routine clinical care, many therapeutic questions actually remain only partially addressed before market authorisation. Hence, INCa could support projects studying unanswered clinical questions just before or after market authorisation. For example, patient access to innovative drugs outside approved indications is the main objective of INCa’s AcSé programme. Similarly, such a programme could also be evaluated for treatments other than targeted drugs when they are transferred into clinical care. Studies conducted in routine clinical care with the aim of providing confirmation of results obtained in experimental conditions could also be part of a specific programme geared towards late‑phase clinical trials.

On the other hand, since improving patient survival is crucially relevant in some cancer diseases, especially in those with poor prognosis, clinical trials could also provide real therapeutic options beyond aiming to answer clinical research questions. That would mean conducting long‑term clinical trials in which specific designs, for example n‑1 design or adaptive designs, such as Multi Arm Multi Stage (MAMS) design and Pick a Winner design trials, could be useful.

Central to such a programme, large‑scale or very large‑scale therapeutic trials will be welcome.


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3.2. IDENTIFYING THE MAIN CHALLENGES OF CURRENT CLINICAL PRACTICES

As requested by the 2014‑2019 Cancer control plan, cooperative intergroups, designated by INCa between 2012 and 2015, will be mobilised to conduct these trials. Large‑scale or very large‑scale clinical trials can provide huge numbers of recruitment and therefore significantly contribute to meeting the objective of including 50,000 patients each year in therapeutic clinical trials in 2019, particularly when investigational centres are open in university hospitals, general hospitals and cancer centres, and when conducted by cooperative intergroups. Given the progression of number of enrolment of patients in clinical trials actually observed in 2015, INCa will certainly have to determine a minimum number of patients to be enrolled in each clinical trial project it will support. Moreover, the number of large‑scale or very large‑scale clinical trials to be selected each year should be determined: the aim could be to fund on average one project by INCa’s designated cooperative intergroup, i.e., 13 projects, by the end of the Cancer control plan in 2019.

As the programme would also contribute to improve the healthcare organisation in France as a whole, INCa will propose a partnership with the French Ministry of Health in order to fund the selected projects.

To achieve this goal and define the scientific priorities of this programme, first of all, INCa will setup a working group including

physicians and medical researchers, drawing specifically on the dynamics of INCa’s designated cooperative intergroups as well as on their ability to design study protocols and enrol patients in trials. The mission of this working group will be to identify the most relevant fields and issues of current clinical practice that may warrant launching large‑scale therapeutic clinical trials to improve healthcare. Ultimately, these therapeutic clinical trials will also provide an optimal framework for patient treatment and clinical follow‑up. In addition, the working group will be asked to discuss prior prospects of the programme from INCa. Finally, it will also focus on practical aspects, i.e. the specific ways and means that the institute would need to muster, in terms of potential new actions to implement, or to provide further reinforcement to already existing programmes, in order to stimulate the attainment of these objectives and those defined by the 2014‑2019 Cancer control plan.

The working group will be set up between September and December 2016 in order to allow INCa to launch the programme in 2017. The programme should include a specific call for proposals through which the first projects selected could be funded in 2017.

Thereafter, the working group will meet once a year to follow‑up the programme and to review the scientific priorities, to help INCa oversee the follow‑up of projects funded and find solutions to any arising difficulties.


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4 4STRENGTHENING THE STRUCTURING OF CANCER PUBLIC HEALTH RESEARCH

Recognising their importance in cancer control strategies, the role of social and human sciences, epidemiology and public health has been confirmed in the successive Cancer control plans. Indeed, one of the INCa’s goals when it was established was to bring social sciences and public health research applied to oncology in France up to the best international standards. Since 2005, INCa has therefore launched numerous thematic and investigator‑driven CFPs in order to increase the number of research projects funded in these disciplines. In this way, over the last decade, more than 350 research projects, covering all relevant disciplines, have been funded for a total amount of more than €55M. Although the CFPs were effective in increasing the number of isolated research projects, structuring initiatives are needed to increase multidisciplinary research projects and maximise the value of their outputs.

4.1. FOSTERING THE CAPABILITIES OF HUMAN AND SOCIAL SCIENCES, EPIDEMIOLOGY AND PUBLIC HEALTH

This type of initiatives started in 2015 with the creation of a new university research chair dedicated to cancer prevention. This chair is the result of the implementation of the recommendations of the 2012 report addressed to the INCa’s International SAB. University‑based research chairs have demonstrated their value in building research capabilities, in different countries, particularly in Canada with the 2000 Research Chairs Program. For this reason, INCa will continue to support the creation of research chairs, particularly in underserved disciplines in social and human sciences.

