Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Measures 1, 2, 3, 4 and 5 RESEARCH 1 French National Cancer Institute Scientific Report 2012-2013 www.e-cancer.fr INCArapportGB2013.indd 1 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 2 THIS PUBLICATION IS PART OF THE IMPLEMENTATION OF THE CANCER PLAN 2009-2013. Measures 1, 2, 3, 4 and 5 of the Research area. 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 character or information of the work into which they are incorporated, are authorized. This document was published in October 2013. It is available at the following address: Institut National du Cancer (INCa) Direction de la recherche 52, avenue André Morizet – 92100 Boulogne-Billancourt www.e-cancer.fr © 2013. Institut National du Cancer (INCa) INCArapportGB2013.indd 2 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT INCArapportGB2013.indd 3 3 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 4 TABLE OF CONTENTS PREAMBLE Research Indicators Clinical trial indicators Molecular genetics platforms: activity indicators International actions SUMMARY OF THE REPORT 6 8 10 12 14 19 Part 1. SUMMARY OF PREVIOUS RECOMMENDATIONS DRAWN UP BY MEMBERS OF THE SCIENTIFIC ADVISORY BOARD AND PROGRESS MADE 23 Part 2. REPORT ON CANCER RESEARCH ACTIVITY FOR 2012-2013 AND SYNTHESIS 1. INCREASED SUPPORT FOR TRANSLATIONAL AND INTEGRATED RESEARCH 1.1. Research programmes aiming at boosting transdisciplinarity and transfer of knowledge into clinical practice 31 33 33 1.2. New actions to strengthen organisation and infrastructures devoted to translational/integrated research 44 2. INCREASED SUPPORT FOR CLINICAL RESEARCH AND DEVELOPMENT OF EARLY PHASE TRIALS FOR INNOVATIVE MOLECULES 54 2.1. The clinical cancer research programmes 54 2.2. Organisation of clinical research, and strengthening of structures and infrastructures 59 INCArapportGB2013.indd 4 3. INCREASED SUPPORT FOR RESEARCH IN BIOLOGY, GENOMICS AND CANCER SCIENCES 68 3.1. Dedicated research programmes 68 3.2. The genomics programme and the epigenomics programme 73 4. INCREASED SUPPORT FOR RESEARCH IN SOCIAL SCIENCES, EPIDEMIOLOGY AND PUBLIC HEALTH 78 4.1. The research programmes 78 4.2. Research organisation, structures and infrastructures for epidemiology and public health research 81 5. THE CANCEROPOLES 84 6. MAIN EVENTS IN 2012-2013 87 7. INTERNATIONAL DEVELOPMENTS 90 7.1. European programmes for cancer research 90 7.2. Thailand - 1st results of the research programme ‘PapilloV’ “HPV infections and associated cervical lesions in HIV+ Thai women”. 91 7.3. Africa - Capacity building in cancer control and new steps towards increased coordination 92 8. OBSERVATORY FOR RESEARCH INVESTMENT IN CANCER, AND REVIEW OF RESEARCH INVESTMENT 93 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT Part 3. PERSPECTIVES 101 1. STRATEGIC ORIENTATIONS FOR CANCER RESEARCH 102 1.1. The key challenges 103 1.2. Current situation and strengths in France 104 1.3. Proposals 104 2. FIVE PRIORITY ACTIONS FOR 2013-2014 108 2.1. Fight tobacco-related cancers with an ambitious multidisciplinary programme of research/treatment/ public health actions 108 2.2. Build a shared biological, clinical and epidemiological database 112 2.3. Foster closer ties between teaching and research and increase support for interdisciplinary training 117 5 CONCLUSION 128 APPENDICES 131 2.4. Support ambitious French cancer research to provide the population and patients quick and sizeable benefits 120 2.5. New challenges in cancer control: European and global perspectives INCArapportGB2013.indd 5 124 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 6 PREAMBLE This is the seventh International Scientific Advisory Board report that INCa has published since 2007. It is an opportunity to thank the Board’s members for advising and guiding the Institute during its structuring process and providing inspiration for its initiatives. As two consecutive plans are drawing to a close and the third national plan is under development, the Institut National du Cancer and the Institut Cancer de l’Aviesan will have spearheaded and shaped farreaching changes in the cancer research landscape in France. 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 during budget restrictions) by relying on transparent methods, international assessments and participation of patient advocates in all the calls for proposals and in every field of research: biology, clinical, transfer, human and social sciences, epidemiology and public health. All of the research objectives in the 2009-2013 plan were achieved or even surpassed. In addition to the actions that the next plan will prioritise, over the next few years efforts will be undertaken to bolster the programmes already in progress with a particular focus on the SIRIC Programme. The eight designated sites have begun coordinating their programmes and should be the drivers behind clinical genomics and the assessment and dissemination of innovation, provide a wider platform for human and social sciences, mathematics and physics, and serve as local and regional authorities on clinical research and expanding the use of their scientific evidence to benefit patients. Through their interactions with the clinical biological databases, the molecular and constitutional genetics platforms and the cooperative inter-groups, they are also expected to prepare France for building large-scale interactive clinical and biological databases available to the national and international communities to advance our understanding of cancer and cancer treatment. The cooperative inter-groups have pushed beyond the individual aspirations of groups INCArapportGB2013.indd 6 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 7 and learned