OCTOBER 2016

For more information e-cancer.fr 2015-2016

Institut National du Cancer 52, avenue André Morizet FRENCH NATIONAL 92100 Boulogne-Billancourt France Tel. +33 (0) 1 41 10 50 00 CANCER INSTITUTE [email protected] SCIENTIFIC REPORT / 2015-2016 SCIENTIFIC REPORT / REPORT SCIENTIFIC CANCER INSTITUTE FRENCH NATIONAL RAPCSANG16 FRENCH NATIONAL CANCER INSTITUTE FRENCH NATIONAL CANCER INSTITUTE SCIENTIFIC REPORT / 2015-2016 SCIENTIFIC REPORT / 2015-2016

The French National Cancer Institute is the health and science agency in charge of cancer control.

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 52, avenue André Morizet strategy to fight cancer; the second Cancer Control Plan (2009-2013) introduced the notion of 92100 Boulogne-Billancourt personalised care. France The 2014-2019 Cancer Control Plan intends to give each and every person, all over France, the Tel. +33 (0) 1 41 10 50 00 same chances for recovery and implement innovation even faster for [email protected] Plan patient benefit. Cancer This plan includes 17 objectives, all gathered around four major 2014-2019 health priorities: l Cure more patients l Preserve continuity and quality of life l Invest in prevention and research l Optimise management and the organisations efficiency The 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.

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, Published by the French National Cancer Institute are authorised. All rights reserved – Siren 185 512 777 Conception: INCa This document was published in October 2016. It is available at the following address: Realised by Institut National du Cancer (INCa) ISSN 2276-5751 Direction de la recherche ISBN : 978-2-37219-242-2 52, avenue André Morizet – 92100 Boulogne-Billancourt ISBN net : 978-2-37219-243-9 e-cancer.fr © 2016. Institut National du Cancer (INCa) DEPÔT LÉGAL OCTOBRE 2015 FRENCH NATIONAL CANCER INSTITUTE 3 2015-2016 SCIENTIFIC REPORT

SCIENTIFIC REPORT 2015-2016 FRENCH NATIONAL CANCER INSTITUTE 4 2015-2016 SCIENTIFIC REPORT

TABLE OF CONTENTS

PREAMBLE 6 3. CLINICAL RESEARCH AND DEVELOPMENT OF EARLY-PHASE TRIALS FOR INNOVATIVE DRUGS 56 Key figures 8 3.1. Clinical cancer research programmes 56 Clinical trials indicators 11 3.2. Early -phase clinical trials for innovative drugs 59 Molecular genetics centres: activity indicators 12 3.3. Personalised medicine tools and programmes 62 International framework 14 3.4. Organisation of clinical research and strengthening of structures, infrastructures and tools 68 SUMMARY OF THE REPORT 17 4. RESEARCH IN HUMAN AND SOCIAL SCIENCES, Part 1. EPIDEMIOLOGY AND PUBLIC HEALTH 72 Summary of previous recommendations 4.1. The recurrent programme for Human and social of the members of the international Scientific Sciences (HSS), Epidemiology and Public Health (EPH) Advisory Board and corresponding achievements 19 Research 72 Part 2. 4.2. Population Health Intervention research 75 Report on 2015-2016 cancer research activity 29 4.3. Initiatives developed to support research on environmental risks 77 1. SUPPORT IN BIOLOGY AND BASIC SCIENCES 4.4. PhD Programme in HSS-EPH 2016 in collaboration FOR CANCER RESEARCH 31 with academic partners 79 1.1. Research programmes 31 1.2. The genomic and the epigenomic programmes 40 5. INTERNATIONAL COMMITMENTS 81 5.1. Strategic vision, mission and values 81 2. TRANSLATIONAL AND INTEGRATED RESEARCH 45 5.2. INCa’s European commitments 82 2.1. Research programmes aiming to accelerate 5.3. INCa’s global commitments 84 cross‑disciplinarity and transfer of knowledge to clinical practice 45 6. BIBLIOMETRIC STUDY, EVALUATION AND REVIEW 2.2. The Translational and multisdisciplinary Research OF RESEARCH INVESTMENT 90 Training Programmes 50 6.1. Bibliometric study 90 2.3. Strengthening of organisation and infrastructures 6.2. Focus: Trends in the French funding stream dedicated to translational/integrated research of intervention research addressing all aspects in integrated cancer research sites (SIRICs) 54 of cancer control, a cross-sectional analysis 2010-2014 95 6.3. International evaluation 97 6.4. Review of research investments 98 FRENCH NATIONAL CANCER INSTITUTE 5 2015-2016 SCIENTIFIC REPORT

Part 3. Conclusion 118 Focus on strategic topics for advancing cancer research 103 Appendices 119 1. CHALLENGES ASSOCIATED WITH THE ARRIVAL OF IMMUNOTHERAPIES 106 1. CLINICAL TRIALS REGISTRY 120 1.1. Biological and clinical databases: a unique tool to assess and monitor immune checkpoint inhibitors efficacy 106 2. CSO-COMMON SCIENTIFIC OUTLINE 122 1.2. Resources and infrastructures integration to face the immunotherapy challenges 107 3. 2014-2019 CANCER CONTROL PLAN ACTIONS PROGRESS RELATED TO CANCER RESEARCH 123 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 FRENCH NATIONAL CANCER INSTITUTE 6 2015-2016 SCIENTIFIC REPORT

PREAMBLE

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 FRENCH NATIONAL CANCER INSTITUTE 7 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 Prof. Christine contributions to the programmes and this report. Chomienne Director of INCa's Research and Innovation programmes Director of the Inserm Cancer institute Director of ITMO Cancer-Aviesan FRENCH NATIONAL CANCER INSTITUTE 8 2015-2016 SCIENTIFIC REPORT

KEY FIGURES

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

35 PRME-K* IBiSA Platforms* PHRC-K* Equipments* 30 PLSS-EPH Cooprative intergoups 25 PRT-K* PLBIO Clinician training in biology 20 FDV PhD 15 Heterogeneity* ATIP-Avenir (cancer field)

€ Million Tobacco programme Translationnal training 10 Anses HSS research chair* 5 Environment HSS PhD Physics, mathematics 0 Intervention reseach INCa Inserm DGOS Transcan

Investigator-driven projects Research training and young teams of excellence Strategic research initiatives/thematic programmes Platforms, resources, infrastructures

2007-2015 FUNDING ALLOCATION PER PROGRAMME TYPE

3%

24% 4% Investigator-driven calls % 8 HSS-EPH Strategic research initiatives/ thematic programmes 18% Translational Platforms/resources/ 53% infrastructures Biology and basic sciences Research training/ Young teams of excellence 23% Clinical

20% FRENCH NATIONAL CANCER INSTITUTE 9 2015-2016 SCIENTIFIC REPORT

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

400 80 350 70 300 60 250 50 200 40 150 30 Nb of projects Nb of projects 100 20 50 10 0 0 2016201520142013201220112010200920082007 2016201520142013201220112010200920082007

Clinical Clinical* Translational* Translational* Human and Social sciences, epidemiology, public health Human and Social sciences, epidemiology, public health Biology and basic sciences Biology and basic sciences

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

25

20

15

€ M 10

5

0 201520142013201220112010200920082007 2016

Clinical* Translational* Human and Social sciences, epidemiology, public health Biology and basic sciences FRENCH NATIONAL CANCER INSTITUTE 10 2015-2016 SCIENTIFIC REPORT

TRENDS IN THE MEDIAN VALUE OF THE 3 MOST FUNDED INVESTIGATOR-DRIVEN CFPS MANAGED BY INCa Clinical research 600,000 500,000 400,000 300,000 200,000 100,000 0 2013201220112010200920082007 2014 2015

Biology and basic sciences 600,000 500,000 400,000 300,000 200,000 100,000 0 2013201220112010200920082007 2014 2015

Translational* 600,000 500,000 400,000 300,000 200,000 100,000 0 2013201220112010200920082007 2014 2015

Median value of projects submitted Median value of projects selected

*No translational research projects in 2008 FRENCH NATIONAL CANCER INSTITUTE 11 2015-2016 SCIENTIFIC REPORT

CLINICAL TRIALS INDICATORS

TRENDS IN PATIENT ENROLMENT IN CANCER CLINICAL TRIALS

48,246 50,000 44,023 40,000 37,492 28,167 42,803 30,000 26,003 34,067 20,000 24,037 10,000 Nb of patients enrolled Nb

0 2006200520042003 2007 20092008 2010 2014201320122011 2015

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

800 700 687 643 602 600 553 517 500 592 400 417 528 300 233 200 100 0 108 Jul-09 Jul-07 Jul-08 Jul-10 Oct-14 Jun-11 Apr-07 Apr-16 Jun-12 Jun-13 Dec-11 Dec-15 Dec-14 Dec-08 Dec-09 Dec-07 Dec-12 Dec-13 Dec-10 May-14 May-16 May-15 FRENCH NATIONAL CANCER INSTITUTE 12 2015-2016 SCIENTIFIC REPORT

MOLECULAR GENETICS CENTRES: ACTIVITY INDICATORS

Predictive molecular testing in France in 2015: Activity of the 28 molecular genetics centres

Paris Lille AP-HP Curie

Amiens Gustave Roussy Rouen Nancy Caen Paris Reims Brest Strasbourg

Rennes Number of patients Angers who benefited from predictive molecular Dijon testing in 2015 Tours - Nantes Orléans Besançon 10,000

Poitiers 6,000 Limoges Lyon Clermont-Ferrand 3,000 Bordeaux - St-Etienne Grenoble La Réunion 1,500

Montpellier - Nîmes Nice

Toulouse Marseille

Source: INCa, 2016 Drafted by INCa’s Research Division, 2016 FRENCH NATIONAL CANCER INSTITUTE 13 2015-2016 SCIENTIFIC REPORT

EXAMPLE: SCREENING FOR KRAS MUTATIONS IN PATIENTS WITH COLORECTAL CANCER

25,000 21,375 19,347 20,000 17,246 17,003 21,855 15,000 16,581 18,568 10,000 10,012

Nb of patients enrolled 5,000

0 1,100 201520142013201220112010200920082007

EXAMPLE: SCREENING FOR EGFR MUTATION IN PATIENTS WITH LUNG CANCER

30,000 26,614 23,336 20,750 20,000 24,558 16,834 21,995

10,000 Nb of patients enrolled 1,269 2,667 0 20152014201320122011201020092008 FRENCH NATIONAL CANCER INSTITUTE 14 2015-2016 SCIENTIFIC REPORT

INTERNATIONAL FRAMEWORK

CCP Transversal objectives

Childhood, Reducing Enabling Public adolescents inequities earlier diagnosis health and young adults (Objective 1) (Objective 15) cancers

JARC CANCON EUROMED IARC - GICR Joint Action on RARE Quality improvement Screening & Global initiative on CANCERS in cancer control early diagnosis in cancer registry Mediterranean WP9 – Childhood (WP8 – Survivorship & countries cancers rehabilitation)

COFAC COL

JARC Collaborative network CANCON on cervical cancer Joint Action on RARE control CANCERS Quality improvement in cancer control WP5 – Quality of care (WP9 – Screening) LAOS / THAILAND Research & public health projects on cervical cancer control

SENEGAL Agreement on cancer control

WHO Implementation of WHO guidelines on cervical cancer control

Global Partnerships Bilateral agreements

Europe Regional Networks FRENCH NATIONAL CANCER INSTITUTE 15 2015-2016 SCIENTIFIC REPORT

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

2014-2019 Cancer Control Plan objectives

Innovation Personalized Comprehensive Tobacco control Global Partnership & research medicine and personalised (Objective 10) / Cancer Control (Objectives 5 & 13) (Objective 6) cancer care (Objective 16) (Objective 7)

CANCON ICGC CANCON ICART European Commission EXPERT Quality improvement International Cancer Quality improvement International GROUP on cancer in cancer control Genomic Consortium in cancer control Consortium for Action control and Research on (WP6 – cancer care (WP8 – Survivorship & Tobacco Control network) FLAG ERA rehabilitation) US NCI Digital medicine US National Cancer for cancer Institute - Global coordination TRANSCAN 2 Translational research GA4GH NCC – CHINA Global Alliance National Cancer Center for Genomics – cancer control and Health ICRP IARC International Cancer International Agency Research Partnership for Research on Cancer – INCa sits at IARC Board of Directors ICGC International Cancer FRENCH Genomic Consortium POLYNESIA Cancer control 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 FRENCH NATIONAL CANCER INSTITUTE 16 2015-2016 SCIENTIFIC REPORT FRENCH NATIONAL CANCER INSTITUTE 17 2015-2016 SCIENTIFIC REPORT

SUMMARY OF THE REPORT

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. FRENCH NATIONAL CANCER INSTITUTE 18 2015-2016 SCIENTIFIC 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. FRENCH NATIONAL CANCER INSTITUTE 19 2015-2016 SCIENTIFIC REPORT

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

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. FRENCH NATIONAL CANCER INSTITUTE 20 2015-2016 SCIENTIFIC REPORT

Priority given to translational research and multidisciplinary training

••The Board supports the investment plan prepared by INCa for training physicians/scientists and investigators in translational research. 2007 ••Focus on a few high priority programmes. ••Reduce the number of calls for proposals. ••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. 2009 ••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. ••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 2011 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. ••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 2012 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. ••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 2013 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. ••The Board acknowledges the potential of the Cancéropôles and the SIRICs, however, both programmes should 2014 undergo a regular international peer-review and possibilities for interaction between these organisations should be implemented. ••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 2015 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. FRENCH NATIONAL CANCER INSTITUTE 21 2015-2016 SCIENTIFIC REPORT

Achieved 2008: 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. Actions 2012: First evaluation of training programme provided to medical students to perform translational achieved or research. in progress 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. FRENCH NATIONAL CANCER INSTITUTE 22 2015-2016 SCIENTIFIC REPORT

Molecular genetics, cancer biology and sciences

••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. 2007 ••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. ••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. 2010 ••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. ••The Board encourages the development of data processing systems for bioinformatics and medical data, and 2011 research on complex systems in collaboration with other research organisations. ••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 2012 must be available at these centres. ••The research programme for cancer biology is an important asset, and requires sustained funding. ••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 2013 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. ••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 2014 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. FRENCH NATIONAL CANCER INSTITUTE 23 2015-2016 SCIENTIFIC REPORT

••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 2015 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. Achieved 2011-2016: 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; Actions - research projects based on microenvironment and tumour heterogeneity. achieved or 2011: Publication of institutional recommendations for the creation of tumour collections in progress 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. FRENCH NATIONAL CANCER INSTITUTE 24 2015-2016 SCIENTIFIC REPORT

Evaluation and key performance indicators in clinical research

••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 2008 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. ••The Board supports the implementation of key performance indicators (KPIs) and milestones to confirm 2010 the efficacy of scientific strategy. 2012 ••The Board encourages the design of innovative clinical trials and methodology in assessing the value of NGS. ••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 2013 of cooperative groups to optimise the use of clinical trial resources in an integrated manner and minimise duplication of infrastructure. ••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. 2014 ••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. ••The Board applauds the comprehensive approach to precision cancer medicine for paediatric patients across 2015 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. Actions 2012-2015: Designation of 13 cooperative intergroups. achieved or 2013: Development of the Health Investments Observatory (HELIOS). in progress 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 progress Design of the AcSé immunotherapy clinical trial. FRENCH NATIONAL CANCER INSTITUTE 25 2015-2016 SCIENTIFIC REPORT

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. ••The Board recommends the development of a specific strategy for preventive research (including behavioural 2010 and social sciences, epidemiology, public health, statistics, economics, etc.). ••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 2012 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. ••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 2013 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. ••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 2014 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. ••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 2015 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. Achieved 2012: 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. Actions Launch of the National Programme to Reduce Smoking (PRNT) achieved or 2015: Launch of the first joint programme of actions in research/public health to combat tobacco-related in progress 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. FRENCH NATIONAL CANCER INSTITUTE 26 2015-2016 SCIENTIFIC REPORT

National, European and international Partnerships

••The Board encourages an integrated approach within the European Union. 2007 ••The Board encourages financial incentives for cooperative groups wishing to consolidate and study specific subjects. ••Whenever possible, priority should be given to projects where European collaborations are ongoing or planned. This information should be contained in the application. 2008 ••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. ••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. 2009 ••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. ••The Board encourages more interaction with the 2 main cancer charities and the development of optimum synergy. 2010 ••The Board supports the efforts made to increase collaboration between the various cooperative groups at national and international levels. ••The Board is pleased by INCa’s leadership into the planning of the preparation of Third Cancer Plan. INCa is 2013 encouraged to use this opportunity to refine its portfolio of projects to better reflect the strategic priorities of the Cancer Plan. ••The Board acknowledges INCa participation to the ICART project and encourages INCa to engage 2015 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. Actions 2009-2016: Recurrent CFPs with French charities: PAIR programme. achieved or 2010-2015: Involvement in 4 European projects. in progress 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. FRENCH NATIONAL CANCER INSTITUTE 27 2015-2016 SCIENTIFIC REPORT

Communication

••As an integral part of its responsibility as a leader in the fight against cancer, INCa should: ––Sponsor international symposia; 2008 ––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. ••The Board encourages INCa to promote international scientific events regularly, and to foster better 2010 communication with regard to scientific strategy. 2012 ••The Board is very pleased with the quality and conciseness of the Scientific Report. ••The Board would like to encourage INCa to continue to develop the communication tools, and dissemination 2013 of science towards the lay person, and the interactions with patients’ advocacy groups. ••The Board compliments the INCa teams for the efforts introducing very useful, comprehensive and clear 2015 activity and scientific report documents. Achieved 2008-2016: 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 microenvironment 2012: Symposium on cancer and Inequalities International R&D Dating International forum on prospective in cancer research and treatment Actions 2012: Strategic report on a programme for cancer prevention research: Changing Health Behaviours achieved or and their Individual and Collective Determinants in progress 2013: 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. FRENCH NATIONAL CANCER INSTITUTE 28 2015-2016 SCIENTIFIC REPORT FRENCH NATIONAL CANCER INSTITUTE 29 2015-2016 SCIENTIFIC REPORT

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. FRENCH NATIONAL CANCER INSTITUTE 30 2015-2016 SCIENTIFIC REPORT

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

Call for proposals (funders) Number of proposals Number of projects selected submitted (% 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 186 192 37 (20%) pending 20.14 pending Cancer Research (DGOS) PRME-K Programme for Medico- 16 10 4 (25%) pending 1.46 pending Economic Cancer Research (DGOS) PRIORITE Tabac Programme on tobacco- related cancers (INCa-ARC Foundation- NA 21 NA 7 (33%) NA 3.52 LNCC) PRT -K Programme for Translational 162 153 21 (13%) pending 8.45 pending Research (INCa-DGOS) Training in Translational Research 101 115 25 (25%) 29 (25%) 2.11 2.01 (Inserm) Human and Social Sciences, Epidemiology 66 86 17 (26%) 16 (18%) 4.27 3.51 and Public Health (INCa) Population Health Intervention Research 29 22 7 (24%) pending 1.07 pending (INCa) Epigenomics (Inserm) 45 NA 10 (22%) NA 4.57 NA Physics, Mathematics, Engineering 79 67 15 (19%) 13 (19%) 4.94 5.02 Sciences and Cancer (Inserm) 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) Research Cancéropôles* 7 Multidisciplinary 2011 & 2015 7.35 coordination Tumour biobanks** 58 Biology Research tools 2004 12.6 Biological and clinical databases 14 Translational Research tools 2011, 2012 & 2013 1.24 Research SIRIC* 8 Multidisciplinary 2011 & 2012 15.23 programmes Clinical research & Molecular genetics centres 28 Infrastructures 2006 24.51 Care Research Cooperative intergroups* 13 Clinical research 2012, 2013 & 2014 0.69 coordination Research CLIP²* 16 Clinical research 2010 & 2015 2.73 programmes 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) FRENCH NATIONAL CANCER INSTITUTE 31 2015-2016 SCIENTIFIC REPORT

1SUPPORT IN BIOLOGY AND BASIC SCIENCES 1 FOR CANCER RESEARCH Research focused on cancer biology helps to increase the tends to be consistent with the recommendations of the INCa’s basic knowledge of oncogenesis, and of the development SAB and international standards. In 2016, overall funding for and progression of cancer. The understanding of biological the 38 selected projects is €20.30M. mechanisms opens up new prospects for advances in treatment, inhibition of resistance mechanisms and the development of Table 3. Features of the programme Biology and Basic tools through the establishment of projects involving physics, Sciences for Cancer Research mathematics or information technology. To acquire new knowledge and develop In order to promote and support this progress in the long term, new tools to create new therapeutic INCa launches a recurrent call for proposals, focussed on cancer approaches. biology and basic sciences, and completed by thematic CFPs Open to all areas of cognitive research programmed by ITMO Cancer-Aviesan in order to strengthen and to scientific disciplines involved in tumour biology research, this call has the new areas of research. Objectives been launched to: Because of the evolution of cancer research trends and the ••enable the achievement of original growing number of multidisciplinary projects submitted to projects; the ITMO Cancer-Aviesan programmes, the Systems biology, ••strengthen multidisciplinary Epigenome and Cancer (section 1.1.3 and 1.2.2, respectively) and collaborations; Research in Physics, Mathematics and Engineering sciences related ••develop research in emerging areas. to cancer (section 1.1.2) CFPs were merged to launch a new call Programming INCa for proposals dedicated to functional tumour heterogeneity and institution the tumour microenvironment. Operating institution INCa 1.1. RESEARCH PROGRAMMES Funding institution INCa 1.1.1. BIOLOGY AND BASIC SCIENCES FOR CANCER Year 2015 2016 RESEARCH PROGRAMME (PLBIO) Funding (in €M) 17.21 20.30 Since 2005, INCa has issued to the French scientific community an investigator-driven call for proposals for the funding of original Proposals submitted 267 281 and promising projects in different areas and disciplines of Projects selected 34 38 cognitive research in oncology. This annual call for proposals represents approximately 30% of the total expenditure on Selection rate 12.7% 13.5% investigator-driven calls for proposals every year. To comply with the objectives of the CFP, nearly 90% of the The programme in 2016 projects funded aim to study the biological mechanisms of In 2016, 38 projects were selected from the 281 proposals cell transformation and disease progression, according to the submitted. The selection rate is approximately 13.5%, which international CSO classification1 (Figure 1).

1 – The detailed description of the CSO classification is presented in Appendix 2 FRENCH NATIONAL CANCER INSTITUTE 32 2015-2016 SCIENTIFIC REPORT

Fig. 1. Distribution of selected projects for the Biology Fig. 2. Detailed analysis of the distribution of funded projects and Basic Sciences for Cancer Research programme in for the Biology and Basic Sciences for Cancer Research 2016 according to the CSO classification programme in 2016

% % 7 5.3 Systemic Therapies - 4 Discovery and Development Treatment 2.1 Exogenous Factors Biology in the Origin and Cause of Cancer Aetiology Aetiology Prevention 1.5 Resources Early detection,Biology diagnosis, and Infrastructure and prognosisAetiology TreatmentTreatment 1.4 Cancer Progression and Metastasis Cancer control Scientific models 1.3 Cancer Initiation: Oncogenes and Tumour Suppressor Genes 89% Biology 1.2 Cancer Initiation: Alterations in Chromosomes 1.1 Normal Functioning 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). The programme over the 2007-2016 period Approximately 28% of these study oncogenes, tumour suppressor Since 2007, 345 projects have been selected from the genes and signalling pathways involved in cell proliferation and 2,268 proposals submitted to the cancer biology research cell transformation (CSO 1.3), whereas 21% of the funded programme, for a total budget of €165.18M (Table 4). projects focus on processes linked with the development and spread of cancer, and the interaction between the tumour The number of letters of intent (LoI) submitted in 2016 remains and its microenvironment (cell mobility, tumour invasion, very high (281). This is the Institute’s most attractive programme metastasis, cancer stem cells, immunological microenvironment, in terms of number of applications. These observations lead to or angiogenesis, CSO 1.4). two conclusions: •• This programme is fulfilling its goals, namely by supporting The second area of interest in the CSO classification deals with research in a number of diverse areas in cancer-related basic treatment. As such, 6.6% of projects study either molecular sciences; mechanisms of response and resistance to treatments, or •• INCa is consolidating its position as a major funding agency identification of new therapeutic targets (CSO 5.3). for cancer-related research programmes, alongside the French National Research Agency (ANR), which funds basic research Finally, it is interesting to note that nearly 13% of the projects (cancer excluded). 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. FRENCH NATIONAL CANCER INSTITUTE 33 2015-2016 SCIENTIFIC REPORT

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

100% 2007 2008 80% 2009 60% 2010 2011 40% 2012 2013 20% 2014 2015 0% 2016 CSO1 CSO2 CSO3 CSO4 CSO5 CSO6 CSO7 Biology Aetiology Prevention Early detection, Treatment Cancer control Scientific diagnosis and Survivorship models and prognosis

60% 2007 50% 2008 2009 40% 2010 30% 2011 2012 20% 2013 10% 2014 2015 0% 2016 1.1 Normal Functioning 1.2 Cancer Initiation: 1.3 Cancer Initiation: 1.4 Cancer Progression 1.5 Resources Alterations in Oncogenes and Tumour and Metastasis and Infrastructure Chromosomes Suppressor Genes FRENCH NATIONAL CANCER INSTITUTE 34 2015-2016 SCIENTIFIC REPORT

The distribution of the projects among the various sub-categories as the identification of new mechanisms and regulators involved in the biology section has changed since 2007, especially in the in the fine-tuning of gene expression. Moreover, gene regulation CSO 1.2 section (Cancer initiation: alterations in chromosomes), is a dynamic and competitive field. dedicated to gene expression regulation. Indeed, it can be noted that the proportion of projects studying DNA repair mechanisms, An in-depth analysis highlights that this increase is related epigenetic regulation and microRNA-dependent regulation of to the projects focussing on chromatin stability (DNA repair transcription has increased over the years. This trend can be mechanism, replication regulation, chromosomal translocation linked with the proliferation of tools available for carrying out and remodelling, etc.) (Figure 4). this type of research, such as gene expression profiling, as well

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

35 2007 2008 30 2009 2010 25 2011 2012 20 2013 2014 15 2015 2016 10

5

0 Chromatin stability Gene expression

ienetics

2016201520142013201220112010200920082007 FRENCH NATIONAL CANCER INSTITUTE 35 2015-2016 SCIENTIFIC REPORT

The gene expression projects have been relatively stable over the Studies related to the development and progression of cancer, years. Of these projects, the proposals that study epigenetics based on interactions with the tumour microenvironment (mainly mechanisms present an interesting profile. Indeed, the number of on the regulation of processes in tumour invasion, metastasis, projects has increased over the years. The launch of the dedicated angiogenesis and immune microenvironment) also remain programme for epigenetics (section 1.2.2) made it possible to strongly represented (CSO 1.4). The profile seems relatively stable address the needs within this research field, then the percentage over the years but in-depth analyses show that the study topics of epigenetics projects decreased. In 2016, the increase observed vary over time. Interestingly, a further analysis of these projects in the framework of the PLBIO is most probably due to the highlights that the projects focussing on invasive process and discontinuation of this dedicated research programme. metastatic progression have increased over time (Figure 5).