For the year 2017, INCa will set up multidisciplinary working groups in order to identify research priorities in human and social sciences, epidemiology and public health across the cancer control continuum, ranging from prevention, detection,

diagnosis, treatment to survivorship. An initial analysis of the INCa’s funded research portfolio in these disciplines, according to the CSO classification system developed by the International Cancer Research Partnership (ICRP), would be conducted in order to help experts identify research gaps.

The second step after the identification of the research priorities will be to launch a call for the creation of research networks, with dedicated funding, on cross‑cutting issues related to cancer control such as social, ethical and economical aspects of genetic testing, dissemination of evidence‑based interventions, quality of cancer care, social determinants of health disparities, etc. This initiative is planned to start in 2017, but will be pursued in the following years. It has the potential to encourage collaborative studies, given that the networks may involve several cancer centres, as well as other partners in research settings and the community.

4.2. SUPPORTING THE VISIBILITY OF HUMAN AND SOCIAL SCIENCES, EPIDEMIOLOGY AND PUBLIC HEALTH RESEARCH

To strengthen the visibility of human and social sciences, epidemiology and public health research, but also to create a meeting ground for social sciences researchers, INCa will organise regularly, from 2017, national and international conferences and workshops. For example, the international congress organised in 2014 has been a catalyst for the development of numerous initiatives on population health intervention research in France and beyond the cancer field.

Special attention will be focussed on human and social sciences disciplines applied to cancer. There is actually a strong need to narrow the gap between research and actions, particularly with regard to human and social sciences. Social inequalities in


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health and in cancer in particular are more than ever a major concern in our modern societies and strengthening the role of human and social sciences would be a first step towards tackling these inequalities. For these reasons, INCa will set up a working group encompassed of different experts from human and social sciences disciplines, in order to develop a common language about what is important when evaluating a research

project in these disciplines. Ultimately, an evaluation guideline will be produced and will be addressed to both reviewers and researchers. This guide will help improve the quality of the projects submitted and the quality of the reviewing process, needed to reduce the gap between disciplinary categories observed in the CFPs and in the call for applications in 2016.


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5 5NEW INTERNATIONAL COMMITMENTS

Fig. 52. New European and international partnerships

Europe

• JARC : Joint Action on Rare Cancer • FLAG ERA : Digital Medicine for Cancer

France - Caribbean - Africa

• Francophone research network on prostate cancer

China

• MoU with Chinese NCC on Cancer Control

Polynesia

• Cancer control plan implementation


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5.1. EUROPEAN INITIATIVE FLAG-ERA ON DIGITAL MEDICINE FOR CANCER

INCa has joined the European initiative FLAG-ERA on digital medicine for cancer. The FLAG‑ERA initiative of the European Commission focuses on future and emerging technologies, with an ERANET‑like mechanism, bringing together national and regional funding organisations in Europe and beyond. It addresses major scientific and technological challenges. Proposals are submitted by international consortia with partners from multiple countries. The selection process is international, but grant agreements for the selected projects are established directly between the funding organisations and the consortium partners.

INCa has joined this initiative and supports the first transnational CFP dedicated to digital medicine for cancer. The primary goal of this CFP is the development of detailed patient‑specific computer models and simulations of the complex biological processes involved in cancer. These models are expected to cover multiple levels spanning molecules, cells, tissues, whole body and populations, take into account various genetic and environmental factors, and have predictive capabilities. The applicants are also expected to tackle data sharing challenges taking into account the constraints of patient privacy, so that models can be trained and tested on common datasets, using natural language processing technology in order to make sense of the data annotation expressed in unstructured natural language.

Project selection is ongoing. Since the objective is to promote large‑scale cooperation on a European level, only one inclusive and ambitious project will be considered for funding.

5.2. JOINT ACTION ON RARE CANCERS

INCa is taking part in the new Joint Action on Rare Cancers.The new Joint Action on Rare Cancers (JARC) launched by the European Commission is responding to the many challenges of rare cancers, including the implementation of the Directive 2011/24/EU of the European Parliament and the Council of 9 March 2011 on the application of patients’ rights in cross‑border healthcare. This directive is meant to grant EU patients the right to access safe and high‑quality healthcare across European borders, and foresees the designation of European Reference Networks (ERNs) for rare and complex diseases, including rare cancers. ERNs will link up healthcare providers and centres of expertise of highly specialised healthcare, for patients with conditions requiring a particular concentration of resources or expertise regardless of where they are in Europe.

The JARC will help shape ERNs, but also contribute to improving health outcomes for patients with rare cancers in the EU.

The general objectives of JARC are: • to prioritise rare cancers in the agenda of the EU and Member States with a view to promoting quality and harmonisation of clinical practices, as well as innovation through clinical and translational research;

• to develop shared solutions, to be mainly implemented through the future European Reference Networks on Rare Cancers, for quality care, research & education, prevention & diagnosis of rare cancers.