societies to organise themselves into national pathology groups and develop major clinical and biological research projects designed to improve patient survival. The Programme for Hospital Clinical Research in oncology managed by INCa should help them make their projects a reality, expand their international exposure and embrace new opportunities to bring in international cooperation. Primary prevention in France is still not as rooted in the collective conscious as it should be. Our smoking rates remain dismal, particularly among the younger generation. Talks have begun with other agencies working on this issue and solutions will include funding research projects on primary prevention and launching a new recurrent multidisciplinary research programme on smoking-related cancers. In the last few years, INCa has established a highly proactive policy that has been recognised by our European and American colleagues to expand access to targeted therapies for patients identified as candidates through molecular tests. In 2012, these tests were administered to over 60,000 patients. Our goal is to support the foreseeable development of medicine based on the tumour’s specific biological parameters and individual patients by providing research and treatment facilities a greater capacity to conduct more advanced testing, including exome sequencing, RNAs and normal or altered protein quantification. It entails bringing a serious health issue under control to prove these sophisticated and more costly tests are pertinent and a valuable component of treatment and therapeutic decisions because they improve survival and quality of life. Over the next five years, this is one of the innovation challenges that INCa, the authorities and healthcare institutions have to tackle in order to give patients in France the best treatment possible. INCArapportGB2013.indd 7 Prof. Fabien Calvo Director of Research and Innovation 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 8 RESEARCH INDICATORS TRENDS IN THE NUMBER OF PROJECTS SUBMITTED TO CALLS FOR PROPOSALS MANAGED BY INCa ANNUAL FUNDING OF CANCER RESEARCH PROGRAMMES * The 2013 amounts are calculated on a previsional budget * No CFP for translational research in 2008 120 400 350 300 80 Nb of projects Funding in €M 100 60 40 250 200 150 100 20 50 0 0 2007 Total Total INCa Total DGOS Total Aviesan 2008 2009 2010 2011 2012 2013 2007 2008 2009 2010 2011 2012 2013 2012 2013 Clinical Translational* Human and social sciences, epidemiology, public health Cancer biology and sciences TRENDS IN FUNDING AWARDED TO CFPs MANAGED BY INCa * No CFP for translational research in 2008 25 Funding in €M 20 15 10 5 0 2007 2008 2009 2010 2011 Clinical Translational* Human and social sciences, epidemiology, public health Cancer biology and sciences INCArapportGB2013.indd 8 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT TRENDS IN THE NUMBER OF PROJECTS SELECTED TO CALLS FOR PROPOSALS MANAGED BY INCa TRAINING IN TRANSLATIONAL RESEARCH * No CFP for translational research in 2008 55 50 45 40 35 30 25 20 15 10 5 0 80 70 50 40 30 20 10 0 2012 2013 Clinical Translational* Human and social sciences, epidemiology, public health Cancer biology and sciences 600 Funding in €M 500 400 300 200 100 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 0 2008 2009 2010 2011 Clinical Translational* Human and social sciences, epidemiology, public health Cancer biology and sciences INCArapportGB2013.indd 9 2013 FUNDING (€M) AWARDED TO CALLS FOR PROPOSALS MANAGED BY INSERM UNDER THE CANCER PLAN * No CFP for translational research in 2008 2007 2012 Nb of projects selected Nb of projects submitted TRENDS IN AVERAGE BUDGET ALLOCATED BY RESEARCH PROJET Average budget per project, € in thousands 2011 2012 2013 2013 2012 2011 Spontaneous tumour models 2011 25 Physics, maths, engineering sciences 2010 19 27 Cancer and environment 2009 36 35 Systems biology and cancer 2008 52 Training in translational research Nb of projects 60 2007 9 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 10 CLINICAL TRIALS INDICATORS NUMBER OF CLINICAL TRIALS OPEN FOR PATIENT RECRUITMENT ADVERTISED IN THE NATIONAL REGISTRY (15 May 2013) TRENDS IN RECRUITMENTS IN CANCER CLINICAL TRIALS 37,492 40,000 800 687 30,000 24,037 26,003 553 600 500 506 400 20,000 300 200 10,000 100 233 INCArapportGB2013.indd 10 May 13 Dec.12 June 12 Dec.11 June 11 Dec.10 Jul.10 Dec.09 July.09 Dec.08 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Jul.08 0 0 Dec.07 Nb of patients recruited 700 28/10/13 14:13 6 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 11 EARLY PHASE CLINICAL TRIALS IN INCa-DESIGNATED CENTRES-CLIP2 2,808 3,000 2,500 2,000 1,000 500 1,788 1,569 1,500 890 230 0 2009 153 166 2010 2011 187 2012 Number of phase I/II trials Number of patients recruited in phase I/II trials INCArapportGB2013.indd 11 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 12 MOLECULAR GENETICS PLATFORMS: ACTIVITY INDICATORS Molecular characterisation of tumours has become a decisive factor in the choice of therapeutic strategies for patients with cancer, and molecular testing is mandatory in order to satisfy marketing authorisation requirements for drugs targeting molecularlystratified tumour subgroups. In order to ensure wide access to molecular profiling of tumours, INCa and the French Ministry of Health have established and developed a national network of 28 regional molecular genetics centres. In 2011, molecular testing was carried out on 61,784 cancer patients as part of their care. Predictive molecular testing in France in 2011: genetics centres. activity of the 28 molecular Lille Rouen Brest Paris AP-HP Caen Curie Rennes Nantes Angers Tours Reims Nancy IGR Strasbourg Besançon Dijon Number of patients