Moreover, French epigenetic research is particularly strong, In 2016, ITMO Cancer-Aviesan launched a specific call for offering of a wealth of prospects, and many teams have been proposals addressing these issues (section 1.1.4) and this may established in this field in recent years. With the United Kingdom, explain the slight decrease observed this year. France ranks first in Europe for research in epigenetics. These observations confirm the complementarity between the Projects studying tumour suppressor genes, oncogenes investigator-driven PLBIO and the ITMO Cancer-Aviesan thematic and signalling pathways involved in cell transformation programmes in addressing the needs of cancer research. and cell proliferation have been relatively stable over the 2007-2016 period (CSO 1.3).

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

25% 2007 2008 20% 2009 15% 2010 2011 10% 2012 2013 5% 2014 2015 0% 2016 Apoptosis Immune microenvironment Metabolism Angiogenesis Stromal interaction Invasive process

Finally, the number of projects focussing on early cancer detection and cancer treatment has decreased steadily since the Institute Highlights launched a call for proposals dedicated to translational research (CSO 4 and CSO 5). However, it should be important to note In 2016, 38 projects funded out of the 281 proposals that the projects in the CSO 5.3 section are specifically directed submitted for a total budget of €20.30M. at understanding molecular mechanisms of action and resistance, the characterisation of molecular signatures of treatment response, and the identification of new druggable targets. FRENCH NATIONAL CANCER INSTITUTE 36 2015-2016 SCIENTIFIC REPORT

1.1.2. PROGRAMME FOR RESEARCH IN PHYSICS, In 2016, the wording of the call for proposals was amended to MATHEMATICS AND ENGINEERING SCIENCES promote radio-physics and radiotherapy issues and to exclude RELATED TO CANCER studies addressing the tumour microenvironment, as they Initiated in 2011, this programme aims to bolster multidisciplinary are covered by the new tumour heterogeneity and ecosystem partnerships to provide a different point of view and a different programme (section 1.1.4). Finally, 67 proposals were submitted way to tackle the understanding of cancer progression and to and 13 projects were selected for a total amount of €5.02M. improve the detection, diagnosis and management of the disease. Several projects study nanoparticles to prevent cancer cell Table 5. Features of the programme for Research in physics, migration, to target cancer cells or to measure the absorbed mathematics and engineering sciences related to cancer dose and the biological effects of irradiated tissues.

To attract physicists, mathematicians Other projects address new physics-based approaches: and engineers to cancer research in •• To develop and to characterise non-linear endomicroscope Objectives order to improve the understanding, prototypes to minimise invasive oncology surgery; diagnosis or therapeutic management of •• To improve hadron therapy protocols; cancer. •• To reduce the number of images per patient without impairing Programming the accuracy of dosimetry, to minimise constraints on patients ITMO Cancer-Aviesan institution receiving radioimmunotherapy; Operating institution Inserm •• To develop preclinical imaging devices that simultaneously acquire positron emission tomography (PET) and ultrafast Funding institution Inserm for ITMO Cancer-Aviesan ultrasound images (UUI) or that allow retrieval of dynamic Year 2015 2016 aspects (oxygen and blood saturation) in addition to localised images; Funding (in €M) 4.94 5.02 •• To model numerically the effect of electroporation-based Proposals submitted 79 67 therapies and their biological effect on tumours. Projects selected 15 13 Over the 2011-2016 period, 97 projects have been funded in Selection rate 19% 19% 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 As confirmed by the analysis of the funded projects with the CSO projects whose scientific outcomes would have major medical classification, the studies mainly focus on the development of new impact by improving the diagnosis and monitoring of anticancer tools dedicated to localised therapies and the development of therapy response. In addition, they help involve physicists and technologies for cancer detection, staging, diagnosis, theranostics engineers in cancer research. and/or prognosis. FRENCH NATIONAL CANCER INSTITUTE 37 2015-2016 SCIENTIFIC REPORT

Fig. 6. Distribution of the selected projects according to the 1.1.3. PROGRAMME FOR RESEARCH IN SYSTEMS CSO classification over the 2011-2016 period BIOLOGY FOR CANCER Systems biology research is a priority set out in the 2009- 2013 Cancer control plan, and a first call for proposals was % 15 % 10 launched in 2012, programmed by ITMO Cancer-Aviesan in close 1% collaboration with INCa. In 2016, this programme was not renewed since it was replaced Biology by the call for proposals dedicated to the tumour heterogeneity Aetiology and ecosystem that also addresses systems biology (section 1.1.4). Early detection, diagnosis, prognosis 27% Table 7. Features of the systems biology programme in Treatment 2014 and 2015 Scientific models Support upstream multidisciplinary research (mathematics, physics, chemistry, information technology, Objectives 47% biology etc.), in order to progress to the modelling of complex processes or integral biology in the area of cancer. Programming institution ITMO Cancer-Aviesan Operating institution Inserm Funding institution Inserm for ITMO Cancer-Aviesan Year 2014 2015 Funding (in €M) 2.95 4.41 Proposals submitted 24 35 Projects selected 6 7 Selection rate 25% 20% FRENCH NATIONAL CANCER INSTITUTE 38 2015-2016 SCIENTIFIC REPORT

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 involved in tumour dynamics, metabolic remodelling, cancer cells 102 applications submitted to this multidisciplinary programme mobility and metastatic spread and the multilevel nature of the for a total amount of €11.60M. immune microenvironment.

The analysis of the projects according to the CSO classification The projects also address computer-assisted modelling of the shows that the funded projects mainly focus on biology and response of tumour cells to therapeutic strategies and the the development of specific scientific models, particularly on development of new technologies and the identification of novel computational modelling of gene expression and signalling biomarkers for early detection. pathways involved in cancer initiation, deciphering the networks

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

14%

5% Normal Functioning % Cancer Initiation: Biology 12 Alterations in Chromosomes Early detection, % Cancer Initiation: Oncogenes 21% diagnosis, prognosis 53% 9 and Tumour Suppressor Genes Treatment 10% Cancer Progression Scientific models and Metastasis 17% Resources and Infrastructure

12%

Highlights 2012-2015:

21 projects selected for a total amount of €1.60M in the framework of the Systems biology programme. FRENCH NATIONAL CANCER INSTITUTE 39 2015-2016 SCIENTIFIC REPORT

1.1.4. TUMOUR HETEROGENEITY AND ECOSYSTEM Table 9. Features of the tumour heterogeneity and ecosystem PROGRAMME programme The 2014-2019 Cancer control plan and INCa’s Scientific Advisory Board strongly supports the priority of basic understanding of To promote the implementation of a the tumour ecosystem. critical mass in terms of resources and skills to conduct research projects of an In this context, ITMO Cancer-Aviesan, in collaboration with interdisciplinary nature in an integrated way in the field of heterogeneity Aviesan’s Cell Biology, Development and Evolution Institute Objectives (ITMO BCDE) and Aviesan’s Health Technologies Institute of tumour cells in their ecosystem, (ITMO TS) launched, in 2016, a programme to fund research requiring cooperation between projects in the field of tumour cell heterogeneity and cell teams from the fields of cell biology, relationships in their ecosystem. mathematical modelling, genetics and (epi) genomics, mechanobiology. As mentioned previously, this CFP is intended to address the issues Programming ITMO Cancer-Aviesan of the Epigenome and Cancer, Systems Biology programmes institution and the modelling and mechanobiology aspects of the Physics, Operating institution Inserm Mathematics and Engineering sciences related to cancer CFP. Funding institutions Inserm for ITMO Cancer-Aviesan The objectives of the Tumour heterogeneity and ecosystem Year 2016 programme are to promote the implementation of a critical mass in terms of resources and skills to conduct research Proposals submitted 73 projects of an interdisciplinary nature which require cooperation between national teams from different thematic fields such as cell Projects pre-selected 27 biology, mathematical modelling, genetics and (epi) genomics, and mechanobiology in an integrated way. It covers both fundamental and translational aspects, and takes into account For the first edition, 73 letters of intent were submitted and that the developments of new therapeutic strategies are needed 27 were pre-selected, including proposals from 5 individual considering tumour heterogeneity to elaborate truly effective teams. The latter are specialised in developing multicontrast personalised or targeted medicine. magnetic resonance image acquisition methods tailored to the accurate quantification of tumour heterogeneity with robust Prior to the launch of this programme, ITMO Cancer-Aviesan texture analysis, Magnetic Resonance Histology, or studying the determined the French strengths and the unmet needs in this deregulated mechanisms on the supportive signals emanating field. This study shows that about 300 teams ranging from from the microenvironment of leukaemia-initiating cells. biology, mathematics, bioinformatics and clinicians express their interest in meeting for the programme. The structuring of Following on from the scientific evaluation committee, a the communities involved took place several months prior to the dedicated workshop was organised to promote the establishment deadline for submission, to ensure that multidisciplinary networks of multidisciplinary networks, where the pre-selected investigators could be set up to apply. For this purpose, ITMO Cancer-Aviesan met before the complete project submission, as per committee publicised the new programme and met the different teams at recommendations. Around 185 business-to-business meetings the regional level through the different Cancéropôles. 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. FRENCH NATIONAL CANCER INSTITUTE 40 2015-2016 SCIENTIFIC REPORT

1.2. THE GENOMIC AND THE EPIGENOMIC are of clinical and societal importance across the globe and PROGRAMMES make the data available to the entire research community as 1.2.1. THE ICGC PROGRAMME quickly as possible, and with minimal restrictions, to accelerate The International Cancer Genome Consortium (ICGC) was research into the causes and control of cancer. As of December established in 2008 to bring together researchers worldwide 2015, the consortium had received commitments from funding to comprehensively analyse the genomic, transcriptomic and organisations in Asia, Australia, Europe North and South America epigenomic changes in different tumour types or subtypes that for 85 projects (Figure 8).

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

INCa and ITMO Cancer-Aviesan support the French involvement •• Prostate Cancer project launched in 2011, directed by Prof in the programme: Olivier Cussenot; •• Liver project launched in 2008, directed by Prof Jessica •• Ewing Sarcoma project launched in 2012, directed by Prof Zucman-Rossi; Olivier Delattre; •• Breast cancer project launched in 2008, directed by Dr Alain •• Retinoblastoma project launched in 2013, directed by Viari and Prof Gilles Thomas (†); Dr François Radvanyi; FRENCH NATIONAL CANCER INSTITUTE 41 2015-2016 SCIENTIFIC REPORT

•• Gynaecological Carcinosarcoma project launched in 2013, signature analysis was extended to genome rearrangements directed by Prof Alain Puisieux; and revealed 12-base substitution and six rearrangement •• Leiomyosarcoma project launched in 2013, directed by signatures. Three rearrangement signatures, characterised by Dr Frédéric Chibon; tandem duplications or deletions, appear to be associated with •• Prolymphocytic B-cell leukaemia project launched in 2014, defective homologous recombination-based DNA repair: one directed by Dr Olivier Bernard. with deficientBRCA1 function; another with deficientBRCA1 or The retinoblastoma, gynaecological carcinosarcoma, BRCA2 function; the cause of the third is still unknown. leiomyosarcoma and prolymphocytic B-cell leukaemia projects are part of the rare tumours programme. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer Focus on Breast programme results genes and mutational processes in operation, and progresses The first paper on the 560 breast cancer whole genomes generated towards a comprehensive account of the somatic genetic basis and analysed under the auspices of the ICGC Breast Cancer of breast cancer. Working Group has been published in Nature (May 2016), co- signed by Gilles Thomas and Michael Stratton1. There has been a major French contribution to this programme, fully funded by the INCa, focussed on HER2-positive tumours. This publication is the result of an international and HER2-positive breast cancer has long proven to be a clinically intercontinental project and a substantial scientific and logistic distinct class of breast cancers for which several targeted achievement. It represents the clear fruition of the vision for therapies are now available. However, treatment resistances, cancer genomes articulated by the ICGC in Toronto in 2007 and associated with specific gene expressions or mutations, have illustrates perfectly all the benefits of international collaboration been observed, revealing the underlying diversity of these cancers that genome projects have induced over the last 25 years. Indeed, and understanding the full extent of HER2-positive disease it currently represents the largest number of whole genome heterogeneity is still a challenge. sequences of any cancer type. The work will stand as a milestone in the somatic genetics of breast cancer, since essentially the In the first French paper, published inNature Communications2, an whole genome has now been covered and all types of mutation in-depth genomic characterisation of 64 HER2-positive breast have been analysed in a substantial number of cases, covering tumour genomes was carried out that exhibited 4 subgroups with all subtypes, supported by expression and methylation studies distinctive genomic features (in terms of somatic mutations, copy and addressing the major questions that can be elucidated by number changes or structural variations) and based on expression genetics. The results will continue to be analysed for many years data. The figure 9 shows that, in addition to HER2 amplification, and will undoubtedly yield further insights. the tumours harbour different genetic characteristics leading to the 4 sub-categories identified. This study suggests that, despite The results show that 93 protein-coding cancer genes carried being clinically defined by a specific gene amplification,HER2 - likely driver mutations, including 5 new identified genes. Some positive tumours merge with the whole luminal-basal breast non-coding regions exhibited high mutation frequencies but most cancer spectrum rather than standing apart. Moreover, these have distinctive structural features probably causing elevated results lead to a refinedERBB2 amplicon of 106kb. mutation rates and do not carry driver mutations. Mutational

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/nature17676 2 – 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 FRENCH NATIONAL CANCER INSTITUTE 42 2015-2016 SCIENTIFIC REPORT

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

RNA.C RNA.A RPS6KB1.A

CCND1.A PR.NEG SV17.H TP53.WT ER.NEG FGA.L mLum.L LST.L Her2

0.0 0.5LumB 1.0 LST.H pLum.L ER.POS mLum.H pLum.H

Axis_2 12% PR.POS SV17.L TP53.M Basal FGA.H RNA.D –0.5

RNA.B –1.0

–1.0 –0.5 0.0 0.5 1.0 1.5

Axis_1 74%

This map has a simple geometrical interpretation: a category is By way of example, patient points have been linked with the plotted at the centre of gravity of the patient points for those RNA group that they belong to (grey ellipses). Therefore, the patients that choose that category (conversely, at a scaling factor, proximity of two categories suggests that they are chosen by a patient points are located at the centre of gravity of categories similar set of patients. they choose). FRENCH NATIONAL CANCER INSTITUTE 43 2015-2016 SCIENTIFIC REPORT

Focus on Retinoblastoma programme results 1.2.2. EPIGENOME AND CANCER PROGRAMME Retinoblastoma is the most common intraocular paediatric Launched in 2013 and managed by ITMO Cancer-Aviesan in close cancer with an incidence of one case per 15,000–20,000 live collaboration with INCa, this programme aims to decipher the births. Most patients are diagnosed before the age of five years. epigenetic mechanisms associated with cancer. As mentioned In high-income countries, patients have an excellent prognosis. previously, this programme was not renewed in 2016 because However, in the majority of cases, enucleation of the affected it was merged with other programmes to form the tumour eye has to be performed. In middle and low-income countries, heterogeneity and ecosystem programme (section 1.1.4). retinoblastoma is still a deadly disease. An early event in retinoblastoma genesis is the functional loss of both alleles of Table 10. Features of the Epigenome and cancer programme the RB1 gene. However, other genes are likely to be involved in the development of this cancer. Promote the critical mass and skills to decipher the epigenetic mechanisms This project is aimed at identifying additional events that lead associated with cancer, based especially on developments of the production of to retinoblastoma development, whether they are genetic or Objectives epigenetic. Using transcriptome data, the first results show that high-quality reference epigenome maps, two different tumour subtypes exist in retinoblastoma, cone-like to pave the way for innovative ideas to tumours and bivalent tumours that present both cone-like and unravel the processes related to tumour ganglion-like cell characteristics. Additionally, genomic alteration development and recurrence. analysis and exome sequencing show that bivalent tumours Programming ITMO Cancer-Aviesan present higher genomic instability and coding mutations than institution cone-like tumours. Moreover, methylome analyses also allow Operating institution Inserm the differentiation of cone-like and bivalent-type tumours since Funding institution Inserm for ITMO Cancer-Aviesan the latter are hypomethylated. Year 2013 2014 2015 These first results demonstrate that retinoblastoma is a Funding (in €M) 4.15 4.61 4.57 heterogeneous disease and have been submitted for publication. Proposals submitted 30 34 45 Projects selected 11 12 10 Selection rate 36% 35% 22%

Launch of the ICGCmed Programme The International Cancer the end of 2025 and linking this data to high-quality clinical Genome Consortium for information including treatment information and outcomes. Medicine (ICGCmed) Using these large-scale integrated data, researchers, scientists, aims to link the wealth policy-makers and clinicians will be able to work with patients, of genomic data already healthcare providers and others to develop preventative amassed, as well as new genomic data being generated, strategies, markers for early detection of disease, more to clinical and health information, including lifestyle, specific criteria and methods for diagnoses and prognoses, patient history, cancer diagnostic data, and response to and and interventions based on matching the patient’s disease survival following therapies, across the cancer spectrum. molecular subtype with the most effective combinations As a worldwide consortium, ICGCmed has the research and of therapies. organisational expertise to implement the ambitious project More information available on ICGCmed website: of analysing the genomes of more than 200,000 patients by http://icgcmed.org/ FRENCH NATIONAL CANCER INSTITUTE 44 2015-2016 SCIENTIFIC REPORT

Since 2013, 33 proposals have been selected for a total amount Moreover, it is interesting to note that the projects are technically of €13.33M. innovative and present multidisciplinary approaches by combining high-throughput epigenomic screening, bioinformatics, in The projects mainly address the epigenetic mechanisms leading vivo studies and in cellulo approaches. For example, the NGS to oncogenesis and tumour progression in order to identify or to approach is used to characterise the methylome landscape for decipher cancer development mechanisms (78%). The analysis of different processes such as chromatin remodelling in the tumour the funded projects based on the CSO classification highlights microenvironment, cancer-induced inflammation, or B and T-cell that the projects also address the epigenetic mechanisms differentiation in leukaemia. 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).

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

4 % 3 %

Biology % Aetiology 6 Prevention 7% Cancer progression and Metastasis Early detection, diagnosis, and prognosisBiology Cancer initiation: Oncogenes and TreatmentAetiology 93% Tumour Supressor Genes Cancer controlTreatment 78% Scientific models Cancer initiation: Alterations in Chromosomes Normal functioning 2%

Highlights

2013-2015: 33 projects selected for a total amount of €13.33M in the framework of the Epigenome and cancer programme. FRENCH NATIONAL CANCER INSTITUTE 45 2015-2016 SCIENTIFIC REPORT

2TRANSLATIONAL AND INTEGRATED 2 RESEARCH Translational research in oncology aims to bridge the gap between Table 11. Features of the PRT-K programme basic research and clinical research in order to translate scientific progresses into products and procedures that benefit patients. To hasten the transfer of knowledge with a view to its prompt application In line with the previous Cancer control plans, translational in clinical practice for the benefit of research receives significant support through dedicated calls for patients, by giving researchers an incentive to develop multidisciplinary proposals, programmes to strenghten training in this research Objectives field and a policy of designated multidisciplinary integrated projects in close collaboration with research sites. clinical players, in order to improve prevention, early detection, diagnosis, 2.1. RESEARCH PROGRAMMES AIMING treatment and comprehensive care of TO ACCELERATE CROSS‑DISCIPLINARITY cancer patients. AND TRANSFER OF KNOWLEDGE Programming INCa/Ministry of Health (DGOS) TO CLINICAL PRACTICE institution Alongside the national investigator-driven CFP operated by INCa, Operating institution INCa integrated and thematic programmes have been set up such as Funding institution INCa/Ministry of Health (DGOS) the programme dedicated to tobacco-related cancers and the integrated actions programme dedicated to specific pathologies, Year 2015 2016 in partnership with other agencies and charities. The support to 8.45 translational research has also been extended since 2012, on a Funding (in €M) INCa: 5.58 Pending European level in the context of coordinated actions against DGOS: 2.86 cancer, particularly through the TRANSCAN network. Proposals submitted 162 153 2.1.1. THE TRANSLATIONAL RESEARCH PROGRAMME Projects selected 21 Pending (PRT-K) Selection rate 13% Pending 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 Unlike the 2014 selection which included a large spectrum of projects, bringing together laboratory researchers and clinicians. studied tumour types (including adrenal tumours and uveal Sharing of specific expertise, skills and knowledge should promote melanoma, for example), the 2015 selection is more focussed the translation of scientific and medical discoveries into clinical on high-incidence cancers (breast, ovarian, colorectal, lung, advances for cancer patients. liver, prostate, leukaemia) and includes projects using innovative technologies such as proton minibeam radiation therapy, In 2015, 21 projects were selected for funding representing a targeted drug delivery with ultrasound and microbubbles and global budget of €8.45M (€5.6M INCa + €2.9M DGOS). In immunotherapy using CAR-T cells. One project focuses on 2016, 153 letters of intent were received and 46 pre-selected medulloblastoma which is a tumour appearing predominantly in for the full proposal step. children. It is also noteworthy that 2 projects address survivorship issues, one on fertility preservation and the other on risk of second cancer. FRENCH NATIONAL CANCER INSTITUTE 46 2015-2016 SCIENTIFIC REPORT

Since 2007, 1,030 proposals have been submitted in response Fig. 12. Distribution of the selected projects to the to this call for proposals, and 149 have been selected and Translational Research Programme since 2007 funded for a total amount of €59.9M (2016 results not included, final selection in progress). The overall selection rate for this call 2% 2% for proposals is 14.5% (Figure 11). 13% Fig. 11. Trends in selection for the Translational Research Programme12 over the 2007-2015 period 30 26% BiologyBiology AetiologyAetiology 10% 10 25 PreventionPrevention EarlyEarly detection, detection, diagnosis,diagnosis, andand prognosis prognosis 8 20 TreatmentTreatment CancerCancer control control Scienti cScientific models models 6 15 Nb of projects Funding in €M 4 10 47 % 2 5

0 0 20152014201320122011201020092007 Highlights

Funding in €M 2015: 21 projects funded for a total amount Nb of projects of €8.45M 2016: 153 proposals submitted

The CSO typology of the projects funded since 2007 corresponds to the characteristic profile for translational research (Figure 12), 2.1.2. THE EUROPEAN TRANSLATIONAL CANCER especially allocated to two main categories of research projects: RESEARCH PROGRAMME •• projects that involve the development of techniques for early The ERA-Net TRANSCAN-2 is pursuing its now well-established detection, diagnosis, prognosis using biomarkers (genetic, coordination mandate of translational cancer research funding biological, immunochemical, microbiological); across Europe, with the involvement of 29 funding agencies and •• projects based on the improvement of patient care thanks ministries from 15 Member States, 3 Associated Countries, and to the development of new therapeutic strategies and to the a third country (Taiwan). With the support of the European understanding of mechanisms of treatment resistance. 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. FRENCH NATIONAL CANCER INSTITUTE 47 2015-2016 SCIENTIFIC REPORT

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

Call steps Global for TRANSCAN-2 Outcomes for France 93 French research teams involved in 73 LoI Eligibility 117 LoI 19 LoI with French coordination 26 French research teams involved in 20 LoI 1st step: LoI selection 33 LoI selected 6 LoI with French coordination 16 full proposals selected, including 13 French teams in 11 projects 2nd step: full proposals selection 85 research teams 2 projects with French coordination Selection rate 13.7% 15.1% €3.08M shared as follows: ••€2.1M (INCa’s budget including €0.58M of €17.2M (Global Budget, including €4M of co‑funding from the European Commission) Funding 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 partnership programme in order to establish research and immunology and immunotherapy of cancer: strengthening the actions priorities on tobacco and tobacco-related cancers. translational aspects. The selection process is ongoing. Fourteen This programme is part of the 2014-2019 Cancer control plan letters of intent have been selected out of the 33 submitted. The and is linked with the “French National Programme to Reduce next and final selection step will proceed in September 2016. Smoking” (PNRT).