INCa’s participation in the new JARC is grounded on the specific organisational framework for rare cancers in adults developed in France since 2009 by INCa and the Ministry of Health. This national framework comprises regional or interregional designated expert centres coordinated on a national level by an expert centre.


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5.3. GLOBAL NETWORK ON PROSTATE CANCER

INCa is supporting the development of a global network on prostate cancer across Sub-Saharan Africa, the Caribbean and Metropolitan France.Prostate cancer is the second most common cancer and the 5th leading cause of death from cancer in men worldwide. Incidence rates are relatively high in certain less developed regions and in certain overseas regions such as the Caribbean. Likewise, mortality rates are generally high in predominantly black populations (Caribbean, 29 per 100,000 and sub‑Saharan Africa, ASRs 19‑24 per 100,000).

Hence, the purpose of setting up a global network on prostate cancer across Sub-Saharan Africa, the Caribbean and Metropolitan France is to analyse the respective contribution of genetic, environmental and life‑style factors linked with the development of prostate cancer in populations of men of African descent, living in various settings. In November 2015, INCa convened the first meeting of the future network during the 10th international conference of AORTIC, the African Organisation for Research and Training in Cancer. Prostate cancer professionals from 5 Sub‑Saharan African countries (Senegal, Burkina Faso, Cameroon, Benin and Gabon), from the French West Indies (Guadeloupe) and from Metropolitan France were invited to confer about shared objectives. They agreed that the network should jointly pursue the following overarching goals: • Research: to provide new information about key determinants (such as genetic, environment, diet, life‑style, etc.) involved in prostate cancer;

• Education & training: to promote and strengthen cancer control training for urologists;

• Medical objective: to improve diagnostics of more aggressive forms of prostate cancer;

• Societal objective: to inform the population and professionals; • Capacity: to share resources (protocols, biological resources, pathology, etc.).

A draft study has been circulated among the network members.


The 2015‑2016 period has been rich at INCa's instances as well as in the cancer research field in general. While pursuing its gold standard funding and support in all research aspects (clinical, fundamental, translational, human and social sciences, epidemiology and public health) and in line with the Scientific Advisory Board’s recommendations, INCa has further enhanced during this past year multidisciplinarity in fundamental research projects, awareness in children cancer research and tertiary prevention, and in particular for tobacco, through specific programmes launched to address these issues. INCa's support to access to innovation and to targeted therapies medicine has gained momentum, in line with the willingness of the Institute and the 2014‑2019 Cancer control plan to strengthen the development of personalised medicine. Training in cancer research and dissemination of information of unmet medical needs and research gaps in cancer research have also been made a priority. The future perspectives highlighted in this report reflect how INCa will help French clinicians and researchers to tackle the coming challenges of immunotherapy, genomic medicine. These challenges are planned to be accompanied by the different INCa's designated structures, that have been set up over the last past years and that should be extended to the structuring of cancer research in human and social sciences, epidemiology and public health. These strategic orientations and the cross‑functional missions and values of INCa in the fight against cancer are also reflected in the pattern of INCa’s international commitments, with a particular attention on digital medicine, the implementation of actions at the European level and the development of global networks across African French‑speaking countries. This international overture based on strong partnerships should help to confront our scientific strategy and find synergies among worldwide organisations.This year has also seen profound changes in INCa's organisation, Christine Chomienne has been appointed as Director of the Research and Innovation Division and she has taken these tasks with energy and I am delighted to have joined the Institute as Chairperson.

CONCLUSION

Prof. Norbert Ifrah

Chairperson of the National Cancer Institute



APPENDICES


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1 6CLINICAL TRIALS REGISTRY

Milestones in managing the INCa clinical trials registry

2007-2008 2009-2010 2011-2012 2013 2014 2015

National collaborations

• Initiation of dialogue with ANSM (French National Agency for Medicines and Health Products Safety, 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 transmitted by ANSM (From September 2010 onward); 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 a 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 LNCC to make the patient committees aware of clinical research and how to use the clinical trials registry.

• Modification of the agreement between INCa and ANSM: all authorised trials in cancer are transmitted 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.