who benefited from predictive molecular testing in 2011 Poitiers 8,000 Limoges Bordeaux Toulouse Lyon Clermont Ferrand 4,000 2,000 1,000 500 Saint-Étienne Montpellier Grenoble Marseille Nice Source: INCa, Molecular genetics centres activity report 2011; Drafted by Research and Innovation Division - INCa – 2013 INCArapportGB2013.indd 12 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 13 SCREENING FOR KRAS MUTATIONS IN PATIENTS WITH COLORECTAL CANCER Nb of patients 20,000 17,246 18,306 16,581 10,012 10,000 17,003 1,100 0 2007 2008 2009 2010 2011 2012 SCREENING FOR EGFR MUTATIONS IN PATIENTS WITH LUNG CANCER Nb of patients 30,000 20,750 20,000 21,995 16,834 10,000 1,269 2,667 0 2008 INCArapportGB2013.indd 13 2009 2010 2011 2012 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 14 INTERNATIONAL ACTIONS WHO FCTC Framework Convention on Tobacco Control WHO - Funding/participation in work IARC - Seat on Board of Directors US NCI CTEP - Early phase clinical trials Coordination - Programmes to support southern countries INTERNATIONAL CONSORTIA ICGC - International Cancer Genomics Consortium ICRP - International Cancer Research Partnership ICISG - International Cancer Information Service Group INCArapportGB2013.indd 14 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 15 EUROPEAN CONSORTIA TRANSCAN - Translational research: 25 partners, 19 countries EPAAC - European Partnership for Action Against Cancer: 36 partners, 27 countries BASIS - Research: Breast cancer somatic genetic study: 13 partners, 8 countries CSA PerMed - Personalised medicine: 30 partners, 16 countries CANCON - European guidelines for quality improvement in comprehensive cancer control AIEA-PACT Capacity building, education and training, comprehensive cancer control programmes ASIA: THAILAND/LAOS Research: Public health Cervical cancer (HPV/HIV) IARC/Global initiative for cancer registry development in LMICs Technical support, training and help with networking AFRICA Telepathology network - Support for diagnosis (lymphoma) Mauritania - Cooperation and training agreement Senegal - Agreement on cooperation, research coordination, training, capacity building Cote d’Ivoire - Agreement on cooperation, public health/ research/training Coordination with AORTIC INCArapportGB2013.indd 15 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 16 INCa’S INTERNATIONAL PORTFOLIO Notable international activities, consortia & programmes 2013–2014 EUROPE & high income countries EPAAC – European Partnership for actions against cancer (INCa is co-leader of WP “research coordination” and member of WP “cancer care/ rare cancers”). CANCON - European guidelines for quality improvement in comprehensive cancer control (INCa is leader of WP “survivorship & rehabilitation”, and active member of WP “integrated cancer control” and of WP “screening”) – start date Feb. 2014. ICGC – International cancer genomic consortium (INCa is founding member & sits on ICGC executive committee/4 projects funded: breast, liver, prostate and Ewing sarcoma cancer). GLOBAL ALLIANCE (dedicated to enabling secure sharing of genomic and clinical data). BASIS – European research project on Breast cancer somatic genetic study. TRANSCAN – European network on translational research (3 joint European calls for research proposals launched: “validation of biomarkers”, “primary & secondary prevention”, and “tertiary prevention”). Clinical research US NCI CTEP – INCa coordinates French clinical research centre’s participation to the US NCI mass solicitation in early phase clinical trials. IRCI – International Rare Cancer Initiative (INCa to join the Board of the International Rare Cancers Initiative and contribute to the development of the initiative and delivery of its research objectives). EPAAC – European Partnership for actions against cancer (INCa is co-leader of WP “research coordination”/ CLIP² like pilot project on early phase clinical research is being developed). WHO (World Health Organization) Framework Convention on Tobacco Control. TRANSCAN – European network on translational research (2 joint European calls for research proposal targeting “primary & econdary prevention” and “tertiary prevention”). CANCON - European guidelines for quality improvement in comprehensive cancer control (INCa is an active member of WP “screening”) – start date Feb. 2014. Diagnosis/ screening Prevention Lo IA co CSA PerMed – European concerted action on personalised medicine (global objective is to develop a European strategic research agenda in personalised medicine). Translational research PersoCancer biology/ nalised genomics medicine Cancer control International consortia Th inf M La vs Cancer registries Research networking Se Co M IA ed Te ICRP - International Cancer Research Portfolio. ICISG International Cancer Information Service Group. Global health IA su m Capacity building and training programmes Cancer care/ survivorship EPAAC – European Partnership for actions against cancer (INCa active member of WP “cancer care/ rare cancers”). CANCON - European guidelines for quality improvement in comprehensive cancer control (INCa is WP leader “survivorship & rehabilitation”, member of WP “integrated cancer control) – start date Feb. 2014. Cancer research funders annual meeting. INCArapportGB2013.indd 16 Co 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 17 Low and medium income countries IAEA (International Agency for Atomic Energy) – PACT programme on cancer/(INCa is contributor to PACT’s comprehensive cancer control programmes & training directed to French speaking low & medium income countries). Thailand: Research study funded by INCa: “PapilloV - Human papilloma virus (HPV) infection and cervical lesions in HIVinfected women receiving