2.1.3. RESEARCH AND ACTION PROGRAMME Three CFPs, focussing on cancers related to tobacco and its TO REDUCE SMOKING AND CHANGE CURRENT components, are scheduled during the Cancer control plan PREVALENCE OF TOBACCO-RELATED CANCERS (2015, 2016 and 2018). The objective of the CFPs is to cover (PRIORITE TABAC) a wide range of disciplines, from basic and clinical science to Smoking remains the leading avoidable risk factor for cancer public health, via information and communication technologies, in France. The latest estimate of the number of cancer deaths economics and political science, sociology, law, biology and attributable to tobacco in France is approximately 44,000, not epidemiology. including cancers associated with passive smoking. Tobacco is the primary causal factor for 80% of deaths from lung cancer, The CFPs are also intended to promote intervention research and is associated with an increased risk in 17 other types of projects on this topic, and welcome studies on specific cancer (especially bladder, pancreas, urinary and kidney, stomach, populations including women, teenagers and young adults and cervical, etc.). vulnerable populations. Social, economic, cultural and spatial inequalities should also be considered as cross-cutting topics Despite a large number of initiatives launched in recent years, for all research areas. the prevalence of smoking in France remains high compared with other developed countries. More than 30% of 15-75 year For each edition, the areas will be updated based on projects olds smoke daily in France, i.e. 13 million people, whereas this that have been supported, advanced research in this field and figure is 19% in Great Britain, below 20% in the United States, to address the research gaps identified. and 16% in Australia. The first edition, launched in 2015, presents 5 areas: In this context, INCa, in collaboration with other agencies, •• Area 1: Determinants and trajectories of smoking; ministries and research teams, has set up a multidisciplinary •• Area 2: Consumer and stakeholder behaviours; FRENCH NATIONAL CANCER INSTITUTE 48 2015-2016 SCIENTIFIC REPORT

•• Area 3: Electronic nicotine delivery systems (electronic The other project hypothesises that it is possible to identify a cigarettes); limited panel of risk biomarkers and develop a lung cancer risk •• Area 4: Smoking cessation in cancer patients; prediction model that substantially improves existing models •• Area 5: Screening for tobacco-related cancers and innovative in identifying those subjects that are most likely to benefit from research on new screening methods. screening.

This first session led to the selection of 7 projects for funding A translational approach on rodents was also selected by the among the 21 proposals submitted and the selection rate is 33%. committee. Indeed, this study assumes that in the context of The total amount of funding is €3.52M, including €1M allocated the study of chains of causes and trajectories of smoking (i.e. by the charities ARC Foundation for Cancer Research (ARC factors related to starting and stopping smoking, and the role of Foundation) and the National Cancer League (LNCC). inequalities, including social inequalities and social determinants), animal models can help in understanding the mechanisms that Fig. 13. Distribution of the selected projects according underlie vulnerability to addiction. This project will generate to the CSO classification 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 7% cancers.

Two projects focus on electronic cigarettes (e-cig). The first aims to describe the e-cig and smoking trajectories in the Constances Biology 21% cohort. The second project addresses the nature and impact AetiologyBiology of e-cig messages on youth during the formative teenage years PreventionPrevention Early detection, diagnosis, (13-17). andEarly prognosis detection, Treatmentdiagnosis, prognosis Two integrated smoking cessation programmes for patients with 43% CancerCancer control control HNSCC may start in the next months. These patients represent a Scientific models 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 29 tobacco cessation programme. The proposed interventions are also intended to help reduce the side effects of surgery and/or The analysis the projects selected according to the CSO typology radiotherapy. 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. FRENCH NATIONAL CANCER INSTITUTE 49 2015-2016 SCIENTIFIC REPORT

Table 13. Distribution of the projects submitted and selected 2.1.4. THE INTEGRATED RESEARCH ACTION by area PROGRAMME: PAEDIATRIC PAIR Since 2007, INCa has launched an annual thematic programme Submitted Selected dedicated to a specific pathology, the Integrated Research Action projects projects Programme (PAIR). Area 1: Determinants and 5 2 trajectories of smoking The 2014-2019 Cancer control plan has made paediatrics one Area 2: Consumer and stakeholder of its cross-cutting priorities. In order to further improve access 2 0 behaviours to innovation and research for children, adolescents and young Area 3: Electronic nicotine delivery adults, several actions have been drawn up by INCa, since 2014. 3 1 systems (electronic cigarettes); Area 4: Smoking cessation in Among these actions, INCa, ARC Foundation and LNCC propose 5 2 cancer patients a PAIR dedicated to childhood, adolescent and young adult cancer, scheduled for 2016. Area 5: Screening for tobacco- related cancers and innovative 6 2 This programme intends to elucidate childhood cancers and research on new screening methods improve their care based on fundamental and translational research integrating all fields, including biology, epidemiology, and human and social sciences. This programme should also Focus in the fight against offer an opportunity to bolster integrated paediatric research smoking and to develop and to strengthen research in emerging areas. The writing of the call for proposals has involved a After Australia in 2012, plain packaging on cigarette packs multidisciplinary committee, in close partnership with parents arrived in France in May 2016. The Institute has played a key and patient representatives. 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 The Paediatric PAIR in France, and actively participated in disseminating this workshop information especially to parliamentarians. The Institute continues its efforts in combating smoking Organised in April 2016 in collaboration with ARC by funding the evaluation of the implementation of plain Foundation and LNCC, this national workshop promoted packaging on cigarettes. This study is one of the major discussions around 5 areas: milestones of the PNRT. ••Predisposition and susceptibility; ••From cancer biology to therapeutic innovations, example of acute lymphoid leukaemia; The 2016 edition includes a new area focused on biology of ••New concepts in immunotherapies; tobacco-related cancers. As for the other areas, the priority issues were identified during a workshop gathering several experts in ••Post-cancer: a research topic; this field. ••Expectations of patient associations.

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. FRENCH NATIONAL CANCER INSTITUTE 50 2015-2016 SCIENTIFIC REPORT

2.2. THE TRANSLATIONAL AND Table 14. Features of the 2015-2016 translational research MULTISDISCIPLINARY RESEARCH TRAINING training programme PROGRAMMES Support to translational research is completed by an investment To promote training of students or plan to promote training and career development for the next young medical, pharmacy and veterinary science graduates in translational generation of investigators. Objectives research by funding master’s degrees, Training support in translational research and in interdisciplinary doctoral theses or post-doctoral research is pursued, even increased, in compliance with the SAB research. Programming recommendations. These initiatives are supported by dedicated ITMO Cancer-Aviesan calls for applications in translational research training, in biology institution training for clinicians and in multidisciplinary training through Operating institution Inserm a specific PhD programme. Funding institution Inserm for ITMO Cancer-Aviesan 2.2.1. THE TRANSLATIONAL RESEARCH TRAINING Year 2015 2016 PROGRAMME Funding (in €M) 2.11 2.01 Initiated by INCa in 2007 and continued by ITMO cancer-Aviesan in 2012, this programme aims to facilitate complementary Proposals submitted 101 115 translational research training of graduates of medicine, Projects selected 25 29 pharmacy, dentistry and veterinary science. Selection rate 25% 25%

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. FRENCH NATIONAL CANCER INSTITUTE 51 2015-2016 SCIENTIFIC REPORT

Fig. 14. Distribution of the selected applications according to the degrees over the 2008-2016 period 20 35 30 29 16 22 25 25 28 22 12 17 19 21 17

8

14 Nb of projects

4 7 Number of projects according to the degrees

0 0 2008 2009 2010 2011 2012 2013 2014 2015 2016 Master PhD Post-doc Total

Since 2014, the number of proposals submitted has significantly young clinicians, pharmacists and veterinarians in a cancer increased and highlights the increased interest of students or 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). FRENCH NATIONAL CANCER INSTITUTE 52 2015-2016 SCIENTIFIC REPORT

Fig. 15. Distribution of the selected applications according to This training is also supported by the Bettencourt-Schueller the CSO classification over the 2007-2015 period Foundation.

% The support to this programme aims to promote multidisciplinary 3 training to adapt and to meet the needs of cancer research.

Table 16. Features of the PhD programme Frontiers in Life 27% Sciences in the field of cancer Biology Aetiology % The PhD programme aims at promoting 42 ambitious research projects using a Early detection, Objective diagnosis, prognosis broad range of academic disciplines in Treatment order to understand living systems. Scientific models Programming institution Frontiers in Life Sciences graduate school Operating institution Frontiers in Life Sciences graduate school 23% Funding institution Inserm for ITMO Cancer-Aviesan 5% Year 2015 2016 Funding (in €M) 0.31 0.42 Proposals submitted 4 5 The analysis of the trajectories of the recipients indicates that they continue working in translational research after their training, Projects selected 3 4 suggesting that the programme is meeting its objectives. According to the INCa's SAB recommendations, ITMO Cancer- 2.2.2. SUPPORT FOR TRAINING Aviesan increased in 2016 its support to this programme. Four IN INTERDISCIPLINARY RESEARCH FRONTIERS cancer thesis projects were selected out of the 5 proposals IN LIFE SCIENCES (FdV) submitted. The FdV graduate school recruits students trained in various disciplines (e.g. biology, physics, mathematics, medicine, The projects address complex tumour microenvironment economy, linguistics, etc.) from around the world. This constraints during tumour initiation and progression combining programme is hosted by PRES Sorbonne Paris Cité under the biological, mathematical and physical approaches to model guidance of Paris-Descartes and Paris-Diderot Universities. 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 FRENCH NATIONAL CANCER INSTITUTE 53 2015-2016 SCIENTIFIC REPORT

Since 2010, 17 PhD candidates have received funding, for a total the emergence of resistance to specific therapies (Figure 16). amount of €1.78M. These studies are in line with the scientific evaluation committe recommendations by addressing, for example, the mechanical The analysis of the thesis projects based on the CSO typology properties changes of the extracellular matrix leading to invasion shows that the studies are intended to unravel the fundamental and how physical forces involved in basal membrane removal mechanisms of cancer cell invasion, decipher complex tumour contribute to the invasive process. constraints or to identify new cancer biomarkers responsible for

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

6% 12% 12%

17% Normal functioning Biology Cancer initiation: Early detection, 82% Alterations in Chromosomes diagnosis, prognosis Cancer progression Scientific models 44% and Metastasis Resources and Infrastructure 9%

Highlights

June 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. FRENCH NATIONAL CANCER INSTITUTE 54 2015-2016 SCIENTIFIC REPORT

2.3. STRENGTHENING OF ORGANISATION integrated research programmes, strategically deployed thanks AND INFRASTRUCTURES DEDICATED to the strengths and expertise present. TO TRANSLATIONAL/INTEGRATED RESEARCH IN INTEGRATED CANCER Within the framework of the coordination of this SIRIC RESEARCH SITES (SIRICS) programme, over the 2015-2016 period, INCa organised a In 2011 and 2012, 8 French cancer research sites were designated seminar with SIRIC directors, offering some valuable time for as a SIRIC (Integrated Cancer Research Site) for a five-year discussions and sharing of experience. In addition to presenting period, and have thus become national reference centres for the progress in each SIRIC’s activities, the day was also an cancer research. The budget allocated to this programme opportunity, as it is the case every year, to address specific topics is €64M, funded jointly by INCa, Inserm for ITMO Cancer- or issues. More operational, but equally important, meetings Aviesan and the French Ministry of Health (DGOS). The SIRIC were also arranged with managers to promote further progress programme aims to strengthen the relationship between the in the programmes. various aspects of research (fundamental, clinical, public health, epidemiology, and human and social sciences), by combining a Furthermore, during the 2015-2016 period, many SIRIC teams critical mass of stakeholders (physicians, researchers, engineers, continued to invest in collaboration initiatives between sites caregivers and patients) committed to working according to the with a view to speeding up progress in the research conducted specificities and constraints of translational research. Thus, this (Figure 17). For example, the OSIRIS group (Inter-SIRIC Group programme intends to optimise and speed up the generation for sharing and integration of clinical, biological and genomic of new knowledge and foster the distribution and application data) aims to publish the work conducted on the definition of of this knowledge in standard practice. Each SIRIC has its own clinical, biological and genomic items by the end of 2016.

Fig. 17. Inter-SIRIC working groups

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

January 2014 January 2015 January 2016

In 2015, within the framework of its evaluation role, INCa in conjunction with the financial partners ITMO Cancer-Aviesan organised the mid-term assessment of the 8 designated SIRICs, and DGOS. FRENCH NATIONAL CANCER INSTITUTE 55 2015-2016 SCIENTIFIC REPORT

The international scientific committee in charge of this review The committee also made the following recommendations to congratulated the SIRIC sites for all the research done and SIRICs: recognised the structuring work implemented and the impact of •• To simplify governance structure with the SIRIC management the activities carried out on the quality of the research produced having a strong role; and the dissemination of its findings. The committee encouraged •• To simplify SIRIC programme, platform and activity them to continue their work and initiatives during the second organisation; period, placing particular emphasis on: •• To schedule regular meetings of their respective international •• Strong focus on multidisciplinary approaches in research scientific board; projects; •• To involve patient representatives in disseminating actions •• Development of high-quality projects in human and social and in SIRIC governance and/or the integrated research sciences and public health initiated on the basis of a clear programmes; and ambitious strategy; research in health economics being •• To highlight the added value of SIRIC sites with a view to of particular interest in the context of the development of raising their national and international profile (and more precision medicine; specifically though publications having benefited from •• Reinforcement of dissemination actions (not only in terms of contributions from SIRIC sites); communication of findings but also with a view to transfer •• To promote gender equality for senior positions, wherever to clinical practice); possible. •• Continuation and reinforcement of collaboration projects between SIRICs. 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 Highlights

Qualitative analysis In parallel with this evaluation, the Centre de (SIRIC as structuring processes, as a cognitive Sociologie des Organisations research institute map of ocal, scientific assets and/or as a label) conducted a qualitative analysis. The purpose and according to their local anchoring. of this study was to shed light on the organisational SIRIC management depends strongly on their mechanisms that facilitate or restrict cooperation relationships with some key stakeholders, among within the SIRIC sites and, in particular, links them the local leading scientists and hospital top and exchanges between research and clinical management. Facing strong constraints, their activity. The results of this analysis were reported steering teams promote the creation or reinforcement in September with the SIRICs staff who took part. of platforms, the creation of new organisational The report is summarised below: entities devoted to translational research or SIRICs act as catalysts of local dynamics, and also the recruitment of new profiles, specialised in international dynamics. Although they share some translational research. Two activities appear to be common features, such as a strong involvement key factors to be integrated for SIRIC stakeholders: in internationally hot topics, they vary from one pathology and bioinformatics. However, this another, as regards how stakeholders use them integration is far from self-evident. FRENCH NATIONAL CANCER INSTITUTE 56 2015-2016 SCIENTIFIC REPORT

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

Within the framework of the successive Cancer control plans, •• Clinical validation of the efficacy of innovative health INCa has implemented several actions to support clinical technologies for treatment or diagnosis; research through CFPs, specific programmes to roll out targeted •• Increase of survival; therapies and personalised medicine and the setting up of specific •• Reduction in the medium and long term toxicity of treatments, infrastructures. In addition, the support to clinical research and its assessment, especially for children and young adults; has been extended through international collaborations, the •• Palliative care; establishment of public-private partnerships and the support •• Meta-analyses addressing controversial issues in treatment to access to innovation. efficacy.

3.1. CLINICAL CANCER RESEARCH In addition, strong involvement of cooperative intergroups is PROGRAMMES warranted, particularly with regard to proposing and conducting Nationwide funding of academic clinical research is organised clinical trials aimed at responding to the major therapeutic through 2 annual calls for research proposals operated by INCa, questions of increasing survival, reducing the side-effects and and funded by Ministry of Health (DGOS). delaying effects of treatments.

3.1.1. THE NATIONAL PROGRAMME FOR HOSPITAL To this end, up to 50% of the budget could be devoted to large- CLINICAL RESEARCH ON CANCER (PHRC-K) scale projects conducted by cooperative intergroups. PHRC-K funds cancer clinical research projects with the following objectives: Table 18. Features of PHRC-K programme •• Evaluation of the safety, tolerance or feasibility of the use of health technologies in humans; Evaluate safety, tolerance or feasibility •• Assessment of the efficacy of health technologies. To meet of the use of health technologies in this objective, priority is given to funding research that, using Objectives humans; controlled comparative methods, randomised or not, should Assess the efficacy of health help achieve recommendations with strong scientific evidence. technologies. Programming INCa/Ministry of Health (DGOS) In accordance with the 2014-2019 Cancer control plan, the institution orientations of the PHRC-K programme particularly concern: Operating institution INCa •• Areas pertaining to advanced forms of tumour diseases, Funding institution Ministry of Health (DGOS) oncogeriatrics and paediatric oncology; •• Research projects addressing individual or collective Year 2015 2016 behavioural modifications, or exploring drug-based Funding (in €M) 20.14 21* approaches in the prevention of cancer risks; •• Projects that include assessment of patients’ quality of life Proposals submitted 186 192 (during and/or after illness); Projects selected 37 Pending •• Combination of several targeted drugs, or combinations of targeted drugs with chemotherapy or radiotherapy; Selection rate 19.9% Pending * Provisional FRENCH NATIONAL CANCER INSTITUTE 57 2015-2016 SCIENTIFIC REPORT

In November 2015, of 186 letters of intent submitted to PHRC-K, Since 2007, 1,979 proposals have been submitted to the PHRC-K 37 projects were finally selected for funding for a total amount programme and 479 projects have been selected for an overall of €20.14M. amount of €166.54M (results for 2016 are not included as the selection process is in progress). The overall selection rate for Table 19. Types of projects selected through PHRC-K 2015 this call for proposals is 24.2%.

Number of projects selected1 Fig. 18. Trends in selection and funding for PHRC-K over the 2007-2015 period Drug therapy 20 Immunotherapy 3 25 80 Surgery or other innovative 70 techniques 4 20 Radiotherapy 8 60 Imaging (including PET) 1 15 50 Nuclear medicine (excluding PET) 2 Biomarkers (diagnosis, 40 5 prognosis) 10 Funding in €M

30 Nb of projects Management strategy 3 20 Prevention 1 5 10 In the framework of the 2015 CFP, 12 paediatric and 5 geriatric 0 proposals were submitted. Of these, 3 paediatric projects 0 (therapeutic studies) and 1 project on adolescents and young 201520142013201220112010200920082007 adults were selected, but none of the geriatrics projects were funded. Funding in €M Nb of projects 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 In compliance with the objectives of the CFPs, the CSO analysis combination for children and teenagers with refractory/relapsing of the projects funded shows that this programme is intended to solid tumours. The 3rd project is an international prospective support clinical applications of localised and systemic therapies, randomised study in children younger than 5 years with early-phase clinical trials and studies related to cancer control medulloblastoma (MB) that aims to stratify paediatric brain and prevention (Figure 19). 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.

1 – As the same project may fall under more than one category, the total value is over 37. FRENCH NATIONAL CANCER INSTITUTE 58 2015-2016 SCIENTIFIC REPORT

Fig. 19. Distribution of the selected projects according to the CSO classification over the 2007-2015 period

Localised Therapies - Clinical Applications Systemic Therapies - Discovery and Development Treatment Systemic Therapies Prevention - Clinical Applications Early detection, diagnosis, prognosis Combinations of Localised and Systemic Therapies Cancer control Complementary and Alternative Treatment Approaches Resources and Infrastructure Related to Treatment and the Prevention of Recurrence

3.1.2. THE NATIONAL PROGRAMME FOR MEDICO- In 2015, 16 proposals were submitted and 4 projects were ECONOMIC CANCER RESEARCH (PRME-K) selected (25%). Two of them were aimed at evaluating the The PRME-K comprises two main areas: cost/effectiveness and cost/benefit ratios of different surgical •• Innovation in cancer care, aiming to validate the effectiveness of approaches: innovative health technologies for cancer care in anticipation of •• two approaches for the resection of small rectal tumours; their evaluation by the French National Authority for Health (HAS); •• two strategies of perineal reconstruction after abdomino­ •• Cancer care management pathways aiming to compare in perineal resection for anorectal carcinoma. real life the effectiveness of alternative care strategies involving A third will assess the budgetary impact of tyrosine kinase health technologies in order to optimise cancer care. inhibitor discontinuation in chronic myeloid leukaemia patients with deep molecular response and the final one will evaluate Table 20. Features of the PRME-K programme prospectively, in a randomised way, the cost-benefit, safety and feasibility of ambulatory surgery versus traditional pathways in Validate the effectiveness of innovative the management of endometrial cancer. technologies for cancer care; Compare in real life the effectiveness Objectives of alternative care strategies involving health technologies in order to optimise Highlights cancer care. • Programming 2015: 41 projects funded in the framework of the institution INCa/Ministry of Health (DGOS) clinical research programmes for an overall budget of €21.6M. Operating institution INCa • 2016: 192 and 10 proposals submitted to the PHRC-K Funding institution Ministry of Health (DGOS) and PRME-K programmes, respectively. Year 2015 2016 Funding (in €M) 1.46 2* Proposals submitted 16 10 Projects selected 4 Pending Selection rate 25% Pending

* Provisional FRENCH NATIONAL CANCER INSTITUTE 59 2015-2016 SCIENTIFIC REPORT

3.2. EARLY-PHASE CLINICAL TRIALS This collaboration includes investigational agents provided to FOR INNOVATIVE DRUGS CTEP from NCI collaborators1. This partnership should enable the CLIP² structures to develop innovative projects based on the 3.2.1. COOPERATION BETWEEN US-NCI AND INCa proposed CTEP molecules, especially for rare diseases. As such, FOR EARLY-PHASE CLINICAL TRIALS CLIP² investigators have the opportunity to network with those Since 2009, INCa has collaborated with the US National Cancer of the NCI, prior to the submission of a proposal. Institute (NCI)-Cancer Therapy Evaluation Program (CTEP) and a new Consortium Agreement was signed on October 2015. This The first collaboration allowed to set-up 4 clinical trials with agreement is the result of the willingness of INCa and the NCI CTEP molecules in INCa’s designated CLIP² centres, and 2 are to enhance the discovery and development of novel anti-cancer still recruiting (Table 21). agents and to facilitate joint development of research projects.

Table 21. Collaboration between INCa and NCI

Agent Title Details Status A Phase II study of GDC‑0449 45 enrolled patients in patients with advanced 2 patients still on treatment Hedgehog inhibitor (vismodegib) Institut Bergonié, Bordeaux chondrosarcomas - Closed to accrual (Open CHONDROG study 12/2010) 22 enrolled patients A Phase II study of MK‑2206 Enrolment was stopped AKT inhibitor in patients with relapsed or following the interim analysis Centre Léon Bérard, Lyon (MK-2206) refractory diffuse large-B cell of first stage of Simon two- lymphoma - AKTIL study stage design Complete (Open 12/2011) A Phase II study of XL184 (Cabozantinib) in treating Met and VEGFR2 inhibitor Active (12/2014) patients with relapsed Institut Bergonié, Bordeaux (cabozantinib) 50/90 enrolled patients osteosarcomas and ewing sarcomas - CABONE study A pilot trial of AVD and Brentuximab Vedotin Anti-CD30 Antibody-Drug (SGN‑35) in the treatment Active (5/2015 in France) LYSARC-AMC joint protocol Conjugate (brentuximab-vedotin) of stage II-IV HIV-associated 9/20 enrolled patients Hodgkin lymphoma - AMC‑085 study

1 – See investigational agents at the link: http://ctep.cancer.gov/protocolDevelopment/docs/ctep_active_agreements.xlsx FRENCH NATIONAL CANCER INSTITUTE 60 2015-2016 SCIENTIFIC REPORT

3.2.2. FRENCH PUBLIC-PRIVATE PARTNERSHIPS In total, INCa launched 12 specific CFPs to propose 21 molecules FOR EARLY-PHASE CLINICAL TRIALS in development and 18 projects were selected to evaluate these Since 2011, INCa has promoted public-private partnerships with molecules. Among the 18 selected projects, 15 have actually pharmaceutical companies in order to propose new therapies started, 12 were co-funded by the ARC Foundation. The being evaluated by the CLIP² centres. The goal is to select characteristics and the statuses of these projects are summarised academic clinical trials to assess drugs in indications or conditions in Table 22. Figure 20 presents the different cancer sites covered other than those included in pharmaceutical firms’ development in this programme. 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.