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Distribution of clinical trials registered (15 May 2016)

Total Open

Total 2,098 592

Academic 1,297 448

Industrial 801 144

ANATOMICAL CLASSIFICATION* Total Open INTERVENTION* Total Open

Breast 316 87 Drug** 1,540 394

Prostate 119 40 Radiotherapy 214 74

Respiratory system 232 52 Imaging 138 51

Colon and rectum 185 62 Surgery 145 72

Upper aerodigestive tract (UADT) and ENT 101 32 Transplant 66 19

Liver and bile ducts 86 25 Pharmacology – Translational Research 142 25

Urinary system 72 13

Female genital organs 117 44 Digestive system

(other than colon or rectum) 123 37

Skin – Melanomas 77 19 PHASE Total Open

Blood – Haematology 456 120 I 192 49

Nervous system 105 34 I-II 152 49

Sarcomas 66 22 II 693 164

Male genital organs 9 2 II-III 31 7

Endocrine system 31 11 III 571 144

Metastases 80 20 IV 33 4

Others 217 66 None 425 174*The sum may be greater than the total, since some trials belong to several categories**Also includes vaccines


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2 7CSO-COMMON SCIENTIFIC OUTLINE

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, INCa and its partners use this classification. The types of research projects funded by INCa, Ministry of Health and Inserm for ITMO Cancer‑Aviesan that are presented in this report are based on this CSO classification.

The different categories CSO 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 that Affect Cancer Risk

• 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

CSO 6 CANCER CONTROL, SURVIVORSHIP, AND OUTCOMES RESEARCH • Patient Care and Survivorship Issues • Surveillance • Behaviour • Cost Analyses and Health Care Delivery • Education and Communication • End‑of‑Life Care • Ethics and Confidentiality in Cancer Research • Complementary and Alternative Approaches for Supportive Care of Patients and Survivors

• Resources and Infrastructure Related to Cancer Control, Survivorship, and Outcomes Research

CSO 7 SCIENTIFIC MODEL SYSTEMS • Development and Characterisation of Model Systems • Application of Model Systems • Resources and Infrastructure Related to Scientific Model Systems


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3 82014-2019 CANCER CONTROL PLAN ACTIONS PROGRESS RELATED TO CANCER RESEARCH

GUARANTEEING THE CREATIVITY AND COMPETITIVENESS OF BASIC RESEARCH TO INCREASE OUR KNOWLEDGE OF THE DETERMINANTS OF CANCER

Basic 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 non‑earmarked 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.


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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 InVS Associates Anses; INCa; IReSP; ITMO Cancer

MILESTONES DATE STATUS

Study of Health impact of exposure to drinking‑water chlorination by‑products on the cancer of bladder (InVS/E1). 30‑06‑2015 Done

Projects selected for funding through the 2015 Employment‑Health‑Environment call for proposals (Anses). New Employment‑Health‑Environment call for proposals launched at the end of 2015 for funding in 2016

01‑10‑2015 Done

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 Done

Feasibility study for the multi‑sites surveillance multi‑sites of the cancers incidence around nuclear power plants (InVS/E3). 31‑12‑2015 Done

Pilot study on the evaluation of the environmental exposures on collected mesothelioma within the framework of DO (InVS/E2). 31‑12‑2015 Done

Analysis of the relation between adult bladder cancers incidence and the exposure of chlotination by‑products in water. 30‑06‑2016 In progress

Study of spatio‑temporal variations of testis cancer incidence in the context of endocrine disruptors exposure (InVS/E6). 30‑06‑2016 In progress

According to the results of E2 study, generalisation of the assessment of the environmental exposures for the DO‑mesotheliomas. 30‑06‑2016 Not started

Projects selection for the call for proposals EST 2016 and launch of the 2017 edition with a specific section dedicated to “cancer and environment” (Anses). 01‑10‑2016 In progress

National study evaluating the relationship between air pollution and lung cancer from the Gazel‑Air project data (InVS/E7). 31‑12‑2016 In progress

PROGRESS

The results of the call for proposals “Cancer & environment” have been published: 6 projects have been selected for funding, among the 37 submitted projects, for a total amount of €3.74M. In 2016, 35 cancer related proposals were submitted to the programme Employment‑Health‑Environment (Anses) and 6 projects were selected for funding for a total amount of €1.01M.

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 INCa; ITMO Cancer Associates


Investigator‑driven call for proposals in biology and basic science ‑ PLBIO2015 31‑12‑2015 DoneThematic call for proposals dedicated to basic research ‑ 2015 31‑12‑2015 DoneInvestigator‑driven call for proposals in biology and basic science ‑ PLBIO2016 30‑12‑2016 In progressThematic call for proposals dedicated to basic research ‑ 2016 30‑12‑2016 In progressPROGRESS

In 2016, 281 letters of intent were submitted to the call for proposals Biology and basic sciences for cancer research, 38 projects were selected for funding for a total amount of €20.3M. For the programme Research in Physics, Mathematics and Engineering Sciences related to Cancer, 13 projects were selected for a total amount of €5.02M. A call for applications dedicated to fund cancer research equipment was launched and the evaluation is scheduled for September 2016.