antiretroviral therapy in Thailand (Principal investigators: Institute for Development Research and Ministry of Public Health of Thailand). Laos: Research study funded by INCa: LaoCol-VP – Efficacy & cost/effectiveness of cervical lesions screening by HPV detection vs pap smear in HIV-infected women in Laos (principal investigator: Centre Infectiologie Charles Mérieux du Laos). IARC/Global initiative for cancer registry development in LMIC (low and medium income countries) – support to regional network hubs/capacity building in sub-Saharan francophone countries/development of training materials & modules in French (to be formalised). Senegal - cooperation agreement/ research & public health, capacity building, training, cancer control Cote d’Ivoire - cooperation agreement research & public health, capacity building, training, cancer control Mauritania - cooperation agreement Training. IAEA (International Agency for Atomic Energy) – PACT programme on cancer/capacity building, education and training, cancer control programmes. Telepathology network: lymphoma diagnosis. Coordination with AORTIC - African Organisation for Research & Training in Cancer (to be formalised). INCArapportGB2013.indd 17 28/10/13 14:13 18 INCArapportGB2013.indd 18 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 19 SUMMARY OF THE REPORT The seventh report for INCa’s International Scientific Advisory Board marks the final year of cancer research actions undertaken under the two successive Cancer Plans, 2003-2007 and 2009-2013. The research and health landscape for oncology has undergone a major upheaval in recent years, giving France major opportunities to strengthen its innovative programmes and initiate new ones. Among the key initiatives, the organisation of 8 SIRICs - integrated cancer research sites - and 16 CLIP2 - early phase clinical trial centres - together with the network of 28 molecular biology platforms, has established a solid basis for cancer research activity of the highest standard in France. The first part of the present report summarises the recommendations of the INCa Scientific Advisory Board since 2007, and describes how these recommendations have been followed by initiating or reinforcing major actions. Six areas of action have been considered: translational research: the creation of a coordination system for the SIRIC network, a qualitative analytical study of the main organisational and scientific challenges for the SIRICs, and preparation for the establishment of chairs of excellence are the main actions completed in 2013. • Molecular genetics and research synergy: the most recent actions reflect improved integration between research programmes and the clinical platforms in order to spur the development of individualised medicine • Strategy for public health research: the most recent actions reflect stronger collaboration between the different agencies, particularly in the conduct of calls for proposals. INCArapportGB2013.indd 19 28/10/13 14:13 20 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT • Assessment and performance of clinical research: the most recent actions reflect the acceleration of public-private partnerships and the establishment of early phase trials for innovative drugs (8 such molecules since 2009), along with monitoring of recruitment, which has shown a 72% increase from 2008 to 2013. • International: the most recent actions reflect the establishment of new pilot actions to coordinate cancer research under the European framework programme EPAAC, particularly aimed at organising and involving stakeholders in the early phases of clinical trials. • Communication: scientific events organised in 2012 and 2013 had the benefit of high visibility, notably through the presence of the most senior representatives of the State. The second part of this report sets out a detailed review of the situation of research actions carried out in 2012 and 2013, and takes stock of actions undertaken since 2007 in the 4 broad research areas: Translational Research; Clinical Research; Cancer Biology and Sciences; and Research in Human and Social Sciences, Epidemiology and Public Health. In total, for all partners involved in research actions included in the 2009-2013 Cancer Plan, 900 proposals were submitted in response to calls for proposals in 2013, i.e. an increase of nearly 5% compared with 2012 (859 proposals submitted in 2012). Investment for the 12 calls for proposals reviewed at the time of writing the present report (July 2013), and which led to the selection of 154 research projects, is over €46 M (Proposals submitted under the PHRC and PRME-K calls for proposals for clinical research will not be reviewed until November 2013; the estimated investment for clinical research for 2013 is €22 M, based on expenditure in previous years). The selection rate for calls for proposals has remained stable for the investigator-driven biology programme (15.8% vs. 16.7% in 2012-2013), and has increased slightly for the translational research programme (12% vs. 16% in 2012). The selection rate for the investigator-driven programme in human and INCArapportGB2013.indd 20 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 21 social sciences, epidemiology and public health is over 30% (37% in 2013 vs. 39% in 2012). A selection rate of 30% (32% vs. 39% in 2012) also applies to the programme for research in physics, mathematics and engineering sciences applied to cancer, managed by the Aviesan Alliance’s Multi-Organisation Thematic Institute for Cancer (ITMO Cancer). To these investments in research programmes can be added support for research structures and infrastructure, which in 2012-2013 includes designation of cooperative intergroups (a total of 8 