Table 22. Projects funded by INCa

Agent Title Details Status A Phase II, multicentre trial aiming to evaluate BKM120 in monotherapy in patients with recurrent PI3K inhibitor Active (12/2012) or progressive metastatic head and neck cancer under Léon Bérard centre (Buparlisib) 53/70 enrolled patients platin and cetuximab-based chemotherapy – PIK-ORL Study An open-label multicentre, phase I-II study with tumour molecular pharmacodynamic evaluation and pharmacokinetics of PD-0332991 combined with CDK4/6 inhibitor vemurafenib in patients suffering from metastatic Active (04/2014) AP-HP St Louis (Palbociclib) melanoma with BRAFV600 mutated and CDKN2A 16/40 enrolled patients loss defined by either low CDKN2A mRNA expression, or mutation or loss of CDKN2A gene and expression of Rb – Optimum Study Efficacy and safety of PD-0332991 in patients CDK4/6 inhibitor with advanced gastrointestinal stromal tumours Active (01/2014) Bergonié Institute (Palbociclib) refractory to Imatinib and Sunitinib: 26/63 enrolled patients A Phase II study – CYCLIGIST Study Phase II clinical trial evaluating the efficacy of the dual inhibition of PIK/Akt/mTor signalling pathway PI3K/mTor inhibitor by PF-05212384 (PKI-587) for patients with myeloid Active (06/2015) Curie Institute (PF-5212384) neoplasm secondary to chemo-radiotherapy (t-AML/ 11/39 enrolled patients MDS) or de novo relapsed or refractory AML – LAM- PIK Study A Phase Ib, open-label, dose escalation study of the safety, tolerability and efficacy of LY2780301 (a p70/ 52 enrolled patients P70/AKT inhibitor LY2780301 Akt inhibitor) in combination with Gemcitabine in Gustave Roussy Closed to Accrual patients with advanced or metastatic cancer – INPAKT (Opened 09/2013) Study FRENCH NATIONAL CANCER INSTITUTE 61 2015-2016 SCIENTIFIC REPORT

Agent Title Details Status A prospective, multicentre, uncontrolled, phase Ib/ Active (01/2014) II study of LY2780301 in combination with weekly P70/AKT inhibitor Phase I complete paclitaxel in HER2-negative metastatic or locally Paoli-Calmettes Institute LY2780301 10/50 enrolled patients, advanced breast cancer in patients with and without phase II PI3/AKT/S6 pathway activation - TAKTIC Study Phase I/II study of LY2228820 with radiotherapy plus P38/MAPK inhibitor Active (01/2015) concomitant TMZ in the treatment of newly diagnosed Jean Perrin centre LY2228820 9/50 enrolled patients glioblastoma – GLYRad Study A randomised open-label phase II multicentre trial P38/MAPK inhibitor assessing the efficacy and safety of Tamoxifen plus Active (01/2015) François Baclesse centre LY2228820 LY2228820 in advanced or metastatic breast cancer 4/114 enrolled patients progressing on aromatase inhibitors – OLYMPE Study A phase Ib/II study of metronomic cyclophosphamide Active (09/2015) Oncolytic virus and the oncolytic poxvirus JX-594 in patients with Bergonié Institute 7/30 enrolled patients JX-594 advanced breast cancer and soft tissue sarcoma – in phase I METROmaJX Study Multicentre phase I-IIa trial of tasquinimod in combination with megestrol acetate in advanced Tasquinimod François Baclesse centre Closed hormonosensitive endometrial adenocarcinoma – TASQUENDO Study A phase Ib study of olaparib with concomitant PARP inhibitor Active (06/2016) radiotherapy in locally advanced/unresectable Bergonié Institute Olaparib 0/42 enrolled patients soft‑tissue sarcoma – RADIOSARP Study A dose escalation Phase I study with an extension part evaluating the safety and activity of an anti- Anti- PDL1 antibody (DURVALUMAB) combined with Active (06/2016) PD-L1 Antibody Léon Bérard centre (Durvalumab) a small molecule CSF-1R tyrosine kinase inhibitor 2/58 enrolled patients (PEXIDARTINIB) in patients with metastatic/advanced pancreatic or colorectal cancers – MEDIPLEX Study A multicentre, randomised, non-comparative, open-label Phase I/II evaluating AZD2014 (dual Dual mTORC1/ mTORC1/mTORC2 inhibitor) in combination with Léon Bérard centre Active (04/2016) mTORC2 inhibitor AZD2014 anastrozole versus anastrozole alone in the treatment 1/72 enrolled patients of metastatic hormone receptor-positive endometrial adenocarcinoma – VICTORIA Study A phase I/II trial to assess the safety and efficacy PARP inhibitor of metronomic cyclophosphamide, metformin and Active (04/2016) Hospices Civils de Lyon Olaparib olaparib in recurrent advanced/metastatic endometrial 0/33 enrolled patients cancer patients – ENDOLA Study Phase I trial evaluating the safety of MEDI4736 in Anti‑PD-L1 combination with Docetaxel, Cisplatin and 5 FU Antibody Gustave Roussy Pending approval (Durvalumab) in induction for locally advanced head and neck squamous cell carcinoma – MEDINDUCTION Study FRENCH NATIONAL CANCER INSTITUTE 62 2015-2016 SCIENTIFIC REPORT

Fig. 20. Innovative molecules: funding distribution by organ Fig. 21. Implementation of NGS in clinical diagnostics in molecular genetics centres

7% 12% 5% 4% 6 Haematology BiologyGastrointestinal cancers 3% Biology AetiologyColorectal / Anus Aetiology Number of centres where NGS PreventionMelanoma Prevention 4% is in routine practice since 2014 23% EarlyLung detection,/ Upper aerodigestive diagnosis, tract Early detection, diagnosis, andBreast prognosis 15 Numberand prognosis of centres where NGS TreatmentUrinary and genital systems is inTreatment routine practice since 2015 Central nervous system Cancer control % Sarcoma and connective tissues 11 NumberCancer of control centres where NGS ScientificOther locations models is inScientific validation models stage Non-specific 7 4% 14% 13%

Fig. 22. Implementation of NGS in clinical diagnostics in 3.3. PERSONALISED MEDICINE TOOLS AND oncogenetics laboratories PROGRAMMES

3.3.1. NEXT GENERATION SEQUENCING FOR CLINICAL APPLICATIONS 5 Since 2013, INCa has supported the development of targeted Biology NGS for diagnostic purposes in the 25 oncogenetics laboratories Aetiology Number of lab where NGS 8 and in the 28 molecular genetics centres. In 2013, INCa launched Prevention is in routine practice since 2014 a specific CFP and selected 11 pilot teams in order to carry Early detection, diagnosis, out an implementation phase for NGS. As of the end of 2015, Numberand prognosis of lab where NGS 20 oncogenetics laboratories and 13 molecular genetics centres is inTreatment routine practice since 2015 had started to use NGS for clinical diagnostics for some of their NumberCancer of control lab where NGS patients (Figures 21 and 22). Based on experience gained during is inScientific validation models stage 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. 12 FRENCH NATIONAL CANCER INSTITUTE 63 2015-2016 SCIENTIFIC REPORT

Accreditation of NGS analysis according to the ISO15189 standard is the next milestone to ensure the quality of the 2015 Highlights tests performed for clinical purposes. None of the somatic genetics laboratories and only 3 oncogenetics laboratories NGS clinical diagnostics used in 20 oncogenetics were accredited for NGS technology in 2015. Accreditation is laboratories and in 13 molecular genetics centres. 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 3.3.2. THE AcSé PROGRAMME definition of good practices. A guide for validating NGS has been INCa developed the AcSé Programme in 2013 (Secured Access issued in 2015, and serves as a reference for the accreditation to innovative therapies) to provide a secured access to targeted of laboratories. This work is still ongoing to complete these therapies for patients in treatment failure situations, and the recommendations for informatics and bioinformatics processes. programme has been open recently to paediatric tumours.

In 2013, INCa also selected 5 reference teams in bioinformatics. The AcSé programme is managed by a scientific steering Their role is to provide their expertise to clinical laboratories, to committee1, whose main tasks are the choice of eligible drugs, develop, validate and release analytical solutions and to facilitate the definition of the programme guidelines, communications networking between bioinformatics engineers. Since 2013, the with patients and oncologists. 5 teams have developed dedicated analytical pipelines for each type of activity, and have validated these pipelines on data AcSé addresses the safety issues in patients with administered generated locally by the different laboratories using NGS. Several drugs that are not authorised for these indications, based on solutions are being studied in order to make these pipelines the patients’ molecular profile defined in the 28 INCa molecular available to the community (virtualisation, direct access on a genetics centres. In this context, all patients in France with remote server, etc.), and are being tested to determine those advanced malignancies carrying the drug biomarker are eligible most suitable for the information systems of the facilities to for inclusion, if there is no other clinical trial in which they could which the laboratories belong. The “test” data sets compiled be enrolled. Moreover, AcSé trials may also include patients to evaluate the pipelines could also become a reference data <18 years if safe dosing data are available. set that all laboratories could use to evaluate their protocol locally. The work undertaken by the bioinformatics reference The achievements of the first two clinical trials, sponsored by teams since 2013 must be maintained in order to continue the UNICANCER ongoing work and to support the roll-out of NGS throughout all Proof of concept is currently being demonstrated through the laboratories. A special effort will be focussed on technology two ongoing trials: transfer of the pipelines and the expertise from the reference •• AcSé-crizotinib was implemented in 2013 and is funded team to the clinical laboratories. by INCa and ARC Foundation. Currently, prescription of crizotinib is allowed only to adult patients with lung cancer The medical interpretation of results is another issue that with a specific molecular alteration,ALK gene translocation. needs to be addressed, in order to make the best use of NGS However, crizotinib targets different molecular alterations results to improve patient outcome on a national scale. This that may be found in other cancers. requires improving the assessment of the biological and clinical To date, the AcSé-Crizotinib trial allowed treating significance of the rare mutations identified with NGS techniques. 180 patients in France who presented the specific mutation Clinical follow-up of patients with some mutations in their in 20 cohorts. In order to identify the potential genetic tumour will also be essential to improve the knowledge base on alterations - ALK, MET and ROS1 - targeted by crizotinib, these mutations. This applies to INCa’s participation in Global more than 8,000 patients benefited from a biomarker Alliance, and can be supported by the inter-SIRIC working group analysis performed in INCa molecular genetics centres. on data integration which aims to improve data sharing.

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). FRENCH NATIONAL CANCER INSTITUTE 64 2015-2016 SCIENTIFIC REPORT

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

1. ALCL - children and adults - ALK translocated 2. Colorectal cancer - adults - ALK translocated 3. Colorectal cancer - adults - MET amplified 4. Colorectal cancer - adults - MET mutated 5. NSCLC - adults - MET amplified 6. NSCLC - adults - ROS1 translocated 7. Breast cancer - adults - ALK translocated 8. Gastric and gastroesphageal junction cancer - adults - MET amplified 9. Cholangiocarcinoma - adults - ROS1 translocated 10. Ovarian cancer - adults - MET amplified 11. Clear cell renal carcinoma - adults - ALK translocated 12. Clear cell renal carcinoma - adults - ALK amplified 13. Papillary renal cell carcinoma - adults - MET mutated or MET amplified 14. Hepatocarcinoma - adults - MET amplified 15. Neuroblastoma - children and adults - ALK amplified or ALK mutated 16. Inflammatory Myofibroblastic Tumour - children and adults - ALK translocated 17. Rhabdomyosarcoma - children and adults - ALK amplified 18. Glioblastoma - adults - MET amplified 19. Anaplastic thyroid cancer - adults - ALK mutated or ALK translocated 20. Thyroid cancer (follicular + medullary + papillary) - adults - MET mutated 21. Rare paediatric malignancies Miscellaneous adults malignancies 0 5 10 15 20 25 30 35 40

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

By age

0-10 11-17 18-30 31-40 41-50 51-60 61-70 71-80 81-90 91-100 0 10 20 30 40 50 FRENCH NATIONAL CANCER INSTITUTE 65 2015-2016 SCIENTIFIC REPORT

•• AcSé-vemurafenib, launched in October 2014, is intended to Vemurafenib is exclusively prescribed for patient-specific evaluate the efficacy and the safety of vemurafenib treatment BRAF-V600E-mutated melanomas, the objective of the AcSé- in 500 patients with various types of cancer, all carrying vemurafenib trial is to determine whether patients with a cancer the BRAF V600 specific genetic abnormality, targeted by other than melanoma and carrying this mutation could receive this treatment. 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)

1. Non-small cell lung cancer - mutation V600 2. Ovarian cancer - mutation V600 3. Cholangiocarcinoma - mutation V600 4. Thyroid cancer - mutation V600 5. Prostate cancer - mutation V600 6. Bladder cancer - mutation V600 7. Sarcoma / Gastrointestinal stromal tumours GIST - mutation V600 8. Multiple myeloma - mutation V600 9. Chronic lymphocytic leukaemia - mutation V600 10. Hairy Cell Leukaemia - mutation V600 Miscellaneous malignancies 20 0 10 20 30 40 50 60

Fig. 26. AcSé-vemurafenib: Description of recruitment by age (May 2016) 2016 highlights By age • 1 international publication in Nature Reviews Clinical 18 - 30 Oncology “Equal Access to innovative therapies and 31 - 40 precision cancer care”1; 41 - 50 • 2 presentations at international conference: 51 - 60 –– Oral communication in ASCO 2016 “Crizotinib in children and adolescents with advanced ROS1, 61 - 70 MET or ALK-rearranged cancer: result of the AcSé 71 - 80 phase II trial”; 81 - 90 –– Poster presentation in ASCO 2016: 0 5 10 15 20 25 30 35 “Biomarker-driven access to vemurafenib in BRAF‑positive cancers: Second study of the French National AcSé Programme”.

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 FRENCH NATIONAL CANCER INSTITUTE 66 2015-2016 SCIENTIFIC REPORT

The new AcSé clinical trials In recent years, the AcSé steering committee has worked on 2016 highlights the next AcSé projects including the development of paediatric components: Massive impact in the French press following the •• Two clinical trials in immunotherapy, AcSé-nivolumab & launch of the eSMART trial in paediatric cancers. 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; 3.3.3. THE PAOLA CLINICAL TRIAL •• The eSMART trial, as part of the AcSé programme dedicated Olaparib, a PARP inhibitor, was granted European market to paediatrics, was launched in June 2016, and is funded approval in late 2014 for maintenance treatment of high-grade by INCa and the association Imagine for Margo. This study ovarian cancer patients, fallopian tube and primitive peritoneal should address the specific needs of children and teenagers cancer patients, carrying a BRCA mutation (germline and/ with relapsed life-threatening malignancy, and their access to or somatic). In this context, the patient’s BRCA status, both investigational drugs based on their molecular profile. somatic and germline genetics, will need to be acquired, within AcSé-eSMART will include 260 children in therapeutic failure timelines consistent with the patient’s therapeutic management. situations and is intended to test 10 innovative molecules The introduction of a somatic component will require the (targeted therapies, immunotherapies, alone or in combination) development of NGS on tumour samples. In this way, setting in a single clinical trial, and expects to double the number of up a pilot phase was essential, building on the oncogenetics new drugs proposed for treating children over the next 3 years. 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 Support to NGS development at the national level eligible to PAOLA1 clinical trial

• 5 French partners selected • 10 French teams supported • 1 May 2015 – 30 April 2017 • 1 September 2015 – 31 August 2016 • INCa funding: €560,000 • INCa funding: €400,000 • ARCAGY-GINECO funding: €250,000 • 1st mid-year activity report: June 2016 • Expected recruitment: 636 patients • 307 patients tested in 1 year FRENCH NATIONAL CANCER INSTITUTE 67 2015-2016 SCIENTIFIC REPORT

PAOLA1 is a comparative clinical trial of olaparib-bevacizumab During the first year, 392 samples were received by the 5 centres: versus bevacizumab in maintenance treatment (following first-line •• 218 from French patients; chemotherapy). This clinical trial aims to include 612 European •• 174 from European patients. patients presenting with BRCA mutation or not. Hence, all Of the 147 French patients who were tested for germline and patients should be tested for the BRCA status and 5 French somatic genetics, 29 had both germline BRCA and tumour BRCA centres have been selected for testing: mutations (19.7%) while 11 had a tumour BRCA mutation of •• both somatic and germline BRCA statuses for French patients; somatic origin without a germline BRCA mutation reported (7.5%). •• only somatic BRCA status for other European patients (Germany, Italy, Spain, Sweden, Denmark, Finland, Belgium, Moreover, 48 tumours BRCA-mutated were detected in Austria). 160 patients tested for somatic genetics only (30%, 27 French The analyses started in May 2015. 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 88 (28.7%) (germline and somatic BRCA mutations or somatic BRCA mutations)

French patients tested and included in PAOLA1 100 European patients tested and included in PAOLA1 51 Highlights

100 French and 51 European tested patients included in the PAOLA1 clinical trial over the first year. FRENCH NATIONAL CANCER INSTITUTE 68 2015-2016 SCIENTIFIC REPORT

3.4. ORGANISATION OF CLINICAL RESEARCH This objective is being pursued in the 2014-2019 Cancer control AND STRENGTHENING OF STRUCTURES, plan by undertaking a new designation of these structures. These INFRASTRUCTURES AND TOOLS new centres, most of which have been renewed, have seen their scope of activity somewhat extended. Particularly, this designation 3.4.1. EARLY-PHASE CLINICAL TRIALS CENTRES allowed the collaboration of CLCC centres and University (CLIP² CENTRES) hospitals, locally closed, to apply for a common early-phase Promoted by the 2009-2013 Cancer control plan, the initiative to clinical trials centre, and for 6 of them to integrate paediatric structure clinical and translational research is supported by INCa activities (Figure 28). through a specific designation: early-phase clinical trials centres.

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

Paris C C2C ille C ille Centre ital aint-ois nstitt Crie scar abret ital Piti- altrire ital enri stave oss onor Centre ranois aclesse

Centre ne aris

Adults + Paediatrics C C C antes Centre eores-ranois eclerc nstitt e Cancroloie Adults e lest aeloe ane Centre on rar

osices Civils e on

nstitt eroni artinie nstitt niversitaire Cancer e olose ncole nstitt Clais ea nstitt Paoli-Calettes nstitt ional a nion aotte Cancer ontellier ssistance Pblie al relle es ita e arseille Source: INCa, 2015 Drafted by INCa’s Research Division, 2015

This initiative has contributed to the overall increase in the CLIP² designation for the 2015-2019 period was initiated in number of clinical trials launched (+86%) in each designated 2014, for designation of centres effective at the end of April 2015. centre and in the number of patients (+136%), especially in Therefore, 2014 is considered to be a transition year for the CLIP² phase I (Figure 29). network and the activity data cannot be taken into consideration. FRENCH NATIONAL CANCER INSTITUTE 69 2015-2016 SCIENTIFIC REPORT

Fig. 29. CLIP² activity of €3M. Furthermore, since 2004, additional funding of €3M is annually allocated to University Hospitals and Cancer Care 5000 45 Centres by the Ministry of Health. The objective of this support is to create conditions to promote the involvement of public 40 and private researchers in clinical trials. Approximately 140 FTE 4000 35 positions, mainly research nurses, have been hired, based in over 160 different hospitals throughout France. Another aim is to 30 ensure equal access to clinical trials for patients in all types of 3000 25 hospitals in France and the best quality of data collected during clinical trials. In 2015, INCa carried out an annual survey of 20 2000 clinical cancer research activities in these hospitals. The results 15 show that the number of patients in the clinical trials increased

Nb of patients enrolled significantly over the 2008-2015 period: 1000 10 •• +122% increase in total; Average nb of new trials per CLIP² Average •• +148% for patients participating in academic trials; 5 •• +50% for patients participating in industrial trials during the 0 0 same period. 2010 2011 2012 2013 2014 2015 CLIP² 2010-2014 CLIP² The ratio of enrolment in academic vs. industrial trials is stable 2015-2019 over the years (82/18). A substantial increase in 2015 versus Nb of patients enrolled 2014 can be observed that could be explained by an increase of Average nb of new trials per CLIP² recruitment in University hospitals, mainly those in the Paris area.

Figures 30 and 31 present the progression of recruitment of 3.4.2. ENROLMENT OF PATIENTS IN CLINICAL TRIALS patients recorded in INCa’s annual survey, and the distribution Since 2006, INCa and the French Ministry of Health have funded of this recruitment among the different types of care facilities, 26 Mobile Clinical Research Teams (EMRC) for a total amount respectively.

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

50,000

40,000

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20,000

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0 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Nb patients enrolled - academic trials Nb patients enrolled - industry-sponsored trials All FRENCH NATIONAL CANCER INSTITUTE 70 2015-2016 SCIENTIFIC REPORT

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

50%

40%

30%

20%

10%

0% 2008 2009 2010 2011 2012 2013 2014 2015 University Hospitals Cancer Care Centres Community Centres (public) Community Centres (private)

3.4.3. INCa’S CANCER RESEARCH CLINICAL TRIALS Table 24. Registry of Clinical Trials in Cancer Research REGISTRY The clinical trials registry in cancer research managed by INCa To provide information relevant to clinical provides easy access to information on clinical trials using a Objectives trials in the field of cancer open to inclusion multicriteria search engine, making it possible to search for clinical in France. trials, using various criteria such as the sponsor or the organ 2,098 clinical trials published through under study, as well as the geographical location of recruiting the registry on INCa’s website in May 2016: centres using a geolocation module. ••592 trials opened to patient recruitment, Results proposed by more than 250 industrial From 2007 onwards, the registry of clinical trials in cancer or academic/public sponsors; research has allowed easy access to relevant information on trials ••62% of the clinical trials have an academic performed in France. Available in open access on INCa’s website, sponsor. it provides a wealth of high-quality data and regular updates for patients, healthcare professionals and the general public. FRENCH NATIONAL CANCER INSTITUTE 71 2015-2016 SCIENTIFIC REPORT

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

1,400

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0 Oct-14 Apr-16 Jun-13 Dec-08 Dec-14 Dec-15 July-10 Apr-07 Jun-11 Jun-12 Dec-07 Dec-09 Dec-10 Dec-11 Dec-12 Dec-13 May-15 May-16 July-07 July-08 July-09 May-14 Academic Trials Industry Sponsored Trials Open Trials

In 2014, in accordance with actions 5.4 and 7.16 of the 2014- through the registry. Since the launch of the new internet portal 2019 Cancer control plan, INCa initiated a process aiming to in 2012, between 20,000 and 30,000 visits/month have been collect the results of clinical trials, in order to publish them recorded. FRENCH NATIONAL CANCER INSTITUTE 72 2015-2016 SCIENTIFIC REPORT

4RESEARCH IN HUMAN AND SOCIAL SCIENCES, EPIDEMIOLOGY 4 AND PUBLIC HEALTH One of INCa’s goals is to bring social sciences and public The general objectives of the present call for proposals are as health research applied to oncology in France up to the best follows: international standards. In line with the Cancer control plan, •• To encourage the emergence of original research proposals particular efforts are being devoted to increasing basic and health of scientific excellence in the different HSS-E-PH disciplines intervention research in order to reduce social inequalities related applied to cancers; to cancer, and increase the impact of cancer prevention measures, •• To develop and to strengthen multidisciplinary scientific participation in screening and access to care. research that unites teams, disciplines and technological resources around one specific research issue or objective. To achieve this goal, INCa has established links with other national organisations in order to combine experience and know- 4.1.2. INDICATIVE TOPICS FOR how in deciding how to modify the approach to environmental RESEARCHERS’ ATTENTION and behavioural risk factors. Although the present CFPs is an investigator-driven programme, some aspects related to the public health objectives of the 2014- 4.1. THE RECURRENT PROGRAMME 2019 Cancer control plan were proposed as indicative research FOR HUMAN AND SOCIAL SCIENCES (HSS), topics. The researchers were free to use these topics as a basis, EPIDEMIOLOGY AND PUBLIC HEALTH (EPH) but it was not a condition for the scientific evaluation of the RESEARCH projects. Tentative topics for the year 2016 were as follows: •• Modelling the costs of caring for patients with cancer; 4.1.1. BACKGROUND AND OBJECTIVES •• Palliative care/end of life care (Action 7.6); OF THE CALL FOR PROPOSALS •• Comorbidity and cancer (Action 2.16); The role of human and social sciences, epidemiology and public •• Improved knowledge of the experience of patients and their health (HSS-EPH) in cancer research is confirmed by the 2014- families (Actions 9.17.1; 9.17.3; 9.18.1). 2019 Cancer control plan. The objectives of several strategic The analysis of the projects submitted shows that about 23% of measures presented in the Plan are based on the progress that the proposals meet the proposed indicative topics, suggesting could be made through HSS-EPH research. Research conducted that they might influence the investigators’ choices. in these areas should facilitate and build multidisciplinary collaboration between researchers from the HSS-EPH disciplines: 4.1.3. 2016 RESULTS psychology, sociology, economics, anthropology, political In 2016, 86 proposals were submitted and 16 projects were science, epidemiology, biostatistics, public health — prevention selected for funding for a total amount of €3.51M. The table and screening — as well as history of science, communications 25 presents the features of the HSS-EPH programme in 2015 theory, geography and law, especially labour law. It is also crucial and 2016. to encourage interactions with researchers from other disciplines such as biology, genetics, environmental sciences, immunology, toxicology and clinical research. FRENCH NATIONAL CANCER INSTITUTE 73 2015-2016 SCIENTIFIC REPORT