Action 17.11: Maintaining the principle of investigator‑driven and competitive calls as the main method for selecting cancer research projects.

http://mosaic.e-cancer.fr/niku/nu#action:projmgr.taskProperties&id=5182253








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REDUCING THE INCIDENCE, MORTALITY AND SOCIAL IMPACT OF CANCER THROUGH TRANSLATIONAL AND CLINICAL RESEARCH

Translational 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. recruitment 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 trials 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 1.2: Improve the coverage of HPV vaccination through a stronger mobilisation of referring physicians and diversification of access, especially free of charge access, for young girls.

Head and associates: DGS Associates INCa; UNCAM


Award of a public contract to launch studies in humanities and social sciences and descriptive epidemiology about the acceptability of vaccination in schools

31‑12‑2016 In progress

PROGRESS

A symposium is scheduled with researchers and associations to define the study specifications.

Action 1.7: Fight inequalities related to access to and uptake of screening programmes.

Head and associates: INCa Associates DGS; DSS; UNCAM


Launch of the CFP dedicated to Population health intervention research on the actions to counter inequalities (INCa)

31‑12‑2015 Done

PROGRESS

Since 2015, the call for proposals Population health intervention research focuses on the different times of the fight against cancer, including the screening.


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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 Aviesan Associates DGOS; INCa; DGRI


Annual launch of the recurring call for projects for translational research (PRTK 2015) 31‑03‑2015 Done

Annual launch of the recurring call for projects for translational research (PRTK 2016) 31‑03‑2016 Pending

Define the assessment process for the translational research projects funded in the frame of the calls for translational research, training to translational research and Transcan.


PROGRESS

Annual call for projects for translational research 2015, co‑funded by Ministry of Health and INCa: 162 letters of intent submitted, 21 projects selected for funding (€8.45M). In 2016, 153 letters of intent have been submitted; the final results should be published by the end of the year.

Action 5.2: Including 50,000 patients per year in therapeutic trials by 2019.

Head INCa; ITMO Cancer Associates DGOS


Involvement of INCa’s board to strengthen the action plan 31‑07‑2015 Done

Include the cost of research, transport and accommodation in clinical trials budget 31‑12‑2015 In progress

Set up a monitoring scheme for the major therapeutic trials 31‑12‑2016 Not started

PROGRESS

The number of patients recruited in clinical trials in 2015 is 48,246. The number of patients enrolled in academic trials and industry trials have increased of 148% and 50%, respectively, since 2008.

Action 5.3: Pursuing the development effort of early‑phase clinical trials centres (CLIP2) to provide better territorial coverage and promote the creation of dedicated centres for children.



Results of designation of new CLIP² with a paediatric component 31‑03‑2015 Done

2 new clinical trials authorised 31‑12‑2015 Done

Launch of 1 or 2 new Innovative molecules CFP 31‑12‑2016 Not Started

Involvement of the CLIP² centres in the AcSé programme dedicated to paediatrics 31‑12‑2016 In progress

PROGRESS

The trials selected in 2015 have received the authorisations in early 2016, the recruitment should start by the end of 2016.The AcSé paediatrics programme has been approved by ANSM and the paediatrics CLIP² should be the investigators.


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Action 8.3: Paying closer attention to the physical sequelae of cancer treatments.

Head INCa Associates


Launch of the PHRC‑K call for proposals to improve knowledge and support clinical research projects about the mechanisms underlying the development of sequelae as a complication of cancer treatment.

30‑06‑2015 Done

Action 8.7: Promoting observation and research devoted to preventing the risk of second cancer.

Head ARC Foundation Associates INCa; IReSP


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 Done

Workshop gathering the actors interested in call for proposals which will be launched 31‑12‑2015 Done

Kick‑off meeting of the multidisciplinary networkon the "healthcare professionals" topic 31‑12‑2015 Stopped

Publication of INCa’s report on physical activity and cancer 31‑12‑2015 In progress

Launch of the CFP dedicated to tertiary prevention 30‑06‑2016 Done

Set up of the projects selected for the call for proposals 21‑12‑2016 Not started

PROGRESS

The report on physical activity and cancer is delayed to the second half of 2016.The workshop has been held on 24 March 2016. The CFP has been launched in July 2016.


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Action 9.17: Consolidating and coordinating the schemes for observation and research related to life during and after cancer.