intergroups designated in 2012-2013, €0.8 M), support for a new genome sequencing programme for retinoblastomas and carcinosarcomas (€1.2 M) under the International Cancer Genome Consortium, ICGC, construction of clinical-biological databases (BCB in French; 4 in 2012 and others to be selected in 2013). Efforts deployed in clinical research have translated into a steady increase in the recruitment of patients to clinical trials, up 72% since 2008. A major growth of 200% can be seen in recruitment to early phase trials conducted by the CLIP2. Part 2 of the scientific report also shows a synthesis on the costs of chemotherapy in France, estimated at €2.8 billion, and a summary of funding awarded by the canceropoles for the creation of platforms and the sharing of resources within the scientific community. In this part, the HELIOS pilot project is presented, as well as a review research investment, which includes maps showing the distribution of funding for the 4 large calls for proposals during the 2007-2012 period: • Translational research: €34 M; • Clinical research: €12 M; • Cancer biology and sciences €9 M; • Research in human and social sciences, epidemiology and public health: €27 M. The estimated expenditure on research in 2013 for all partners combined is €99 M. INCArapportGB2013.indd 21 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 22 The third part of this report shows the strategic orientations for cancer research established in consultation with Aviesan ITMO Cancer, and some perspectives in terms of priorities for action. The 5 priorities will be discussed with INCa’s International Scientific Advisory Board at the annual meeting of its members on 7 October 2013. • Priority 1: initiate a cross-sectional programme in research/care/ public health to combat tobacco-related cancers; • Priority 2: set up a system for sharing of clinical, biological and epidemiological database; • Priority 3: promote cooperation between Teaching and Research, and increase support for interdisciplinary training; • Priority 4: support French cancer research aimed at achieving rapid and significant benefits for the population and patients; • Priority 5: meet new challenges in the fight against cancer: European and international perspectives. INCArapportGB2013.indd 22 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 23 Part 1. SUMMARY OF PREVIOUS RECOMMENDATIONS DRAWN UP BY MEMBERS OF THE SCIENTIFIC ADVISORY BOARD, AND PROGRESS MADE This section brings together the main recommendations (2007-2012) under 6 broad themes, and summarises the main actions achieved by INCa: 1 - Priority given to translational research; 2 - Molecular genetics, cancer biology and sciences; 3 - Evaluation and key performance indicators of clinical research; 4 - Strategies for research in public health and human and social sciences; 5 - Collaboration at national, European and international levels; 6 - Communication. INCArapportGB2013.indd 23 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 24 PRIORITY GIVEN TO TRANSLATIONAL RESEARCH AND MULTIDISCIPLINARY TRAINING 2007 • The Board supports the investment plan prepared by INCa for training physicians/scientists and investigators in translational research. • Focus on a few high priority programmes. • Reduce the number of calls for proposals. 2009 • The Board gives priority to translational research, which must be a central mission for INCa. • It recommends establishing a specific evaluation process and developing an attractive career path. • Define the criteria for centres of excellence (comparable to the comprehensive cancer centres in Europe and North America), and establish a process before opening a national call. • Strong support for existing actions to simplify the life sciences landscape. 2011 • Strong support for the SIRIC initiative (Integrated Cancer Research Sites). The Board recommends an increase in the number of SIRICs and their budget, and the development of a system for networking the SIRICs. • The Board recommends that balance be maintained between support for the SIRICs, and for studies conducted by the cooperative intergroups and on the initiative of investigators. • INCa should play an active role in promoting training and career development for the next generation of investigators specialising in translational research. 2012 • The Board is very pleased with the implementation of the SIRIC programme and the number of eight centres of excellence for translational research is sufficient. We strongly recommend that the SIRIC sites develop joint activities and platforms. • The Board highly encourages INCa to continue its investment in training and education across all disciplines, including bioinformatics, basic, translational and clinical research, as well as behavioural science. Actions achieved or in progress Achieved • 2009: joint strategic research orientations published by INCa and ITMO Cancer. • Recurrent support for translational research from 2009. • Recurrent support for translational research training from 2008. • Creation and designation of SIRIC integrated research sites: 2 in 2011, 6 in 2012. • Participation in the European ERA-Net initiative to support joint translational research programmes. • 2012: first evaluation of training programme provided to medical students to perform translational research. • 2013: working group for coordination and planning of the methodology used to evaluate the SIRICs. In progress • Chair of excellence for career advancement: chair in translational cancer research, and chair in prevention. INCArapportGB2013.indd 24 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 25 MOLECULAR GENETICS, AND CANCER BIOLOGY AND SCIENCES 2007 • The Board supports the expansion of a national tumour registry. Resource allocation would be more effective if it were based on more accurate data. • Genomics and epigenetics are priority areas for support. • Support for tumour banks at institutional level should be directed toward the collection of biological resources accompanied by high-quality clinical annotation. • Focus on a few high priority programmes. • Reduce the number of calls for proposals. 