Table 25. Features of the programme for Human and social It is important to highlight the differences in success rates Sciences (HSS), Epidemiology and Public Health (EPH) between the 2 phases by disciplinary categories. They were 52% research for the Epidemiology/biostatistics category and 33% for the HSS/public health category for the pre-selection of the LoIs. Promote the emergence of original The corresponding figures were 48%versus 36% during the second research and scientific excellence in phase based on full projects. the various disciplines of HSS-EPH applied to cancer. Finally, the selection rate at the end of these 2 phases was 25% Increase and strengthen the focus of Objectives for the Epidemiology/Biostatistics category and 12% for the HSS/ multidisciplinary scientific research public health category. At least two reasons might explain this around an issue or a clearly identified observation. First, research in HSS and public health applied goal, enlisting teams, disciplines and to cancer is relatively new in France, compared to research in technological means to effectively epidemiology and biostatistics. Based on the comments of referees respond to it. and external reviewers, there seem to be more methodological Programming difficulties and weaknesses in the social and human sciences and INCa institution public health research projects submitted. Additional initiatives Operating institution INCa from INCa might be needed in order to reduce the gap. Some directions are given in the strategic topics section of this report Funding institution INCa (See Part 3 chapter 4). Year 2015 2016 The projects selected for funding in epidemiology are aimed at Funding (in €M) 4.27 3.51 studying environmental, nutritional and genetic risk factors for Proposals submitted 66 86 cancer, even though there is a strong trend towards molecular Projects selected 17 16 epidemiology. For example, two of the three projects aim to study: 1. Biomarkers of dietary fatty acids, lipid metabolism, and risk Selection rate 26% 18.6% of ovarian cancer; 2. Immunity, inflammation and breast cancer risk. The distribution of submitted proposals by major discipline categories is presented in table 26. Projects in biostatistics aim at testing the existence of statistical cure and modelling the time to cure in population-based cancer Table 26. Distribution of LoIs submitted and selected, survival, but also at identifying minimal clinically significant projects selected and amounts funded by major disciplines differences in health-related quality-of-life scores integrating the occurrence of the response shift effect. Selected projects in human LoIs LoIs Projects Funding and social sciences and public health focus on geographical submitted selected selected (€M) inequalities in access to oncology expertise, quality of life for Epidemiology/ 44 23 11 2.47 minor siblings of childhood and adolescent survivors of acute biostatistics leukaemia, medium- and long-term after diagnosis, but also the Social and human impact of mediation on chemotherapy-induced pain neuropathy sciences/public 42 14 5 1.04 and on cooperation between institutions, adults, parents, health clinicians and researchers to improve access to information after TOTAL 86 37 16 3.51 childhood, adolescent or young adult cancer. Breast cancer and sarcomas are the main cancer sites studied in all projects and It should be noted that the number of projects submitted is represent 20% and 12%, respectively. relatively balanced between the major disciplines of the CFPs (epidemiology/biostatistics versus HSS/public health). FRENCH NATIONAL CANCER INSTITUTE 74 2015-2016 SCIENTIFIC REPORT

4.1.4. THE HSS-EPH PROGRAMME OVER THE 2007-2016 PERIOD Since 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 6 30

5 25

4 20

3 15 Funding in €M 2 10 Nb of projects

1 5

0 0 2016201520142013201220112010200920082007

Funding in €M Nb of projects

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

2 % 1,1% 8% 0,8% 7% % 7 Aetiology 5% End-of-Life Care Ethics and Confidentiality Prevention % 3 % Early detection, 7 Resources and Infrastructures diagnosis, prognosis % % Education and Communication Treatment 59 16 Cost Analyses and Health Care Delivery Scientific models 8% Behaviour 21% Cancer control Surveillance 14% Patient care and Survivorship Issues

1,1% Ethics and Confidentia- lity 0,8% FRENCH NATIONAL CANCER INSTITUTE 75 2015-2016 SCIENTIFIC REPORT

In compliance with the objectives of the call, 59% of the funded Table 27. Features of the population health intervention projects relate to cancer control and survivorship issues, with research programme particular emphasis on behavioural factors, patient care and survivorships issues that represent 16% and 14%, respectively. Promote the emergence of projects in Moreover, surveillance methodologies represent 8% and cost intervention research applied to cancers, analyses and health care delivery 7%. that are original and of scientific excellence, and likely to produce Aetiology category encompasses the epidemiology studies and knowledge that is scientifically valid and represents 21% of the funded projects whereas social sciences socially useful. related to treatment and early detection represent 8% and 7%, Encourage original partnerships between respectively. research teams in different disciplines Objectives (human and social sciences, public 4.2. POPULATION HEALTH INTERVENTION health [prevention/health promotion], RESEARCH epidemiology, biostatistics, etc.) and In 2010, the support for human and social science research was practitioners in the field (medical, allied strengthened and completed by a dedicated CFPs in population health, and social services personnel, health intervention research to reduce the inequalities. In 2011, non-profit organisations, etc.), in order the SAB recommended the set-up of a specific strategy for to facilitate the implementation and preventive research that should include behavioural and social transferability of the findings in different sciences, public health, etc. Based on these recommendations and contexts. on the 2012 strategic report on cancer prevention research, the Programming INCa scope of the programme was extended to include interventions institution for promoting behaviour changes and for reducing the inequalities Operating institution INCa in 2013. Funding institution INCa In 2015, the CFPs scope included all aspects of cancer control: Year 2015 2016 ranging from primary prevention, to secondary prevention, Funding (in €M) 1.07 Pending tertiary prevention, healthcare organisation, and survivorship and rehabilitation issues. This call also encourages research in Proposals submitted 29 22 methodological issues. Projects selected 7 Pending

Secondly, two types of proposals are expected: Selection rate 24% Pending •• full research proposals presenting advanced research protocols, with a strong methodological approach and established In 2015, 7 projects were selected, including 4 emerging research partnerships, to be funded for 24 to 48 months; projects, among the 29 submitted proposals, for a total amount •• emerging research projects to encourage the development of €1.07M. of intervention research on a topic relevant to the 2014- 2019 Cancer control plan, to be funded for 12 months for a In 2016, two modalities were added: a transversal area based maximum of €30,000. on the explicit integration of the issue of health inequalities in research plans and an emphasis on justifying and evaluating the Finally, the administrative guidelines strongly recommend the efficiency of the proposed interventions in the research projects. establishment of partnerships between researchers, stakeholders in the field and decision-makers. 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). FRENCH NATIONAL CANCER INSTITUTE 76 2015-2016 SCIENTIFIC REPORT

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: is emerging amongst the projects towards prevention and aetiology, prevention, early detection and diagnosis, cancer survivorship/outcome research. Health behaviour, cost analyses control, survivorship and outcome research. A clear trend 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

4%

6% 3% Aetiology Resources and Infrastructures Prevention 13% Education and Communication 44% Early detection, 48% Cost Analyses and Health Care Delivery diagnosis, prognosis Behaviour Cancer control 23% Patient care and Survivorship Issues

3 %

4 %

Highlights

2015: 7 projects selected for a total amount of €1.07M, including 4 emerging research projects. 2016: 22 projects submitted. FRENCH NATIONAL CANCER INSTITUTE 77 2015-2016 SCIENTIFIC REPORT

4.3. INITIATIVES DEVELOPED TO SUPPORT Table 29. Features of the Cancer and environment RESEARCH ON ENVIRONMENTAL RISKS programme

4.3.1. SUPPORT FOR RESEARCH ON ENVIRONMENTAL To improve the knowledge of delayed RISK FACTORS, CANCER AND ENVIRONMENT effects of exposure of individuals to risk PROGRAMME Objectives factors associated with the environment, Since 2012, a dedicated CFP has been launched by ITMO in terms of analysing the risks of cancer Cancer-Aviesan to strengthen support for research in the area occurrence and progression. of environmental risk factors. Programming institution ITMO Cancer-Aviesan Operating institution Inserm Funding institutions Inserm for ITMO Cancer-Aviesan Year 2015 2016 Funding (in €M) 3.18 3.74 Proposals submitted 32 37 Projects selected 8 8 Selection rate 25% 22%

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 They should result in the development of suitable skin protection were selected for a total funding of €3.74M. They address solutions or serve as experimental models to study the adverse important issues on exposure to endocrine disrupting chemicals effects of other food additives. (EDCs) such as, the targets of low-dose effects of xenoestrogen exposure, the occurrence of testicular germ cell tumours Since 2012, 39 projects have been selected among the and changes in methylation due to exposure to EDCs, the 138 proposals submitted for an overall amount of €15.6M. identification of exposure, diagnostic and prognostic markers of prostate cancer and related to EDC exposure. Half of the projects (50%) address the lines of the CFP in the development of models for analysing the effects of the Other studies address issues on the skin adaptation to UV environment or study interactions and transmission of toxic radiation at the transcriptional level, the effects of exposure to air effects (mutational and epigenetic alterations). They address pollution, throughout one’s lifetime, the risks and the associated important issues in terms of public health and social concerns mechanisms of carcinogenic effects of different exogenous ligands as well as major gaps in environmental epidemiology of cancer or the impact of nanoparticles in food, by using original mouse research. They combine epidemiology, molecular biology/ models. genomics, physics and bioinformatics methods to address issues FRENCH NATIONAL CANCER INSTITUTE 78 2015-2016 SCIENTIFIC REPORT

on everyday-life contaminant concentrations, corresponding to In 2016, 35 cancer-related proposals were submitted and real exposure (i.e. pesticides, UV, radiation, chemical and metal 6 projects were selected for funding for a total amount of €1.01M. pollutants, etc.). Among these funded projects, it is interesting to note that some projects address environmental risk factors for childhood cancers, They potentially open up new scientific and technical prospects to such as leukaemia, brain tumours or embryonic tumours. These identify high risk subgroups and may have scope for policy-makers projects are novel studies on farming pesticides, traffic and air such as generating new standards in environmental toxicology. pollution, high voltage power lines and ionising radiation from natural sources. 4.3.2. PROGRAMME OF THE FRENCH NATIONAL AGENCY FOR FOOD, ENVIRONMENTAL AND Importantly, these projects are multidisciplinary by combining OCCUPATIONAL HEALTH AND SAFETY (ANSES) social sciences, epidemiology, molecular biology studies and TO SUPPORT RESEARCH ON ENVIRONMENTAL RISKS other different experimental methods to address exposure to different compounds (i.e. polycyclic aromatic hydrocarbons, This multi-agency programme addresses various public health PAHs, metals) in order to identify biomarkers to improve early issues related to the environment and employment. Cancer-related detection and/or to open up new prevention strategies or to set projects were covered by INCa in 2010 and ITMO Cancer-Aviesan up new behavioural tests. for the 2011-2016 period. Since 2010, 46 cancer-related projects were funded in the Table 31. Features of the 2015-2016 Research Programme in framework of this programme for a total budget of €6.79M. Employment-Health-Environment in the field of cancer In addition, the Ministry of Labour (DGT) and the French Environment and Energy Management Agency (ADEME) also To evaluate and analyse environmental funded cancer-related projects. risks for human health in the general population or at work. The analysis of the projects funded by INCa and Inserm for To address emerging and known risks, Objectives ITMO Cancer-Aviesan over the 2010-2016 period according which can generate complex scientific to the CSO classification shows that the studies mainly focus debates, and for which a single approach on environmental and occupational exposures and on the can include concepts, methods and tools interactions of exogenous factors with genes and genetic from different disciplines. polymorphisms in order to decipher the causes and origins of Programming cancers (Figure 36). institution Anses Operating institution Anses Funding institution Inserm for ITMO Cancer-Aviesan Year 2015 2016 Funding (in €M) 0.74 1.01 Proposals submitted 35 35 Projects selected 5 6 Selection rate 14% 17% FRENCH NATIONAL CANCER INSTITUTE 79 2015-2016 SCIENTIFIC REPORT

Fig. 36. Distribution of the selected projects according to the CSO classification over the 2010-2016 period

4% 7% 7% 17% 5% Biology Resources and infrastructures Aetiology related to aetiology Early detection, 27% Interaction of genes and/or genetic diagnosis, prognosis 77% polymorphism with exogenous and/or endogenous factors Cancer control Scientific models Exogenous factors in the origin 33% and cause of cancer

4.4. PHD PROGRAMME IN HSS-EPH 2016 To strengthen its support to the training of the next generation IN COLLABORATION WITH ACADEMIC of young researchers in HSS-EPH, working in the cancer field, PARTNERS INCa decided to award in 2016, 7 doctoral fellowships, with a funding of €90,000 during three years. Like the PL HSS-EPH For the 6th consecutive year, INCa, in partnership with the School programme, the distribution of the applications received is for Advanced Studies in Social Sciences (EHESS) and the Public relatively balanced between disciplinary categories, with regard Health PhD Network of the School of Advanced Studies in Public to the associated research potential. However, here again, it is Health (EHESP), launched a call for applications for doctoral noted that the majority of the projects selected relates to the fellowships to promote research in HSS-EPH applied to cancer. epidemiology/biostatistics category, with a total of 5 projects. Among the 28 applications submitted, 11 candidates were from The 2 projects in the HSS/public health group are in psychology the HSS/public health disciplines and 15 from the epidemiology/ and health economics. biostatistics category. Two projects were classified as out of the scope. The results of the 2016 session bring the number of doctoral students funded since 2011 through this programme to 24. The multidisciplinary evaluation committee pre-selected A review process will be set up by INCa to ensure that this 14 candidates, who were then interviewed by the same committee programme has met its objectives. at the end of June 2016. FRENCH NATIONAL CANCER INSTITUTE 80 2015-2016 SCIENTIFIC REPORT

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 Epidemiology applied to nutritional epidemiology. Interpolating between different populations in early-phase Biostatistics clinical trials in oncology. Oral cancer drugs and their social representations: psychosocial study of the process of appropriation of oral Health Psychology cancer drugs by patients and health professionals. Medico-economic evaluation of patients with metastatic Economics melanoma in the MELBASE cohort in real life. Nutrition, biomarkers of exposure to fatty acids and risk of ovarian cancer and endometrial cancer in the European EPIC Epidemiology cohort. Exploitation of genetic and epigenetic signatures detected in tumour DNA to make inferences about the aetiology of cancer Epidemiology in the context of epidemiological studies. Environmental risk factors for childhood brain tumours. Epidemiology FRENCH NATIONAL CANCER INSTITUTE 81 2015-2016 SCIENTIFIC REPORT

5INTERNATIONAL 5 COMMITMENTS Key actions The International programme on cervical cancer control In Europe, the CANCON Joint Action will soon enact its final set up by INCa is gaining momentum, with the active set of recommendations for quality improvement in cancer involvement of 5 Sub-Saharan African countries, 2 Asian control. TRANSCAN-2 is pursuing its now well-established countries and WHO to help the global network transition European mandate in translational research with the launch from research to public health. of its second call for research proposals. The European INCa’s President has had the privilege to be a member on Commission Expert Group on Cancer Control is preparing the Strategic Advisory board of the Global Alliance for the next phases of concerted new efforts to be delivered by Genomic and Health. the Health Programme in cancer control.

5.1. STRATEGIC VISION, MISSION clinical benefits. Networks also represent a shift from competition AND VALUES to cooperation. INCa has a pre-eminent role in France with a national mandate encompassing all activity areas of value in the cancer control INCa’s commitments in Europe and more globally on the chain, from research to prevention and screening, to the international setting reflect the above vision, mission and values. organisation of cancer care and information for patients and their relatives. The specific nature of INCa’s integrative mission At the European level, INCa is involved in 4 European projects provides our Institute with a distinctive voice in the global cancer and joint actions on cancer control: CANCON, TRANSCAN-2, control arena that is valued by other agencies and professionals FLAG-ERA, the Joint Action on Rare Cancers and is representing worldwide. Figure 37 shows how INCa’s global portfolio acts France on the Expert Group on Cancer Control established synergistically with national cancer control objectives in France, by the European Commission. INCa is also committed in the and how the connections between national and network following initiatives: the Global Alliance for Genomics and Health capabilities have a decisive impact on global health. (GA4GH), the International Cancer Genome Consortium (ICGC), the International Cancer Research Partnership (ICRP), the Global A dear principle driving INCa’s global endeavour is its attachment Initiative on Cancer Registry (IARC-GICR), the International Rare to multilateralism with an empowering vision grounded on Cancers Initiative (IRCI) and the International Consortium for solidarity. Action and Research on Tobacco Control (ICART).

Support for the French-speaking countries has become an INCa is actively involved in French-speaking Africa and in Asia, obvious and heartfelt choice for INCa as well. INCa’s support where its international programme on HPV and cervical cancer goes preferentially to initiatives that promote collaboration across control has been implemented. The Institute has also established regions of the world, advancing research towards community privileged bilateral agreements aiming at improving cooperation priorities to build bases of evidence. Global networks are emerging in cancer control with the US-National Cancer Institute, the as a shared response to the challenge of coordinating cancer Senegalese Health Authority, the Chinese National Cancer Center, control more efficiently. They make it possible to spread excellence the Japanese National Cancer Center and the Brazilian National and concentrate resources, with clear advantages in terms of Cancer Institute. FRENCH NATIONAL CANCER INSTITUTE 82 2015-2016 SCIENTIFIC REPORT

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

CCP Transversal objectives 2014-2019 Cancer Control Plan objectives

Childhood, Reducing Enabling Public Innovation Personalized Comprehensive Tobacco control Global Partnership adolescents inequities earlier diagnosis health & research medicine and personalised (Objective 10) / Cancer Control and young adults (Objective 1) (Objective 15) (Objectives 5 & 13) (Objective 6) cancer care (Objective 16) cancers (Objective 7)

JARC CANCON EUROMED IARC - GICR CANCON ICGC CANCON ICART European Commission EXPERT Joint Action on RARE Quality improvement Screening & Global initiative on Quality improvement International Cancer Quality improvement International GROUP on cancer CANCERS in cancer control early diagnosis in cancer registry in cancer control Genomic Consortium in cancer control Consortium for Action control Mediterranean and Research on WP9 – Childhood (WP8 – Survivorship & countries (WP6 – cancer care (WP8 – Survivorship & Tobacco Control cancers rehabilitation) network) FLAG ERA rehabilitation) US NCI Digital medicine COFAC COL US National Cancer for cancer Institute - Global JARC Collaborative network coordination CANCON on cervical cancer TRANSCAN 2 Joint Action on RARE control Quality improvement Translational research CANCERS GA4GH in cancer control NCC – CHINA WP5 – Quality of care Global Alliance (WP9 – Screening) National Cancer Center LAOS / THAILAND for Genomics – cancer control and Health Research & public health projects on ICRP IARC cervical cancer control International Cancer International Agency Research Partnership for Research on Cancer – INCa sits at IARC SENEGAL Board of Directors Agreement on cancer ICGC control International Cancer FRENCH Genomic Consortium POLYNESIA WHO Cancer control Implementation US NCI of WHO guidelines on cervical cancer National Cancer control Institute - Early phase clinical trials

IRCI Global Partnerships Bilateral agreements International Rare Cancers Initiative

Europe Regional Networks JAPAN Memorandum of Understanding with Japan National Cancer Center on research See pages 14 and 15

5.2. INCa’S EUROPEAN COMMITMENTS INCa has actively contributed to the definition 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 The CANCON Joint Action will soon enact its final set of general hospitals and other healthcare institutions (imaging recommendations for quality improvement in cancer control. centres, community care centres, etc.) as well as primary care CANCON is a Joint Action co-funded by DG SANTE which aims providers (general practitioner, home nurses, etc.). Literature at supporting Member States’ cancer control policies, in the areas review shows that CCCNs are emerging as a shared response to of cancer care coordination and population-based screening, the challenge of coordinating cancer care among existing services, survivorship and rehabilitation. Recommendations in these areas with a patient-centred approach. The CCCN model promotes will be compiled into a European guide on quality Improvement equity of access to high-quality care, optimised use of facilities in comprehensive cancer control, to be published in 2017. and improvements in cost-effectiveness. Besides, CCCNs offer optimal conditions to conduct translational, clinical and outcome INCa leads CANCON’s work on survivorship and rehabilitation research. The Regional Cancer Networks established in France (WP8), and is actively involved in 2 other work-packages, on under the Legal act of 25 September 2007 are in line with the comprehensive cancer care network (WP6) and on cancer CCCN model promoted by CANCON; the same is true for the screening (WP9). French SIRICs with regards to research integration into CCCNs. FRENCH NATIONAL CANCER INSTITUTE 83 2015-2016 SCIENTIFIC REPORT

Concerning survivorship (WP8), INCa has coordinated the effectiveness, health-economy and harm-benefit monitoring) of drafting of the 38 recommendations which address the cancer screening. 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 TRANSCAN-2 is pursuing its now well-established European European organisational survivorship care model, embedding mandate in translational research with the launch of its second survivorship and rehabilitation throughout the continuum of call for research proposals. care to improve survivors’ quality of life. Key messages (pending The ERA-Net TRANSCAN-2 project is a unique European network final review) include: of research funding agencies and ministries from 15 Member •• Cancer survivor follow-up, late effect management and States, 3 Associated Countries, and a third country (Taiwan) tertiary prevention needs to be anticipated, personalised and actively involved since 2011, with the support of the European implemented into care pathways, with the active involvement Commission, in financing high-impact translational cancer of survivors and their relatives; research projects. The overarching aim of TRANSCAN-2 is to •• Early detection of patient needs and access to rehabilitation, achieve sustained coordination in the area of translational psychosocial and palliative care services should be improved; cancer research beyond national boundaries or interests (see •• An integrated and multi-professional care approach section 2.1.2). coordinated with community care providers is needed to implement the survivorship care plan; TRANSCAN-2 works as a hub for European research funding •• For children, adolescent and young adult survivor, late health agencies and ministries to coordinate their funding strategy and psychosocial effects of cancer and treatments should be through joint calls for proposals, offering their respective anticipated and addressed; country’s scientists a unique opportunity to collaborate across •• More research in the area of survivorship is needed to Europe, with funding allocated under the known rules of their provide data on late effects, as well as the impact and cost- own country. To ensure research excellence, project selection is effectiveness of supportive care, rehabilitation, palliative and carried out by an international independent high-level scientific psychosocial care interventions. evaluation committee. Five joint transnational calls have already been launched under TRANSCAN 1 & 2, with 46 collaborative INCa is also involved in WP9, the purpose of which is to produce research projects currently funded, while the results of the 5th further advice and guidance for accurate implementation call are expected by the end of this year. of cancer screening in the EU Member States, in accordance with current European quality assurance guidelines for cancer TRANSCAN-2 has placed a particular emphasis on close screening. Challenges in screening implementation, addressed in collaboration with its Scientific Advisory Board, which includes WP9, are related to issues in planning and gradual well-steered eminent scientists. Their opinions serve as the basis to steer the introduction of currently recommended programmes in regions strategic decisions of TRANSCAN-2. or settings where effective and cost-effective programmes are not yet available; modifying or reorganising currently running INCa is the leading party of the TRANSCAN-2 work-package that programmes with new tests, treatments, policies or organisational defines the network’s strategy and scientific research priorities. models; and developing key strategic tools on evaluations needed Under WP4, INCa coordinates in particular the development of for policy-making on possible new cancer screening programmes links with other European and international initiatives, keeping (other than for breast, cervical or colorectal cancer). The current track of their endeavours to provide the network with topical chapter includes 8 policy recommendations on governance inputs. INCa also has been renewed as chair of the TRANSCAN‑2 (structure, quality assurance procedures, and legal framework), network board. organisation (implementation in multiple phases, mandate and resources) and evaluation (linkage and indicators for quality and FRENCH NATIONAL CANCER INSTITUTE 84 2015-2016 SCIENTIFIC REPORT

5.3. INCa’S GLOBAL COMMITMENTS

European Commission expert group on Cancer Control Member State and stakeholder representatives brought together Immediate past President of INCa invited to serve on the in the European Commission Expert Group are preparing the Strategic Advisory board of the Global Alliance for Genomics next phases of concerted new efforts to be delivered by the & Health. Health Programme in cancer control. Immediate past President of INCa has had the privilege of INCa has been appointed by the Health Authorities to sit serving on the Strategic Advisory Board of the Global Alliance for on France’s behalf on the Expert Group on Cancer Control Genomics and Health (GA4GH; http://genomicsandhealth.org/) established by the European Commission pursuant to the Decision which includes the Directors of the Host Institutions, Directors of June 2014 (2014/C 167/05). The mandate of the expert group of major funders of the Alliance (NIH, Wellcome Trust) and a is to assist the Commission, at its request, with drawing up number of independent global leaders from various fields. In policy documents, guidelines and recommendations on cancer accepting this task, INCa wanted to acknowledge the momentum control. Members of the expert group include representatives of created by GA4GH and the challenges ahead to advance the EU, EEA and EFTA countries, as well as representatives of patient implementation phase of data sharing. INCa is committed to organisations, European and international organisations active moving forward and being an active member of this global in cancer prevention, and European professional or scientific endeavour. associations. The last meeting of the group was convened in Luxembourg on February 2016. In line with the roadmap of items GA4GH was formed to help accelerate the potential of genomic established for the group, this session included a review of the medicine to advance human health. It brings together over state of play of various cancer initiatives, so as to provide advice 300 leading institutions working in healthcare, research, disease on the need to reinforce the ongoing European framework on advocacy, life science, and information technology. The partners cancer control and the different options for doing so through in GA4GH work together to create a common framework of the Health Programme. 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. FRENCH NATIONAL CANCER INSTITUTE 85 2015-2016 SCIENTIFIC REPORT

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

COFAC Col LAOS/THAILAND Collaborative Research & Research & Public Public Health Network Health project o on cervical cancer control n cervical cancer in Francophone Africa in HIV+ women Pays : Gabon, Senegal, Cameroon, Cote d’Ivoire, Madagascar LaoCol VP: Multicenter cross-disciplinary study analysing the efficacy and cost/effectiveness Study scope: identification of of cervical lesion screening HPV genotypes associated with by HPV detection vs Pap smear high-grade intraepithelial neoplasia in HIV infected women in Laos. lesions and invasive cancers/ PapilloV: Research study analysing Monitoring of HPV 16/18 prevalence the HPV infection and cervical to assess the potential benefits lesions in HIV+ women receiving of a vaccination programme antiretroviral therapy in Thailand

Senegal Cooperation agreement WHO Cooperation agreement Union for the Mediterranean on Cancer control to help with guidelines' implementation EUROMED (research & public health) in cervical cancer control Mediterranean countries