Head INCa Associates INPES; LNCC; IReSP; ITMO Cancer


Survey for the cancer barometer 31‑05‑2015 Done

Publication of the 2014 Cancer Observatory (LNCC) 23‑04‑2015 Done

Feasibility study for life 5 years after a cancer diagnosis VICAN 5 01‑09‑2015 Done

Data collection and survey for VICAN 5 01‑09‑2015 Done

Definition of a theme for the 2016 Cancer Observatory (LNCC) 31‑12‑2015 Done

Publication of the 2015 Cancer Observatory (LNCC) 30‑06‑2016 Done

Launch of the call of the Public Health Research Institute (IReSP) 30‑11‑2016 In progress

Publication of the cancer barometer 31‑12‑2016 In progress

PROGRESS

The survey for VICAN5 is closed, more 3,000 persons have been interviewed. The LNCC Cancer Observatory should present the report on June 2016.

Action 11.13: Improving the knowledge of cancers risk factors perceptions and behaviours.

Action 11.14: Making intervention research a genuine tool for prevention and behavioural change.

Head INCa Associates ARC Foundation, IReSP


Launch of the recurrent call for proposals of the tobacco Programme 28‑02‑2015 Done

Launch of the recurrent call for proposals of the tobacco Programme 28‑02‑2015 Done

Launch of the recurrent call for proposals in Population Health intervention research 30‑06‑2016 Done

Chair university appointment in prevention and human and social sciences applied to cancer


Organisation of a symposium on the advances of Intervention research in France 31‑08‑2016 In progress

Publication of a report (situational analysis) on pilot projects related to behavioural interventions


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 MEDICINE

During 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 centres 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 centres 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: Define the priorities regarding the development of cancer drugs.

Head ANSM Associates DGOS; DGS; INCa; DGRI


Definition of criteria for drugs development 01‑12‑2015 In progress

Launch of the pilot study based on the criteria 01‑06‑2016 Not started

PROGRESS

Constitution of 2 working groups 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 INCa Associates DGOS; ANSM; DGRI


Authorisation request of at least one genomics‑guided clinical trial either transpathology or assessing the combination of innovative drugs

31‑12‑2015 Done

Working group meeting on the methodology of adaptive trials 30‑06‑2016 In progress

Authorisation request of at least one genomics‑guided clinical trial either transpathology or assessing the combination of innovative drugs

31‑12‑2016 Done

PROGRESS

As a conclusion of the last partners meeting, which held on April 2015, an inventory of the adaptive trials led in France or at an international level appeared to be necessary.Launch of the AcSé programme for paediatric cancers in May 2016: AcSé‑eSMART in the CLIP² designated.


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Action 6.1: Developing the oncogenetics scheme, and improve access to it.

Head INCa Associates DGOS


Publication of the dashboard of the 2014 oncogenetics activity 18‑12‑2015 Done

Publication of the 2013‑2014 assessment of the follow‑up for cancer predisposed people

18‑12‑2015 Done

Lynch syndrome and MSI screening: Finalisation of the actions concerning the improvement to access to oncogenetics scheme

18‑12‑2015 Done

Finalisations of the actions to support PARP inhibitors introduction 22‑04‑2016 In progress

Publication of the dashboard of the 2015 oncogenetics activity 20‑12‑2016 Not started

Publication of the survey results on NGS implementation 20‑12‑2016 Not started

PROGRESS

Reports on oncogenetics activity have been published. Regarding the arrival of PARP inhibitor, INCa has organised support to structures and professionals concerned: ‑ Support to 5 centres for BRCA screening‑ Support to 10 teams to set up NGS sequencing

Action 6.2: Consolidating access to molecular testing.

Head INCa Associates DGOS


Results of the study on economic impact of the use of targeted NGS techniques 31‑12‑2015 Done

Concluding remarks of the working group on pharmacogenetics 31‑01‑2016 Not started

Adaptation of the funding for the molecular genetics centres for targeted NGS 30‑11‑2016 In progress

PROGRESS

The first survey led in the molecular genetics centres allowed to measure the lead times of the molecular testing. The data 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.In march 2016, introduction of the RHIN, especially including NGS for somatic and constitutional genetics.The medico‑economic study on NGS costs should be published.





131

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 INCa Associates Aviesan


Authorisation of new genomic‑guided trials including exome sequencing 31‑12‑2015 In progress

Patients enrolment opening for novel genomic‑guided trials with exome sequencing 31‑12‑2016 Not started

PROGRESS

Implementation of guided by exome sequencing clinical trials are in the course of implementation in the colorectal cancers and the sarcomas.

Action 6.4: Supporting the implementation and performance of high‑throughput sequencing for all cancers by the end of the Plan.

Head INCa Associates DGOS; ITMO Cancer


Elaboration of a guide of best practices for analyses realised by NGS technologies 30‑06‑2015 Done

Technical validation of projects concerning tumour exome sequencing in the clinical trials 31‑12‑2015 Done

Completion of the NGS deployment in the molecular genetics centres and in the oncogenetics laboratories


Identification of the infrastructures involved in exome sequencing in clinics (sequencing centres, data storage, etc.)