2010 • The Board recommends that the number of molecular diagnostic platforms be reconsidered, and recommends improved interaction with basic/translational research, and a focus on information systems for platforms and clinical data. • The Board supports development of research in epigenomics and on the tumour microenvironment. • The Board supports training for clinicians and researchers in the new skills associated with the molecular diagnosis and prognosis of cancer. 2011 • The Board encourages the development of data processing systems for bioinformatics and medical data, and research on complex systems in collaboration with other research organisations. 2012 • The Board recommends that large scale NGS facilities be implemented at some of the SIRIC sites and services shared with the oncology community. Complementary bioinformatics expertise and clinical data management must be available at these centres. • The research programme for cancer biology is an important asset, and requires sustained funding. Actions achieved or in progress Achieved • 2011-2013: Calls for proposals (CFP) 1) Creation of national clinical-biological databases 2) Research projects in mathematics, physics, engineering sciences and cancer 3) Research projects based on systems biology 2011: publication of institutional recommendations for the creation of tumour collections for research programmes. 2013: publication of a report on advances in cancer biology research funded by CFPs from INCa and ARC Foundation: Rôle du Microenvironnement dans la Tumorigénèse et la Progression Tumorale (Role of the Microenvironment in Tumorigenesis and Tumour Progression). In progress • Strategic report for the national organisation of bioinformatics and specific requirements for oncology. • Integration of research programmes for genomics and clinical platforms. INCArapportGB2013.indd 25 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 26 EVALUATION AND KEY PERFORMANCE INDICATORS IN CLINICAL RESEARCH 2008 • The Board encourages the establishment of more key performance indicators (KPIs), especially for clinical trials (e.g. time taken to put the studies in place, number of patients, closure of databases, etc.), and clarification of clinical trial management (e.g. data centres, EMRCs [mobile clinical research teams] etc.). • In anticipation of a less favourable economic climate, the Scientific Advisory Board suggests continuing to provide full funding for the best projects. 2010 • The Board supports the implementation of key performance indicators (KPIs) and milestones to confirm the efficacy of scientific strategy. 2012 • The Board encourages the design of innovative clinical trials and methodology in assessing the value of NGS. Actions achieved or in progress INCArapportGB2013.indd 26 Achieved • Annual review meetings to review successes and failures in clinical research. • Performance indicators for projects selected under the Hospital Clinical Research Programme (PHRC). In progress • Support for randomised trials to assess the contribution of NGS to patient treatment. • Performance indicators for public-private partnerships in early phase clinical trials. • Health Investments Observatory (HELIOS). 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 27 RESEARCH STRATEGIES IN PUBLIC HEALTH AND HUMAN AND SOCIAL SCIENCES 2007 • The Board supports the development of research on screening, early diagnosis and prevention strategies. 2010 • The Board recommends the development of a specific strategy for preventive research (including behavioural and social sciences, epidemiology, public health, statistics, economics, etc.). 2012 • The Board endorses the main recommendations on the excellent prevention strategy report. The key components are capacity building, coordination with other funders and development of measures of behaviour. • In light of the shocking increasing prevalence of smoking in France, the Board specifically recommends to dedicate programmes that aim to develop and evaluate interventions to reverse this trend. Actions achieved or in progress INCArapportGB2013.indd 27 Achieved Strategic report on cancer prevention research: changing health behaviours and their individual and collective determinants. In progress • Preventive research programme prepared in collaboration with IReSP (French Public Health Research Institute) (to be launched at the end of 2013). • Preparation of a joint programme of action in research/public health to combat tobacco-related cancers. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 28 NATIONAL, EUROPEAN AND INTERNATIONAL INTERACTIONS 2007 • The Board encourages an integrated approach within the European Union. • The Board encourages financial incentives for cooperative groups wishing to consolidate and study specific subjects. 2008 • Whenever possible, priority should be given to projects where European collaborations are ongoing or planned. • This information should be contained in the application. • Need to continue our action through the use of effective methods to involve the pharmaceutical industry. One model that could be considered is the CRADA initiative in the US NCI. 2009 • The Board encourages INCa to work with patient associations to strengthen strategic research programmes • The Board strongly recommends the implementation of actions to simplify the life sciences landscape. • The Board recommends that links be strengthened with the regulatory agencies and the existing large cooperative groups, and encourages the development of new large cooperative groups in order to improve the efficacy of clinical trials. 