Feasibility study using Focus on liquid biopsy for HPV detection Screening

Asia infections and associated cervical lesions. The study was also to Two studies have been funded/co-funded by INCa in Asia, provide the distribution of the HPV genotypes involved and assess targeting HIV+ women in Thailand and Laos, with a view to the other risk factors of cervical lesions. The public health goal of collecting evidence and building capabilities for cervical cancer the study is to help design screening algorithms for early detection control in these countries. The results of the studies are reported of cervical cancer based on the identification of HPV-HR and to below. Their principal investigators cooperated and convened an allow the assessment of an HPV vaccine policy in this specific international meeting in June 2016 to discuss the outcomes of population. This study was conducted within a cohort of HIV- the studies and the implementation of their public health goals infected women receiving antiretroviral treatment in Thailand, with the health authorities. the PHPT cohort (PHPT is an International Research Unit of the Institut de Recherche pour le Développement (IRD) in France Thailand: the “PapilloV-HPV infections and associated cervical and the Faculty of Associated Medical Sciences at Chiang Mai lesions in HIV+ Thai women” research programme comes to a University in Thailand). The follow-up of these women includes close. Pap-smear and HPV testing every year, with treatment and more The main objective of the “PapilloV” study was to palliate the lack intensive follow-up for women with cervical lesions or HR-HPV of information concerning HPV ecology and the risk factors of infection. Between February 2012 and June 2013, 829 HIV- cervical cancer in HIV-infected women in Thailand, by assessing infected women were enrolled in the 24 participating public the prevalence, incidence, and clearance rate of HPV cervical hospitals throughout Thailand. At inclusion, a gynaecological FRENCH NATIONAL CANCER INSTITUTE 86 2015-2016 SCIENTIFIC REPORT

exam, a cervical sample for HPV genotyping and a Pap smear for •• In Gabon: Molecular epidemiology and HPV prevalence screening of cervical lesions were performed. These exams were in premalignant lesions and cervical cancers in the female repeated every year for 3 years. At baseline, 26% of the women had population of the River Congo Basin; HPV -infection including 18% high-risk HPV (HR‑HPV). HPV52, •• In Senegal: Prevalence of oncogenic HPV in CIN2+ lesions; HPV39, HPV51, HPV16 and HPV18 genotypes were respectively •• In Cote d’Ivoire: Genotyping of HPV-DNA associated with identified in 20%, 14%, 14%, 12% and 5% of HR-HPV cases. cervical neoplasia; •• In Cameroon: Prevalence and genetic diversity of oncogenic Laos: the LaoCol-VP research programme delivers preliminary HPV types in precancerous lesions and invasive cervical cancers results. in Cameroon; LaoCol-VP is a collaborative study between the Centre of •• In Madagascar: Genotyping and prevalence study of HPV Infectiology Christophe Mérieux located in Vientiane and the Lao associated with cervical neoplasia in Madagascar. National HIV/AIDS Control Programme (CHAS) on the efficacy and cost-effectiveness of HPV-based screening methods vs Pap These research projects are implemented as a collaborative effort smears for the detection of cervical cancer among HIV+ women of the network, with standard protocols and implementation living in Laos. The study is also to compare the performance of issues being discussed during regular teleconferences organised careHPV™ versus Pap smear for the detection of CIN2+ lesions and by INCa. The network is co-coordinated by the Lorraine Institute evaluate the prevalence of the different types of oncogenic HPV of Oncology. A shared online database has been developed by among HIV+ women living in Laos. It is a multicentre transversal the coordinator (Institut Joliot-Curie of Dakar, Senegal) to collect study involving 4 principal hospitals in Laos. The purpose is the data of all participating countries. Each country’s team to raise awareness and capacity of professionals across the involves pathologists, oncologists, virologists and epidemiologists. country. 644 women have been enrolled to date. After informed COFAC-Col is achieving its primary goals as its preliminary consent, careHPV™ testing, Pap smear, colposcopy, with biopsy results have been obtained. if necessary and genotyping with PapilloCheck™, were performed •• In Gabon, 93 patients have been enrolled to date, with among and results analysed separately. Preliminary results show 35% them 57 carcinomas and 20 CIN3. The preliminary results positive careHPV™ tests; 19% abnormal colposcopy results. Of indicate the presence of HPV16 & 18 in 19 samples. these, 52 (41%) are CIN1, 43 (34%) are CIN2+ and 5 present •• In Senegal, 168 patients have been enrolled and pathology invasive carcinoma. CareHPV™ showed a better sensitivity and testing performed on 120 samples. 101 carcinomas, a lower specificity compared to Pap smear for the detection of 3 adenocarcinomas and 3 CIN3 have been found. 44 samples CIN2+. HPV16, HPV52, HPV68, HPV51 and HPV18 genotypes have been analysed for HPV, 23 of which were found to be were respectively identified in 18%, 18%, 16%, 14% and 8% of HPV+. The preliminary results indicate the presence of HPV16 HR-HPV cases. (14 samples), HPV45 (3 samples), HPV18 (2 samples) and HPV31, 33, 35 and 39 in 1 sample respectively. The study is co-sponsored by INCa and the Mérieux Foundation. •• In Cameroon, 40 patients have been enrolled, 22 samples analysed and result show HPV16 in 4 samples. Africa •• In Cote d’Ivoire, the teams are ready to start with a COFAC-Col: the African Consortium for Cervical Cancer control retrospective analysis of 50 samples. is spurring connections between national & network capacities. •• In Madagascar, the retrospective study will concern 448 samples. To date, 160 samples have been amplified by In 2013, INCa launched during the annual meeting of AORTIC, PCR, including 122 squamous cell carcinoma and 14 CIS the African Consortium on Cervical Cancer Control (COFAC- 2&3. The preliminary results indicate the presence of HPV9 in Col) with 5 African countries (Senegal, Gabon, Cote d’Ivoire, 10 samples, HPV16 in 10 samples, HPV18 in 1 sample and Cameroon and Madagascar). The current focus of the network HPV45 in 11 samples. is on identifying the nature of the HPV genotypes associated with high-grade intraepithelial neoplasia lesions and invasive cancers A letter to the editor entitled “COFAC-Col: a cervical cancer in a series of significant cases coming from these countries. Under control networking initiative in 5 French-speaking African COFAC-Col, INCa funds the following research projects: 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 FRENCH NATIONAL CANCER INSTITUTE 87 2015-2016 SCIENTIFIC REPORT

built as a specific sub-study of an ongoing study in France the Next steps purpose of which is to evaluate the specificity and sensitivity of of the programme the test under real conditions. ••Feasibility study using liquid biopsy for HPV detection WHO to help the global programme transition from research to be launched in Senegal. to public health. INCa has entered into an agreement with the World Health ••WHO to help the global programme transition from Organization (WHO) - Department of reproductive health & research to public health. research. The main purpose of the agreement is to promote ••INCa is funding the first stages of an ambitious Union for implementation of WHO guidelines on cervical cancer control the Mediterranean (UfM) project in health, conducted by by French-speaking low and medium-income countries. The the WHO collaborating centre for cancer early detection agreement comprises 3 complementary objectives: and screening. •• 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 Feasibility study using liquid biopsy for HPV detection to be issue among French-speaking countries; launched in Senegal. •• The development of recommendations regarding a A joint study between the Lorraine Institute of Oncology and screening algorithm: “HPV testing followed by Pap smear”, Institut Joliot-Curie of Dakar will be launched using a liquid which is relevant for those countries which have set up biopsy test, CaptHPV, to detect circulating HPV DNA. This cytology capacities and started Pap smear-based screening study is based on recent publications showing that circulating programmes; HPV DNA can be detected in the serum of patients at each •• Technical assistance for the implementation of WHO cervical stage of HPV‑associated carcinoma using droplet PCR (Journal cancer control recommendations in the COFAC-Col countries. of Pathology, 2016, Nature Partner Journal Genomic Medicine, 2016). The methodology and tools developed for English-speaking As the promise of liquid biopsy as a potential screening tool countries will be adapted to the context of the COFAC-Col continues to grow, the Senegalese study should demonstrate that countries, to help upgrade their current cervical cancer control the test is also capable of detecting the HPV genotypes present programmes, with a coherent and homogeneous approach. in the Senegalese patient population. This innovative study is

Implementation of WHO cervical cancer control recommendations French version of WHO Recommendations regarding a screening in the COFAC-Col "Comprehensive cervical countries with adapted cancer control: a guide algorithm "HPV testing followed by Pap smear" methodologies and tools to essential practice" developed for English-speaking countries

Fig. 39. The 3 complementary objectives of WHO – INCa agreement FRENCH NATIONAL CANCER INSTITUTE 88 2015-2016 SCIENTIFIC REPORT

A workshop will be organised jointly by INCa and WHO, with the INCa and China National Cancer Center sign a Memorandum COFAC-Col teams and country health representatives, as well as of Understanding. eminent experts. Technical assistance tailored to each country’s A bilateral Memorandum of Understanding was signed in needs will be provided by WHO to facilitate the implementation June 2016 where INCa and China National Cancer Center of the guidelines (drafting of national strategy papers, training intend to enhance and expand cooperative efforts in the field plans for health professionals, etc.). of cancer control, through mutual exchanges. The focus is on implementation of the Cancer control plan on a national and INCa is funding the first steps of an ambitious Union for the regional/provincial level, including governance and impact Mediterranean (UfM) project in health, conducted by the WHO assessment. Personalised medicine has also been discussed during collaborating centre for cancer early detection and screening. a visit by an NCC delegation to INCa. 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 first 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. © Institut National du Cancer, 2016 FRENCH NATIONAL CANCER INSTITUTE 89 2015-2016 SCIENTIFIC REPORT

INCa has received delegates from the Brazilian National Cancer the implementation of the frame agreement signed between the Institute. Health Authorities of both countries. Discussions have focused As part of the frame agreement signed between the Health on the strategic research programmes implemented by both Authorities of France and Brazil, INCa has received delegates Institutes, as well as on the rolling out of personalised medicine from the Brazilian National Cancer Institute, headed by its in France. The visit of the molecular diagnostic centre of HEGP Deputy General Director. allowed the delegates to grasp the organisational framework developed by INCa. Areas of collaboration have been addressed, The INCa has had the privilege to welcome delegates from the in particular the setting up of a molecular diagnostic collaborative National Cancer Institute of Brazil, in June 2016, as part of network.

© Institut National du Cancer, 2016

Global investments in international programmes Fig. 40. Distribution of the projects allocated to the INCa’s support for the international programmes amounts to international programmes according to the CSO €1.41M. The CSO classification shows that support was primarily classification dedicated to aetiology (HPV genotyping) and early detection, including dedicated equipment and training for diagnosis 14 % (Figure 40).

Aetiology Prevention 38% Early detection, diagnosis, and prognosis Cancer control

43 % 5% FRENCH NATIONAL CANCER INSTITUTE 90 2015-2016 SCIENTIFIC REPORT

6BIBLIOMETRIC STUDY, EVALUATION 6 AND REVIEW OF RESEARCH INVESTMENT Inserm has conducted a bibliometric study for ITMO Cancer- 6.1. BIBLIOMETRIC STUDY Aviesan in order to assess France’s position in the cancer research field1. 6.1.1. FRANCE IN WORLDWIDE RESEARCH Over the 2011-2015 period, 7,287,402 articles, letters and reviews This study is also a major component of the evaluation process published worldwide were indexed in the Web of Science core that INCa proposes to measure the outcomes and the impact of collection. Of these publications, 2,898,196 belong to biomedical cancer research funding, detection of innovation and emerging research. research trends and the definition of research priorities. This information is also shared with the ICRP consortium in When using the citation criterion, France is ranked 5th and 6th in order to discuss and implement appropriate survey tools and scientific research and biomedical research, respectively (Tables methodological approaches for impact assessment. 33 and 34).

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

% international % industry % highly Country Nb of articles Times cited Rank collaborations collaborations 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". FRENCH NATIONAL CANCER INSTITUTE 91 2015-2016 SCIENTIFIC REPORT

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

% international % industry % highly Country Nb of articles Times cited Rank collaborations collaborations 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 55% of French general publications are co-signed with another publications worldwide correspond to the visibility indicators country and 3.3% involve an industrial partner. In the biomedical and position France above the world standard (3rd rank). field, 47% of French publications are international collaborations and 4% with industry. Importantly, France shows high rates of collaboration with international and industrial partners.

6.1.2. FRENCH CANCER RESEARCH Over 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

Nb total Nb % in the cancer Country Rank of publications Cancer publications 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 FRENCH NATIONAL CANCER INSTITUTE 92 2015-2016 SCIENTIFIC REPORT

France is ranked 7th with 40,196 publications on cancer, cancer research field. Moreover, the internationalisation of cancer representing 4.7% of the overall cancer publications. research publications in this corpus is important for the majority of countries, except for USA and China that have less than 50% International profile of French cancer research of publications with an international partner. In the most highly cited papers corpus, France represents 11% and is ranked 4th, highlighting the French contribution to the

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

Nb Part % international % industry Country Rank publications in the corpus (%) collaborations 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 The USA is the leading partner of France in terms of number countries. In general, international partnerships raise the profile of publications with more than 6,800 publications co-signed of French publications. Indeed, the percentages of publications during the 2011-2015 period, while with fewer publications, in the highly cited corpus are greater compared to the world articles co-signed with Australia and the Netherlands have the standards or to France alone. highest profile. FRENCH NATIONAL CANCER INSTITUTE 93 2015-2016 SCIENTIFIC REPORT

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)

Australia USA USA 6,860 40.07% Australia 33.91% 1,375 United Kingdom United Kingdom 35.72% Switzerland 4,577 Switzerland 2,007 34.28%

Canada Canada 2,222 35.87% Germany France Germany France 36.53% 4,407 Belgium Belgium 2,307 35.85% Italy Netherlands Italy 35.47% 2,663 4,294 Netherlands 38.04% Spain Spain 2,867 36.69%

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

Clinical medicine in Cancer research The major medical specialties of the cancer corpus that are Among the worldwide publications, the main research categories highly cited are Oncology, Medicine, research and experimental published are Clinical Medicine, Molecular Biology & Genetics (including general journals such as Nature Medicine, J Exp Med, and Biology & Biochemistry. In total, these publications represent EMBO, etc.) and Urology & Nephrology. 78.8% of the total publications. Moreover, the Oncology, Haematology and Medicine, In clinical medicine in the cancer corpus, the Oncology research and experimental specialties show the highest rates of subcategory represents 45% of publications. collaboration with international and industrial partners. FRENCH NATIONAL CANCER INSTITUTE 94 2015-2016 SCIENTIFIC REPORT

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

Category % % Part % % % Medical specialties Nb Times normalised documents Highly Clinical documents international industry (WoS categories) publications cited citation in Top cited medicine in Top 1% collaborations collaborations impact 10% papers 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 6.22 Radiology, 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 2.71 Source: 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 Health In the cancer corpus, France is ranked sixth with 5.9% of total The visibility indicators show that the French publications publications on human and social sciences related to cancer. are ranked first in the highly cited papers category in journals French publications show the highest rate of highly cited papers. dedicated to social sciences, clinical trials and biology, and Interestingly, for human and social sciences related to second in oncology journals. cancer in journals dedicated to social sciences, in oncology Thus, France exhibits major advantages in human and social and in clinical trials, France is ranked first for publications sciences related to cancer. with industry. FRENCH NATIONAL CANCER INSTITUTE 95 2015-2016 SCIENTIFIC REPORT

6.2. FOCUS: TRENDS IN THE FRENCH These descriptive elements showed diversity amongst the targeted FUNDING STREAM OF INTERVENTION populations and in the types of partnerships involved (Figure 42). RESEARCH ADDRESSING ALL ASPECTS Different disciplines were used in the research proposals: public OF CANCER CONTROL, A CROSS-SECTIONAL health and epidemiology, but also a wide range of human and ANALYSIS 2010-2014 social sciences. Methodological diversity emerged in the projects: quantitative designs (38 projects, 3 funded), qualitative designs Since 2010, INCa has supported population health intervention (4 projects, one funded) and mixed-methods studies (33 projects, research1, in the 2009-2013 and 2014-2019 National Cancer 11 funded) (missing data for 4 projects), as well as a commitment control plans, and through the national and competitive to prevention research. dedicated programme2. This call for proposals is based on WHO recommendations3: It was difficult to identify the logic models of several research •• to improve daily living conditions; proposals. In some cases, several theoretical frameworks were •• to tackle the inequitable distribution of power, money, and used, from different levels of abstraction: conceptual models resources; (e.g. patient navigators, Fiscella, 20114), or middle-range theories •• to measure and understand the problem and assess the impact (e.g. Theory of planned behaviour, Ajzen, 19915). of action. Between 2010 and 2014, the funded projects were predominantly At the present time in France, the development of intervention quantitative. Regarding actions tackling health inequities, the research is a major concern, supported in the National Health interventions mostly addressed individual factors6. Strategy as well as in the National Research Strategy. Between 2010 and 2014, 15 projects were funded by INCa, for a total In 2015, the administrative guidelines strongly encouraged of €7.3 M. original partnerships between research teams in various disciplines (human and social sciences, public health [prevention/health After five years of funding, a specific analysis was needed on promotion], epidemiology, biostatistics, etc.) and practitioners the proposals submitted for funding and/or funded (n=63) in the field (medical, allied health, and social services personnel, in descriptive and analytical perspectives (types of scientific non-profit organisations, etc.). engagement of the investigators, methodological and sociological trends). Based on the findings of this analysis, in 2016, the call for proposal stresses that research proposals need to justify the Findings showed that the principal investigator gender population theoretical framework of the intervention and evaluate the between 2010 and 2014 was balanced (26 woman and 37 men). effectiveness7 of the proposed intervention, and now contains All possible academic diplomas were represented. The majority a transversal axis based on the explicit integration of the issue of the investigators held a PhD degree and half of them a French of health inequalities in research plans. 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.

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; 2015 3 – 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 2010 4 – Fiscella K. et al. (2011). Patient-reported outcome measures suitable to assessment of patient navigation. Cancer, 117, 3603-3617. doi: 10.1002/cncr.26260 5 – 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.2005.037242 7 – 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 FRENCH NATIONAL CANCER INSTITUTE 96 2015-2016 SCIENTIFIC REPORT

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

isciines Sexology 1 Environmental sciences 1 Virology 1 Physical activity sciences 3 Medical Information 3 Work health 1 1 Political Sciences 1 1 Geriatrics 6 1 Biostatistics 9 1 Educational sciences 4 2 Addictology 5 2 Medical oncology 30 3 Nutrition 8 4 Mental Health-oncopsychology-neuropsychology 12 5 Economy 15 5 Human and social sciences 24 5 Public health 29 9 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

utins Migrants 1 Pregnant women 1 1 Supporters 1 1 Farmers 1 1 Population- community 1 1 Decision makers 1 1 Teachers 1 Projects - methodological 1 1 Disabled people 1 Workers 2 Smokers 2 Elderly people 3 Physicians, health professional, social workers 3 1 Survivors 5 Children/ teenagers/ Family 7 4 People in precarious- poor situation 9 2 Patients 23 2 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

tnesis General practitionners (GP) 3 Occupationnal health 1 Prevention project manager 2 2 French Cancer Registries 5 1 Legal sector 1 Healthcare profesionnals 14 Local authority 6 5 Healthcare insurrance (CPAM)/ Pension fund 3 3 University hospital (CHU) 30 7 Local Institutes for health promotion/education (IRESP/CRES) 5 3 International collaboration 4 Associations 25 5 Industrial collaboration 3 1 Health economy 9 Unemployment office (Pôle Emploi) 1 National education sector 2 2 ARC Foundation 6 French National Cancer League 4 Health Regional Observatory (ORS) 2 1 Not funded Multidisciplinary collaboration 28 15 Funded 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% FRENCH NATIONAL CANCER INSTITUTE 97 2015-2016 SCIENTIFIC REPORT

6.3. INTERNATIONAL EVALUATION 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 Established in 2000, the International Cancer Research cancer research being conducted, explore opportunities for Partnership (ICRP) is a unique alliance of cancer organisations, cooperation between funding agencies and enable our members working together to enhance global collaboration and strategic to maximise the impact of their independent efforts.

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

• Canadian Cancer Research Alliance (representing 42 organisations)

• NCRI (Representing 27 organisations)

• KWF Dutch Cancer Society • INCa

• National Cancer Center • 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 • National Breast Cancer • Pancreatic Cancer Action Network Foundation • California Breast Cancer Research Program • Cancer Australia • Oncology Nursing Society Foundation • Cancer Institute New South Wales • National Pancreas Foundation

ICRP organisations share funding information in a common format (known as the Common Scientific Outline orCSO ) 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. FRENCH NATIONAL CANCER INSTITUTE 98 2015-2016 SCIENTIFIC REPORT

Detailed analysis of the international cancer research portfolio Further work is ongoing both within ICRP and in partnership provides contextual data for cancer research organisations. The with other international initiatives to link investment in cancer data allows funders to see the impact of their own investments, research to research outputs (such as publications, patents) and track national and global trends relevant to their own areas of patient impact. 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 Highlight patients. ICRP hosted a panel entitled “ICRP: A Global Thanks to this partnership, INCa enjoys the following benefits: Collaboration Enabling Analyses of Sponsor-Funded •• Access to senior representatives from an active, international Cancer Research” at the prestigious American network of cancer research funding organisations; Evaluation Association meeting in Chicago on •• Ability to share data/information on research evaluation and 11 November 2015. outputs; The topics covered were: •• Disseminate the projects funded in France by INCa and its • Translational research: monitoring trends in the partners (Ministry of Health, ARC Foundation, LNCC); international cancer portfolio; •• Access to the online research portfolio on the ICRP website, • Prevention research: identifying and acting on trends in providing a cost-effective way to display the current and research funding; ongoing cancer research data on an internationally recognised • Global assessment of funding trends across a diverse website; spectrum of breast cancer research; •• Unrestricted use of partner-only analytical tools to conduct • Assessment of the International Cancer Research (pooled) data analyses to identify areas of strengths and gaps Partnership’s lung cancer portfolio. in cancer research, avoiding duplication and enhancing the organisation’s ability to fund strategically; •• Access to a forum for identifying scientific areas for multidisciplinary research and collaborations; 6.4. REVIEW OF RESEARCH INVESTMENTS •• Obtain assistance for the development of databases for its own research portfolio; 6.4.1. TOTAL CANCER RESEARCH FUNDING IN 2015 •• Identify referees for the evaluation process of INCa’s calls In 2015, INCa, Ministry of health and ITMO Cancer-Aviesan for proposals. have allocated a multi-year total amount of €95.5M to research projects selected through competitive calls for research proposals In this way, ICRP provides a network and forum for cancer and grants for designation. In addition ITMO Cancer-Aviesan organisations to discuss investment trends and strategies; and supported in 2015 research lab equipment that amounted identify collaborative opportunities to address gap areas, where approximately €4.9M and not included in the analyses presented appropriate. Moreover, the consortium publishes periodic reports below. on topic areas of interest: •• Trends in global cancer research funding 2005-2012: an Figure 44 shows the funding allocation according to the CSO analysis from the International Cancer Research Partnership; classification. Research projects in cancer biology and treatment •• Translational research methodology report; have represented the most significant investments with 29% and •• Obesity in Cancer report; 41%, respectively. On the other end, cancer prevention represents •• Environmental influences in Breast cancer report; a mere 2% of the budget. •• Landscape analysis chapter in Metastatic Breast Cancer Alliance report. FRENCH NATIONAL CANCER INSTITUTE 99 2015-2016 SCIENTIFIC REPORT

Fig.44. 2015 multi-year cancer research funding Fig.45. Multi-year 2015 research funding of the programmes (INCa, Ministry of Health, ITMO Cancer-Aviesan) operated by INCa and ITMO Cancer-Aviesan according according to the CSO classification to the CSO classification

7% 80 Cancer control Treatment 29% Early Detection, € 6.2M diagnosis, prognosis 70 8% Prevention Biology = €27.7M Aetiology Aetiology = €7M Prevention = €2.2M Biology Early detection, diagnosis, 60 and prognosis = €13.1M Treatment = €39.3M Cancer control = €6.2M 50 € 35.7M 7% 49% 41% 2% 14% 40 € Million

The budget managed by INCa amounted €73.9M, including 30 Minstry of Health funding, while about €21.6M relates to the € 10.6M programmes managed by ITMO Cancer-Aviesan. 14%

Figure 45 shows the budget allocation of the programmes 20 € 2.2M / 3% € 3.6M / 17% 3.1M / 4% operated by INCa and ITMO Cancer-Aviesan according to the € € 2.5M / 12% CSO classification. € 3.9M / 18% 10 € 16.1M Cancer biology represents the highest investment with 53% of 22% € 11.6M the ITMO Cancer-Aviesan budget, aetiology comes second with 53% 18%, then treatment 17% and early detection 12%. 0 ITMO Cancer-Aviesan programmes are essentially thematic calls INCa ITMO Cancer-Aviesan 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 The breakdown of 2015 funding is different for INCa programmes. dedicated to the study of environmental risks. 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 FRENCH NATIONAL CANCER INSTITUTE 100 2015-2016 SCIENTIFIC REPORT

trial of innovative molecules and targeted therapies. This is in •• Strategic research initiatives and thematic projects that line with the precision medicine plan supported and rollout by encompass INCa’s actions to support precision medicine and INCa, in compliance with the objectives of the 2014-2019 Cancer the targeted research programmes managed by ITMO Cancer- control plan. Aviesan and the projects targeting a tumour type through the integrated research programme supported by INCa and the Early detection, diagnosis and prognosis support have represented charities ARC Foundation and LNCC; 14% and aetiology 4% of the programmes operated by INCa, •• Platforms, resources and infrastructures; respectively. Finally, cancer control, survivorship and outcomes •• Research training and young teams of excellence that covers research, and prevention research represented a total of 8% of especially ATIP-Avenir and the translational research training the budget allocated to research. programmes.