31‑12‑2016 Not started

PROGRESS

Based on the acquired experience, NGS was deployed in 2015 in all the molecular genetics centres and the oncogenetics laboratories. INCa funding should support the technical validation of the NGS and the bioinformaticians recruitment.Standard operating protocols for sequencing methodology and tumour analysis have been set up to harmonise practices among the different laboratories and to obtain the ISO 15189 accreditation.



132

Action 6.5: Generating and understanding big data.

Head Aviesan Associates INCa; DGRI


Proposals on the management, storage and interpretation of the data 31‑05‑2015 Done

Programming of the action 30‑09‑2015 In progress

PROGRESS

The French Prime Minister asks to the President of Aviesan to define the required conditions to allow full genome sequencing in routine practice and to provide recommendations on the organisation of sequencing infrastructures, data management and analysis. The report has been published in June 2016.

Action 6.6: Integrating genomic studies in a global scientific vision of tumour heterogeneity and their relationships with the stroma and the immune system.



Launch of the call for proposals Tumour heterogeneity and ecosystem proposed by ITMO Cancer‑Aviesan

31‑12‑2015 Done

Selection of the projects for funding 30‑11‑2016 In progress

PROGRESS

The objectives of the Tumour heterogeneity and ecosystem programme are to promote the implementation of a critical mass in terms of resources and skills to conduct research projects of interdisciplinary nature which require cooperation between national teams from different thematic fields such as cell biology, mathematical modelling, genetics and (epi)genomics, mecanobiology in an integrated way. It covers both fundamental and translational aspects, and takes into account that the developments of new therapeutic strategies are needed considering tumour heterogeneity to elaborate truly efficient personalised or targeted medicine.For the first edition, 27 proposals have been pre‑selected among the 73 letters of intent submitted.

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.


133

DEVELOPING THE STRUCTURES FOR CANCER RESEARCH AND CAREER PATHS

In 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 cancéropôles 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 LNCC Associates INCa


Participation of biomedical research patients’ committees in disseminating of clinical trials results

31‑12‑2015 Done

Publication of results of clinical trials when ended in the INCa’s Cancer research clinical trials registry

31‑12‑2015 Stopped

Conduct a satisfaction survey of patients included in clinical trials, about the information that has been provided


PROGRESS

A hundred proofreaders included in patients' committee in 2015‑ 102 protocols reviewed on 26‑11‑2015.


134

Action 5.11: Clarifying the process of identifying and evaluating technological innovations and the organisational changes they generate

Head DGOS AssociatesINCa; DGRI; ITMO Cancer; ITMO Health Technologies


Adjusting the assessment framework of medical procedures and devices: Evaluation of expensive consumables


Adjusting the assessment framework of medical procedures and devices: Innovation package

30‑06‑2015 Done

Based on international recommendations, papers and communications, establishments of terms of Technology Developments


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 started

Scientific bulletin produced by local actors (pilot phase) 30‑06‑2016 Not started

Publication of the first scientific valorisation notices (pilot phase) 31‑12‑2016 Not started

PROGRESS

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 INCa; ITMO Cancer Associates DGOS; DGRI


Establishment of the international evaluation committee 30‑06‑2015 Done

Audition of SIRICs by the international evaluation committee 31‑12‑2015 Done

Setting up of inter‑SIRIC working groups to support continuum between basic and clinical research

31‑12‑2015 Done

Publication of recommendations issued of working groups 30‑06‑2016 In progress

PROGRESS

Planning and process validated by the partners of the programme (DGOS and Inserm for ITMO Cancer). The conclusions and the recommendations have been sent to the SIRICs.Different working groups have been set up since 2014: sharing and integration of clinical, biological and genomic data, radiotherapy, clinical trials and precision medicine, immunology and immunotherapy, humanities and social and sciences and public health, drug design, etc.


135

Action 13.3: Developing initial training to meet the needs of cancer research.

Head DGESIP Associates INCa; DGRI; ITMO Cancer


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

ITMO Cancer‑Aviesan supports the PhD training “Frontiers in Life Sciences”. In 2016, 4 PhD candidates were granted.

Action 13.4: Increasing the attractiveness of careers in cancer‑related research.

Head Aviesan Associates DGRI


Identification of Inserm researchers in the field of bioinformatics 01‑12‑2015 Done

Definition of the perimeter of the Inserm specialised scientific commissions (CSS) 02‑12‑2015 Done

Setting up of CSS2 dedicated to cancer for 2016‑2020 01‑09‑2016 In progress

Identification in ATIP‑Avenir, University chairs and new recruited researchers the bioinformaticians


PROGRESS

Setting up of CSS2 dedicated to cancer for 2016‑2020 in July 2016.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.In 2016, the overall support is €2.11M.