2010 • The Board encourages more interaction with the 2 main cancer charities and the development of optimum synergy. • The Board supports the efforts made to increase collaboration between the various cooperative groups at national and international levels. Actions achieved or in progress Achieved • INCa is a partner in 5 European projects aimed at coordinating research, namely the BASIS project for cancer genomics research, TRANSCAN for translational research, and EPAAC for the coordination of cancer research on a European scale, CSA PerMed, CANCON. • Exchange/collaboration with the pharmaceutical industry and biotechnology companies. • INCa is showing increased leadership through its international communications on personalised medicine. • 2012-2013: designation of cooperative intergroups. In progress • New pilot actions under the European EPAAC programme in order to involve the pharmaceutical industry and organise academic resources available for early phase clinical research. INCArapportGB2013.indd 28 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 29 COMMUNICATION 2008 • As an integral part of its responsibility as a leader in the fight against cancer, INCa should: - sponsor international symposia, - continue its leading role in providing information to the public, - take a leading role in issues related to cancer survival. 2009 • The Board recommends organising more international symposia to increase INCa’s visibility. 2010 • The Board encourages INCa to promote international scientific events regularly, and to foster better communication with regard to scientific strategy. 2012 • The Board is very pleased with the quality and conciseness of the Scientific Report. Actions achieved or in progress INCArapportGB2013.indd 29 Achieved • Joint funding of the Integrated Research Action Programme: PAIR (INCa/ARC Foundation/French National Cancer League). • Joint funding (ARC Foundation/INCa) for the “Cancer and Employment” research programme. • Annual symposium on inequalities. • Symposium on environment and cancer. • Symposium on quality of life and cancer. • International conference on the tumour microenvironment. • 2012: symposium on Cancer and Inequalities. • 2012: international R&D Dating. • 2012: international forum on prospective in cancer research and treatment. • 2013: international symposium on nutrition and cancer. • Strategic report on a programme for cancer prevention research: changing Health Behaviours and their Individual and Collective Determinants. • 2013: report on the main advances on the tumour microenvironment (programme co-funded by INCa/ARC Foundation). 28/10/13 14:13 30 INCArapportGB2013.indd 30 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 31 Part 2. REPORT ON CANCER RESEARCH ACTIVITY FOR 2012-2013, AND SYNTHESIS INCa’s work in cancer research is based on the management of calls for proposals and monitoring of work done on selected projects, and the coordination of actions and programmes aimed at increasing interdisciplinary links. In addition to the investigator-driven calls for proposals launched each year in the 4 main research areas, namely cancer biology, translational research, clinical research and research in human and social sciences, epidemiology and public health, INCa manages a call for the Integrated Research Action Programme (PAIR programme), which targets specific types of tumours. INCa also renewed its call for proposals for health intervention research on reducing inequalities related to cancer, and in the last three years, new research programmes defined in the Cancer Plan have been organised in cooperation with the Aviesan Alliance’s ITMO Cancer (managed by Inserm): Physics, Mathematics and Cancer, Environmental Risks and Cancer, Spontaneous Tumour Models and Systems Biology. A major effort has been committed to the creation and support of the SIRIC - integrated cancer research sites - and the development of public-private partnerships to support early phase clinical trials of innovative drugs in the INCa-designated CLIP² centres. INCArapportGB2013.indd 31 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 32 Table 1/ Call for proposals funded by INCa, DGOS (Ministry of Health) and Aviesan-ITMO Cancer Call for proposals Nb of proposals submitted Nb of projects selected (% selection) Funding (€M) 2012 2013 2012 2013 2012 2013 Cancer Biology and Sciences (INCa) 191 208 32 (16.7%) 33 (15.8%) 15.9 15.1 Clinical Research PHRC (DGOS) 226 240 54 (23.9%) In progress 20.25 In progress PRME-K (Programme for Medico-Economic Cancer Research, formerly STIC) (DGOS) 12 16 3 (25%) In progress 0.5 In progress Integrated Research Action Programme (INCa-ARC Foundation-French National Cancer League) 39 25 6 (15.4%) 9 (36%) 3.4 5.1 (gynaecology) (melanoma) (gynaecology) (melanoma) (gynaecology) (melanoma) Translational Research (INCa-DGOS) 164 163 26 (16%) 19 (11.6%) 9 8.4 Training in Translational Research (Aviesan-ITMO Cancer) 36 52 27 (75%) 25 (48%) 2.1 1.5 Human and Social Sciences, Epidemiology, Public Health (INCa) 41 54 16 (39%) 20 (37%) 3.8 4.8 Health Intervention Research Aimed at Reducing Inequalities (INCa) 19 10 5 (26.3%) 3 (30%) 2.2 0.7 Research on Inequalities in Access to Cancer Care (IReSP) NA 5 NA 1 (20%) NA 0.1 9 NA 3 (33%) NA 0.48 NA Biostatistics and Cancer (IReSP) NA 23 NA 9 (39%) NA 1.3 Physics, Mathematics, Engineering Sciences and Cancer (Aviesan-ITMO Cancer) 57 54 21 (37%) 19 (35%) 4.1 4 Cancer and