This budget allocation reflects INCa’s cross-functional support This figure shows that 54% of the allocated budget was dedicated to cancer research and the complementarity between the to the competitive investigator-driven CFPs, managed by INCa programmes managed by INCa and ITMO Cancer-Aviesan. whereas the thematic calls for proposals launched by ITMO Cancer-Aviesan and the strategic clinical research initiatives Figure 46 presents the distribution of 2015 multi-year funding supported by INCa represented 27% of the overall 2015 multi‑year according to the different classes of programmes: funding. •• Investigator-driven projects that concern the 4 large research areas (biology, translational, clinical, human and social sciences, epidemiology and public health);

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

5% 14% 4% Investigator-driven calls = €51.5M 9% Strategic research initiatives/ HSS-EPH = €4.3M thematic programmes = €25.9M 18% Translational = €8.4M Platforms/resources/ 54% Biology and basic sciences = €17.2M infrastructures = €13.5M Clinical = €21.6M Research training/young teams of excellence = €4.6M 23% 27%

6.4.2. CANCER RESEARCH FUNDING The figure below presents the distribution of the funded projects FOR THE 2007‑2015 PERIOD and infrastructures according to CSO research categories and Since 2007, a total of 2,071 projects and applications have€ 6.2M highlights the importance of Treatment and Biology areas in been funded through the different competitive calls for research8% cancer research investments with 28% and 24%, respectively. proposals and grants for designation for a global amount of €803.40M. Projects addressing Cancer control and survivorship issues represented 20% of the overall funding during this period FRENCH NATIONAL CANCER INSTITUTE 101 2015-2016 SCIENTIFIC REPORT

that included the renewal of the Canceropôles designation in Figure 48 presents the distribution of the 2007-2015 funding 2014 with special emphasis on social sciences. per programme.

Early detection, diagnosis and prognosis category represented The investigator-driven calls for proposals of the four main 16% and encompassed mainly translational research, the support research areas (biology, translational, clinical and social sciences, to the molecular genetics centres and next generation sequencing epidemiology and public health) represented a total of 53% of implementation. the 2007-2015 investments, approximately €422M.

Fig. 47. Distribution of 2007-2015 multi-year cancer research Importantly, the support to resources and infrastructures funding (INCa, Ministry of Health, ITMO Cancer-Aviesan) represented one fourth of the total funding, i.e. about €195M, according to the CSO classification: €803M investment highlighting the willingness to reinforce the organisational framework and the coordination of cancer research activities. 2% 19% The support of cancer research training and the support to young 24% researchers represented 3% of the total allocated budget for the period 2007-2015, i.e. approximately €26M. BiologyBiology = €196M AetiologyAetiology = €65M PreventionPrevention = €21M EarlyEarly detection, detection, diagnosis, diagnosis, andand prognosis prognosis = €128M TreatmentTreatment = €223M CancerCancer control control = €153M 8% ScientificScientific models models = €17M 3% 28% 16%

Fig. 48. Distribution of 2007-2015 multi-year cancer funding per programme type (INCa, Ministry of Health, ITMO Cancer- Aviesan) 3%

24% 4% Investigator-driven calls = €422M 8% Strategic research initiatives/ HSS-EPH = €33M thematic programmes = €160M 18% Translational = €60M Platforms/resources/ 53% Biology and basic sciences = €145M infrastructures = €195M Clinical = €184M Research training/young teams of excellence = €26M 23% 20% FRENCH NATIONAL CANCER INSTITUTE 102 2015-2016 SCIENTIFIC REPORT

INCa’s research funding strategy, in line with the 2014-2019 Fig. 49. 2009-2015 trends in investment per programme Cancer control plan, is based on investigator‑driven calls for (multi-year grants) proposals, to ensure excellence, independence and creativity. Besides, the analyses of the areas covered by the investigator- 60 driven calls for proposals allow identifying the emerging research 50 fields and the unmet needs, and serve to establish the basis for the strategic programming, including the initiatives dedicated 40 to a specific type of cancer, such as the French support to ICGC programme. 30

In € Million 20 Besides the investigator-driven, the integrated research programmes (PAIR) targets cross-cutting research issues in one 10 pathology or cancer spectrum of clinical relevance. The next 2016 PAIR programme will focus on paediatric cancers. 0 2009 2010 2011 2012 2013 2014 2015 The thematic programmes support emerging research fields, such as Epigenetics, Systems biology, multidisciplinary research for the Investigator-driven calls development of news tools or techniques, Research in Physics, Platforms/resources/infrastuctures Mathematics and Engineering Sciences related to Cancer. This Strategic research initiatives/thematic programmes latter programme also provides different entry points and routes Research training/youngs teams of excelence to confront cancer progression and improve the detection, the diagnosis and the management of the disease. The support to investigator-driven projects, to research training Strategic research initiatives and thematic programmes and young researchers has been sustained over the years. represented nearly 20% of the total investments over the period 2007-2015, approximately €160M. Investments for resources and infrastructures have decreased the two past years. INCa has designated, initiated and implemented The figure 49 shows the trends of the different programmes several research infrastructures in the frame the successive funding over the period 2009-2015 and highlights the significant national Cancer control plans and has been now coordinating, increase of the support to strategic initiatives and thematic maintaining and reinforcing them to ensure an integrated and programmes that include the initiatives to strengthen strategic coordinated cancer research nationwide. clinical research supported by INCa, such as innovative molecules testing or AcSé programme. FRENCH NATIONAL CANCER INSTITUTE 103 2015-2016 SCIENTIFIC REPORT

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 structuring The 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. FRENCH NATIONAL CANCER INSTITUTE 104 2015-2016 SCIENTIFIC REPORT

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. FRENCH NATIONAL CANCER INSTITUTE 105 2015-2016 SCIENTIFIC REPORT

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 commitments In 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 observatory In 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. FRENCH NATIONAL CANCER INSTITUTE 106 2015-2016 SCIENTIFIC REPORT

1CHALLENGES ASSOCIATED 1 WITH THE ARRIVAL OF IMMUNOTHERAPIES After decades of disappointing results, the promising results focusing on a specific disease (Table 38). This involves conducting obtained with immune checkpoint inhibitors for the treatment clinical and biological monitoring of a representative cohort of metastatic melanomas and adoptive modified autologous of the patient population concerned that is suffering from a T cell (CAR-T) transfer therapeutics in leukaemia and B-cell specific disease. Throughout these patient care pathways, a lymphomas have re-established immunotherapy as a major tool set of different types of data (clinical, histopathological and in the cancer treatment arsenal. This therapeutic approach raises biological characteristics, monitoring data (treatments, responses high expectations on the part of clinicians and patients alike, and to treatments), quality-of-life and human and social sciences has already prompted extensive changes in the cancer care sector. data) is documented in a shared database and various types of samples are collected at key stages of the progression of the A number of immune checkpoint inhibitors have demonstrated disease. The aim is to promote collaborative and multidisciplinary remarkable clinical efficacy associated with long-term responses research projects through the provision of biological resources in a large number of cancer sites. The two classes of this type and data analysis. of inhibitors, which are the most advanced in terms of clinical development, are anti-CTLA-4 and anti-PD-1/PD-L1. A number Table 38. Specificities of the BCBs implemented of molecules have already been granted a European marketing authorisation, for melanoma, lung cancer, and more recently BCBs Disease cancer of the kidney. A lot of clinical trials are in progress on MELBASE Melanoma other tumour sites and should lead to Marketing Authorisations in the coming months. Moreover, further checkpoint inhibitors UroCCR Kidney cancer classes are currently under development. FR3LyS Lynch syndrome/colon rectum

Nevertheless, only certain patient subgroups respond to these CRB Foie network Liver treatments, which may also cause major toxicity in some patients. Sarcoma CBDB Sarcomas and connective tissues For this reason, the identification of biomarkers predicting the Glioblastomas Glioblastomas/Central nervous system efficacy or toxicity of these treatments, which are also very costly, is a major research challenge. The identification of specific BIG-RENAPE Peritoneal carcinosis of digestive origin biomarkers needs to be based on clinical trials or specific patient Breast and cohorts. At this stage, the clinical trials are mostly industrial ovarian cancer Breast and ovarian cancer and not very open to ancillary academic research projects. For predisposition predispositions this reason, patient cohorts treated by immunotherapy under CBDB marketing authorisations or temporary authorisations for use BCBLYM Lymphomas currently constitute a vital alternative for academic research. Bone marrow transplant and cellular CRYOSTEM therapy 1.1. BIOLOGICAL AND CLINICAL DATABASES: A UNIQUE TOOL TO ASSESS AND MONITOR BACAP Pancreas IMMUNE CHECKPOINT INHIBITORS EFFICACY FIMBANK Myeloproliferative syndromes MESOBANK Mesotheliomas Since 2014, INCa has been providing support for 14 BCBs that are intended to act as prospective cohorts on a national level FREGAT Oesophago-gastric carcinomas FRENCH NATIONAL CANCER INSTITUTE 107 2015-2016 SCIENTIFIC REPORT

Checkpoint inhibitors are available or under clinical development On a methodological level, it is essential to harmonise detection in a number of indications for which biological and clinical and scoring methods, compare the various antibodies available databases have been developed (cancers of the kidney, and define a positivity threshold for PD-L1 expression before the melanomas, mesotheliomas, sarcomas, pancreatic cancers, routine clinical use of PD-L1 expression as a predictive marker. oesophago-gastric cancers and glioblastomas). In fact, these Moreover, PD-L1 expression is heterogeneous in the same tumour BCBs are becoming unique tools for identifying new predictive and varies over time under the effect of treatments, meaning that biomarkers, new therapeutic targets, validating promising evaluating PD-L1 expression at a given time or in a single region biomarkers or assessing patient care practices and in compliance of the tumour may be insufficient. A specific research project with existing guidelines. INCa's support for building and was initiated in 2015 with pathologists from molecular genetics consolidating these BCBs needs to be maintained, so that the centres and AFAQAP (French Association for Quality Assurance in databases can attain the critical mass and degree of maturity Pathological Anatomy) in order to address these questions, and required to meet researchers’ needs as soon as possible. should be continued. More broadly, besides PD-L1 expression in routine clinical practice, it is essential to anticipate the transfer A large number of molecules are currently under clinical to routine clinical practice of new biomarkers of response to development in various lung cancer subtypes with very promising immunotherapies that need to be validated within the scope results. Due to its incidence and mortality rate, which remain of translational research. This should involve close upstream very high, lung cancer represents a major public health challenge. cooperation between the teams of researchers developing and For this reason, building a BCB for this disease, based on the validating these biomarkers and the molecular genetics centres. model developed by INCa in tandem with the existing BCBs, is As such, the current organisation of molecular genetics centres now a key priority. Commitment from all stakeholders should needs to evolve in order to incorporate predictive biomarkers allow it to become operational without delay. for immunotherapy treatments, as it already the case for constitutional genetics. This involves bringing together the Moreover, in the coming months, INCa is set to initiate two expertise required, implementing new technologies in routine AcSé clinical trials assessing nivolumab and pembrolizumab in clinical practice and adapting specimen and result circuits. 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. FRENCH NATIONAL CANCER INSTITUTE 108 2015-2016 SCIENTIFIC REPORT

Fig. 50. Layout of the integration of cooperating structures for immunotherapy

Molecular BCB genetics centres

Research projects on Implementation of new patients cohorts treated Inter-SIRIC biomarkers in routine with immunotherapy clinical practice working group Immunology & Immunotherapy

Early-phases clinical Ancillary research trials of combinations projects

CLIP²

Moreover, immune checkpoint inhibitors are currently undergoing The immunology research community is the focal point clinical evaluation in combination with a large number of for addressing the different challenges associated with different types of treatments, such as anti-angiogenic agents, immunotherapy development. It has been united within the targeted therapies, standard chemotherapy and radiotherapy. framework of the inter-SIRIC “Immunology & immunotherapy” It is necessary to base research on improving our understanding working group that brings together French experts in this field of the action mechanism of immunotherapies and improving on the SIRICs and elsewhere. This provides an opportunity to the characterisation of the effect of combination partners facilitate the mobilisation of stakeholders and create synergistic on the immune system in order to build a foundation of actions nationwide. 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. FRENCH NATIONAL CANCER INSTITUTE 109 2015-2016 SCIENTIFIC REPORT

2THE TRIPOD PROGRAMME: GENERATION, INTEGRATION AND SHARING OF BIOLOGICAL AND CLINICAL DATA 2 WITHIN THE SCOPE OF PRECISION MEDICINE Precision medicine is based on increasingly precise tumour 2.1. DATA COLLECTION AND INTEGRATION: characterisation with a view to guiding patient treatment. To DEVELOPMENT OF DECISION-MAKING this end, several types of tests are performed in parallel on TOOLS tumour samples taken at the time of diagnosis or at key stages of the disease. Histological tests (immunohistochemistry and The choice of treatment should be made through an integrated in situ hybridisation) and mutations screening using targeted analysis of the molecular characteristics of the tumour, carried NGS have been conducted in an integrated manner in molecular out within a collegial discussion involving the biologists and genetics centres since their creation in 2006. They have required pathologists responsible for each of the tests conducted, the establishment of a specific organisation incorporating bioinformatics engineers involved in the analysis of results, anatomopathology and molecular biology. The arrival of PARP referring clinicians and the patient’s attending clinician. This inhibitors in ovarian cancer during 2015, and in breast cancer in practice is currently being rolled out through the establishment of the near future, has led to the constitutional ongogenetics activity Molecular Tumour Boards (MTB) within the molecular genetics being merged with the existing system. Moreover, the arrival of platform, in the context of implementing targeted NGS as part new immunotherapy molecules will require research to identify of routine clinical practice. new types of biomarkers for clinical practice. For this reason, molecular genetics centres will be required to incorporate this At the present time, there are very limited resources for new skill. Therefore, in the short term, we will see the emergence interpreting sequencing results and choosing the most suitable of integrated centres that will allow for the coordination all of treatment. Therefore, it is essential to provide tools to support the tests required for the characterisation of a tumour sample decision-making and facilitate the interpretation of results in (tumour or fluid biopsy). order to optimise the collegial decisions made in the MTB.

Fig. 51. Aims of the TRIPOD programme 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 Collecting clinical known clinical significance and the platforms will continuously and biological/imaging populate the database with variants of unknown significance data in a format useful for a given patient and and information about the clinical context in which they have for all other patients, been identified. It will also contain a tool kit for predicting the wherever they live or are treated deleterious nature of variants. This database will thus help to facilitate variant annotation, harmonise result reports and identify TRIPOD the variants to be prioritised for functional validation research. Programme However, this database is merely the first stage, as therapeutic Defining a synthetic Offering flexibility sharable digital view and expertise monitoring of patients data (treatment administered according of the tumour for innovative to the molecular characteristics of the tumour and response to and the patient combined therapies this treatment) are an essential component of variant annotation. Indeed, a patient’s data needs to be interpreted in a context of FRENCH NATIONAL CANCER INSTITUTE 110 2015-2016 SCIENTIFIC REPORT

overall knowledge, assisted by algorithms comparing the data arrival of new types of treatments, such as immunotherapy, with those of other patients. and the combined use of multiple therapeutic approaches (targeted therapies, immunotherapy, standard chemotherapy For this reason, the establishment of a national database that, and radiotherapy). As most of these treatments have yet to be for each patient, compiles the molecular characteristics of the granted a marketing authorisation, access to these innovative tumour at different stages of the disease, associated with data treatments in the next years will essentially be provided within generated throughout the patient’s care pathway, is a prerequisite the scope of clinical trials. for the development of such decision-making tools. Clinical investigation centres, and more particularly early-phase Compiling and integrating these multiple data, generated at clinical trials centres such as CLIP², are set to play a major role different times and by different stakeholders, implies the use of in the patient care system. They will need to incorporate the interoperable healthcare information systems by the healthcare evaluation of new therapeutic approaches and new treatment facilities responsible for inputting the data. In the context of the combination methods in their fields of expertise. As an example, rollout of NGS – firstly targeted and then whole genome – in the use of the abscopal effect of radiotherapy in conjunction clinical practice to a very large number of patients, re-entering all with checkpoint inhibitors opens up new perspectives and of the required data is not conceivable. Also, solutions capable of represents a research pathway that is worth examining on the interfacing the numerous professional tools currently available for CLIP² sites. Moreover, clinical investigation centres take on a the purpose of sharing data are essential and a key success factor. central role in the sharing of the data for patients with access to innovative treatments, which must imperatively be used as This challenge is at the core of the Genomic Medicine France the basis for developing specific actions, particularly during the 2025 Plan, which includes a measure dedicated to the creation DCA implementation and DCC roll-out phases. of a data collector/analyser (DCA). This consists of a national data storage centre, associated with an intensive computing As such, research conducted by the OSIRIS inter-SIRIC working infrastructure designed to provide tools that will help the group (the inter-SIRIC working roup for the sharing and healthcare professionals to interpret results. In the field of integration of data) will provide an initial basic tool kit. The oncology, interfacing with the Cancer Communication File objective of this group is to share clinical and “OMIC” data (DCC) is envisaged. This digital file, aimed at improving care generated within the scope of genomics-driven clinical trials coordination, should provide healthcare professionals with conducted by the SIRICs (e.g. the SHIVA, MOSCATO, PROFILER the information contained in the key documents produced at and SAFIR trials). In this context, a minimum set of some one each stage of the care pathway: anatomo-cytopathological hundred clinical items and some one hundred “OMIC” items is reports, surgical reports, the file produced by Multidisciplinary currently being finalised and will be used as a common base for Consultative Meetings, the personalised care plan and the sharing this type of data. Each item will be associated with a set personalised monitoring and surveillance, or “post-cancer”, of values defined according to the national and international plan. These documents are structured in accordance with the guidelines in force. The next stage will consist of conducting a national guidelines1. In line with this approach, work is currently proof of concept on a restricted set of patients in order to evaluate being finalised at INCa on the definition of a standardised report the various technical procedures available and the feasibility of template for molecular tests performed using targeted NGS, in the project. The OSIRIS working group also offers the possibility consultation with the healthcare professionals involved. of addressing the ethical and regulatory constraints associated with data sharing. 2.2. DATA SHARING FOR COORDINATED TARGETED THERAPIES ASSESSMENT Beyond the national initiatives, INCa’s involvement in the ICGCmed international consortium, which aims to conduct a The development of precision medicine enables each patient to complete analysis of the tumour genome of 200,000 patients receive the most suitable treatment in terms of the molecular by the end of 2025 in relation to their clinical data, will help to characteristics of his/her tumour. This is made possible by the address these challenges in a broader context.

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 FRENCH NATIONAL CANCER INSTITUTE 111 2015-2016 SCIENTIFIC REPORT

3STUDYING TO SET UP A SPECIFIC PROGRAMME SUPPORTING LATE-PHASE 3 CLINICAL TRIALS

In previous years, INCa has launched several specific programmes The 2014-2019 Cancer control plan sets out to consider issues of to support early-phase clinical trials, mainly through the 2009- patient survival and reduction of treatment toxicity in therapeutic 2013 Cancer control plan, especially CLIP², public-private trials. In this purpose, an emphasis should be placed on the partnerships and AcSé programme. studies addressing issues close to routine healthcare, such as reducing the length of treatments, whether and when to stop INCa is considering to set up a specific programme aimed at treatment, or evaluating observance of oral chemotherapy drugs. supporting the emergence and funding of late-phase clinical trials to address issues identified by the 2014-2019 Cancer control Although such issues are supposed to be studied thoroughly plan. before transfer to routine clinical care, many therapeutic questions actually remain only partially addressed before market 3.1. LATE CLINICAL TRIALS CLOSE TO authorisation. Hence, INCa could support projects studying CANCER CARE MANAGEMENT TO IMPROVE unanswered clinical questions just before or after market PATIENTS’ SURVIVAL authorisation. For example, patient access to innovative drugs outside approved indications is the main objective of INCa’s Indeed, following the noteworthy achievements of the 2009- AcSé programme. Similarly, such a programme could also be 2013 Cancer control plan in terms of structuring clinical research evaluated for treatments other than targeted drugs when they in the field of cancer, the Action 5.2 of the 2014-2019 Cancer are transferred into clinical care. Studies conducted in routine control plan has raised the bar to 50,000 per year the number clinical care with the aim of providing confirmation of results of patients to be included in France in therapeutic clinical trials obtained in experimental conditions could also be part of a by the end of the plan. This has been identified as an important specific programme geared towards late-phase clinical trials. means toward to boost the pace of clinical progress, favour the earliest access to innovative treatments, as well as provide the best On the other hand, since improving patient survival is crucially possible healthcare framework for patients included in clinical relevant in some cancer diseases, especially in those with poor trials. As of now, this objective mostly relies on the nationwide prognosis, clinical trials could also provide real therapeutic PHRC-K call for proposals that provides each year €20M to options beyond aiming to answer clinical research questions. fund the most promising clinical research projects, competitively That would mean conducting long-term clinical trials in which selected by an international scientific evaluation committee. specific designs, for example -n 1 design or adaptive designs, such as Multi Arm Multi Stage (MAMS) design and Pick a Winner As these projects often aim to assess recent innovations in groups design trials, could be useful. of patients with a relatively modest sample size, it is necessary to pursue further improvements on issues close to clinical care. Central to such a programme, large-scale or very large-scale For example, the optimisation of treatment results in terms of therapeutic trials will be welcome. 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. FRENCH NATIONAL CANCER INSTITUTE 112 2015-2016 SCIENTIFIC REPORT

3.2. IDENTIFYING THE MAIN CHALLENGES physicians and medical researchers, drawing specifically on the OF CURRENT CLINICAL PRACTICES dynamics of INCa’s designated cooperative intergroups as well as on their ability to design study protocols and enrol patients As requested by the 2014-2019 Cancer control plan, cooperative in trials. The mission of this working group will be to identify the intergroups, designated by INCa between 2012 and 2015, will most relevant fields and issues of current clinical practice that be mobilised to conduct these trials. Large-scale or very large- may warrant launching large-scale therapeutic clinical trials to scale clinical trials can provide huge numbers of recruitment improve healthcare. Ultimately, these therapeutic clinical trials and therefore significantly contribute to meeting the objective will also provide an optimal framework for patient treatment of including 50,000 patients each year in therapeutic clinical and clinical follow-up. In addition, the working group will be trials in 2019, particularly when investigational centres are open asked to discuss prior prospects of the programme from INCa. in university hospitals, general hospitals and cancer centres, Finally, it will also focus on practical aspects, i.e. the specific and when conducted by cooperative intergroups. Given the ways and means that the institute would need to muster, in progression of number of enrolment of patients in clinical trials terms of potential new actions to implement, or to provide actually observed in 2015, INCa will certainly have to determine further reinforcement to already existing programmes, in order a minimum number of patients to be enrolled in each clinical to stimulate the attainment of these objectives and those defined trial project it will support. Moreover, the number of large-scale by the 2014-2019 Cancer control plan. or very large-scale clinical trials to be selected each year should be determined: the aim could be to fund on average one project The working group will be set up between September and by INCa’s designated cooperative intergroup, i.e., 13 projects, December 2016 in order to allow INCa to launch the programme by the end of the Cancer control plan in 2019. in 2017. The programme should include a specific call for proposals through which the first projects selected could be As the programme would also contribute to improve the funded in 2017. healthcare organisation in France as a whole, INCa will propose a partnership with the French Ministry of Health in order to fund Thereafter, the working group will meet once a year to follow-up the selected projects. the programme and to review the scientific priorities, to help INCa oversee the follow-up of projects funded and find solutions to To achieve this goal and define the scientific priorities of this any arising difficulties. programme, first of all, INCa will setup a working group including FRENCH NATIONAL CANCER INSTITUTE 113 2015-2016 SCIENTIFIC REPORT

4STRENGTHENING THE STRUCTURING 4 OF CANCER PUBLIC HEALTH RESEARCH

Recognising their importance in cancer control strategies, the diagnosis, treatment to survivorship. An initial analysis of the role of social and human sciences, epidemiology and public INCa’s funded research portfolio in these disciplines, according health has been confirmed in the successive Cancer control to the CSO classification system developed by the International plans. Indeed, one of the INCa’s goals when it was established Cancer Research Partnership (ICRP), would be conducted in was to bring social sciences and public health research applied order to help experts identify research gaps. to oncology in France up to the best international standards. Since 2005, INCa has therefore launched numerous thematic The second step after the identification of the research priorities and investigator-driven CFPs in order to increase the number of will be to launch a call for the creation of research networks, research projects funded in these disciplines. In this way, over with dedicated funding, on cross-cutting issues related to cancer the last decade, more than 350 research projects, covering all control such as social, ethical and economical aspects of genetic relevant disciplines, have been funded for a total amount of testing, dissemination of evidence-based interventions, quality of more than €55M. Although the CFPs were effective in increasing cancer care, social determinants of health disparities, etc. This the number of isolated research projects, structuring initiatives initiative is planned to start in 2017, but will be pursued in the are needed to increase multidisciplinary research projects and following years. It has the potential to encourage collaborative maximise the value of their outputs. studies, given that the networks may involve several cancer centres, as well as other partners in research settings and the 4.1. FOSTERING THE CAPABILITIES community. OF HUMAN AND SOCIAL SCIENCES, EPIDEMIOLOGY AND PUBLIC HEALTH 4.2. SUPPORTING THE VISIBILITY OF HUMAN AND SOCIAL SCIENCES, EPIDEMIOLOGY AND This type of initiatives started in 2015 with the creation of a new PUBLIC HEALTH RESEARCH university research chair dedicated to cancer prevention. This chair is the result of the implementation of the recommendations To strengthen the visibility of human and social sciences, of the 2012 report addressed to the INCa’s International SAB. epidemiology and public health research, but also to create a University-based research chairs have demonstrated their value in meeting ground for social sciences researchers, INCa will organise building research capabilities, in different countries, particularly regularly, from 2017, national and international conferences and in Canada with the 2000 Research Chairs Program. For this workshops. For example, the international congress organised reason, INCa will continue to support the creation of research in 2014 has been a catalyst for the development of numerous chairs, particularly in underserved disciplines in social and human initiatives on population health intervention research in France sciences. and beyond the cancer field.