Action 14.1: Expanding In the area of cancer, the participation of users in steering, managing or delivering cancer care or research bodies.

Head INCa Associates DGOS; DGRI


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

Analysis of the relevance of user's representatives participation in the novel SIRIC missions 30‑06‑2016 Done

PROGRESS

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.


136

Action 16.6: Refocusing the roles of the Cancéropôles 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).



Signing of Objectives and Performance Contract (Contrat d’Objectif et de Performance COP) 29‑05‑2015 Done

Monitoring of cancéropôles' missions according to the COP 30‑12‑2015 Done

Monitoring of cancéropôles’ missions according to the COP 30‑12‑2016 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.



Validation of the process of the call for applications with the partners (Inserm and DGOS)


Launch of the new call for designations 31‑12‑2016 Not started

PROGRESS

The process of a new designation is under discussion with the different partners.

Action 16.8: Coordinating the actions of the SIRICs and Cancéropôles in order to strengthen research in a given territory.



Specific assessment criteria in the mid‑term assessment of SIRIC (reports and auditions) 30‑06‑2015 Done

Specific recommendations in the synthesis form of the mid‑term assessment 31‑03‑2016 Done

Dedicated section in the application form of the new call for designation 31‑12‑2016 Not started

PROGRESS

The importance of coordination between SIRIC and Cancéropôles is a specific article in the COP and in the mid‑term assessment of SIRIC. Specific recommendations are addressed to the SIRICs according to the mid‑term assessment results.



137

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 INCa Associates Aviesan Sud; ITMO Cancer


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

30‑07‑2015 Done

Preparation of the 2015 AORTIC group dedicated to prostate 03‑12‑2015 Done

Support to the Global Initiative for Cancer registries from IARC 31‑12‑2015 Done

PROGRESS

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 French‑speaking countries in 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 INCa Associates Aviesan Sud; ITMO Cancer


Africa/AORTIC HPV Research/ Public Health Multilateral cooperation: funding of projects

19‑03‑2015 Done

Laos Merieux Foundation Research cooperation: HPV – HIV project 10‑09‑2015 Done

Multilateral cooperation France‑Africa‑Caribbean Research/ Public Health on prostate cancer

15‑06‑2016 Done

Collaboration HPV research: HPV project funding in Senegal 14‑10‑2016 In progress

Collaboration CIRMF‑IRD: HPV project funding in Gabon 15‑10‑2016 In progress

PROGRESS

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 diseases.INCa organised a prefiguration meeting with representatives of 9 African countries in order to set up a French‑speaking network for prostate cancer research including French teams from France, Antilles, and sub‑Saharan Africa.




138

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 INCa Associates Aviesan international


Tobacco: International Consortium for Action and Research on Tobacco (ICART) meeting

19‑03‑2015 Done

PROGRESS

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 INCa; ITMO Cancer Associates DGOS


Aviesan Mission for programming research in Health 31‑12‑2015 Done

GIPSI 01‑01‑2016 In progress

PROGRESS

INCa develops a new tool dedicated to the projects submission and the scientific monitoring of the funded projects. INCa and ITMO Cancer organises regularly dissemination workshops on results.

Action 17.13: Developing shared tools for evaluating cancer research projects.

Head INCa Associates Inserm; DGRI


Overview of existing assessment tools at an international level 31‑12‑2015 In progress

PROGRESS

A benchmark on the available evaluation tools is on‑going to improve Helios realised in partnership with HCERES.



139

SHARING AND DISSEMINATION OF RESEARCH RESULTS

Raw 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 INCa Associates LNCC


Sending of the form to get clinical trials results 30‑06‑2015 Stopped

Publication of the first clinical trials results 30‑06‑2016 Stopped

PROGRESS

Display of clinical trials results on the register has been stopped.

Action 13.5: Sharing information and data between professionals and the general public at national and international levels.



Third GLOBAL ALLIANCE meeting 11‑06‑2015 Done

Involvement of patients’ representatives in the different boards managed by INCa (SAB, Cancéropôles, SIRICs, etc.)

31‑12‑2015 Done

PROGRESS

INCa signed the agreement to join Global Alliance for Genomic and Health.In order to incite the researchers to ask an open‑access for their publications, INCa and ITMO Cancer have dedicated part of the needed budget in their calls for proposals.


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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 : 978-2-37219-242-2

ISBN net : 978-2-37219-243-9

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 2016. It is available at the following address:Institut National du Cancer (INCa)Direction de la recherche52, avenue André Morizet – 92100 Boulogne-Billancourte-cancer.fr© 2016. 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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