For the year 2017, INCa will set up multidisciplinary working Special attention will be focussed on human and social sciences groups in order to identify research priorities in human and disciplines applied to cancer. There is actually a strong need social sciences, epidemiology and public health across the to narrow the gap between research and actions, particularly cancer control continuum, ranging from prevention, detection, with regard to human and social sciences. Social inequalities in FRENCH NATIONAL CANCER INSTITUTE 114 2015-2016 SCIENTIFIC REPORT

health and in cancer in particular are more than ever a major project in these disciplines. Ultimately, an evaluation guideline concern in our modern societies and strengthening the role will be produced and will be addressed to both reviewers and of human and social sciences would be a first step towards researchers. This guide will help improve the quality of the projects tackling these inequalities. For these reasons, INCa will set up a submitted and the quality of the reviewing process, needed to working group encompassed of different experts from human reduce the gap between disciplinary categories observed in the and social sciences disciplines, in order to develop a common CFPs and in the call for applications in 2016. language about what is important when evaluating a research FRENCH NATIONAL CANCER INSTITUTE 115 2015-2016 SCIENTIFIC REPORT

5 5NEW INTERNATIONAL COMMITMENTS

Fig. 52. New European and international partnerships

Europe • JARC : Joint Action on Rare Cancer • FLAG ERA : Digital Medicine for Cancer

China • MoU with Chinese NCC on Cancer Control

France - Caribbean - Africa • Francophone research network on prostate cancer

Polynesia • Cancer control plan implementation FRENCH NATIONAL CANCER INSTITUTE 116 2015-2016 SCIENTIFIC REPORT

5.1. EUROPEAN INITIATIVE FLAG-ERA ON 5.2. JOINT ACTION ON RARE CANCERS DIGITAL MEDICINE FOR CANCER 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- INCa has joined the European initiative FLAG-ERA on digital border healthcare. This directive is meant to grant EU patients the medicine for cancer. right to access safe and high-quality healthcare across European The FLAG-ERA initiative of the European Commission focuses borders, and foresees the designation of European Reference on future and emerging technologies, with an ERANET-like Networks (ERNs) for rare and complex diseases, including rare mechanism, bringing together national and regional funding cancers. ERNs will link up healthcare providers and centres organisations in Europe and beyond. It addresses major scientific of expertise of highly specialised healthcare, for patients with and technological challenges. Proposals are submitted by conditions requiring a particular concentration of resources or international consortia with partners from multiple countries. expertise regardless of where they are in Europe. The selection process is international, but grant agreements for the selected projects are established directly between the funding The JARC will help shape ERNs, but also contribute to improving organisations and the consortium partners. health outcomes for patients with rare cancers in the EU.

INCa has joined this initiative and supports the first transnational The general objectives of JARC are: CFP dedicated to digital medicine for cancer. The primary goal •• to prioritise rare cancers in the agenda of the EU and Member of this CFP is the development of detailed patient-specific States with a view to promoting quality and harmonisation computer models and simulations of the complex biological of clinical practices, as well as innovation through clinical processes involved in cancer. These models are expected to and translational research; cover multiple levels spanning molecules, cells, tissues, whole •• to develop shared solutions, to be mainly implemented body and populations, take into account various genetic and through the future European Reference Networks on Rare environmental factors, and have predictive capabilities. The Cancers, for quality care, research & education, prevention applicants are also expected to tackle data sharing challenges & diagnosis of rare cancers. taking into account the constraints of patient privacy, so that models can be trained and tested on common datasets, using INCa’s participation in the new JARC is grounded on the specific natural language processing technology in order to make sense of organisational framework for rare cancers in adults developed the data annotation expressed in unstructured natural language. in France since 2009 by INCa and the Ministry of Health. This national framework comprises regional or interregional Project selection is ongoing. Since the objective is to promote designated expert centres coordinated on a national level by large-scale cooperation on a European level, only one inclusive an expert centre. and ambitious project will be considered for funding. FRENCH NATIONAL CANCER INSTITUTE 117 2015-2016 SCIENTIFIC REPORT

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. FRENCH NATIONAL CANCER INSTITUTE 118 2015-2016 SCIENTIFIC REPORT

CONCLUSION

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.

Prof. Norbert Ifrah Chairperson of the National Cancer Institute FRENCH NATIONAL CANCER INSTITUTE 119 2015-2016 SCIENTIFIC REPORT

APPENDICES FRENCH NATIONAL CANCER INSTITUTE 120 2015-2016 SCIENTIFIC REPORT

1 6CLINICAL TRIALS REGISTRY Milestones in managing the INCa clinical trials registry

2007-2008 2009-2010 2011-2012 2013 2014 2015 National ••Initiation of ••2009: Agreement ••A total of ••Initiation of a ••Modification of ••Initiation of a collaborations dialogue with concluded 325 trials were reflection with the agreement reflection in order ANSM (French between INCa transmitted by the Santor between INCa to develop a web National Agency and ANSM ANSM (From and Springer and ANSM: all portal to register for Medicines and for relaying of September companies for authorised trials clinical trials Health Products information on 2010 onward); the development in cancer are data directly by Safety, formerly clinical trials of 174 trials were of a mobile transmitted to sponsors. AFSSAPS). drugs authorised registered in application, INCa. by ANSM. the INCa registry. «Clinical Trials Registry» ••Initiation of the ••2010: operational ••Discussion with available to clinical trials collaboration ANSM with practising results retrieving with ANSM. regard to relaying oncologists. process in order information on to publish them ••Several meetings non-drug trials. ••Initiation of a on the INCa’s with ASIP collaboration website, with Santé (French ••Collaboration with LNCC to the collaboration Shared Health with the 3 main make the patient of patient Information national public committees committees. Systems Agency) health insurers: aware of clinical to develop access posting the link to research and how to the registry for the INCa registry to use the clinical physicians during on their websites. trials registry. multidisciplinary patient consultations. International ••Collaboration ••Due to collaborations with the US NCI: modifications direct relaying of made by NCI data from French to the trials clinical trials for registration entry into the NCI process, end PDQ registry. of direct INCa submissions to the NCI PDQ registry. Figures ••100 trials ••Over ••Most visited ••Over ••Over ••Over advertised from 1,000 clinical INCa’s web 1,500 clinical 1,780 clinical 2,000 clinical 50 academic trials advertised page: over trials advertised trials advertised trials advertised sponsors. in the registry. 200,000 visits in the registry. in the registry. in the registry. in May 2011. ••2008: advertisement of clinical trials conducted by industry. FRENCH NATIONAL CANCER INSTITUTE 121 2015-2016 SCIENTIFIC REPORT

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) Transplant and ENT 101 32 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 FRENCH NATIONAL CANCER INSTITUTE 122 2015-2016 SCIENTIFIC REPORT

2 7CSO-COMMON SCIENTIFIC OUTLINE The Common Scientific Outline, or CSO, is a classification system •• Chemoprevention organised around seven broad areas of scientific interest in cancer •• Vaccines research. The development of the CSO is laying a framework to •• Complementary and Alternative Prevention Approaches improve coordination among research organisations, making •• Resources and Infrastructure Related to Prevention it possible to compare and contrast the research portfolios of public, non-profit, and governmental research agencies. This CSO 4 EARLY DETECTION, DIAGNOSIS, AND PROGNOSIS classification is subdivided in 7 categories: •• Technology Development and/or Marker Discovery •• Biology •• Technology and/or Marker Evaluation with Respect to •• Aetiology (causes of cancer) Fundamental Parameters of Method •• Prevention •• Technology and/or Marker Testing in a Clinical Setting •• Early Detection, Diagnosis, and Prognosis •• Resources and Infrastructure Related to Detection, Diagnosis, •• Treatment or Prognosis •• Cancer Control, Survivorship, and Outcomes Research •• Scientific Model Systems CSO 5 TREATMENT As a member of the ICRP consortium, INCa and its partners use •• Localised Therapies - Discovery and Development this classification. The types of research projects funded by INCa, •• Localised Therapies - Clinical Applications Ministry of Health and Inserm for ITMO Cancer-Aviesan that are •• Systemic Therapies - Discovery and Development presented in this report are based on this CSO classification. •• Systemic Therapies - Clinical Applications •• Combinations of Localised and Systemic Therapies •• Complementary and Alternative Treatment Approaches •• Resources and Infrastructure Related to Treatment The different categories CSO include: CSO 6 CANCER CONTROL, SURVIVORSHIP, AND CSO 1 BIOLOGY OUTCOMES RESEARCH •• Normal Functioning •• Patient Care and Survivorship Issues •• Cancer Initiation: Alterations in Chromosomes •• Surveillance •• Cancer Initiation: Oncogenes and Tumour Suppressor Genes •• Behaviour •• Cancer Progression and Metastasis •• Cost Analyses and Health Care Delivery •• Resources and Infrastructure •• Education and Communication •• End-of-Life Care CSO 2 AETIOLOGY •• Ethics and Confidentiality in Cancer Research •• Exogenous Factors in the Origin and Cause of Cancer •• Complementary and Alternative Approaches for Supportive •• Endogenous Factors in the Origin and Cause of Cancer Care of Patients and Survivors •• Interactions of Genes and/or Genetic Polymorphisms with •• Resources and Infrastructure Related to Cancer Control, Exogenous and/or Endogenous Factors Survivorship, and Outcomes Research •• Resources and Infrastructure Related to Aetiology CSO 7 SCIENTIFIC MODEL SYSTEMS CSO 3 PREVENTION •• Development and Characterisation of Model Systems •• Interventions to Prevent Cancer: Personal Behaviours that •• Application of Model Systems Affect Cancer Risk •• Resources and Infrastructure Related to Scientific Model •• Nutritional Science in Cancer Prevention Systems FRENCH NATIONAL CANCER INSTITUTE 123 2015-2016 SCIENTIFIC REPORT

82014-2019 CANCER CONTROL PLAN ACTIONS 3 PROGRESS RELATED TO CANCER RESEARCH GUARANTEEING THE CREATIVITY AND approaches that combine biology, mathematics, bioinformatics, COMPETITIVENESS OF BASIC RESEARCH physics, chemistry and human and social sciences will be TO INCREASE OUR KNOWLEDGE OF THE encouraged through these calls for proposals. Actions aimed DETERMINANTS OF CANCER at reducing the impact of cancer determinants require effort and investment in technological fields (biotechnologies for health, Basic research, which helps to advance understanding of the technologies related to all aspects of genomics, imaging, robotics, mechanisms of cancer development, is the source of all advances instrumentation, information technology, etc.), and in the area in prevention, diagnosis and treatment. The Cancer control plan of public health (epidemiology, screening and prevention). guarantees funding for excellent and creative basic research: over 50% of research monies will be devoted to basic research, via Research into the environmental and social determinants of non-earmarked calls for proposals set up by the French National cancer will be intensified and will involve toxicology, epigenetics, Cancer Institute and ITMO Cancer-Aviesan. Interdisciplinary molecular and analytical epidemiology, and the disciplines involved in human and social sciences and health economics. FRENCH NATIONAL CANCER INSTITUTE 124 2015-2016 SCIENTIFIC REPORT

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 01-10-2015 Done launched at the end of 2015 for funding in 2016 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 31-12-2015 Done within the framework of DO (InVS/E2). 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

MILESTONES DATE STATUS Investigator-driven call for proposals in biology and basic science - PLBIO2015 31-12-2015 Done Thematic call for proposals dedicated to basic research - 2015 31-12-2015 Done Investigator-driven call for proposals in biology and basic science - PLBIO2016 30-12-2016 In progress Thematic call for proposals dedicated to basic research - 2016 30-12-2016 In progress PROGRESS 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. FRENCH NATIONAL CANCER INSTITUTE 125 2015-2016 SCIENTIFIC REPORT

REDUCING THE INCIDENCE, MORTALITY including the designation of dedicated centres for children. In AND SOCIAL IMPACT OF CANCER THROUGH addition, increased information will be provided to patients on TRANSLATIONAL AND CLINICAL RESEARCH ongoing and upcoming research.

Translational and clinical researches transform the discoveries In order to support tobacco control, the Cancer control plan made through basic research into progress in public health and provides for development of a multi-year programme of integrated advances in diagnosis and treatment. Research projects aimed at research and intervention regarding issues related to tobacco, identifying new opportunities for early diagnosis and improving the results of which will contribute to the development of more patient survival or that enable a reduction in secondary effects effective strategies to combat smoking. Apart from tobacco, and sequelae – with the help of less toxic treatments or processes intervention research in cancer prevention and screening will of treatment de-escalation – will receive strong support. The most be stimulated to promote behavioural change and to correct vulnerable populations, especially children and older people, and inequalities of access to and uptake of public policy. people with the rarest and most serious forms of cancer must be at the core of this research. Understanding the social consequences of cancer and its repercussions on the lives of patients and those close to them The Cancer control plan provides for a doubling of patient relies on a variety of sources (observatories, barometers, cohorts numbers included in therapeutic trials, i.e. recruitment of and ad hoc studies). Schemes for observation and research will 50,000 patients per year in 2019, while correcting geographic be consolidated, and research in human and social sciences and inequalities in access to clinical research: research centres should public health will be encouraged in order to develop and update be opened in the overseas departments; mobile clinical research the knowledge of patient trajectories and living conditions for teams must be better distributed on the territory and territorial several years after their initial cancer diagnosis. Further upstream, coverage of early-phase clinical trials centres (CLIP2) improved, 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

MILESTONES DATE STATUS Award of a public contract to launch studies in humanities and social sciences and 31-12-2016 In progress descriptive epidemiology about the acceptability of vaccination in schools 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

MILESTONES DATE STATUS Launch of the CFP dedicated to Population health intervention research on the actions 31-12-2015 Done to counter inequalities (INCa) PROGRESS Since 2015, the call for proposals Population health intervention research focuses on the different times of the fight against cancer, including the screening. FRENCH NATIONAL CANCER INSTITUTE 126 2015-2016 SCIENTIFIC REPORT

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

MILESTONES DATE STATUS 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 31-12-2016 In progress 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

MILESTONES DATE STATUS 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.

Head INCa; ITMO Cancer Associates

MILESTONES DATE STATUS 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. FRENCH NATIONAL CANCER INSTITUTE 127 2015-2016 SCIENTIFIC REPORT

Action 8.3: Paying closer attention to the physical sequelae of cancer treatments.

Head INCa Associates

MILESTONES DATE STATUS 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 30-06-2015 Done a complication of cancer treatment.

Action 8.7: Promoting observation and research devoted to preventing the risk of second cancer.

Head ARC Foundation Associates INCa; IReSP

MILESTONES DATE STATUS 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. FRENCH NATIONAL CANCER INSTITUTE 128 2015-2016 SCIENTIFIC REPORT

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

MILESTONES DATE STATUS 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

MILESTONES DATE STATUS 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 30-06-2016 In progress 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 31-12-2016 In progress 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. FRENCH NATIONAL CANCER INSTITUTE 129 2015-2016 SCIENTIFIC REPORT

CONSOLIDATING FRANCE’S LEAD IN Funding for the molecular genetics centres will be placed on a DEPLOYING TARGETED THERAPIES AND permanent footing, and the times taken to carry out testing will be PERSONALISED MEDICINE shortened. Conditions for complete genome analysis of tumours by new sequencing technologies should be in place by the end During the first two Cancer control plans, France acquired a of the Plan, since the feasibility and usefulness of this approach system of organisation that enabled a patient to be treated have been demonstrated. The target for tumour sequencing has according to the genetic and biological features of his/her been set at 50,000 tumours per year by 2019. tumour, while considering the patient’s own unique features affecting his/her sensitivity to the process of carcinogenesis The exponential development of targeted therapies predicts and to treatments. This system, which is unique in the world, a profound change in clinical practice, a revolution in the relies on the oncogenetics scheme on the one hand, and the treatment of many cancers, and economic impacts that call for molecular genetics centres on the other. The new sequencing a comprehensive policy on technologies and drugs in cancer care technologies should help all patients at genetic risk to benefit so that all at once innovation will be stimulated, its access will from individualised diagnosis within times that are compatible be guaranteed to the greatest possible number of people, and with effective treatment. Territorial coverage of genetic counselling its costs will be controlled. This policy will rely on new processes services will also be improved. 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

MILESTONES DATE STATUS 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

MILESTONES DATE STATUS Authorisation request of at least one genomics-guided clinical trial 31-12-2015 Done either transpathology or assessing the combination of innovative drugs Working group meeting on the methodology of adaptive trials 30-06-2016 In progress Authorisation request of at least one genomics-guided clinical trial 31-12-2016 Done either transpathology or assessing the combination of innovative drugs 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. FRENCH NATIONAL CANCER INSTITUTE 130 2015-2016 SCIENTIFIC REPORT

Action 6.1: Developing the oncogenetics scheme, and improve access to it.

Head INCa Associates DGOS

MILESTONES DATE STATUS 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 18-12-2015 Done people Lynch syndrome and MSI screening: Finalisation of the actions concerning 18-12-2015 Done the improvement to access to oncogenetics scheme 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

MILESTONES DATE STATUS 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. FRENCH NATIONAL CANCER INSTITUTE 131 2015-2016 SCIENTIFIC REPORT

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

MILESTONES DATE STATUS 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

MILESTONES DATE STATUS 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 31-10-2016 In progress the oncogenetics laboratories Identification of the infrastructures involved in exome sequencing in clinics (sequencing 31-12-2016 Not started centres, data storage, etc.) 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. FRENCH NATIONAL CANCER INSTITUTE 132 2015-2016 SCIENTIFIC REPORT

Action 6.5: Generating and understanding big data.

Head Aviesan Associates INCa; DGRI

MILESTONES DATE STATUS 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.

Head INCa; ITMO Cancer Associates

MILESTONES DATE STATUS Launch of the call for proposals Tumour heterogeneity and ecosystem proposed by 31-12-2015 Done ITMO Cancer-Aviesan 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. FRENCH NATIONAL CANCER INSTITUTE 133 2015-2016 SCIENTIFIC REPORT

DEVELOPING THE STRUCTURES FOR CANCER The roles of the interregional cancéropôles will be redefined, to RESEARCH AND CAREER PATHS provide better interaction with the SIRICs and with the regional health structures, the most important of which are the Regional In the research area, the strong interaction between the Health Agencies (ARSs) and regional oncology networks (RRCs), INCa and ITMO Cancer-Aviesan will be renewed, via a new with which they will interact to provide easier access of patients framework agreement between the two institutions. The scientific to clinical research. management of research monies from the Cancer control plan will be entrusted to INCa under this framework. Interactions between users’ representatives, patients and researchers will be encouraged, so that issues raised by patients The continuum between basic research, translational research and may be translated into research questions. clinical research, together with collaboration between disciplines, will be consolidated within the integrated cancer research sites Developments in biomedical research also require modifications (SIRICs). The latter will be regularly evaluated, particularly at to career pathways, particularly the decompartmentalisation the time of the new designation procedure following their first of the disciplines involved, from biology to human and social five years of existence. 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

MILESTONES DATE STATUS Participation of biomedical research patients’ committees in disseminating of clinical 31-12-2015 Done trials results Publication of results of clinical trials when ended in the INCa’s Cancer research clinical 31-12-2015 Stopped trials registry Conduct a satisfaction survey of patients included in clinical trials, about 31-12-2016 In progress the information that has been provided PROGRESS A hundred proofreaders included in patients' committee in 2015- 102 protocols reviewed on 26-11-2015. FRENCH NATIONAL CANCER INSTITUTE 134 2015-2016 SCIENTIFIC REPORT

Action 5.11: Clarifying the process of identifying and evaluating technological innovations and the organisational changes they generate

INCa; DGRI; ITMO Cancer; Head DGOS Associates ITMO Health Technologies

MILESTONES DATE STATUS Adjusting the assessment framework of medical procedures and devices: 30-05-2015 In progress Evaluation of expensive consumables Adjusting the assessment framework of medical procedures and devices: 30-06-2015 Done Innovation package Based on international recommendations, papers and communications, establishments 30-06-2015 In progress of terms of Technology Developments Continuation of the PREPS programme allowing the evaluation of innovative 30-06-2015 Done organisational typologies 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

MILESTONES DATE STATUS 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 31-12-2015 Done clinical research 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. FRENCH NATIONAL CANCER INSTITUTE 135 2015-2016 SCIENTIFIC REPORT

Action 13.3: Developing initial training to meet the needs of cancer research.

Head DGESIP Associates INCa; DGRI; ITMO Cancer

MILESTONES DATE STATUS A joint DGESIP, INCa and ITMO Cancer work to identify the appropriate doctoral 31-12-2015 Not started school able to welcome students from other disciplines. 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

MILESTONES DATE STATUS 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 01-12-2016 In progress 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

MILESTONES DATE STATUS Involvement of users’ representatives of our health system in the establishment 30-06-2015 Done of technical permanent groups and especially, dedicated to screening of cancers 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 cancer April 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. FRENCH NATIONAL CANCER INSTITUTE 136 2015-2016 SCIENTIFIC REPORT

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).

Head INCa Associates DGOS; DGRI

MILESTONES DATE STATUS 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.

Head INCa Associates DGOS; DGRI

MILESTONES DATE STATUS Validation of the process of the call for applications with the partners (Inserm and 31-12-2015 In progress 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.

Head INCa Associates DGOS; DGRI

MILESTONES DATE STATUS 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. FRENCH NATIONAL CANCER INSTITUTE 137 2015-2016 SCIENTIFIC REPORT

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

MILESTONES DATE STATUS 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 30-07-2015 Done through HPV screening in the Maghreb countries 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

MILESTONES DATE STATUS Africa/AORTIC HPV Research/ Public Health Multilateral cooperation: 19-03-2015 Done funding of projects Laos Merieux Foundation Research cooperation: HPV – HIV project 10-09-2015 Done Multilateral cooperation France-Africa-Caribbean Research/ Public Health 15-06-2016 Done on prostate cancer 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. FRENCH NATIONAL CANCER INSTITUTE 138 2015-2016 SCIENTIFIC REPORT

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

MILESTONES DATE STATUS Tobacco: International Consortium for Action and Research on Tobacco (ICART) 19-03-2015 Done meeting 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

MILESTONES DATE STATUS 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

MILESTONES DATE STATUS 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. FRENCH NATIONAL CANCER INSTITUTE 139 2015-2016 SCIENTIFIC REPORT

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

MILESTONES DATE STATUS 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.

Head INCa; ITMO Cancer Associates

MILESTONES DATE STATUS Third GLOBAL ALLIANCE meeting 11-06-2015 Done Involvement of patients’ representatives in the different boards managed by INCa (SAB, 31-12-2015 Done Cancéropôles, SIRICs, etc.) 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. FRENCH NATIONAL CANCER INSTITUTE 140 2015-2016 SCIENTIFIC REPORT

9NOTES FRENCH NATIONAL CANCER INSTITUTE 141 2015-2016 SCIENTIFIC REPORT

10NOTES FRENCH NATIONAL CANCER INSTITUTE 142 2015-2016 SCIENTIFIC REPORT

11NOTES FRENCH NATIONAL CANCER INSTITUTE FRENCH NATIONAL CANCER INSTITUTE SCIENTIFIC REPORT / 2015-2016 SCIENTIFIC REPORT / 2015-2016

The French National Cancer Institute is the health and science agency in charge of cancer control.

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 52, avenue André Morizet strategy to fight cancer; the second Cancer Control Plan (2009-2013) introduced the notion of 92100 Boulogne-Billancourt personalised care. France The 2014-2019 Cancer Control Plan intends to give each and every person, all over France, the Tel. +33 (0) 1 41 10 50 00 same chances for recovery and implement innovation even faster for [email protected] Plan patient benefit. Cancer This plan includes 17 objectives, all gathered around four major 2014-2019 health priorities: l Cure more patients l Preserve continuity and quality of life l Invest in prevention and research l Optimise management and the organisations efficiency The 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.

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, Published by the French National Cancer Institute are authorised. All rights reserved – Siren 185 512 777 Conception: INCa This document was published in October 2016. It is available at the following address: Realised by Institut National du Cancer (INCa) ISSN 2276-5751 Direction de la recherche ISBN : 978-2-37219-242-2 52, avenue André Morizet – 92100 Boulogne-Billancourt ISBN net : 978-2-37219-243-9 e-cancer.fr © 2016. Institut National du Cancer (INCa) DEPÔT LÉGAL OCTOBRE 2015 OCTOBER 2016

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Institut National du Cancer 52, avenue André Morizet FRENCH NATIONAL 92100 Boulogne-Billancourt France Tel. +33 (0) 1 41 10 50 00 CANCER INSTITUTE [email protected] SCIENTIFIC REPORT / 2015-2016 SCIENTIFIC REPORT / REPORT SCIENTIFIC CANCER INSTITUTE FRENCH NATIONAL RAPCSANG16