Environmental Risks (Aviesan-ITMO Cancer) 23 22 9 (39%) 7 (32%) 2.4 2.8 Spontaneous Tumours (Aviesan-ITMO Cancer) 9 9 4 (44%) 2 (22%) 1.45 0.57 Systems Biology (Aviesan-ITMO Cancer) 21 22 4 (19%) 4 (18%) 2.7 1.5 Cancer and Employment (INCa-ARC Foundation) INCArapportGB2013.indd 32 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 1 33 INCREASED SUPPORT FOR TRANSLATIONAL AND INTEGRATED RESEARCH 1.1. RESEARCH PROGRAMMES AIMING AT BOOSTING TRANSDISCIPLINARITY AND TRANSFER OF KNOWLEDGE INTO CLINICAL PRACTICE As a flagship measure of the 2009-2013 Cancer Plan, and one of the major actions in research, Action 1.1 aims to strengthen translational research through dedicated funding based on calls for proposals and a policy of designated multidisciplinary integrated research sites. INCa, in partnership with the Ministry of Health (DGOS), has continued to support translational research by launching a dedicated call for proposals, enabling funding for competitive research projects. The goal of this action, launched for the first time in 2007, and recurrent since 2009, is to promote interdisciplinary projects, bringing together laboratory researchers and clinicians so that they share and combine their specific expertise in order to foster the translation of scientific and medical discoveries into clinical advances for cancer patients. INCArapportGB2013.indd 33 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 1.1.1. THE TRANSLATIONAL RESEARCH PROGRAMME Fig. 1/ Trends in selection for the translational Research programme Table 2/ Call for proposals in Translational Cancer Research Year Funding institutions Objectives Funding Results: Proposals submitted Projects selected Selection rate 2012 2013 INCa/DGOS (Ministry of Health) To promote interdisciplinary projects, by bringing together lab researchers and clinicians to share and combine their specific expertise in order to foster translation of scientific and medical discoveries into clinical advances for cancer patients. €8.947 M INCa: €5.065 M DGOS: €3.882 M €8.399 M INCa: €4.445 M DGOS: €3.954 M 164 letters of intent 26 16% 163 letters of intent 19 11.6% Since 2007, 729 proposals have been submitted in response to this call for proposals, and 111 have been selected and funded, giving an overall selection rate of 15.2%. The total amount invested in these projects since 2007 is €42.5 M (Figure 1). INCArapportGB2013.indd 34 Total budget in €M The response to the 2013 edition of the call for proposals for Translational Research (162 proposals submitted) has once again shown the commitment and effort of France’s medical and scientific community to hasten the translation of discoveries into clinical practice for the benefit of patients. 12 30 10 25 8 20 6 15 4 10 2 5 0 0 Number of projects 34 2007 / 2009 2010 2011 2012 2013 Total funding Nb of projects Note that for a similar total budget (€8.4 M vs. €8.9 M respectively for 2013 and 2012), the number of projects funded is smaller for 2013 (19 vs. 26), the average project cost is higher in 2013 (€442,000 compared with €344,000), and the projects are bringing together a large number of teams, with 12 consortia of at least 10 teams, including 2 uniting more than 30 teams. The project selection rate in 2013 is consistent with the quality of the projects as assessed by the international review committee. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT Fig. 3/ Distribution of budget allocated to the translational Research programme in 2013, shown in comparison to the overall profile for 2007-2013 500,000 60% 50% 30% 100,000 20% 0 10% 2009 2010 2011 2012 2013 17% 14.6% 8% The typology of projects funded in 2013 corresponds to the characteristic profile for translational research (Figure 3), with most of the budget allocated to two main categories of research projects: • projects that involve the development of techniques or biomarkers (genetic, biological, immunochemical, microbiological), • projects based on the improvement of patient care, including projects on the development of new strategies, and on mechanisms of treatment resistance. 1% 3.3% 2% 0% 1.6% 0% 0% 0% Aetiology 2008 24% Biology 2007 37% Cancer control 200,000 43.6% Early detection, diagnosis and prognosis 40% Prevention 300,000 2007-2013 2013 49% Treatment 400,000 Scientific models Fig. 2/ Average budget of projects funded, in euro 35 We see that nearly half the projects selected in 2013 employ genomic analyses (genotyping, sequencing). These studies, based on the use of high throughput technologies that generate large quantities of data, justify an increase in the multidisciplinary dimension of the projects, particularly in bioinformatics for the analysis and interpretation of results. Haematology is the most represented speciality in funding for 2013, with 30% of the allocated budget, but many other malignant pathologies are also studied in the selected projects (pancreatic cancer, hepatoblastoma, paediatric tumours, breast cancer, colorectal cancer, etc.). 2012-2013 Highlights 45 “Translational research” projects selected for multi-year funding (INCa and DGOS) of €17 M. INCArapportGB2013.indd 35 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 36 1.1.2. THE TRANSLATIONAL RESEARCH TRAINING PROGRAMME As part of its policy of supporting translational research, INCa, in conjunction with Aviesan for the last three years, also offers a specific recurrent call for applications, initiated in 2007, to facilitate the training of medical students who wish to complete their medical studies by performing translational cancer research. This support is provided through the competitive awarding of grants to applicants for one to three years to complete a master’s degree or post-doctoral residency, or to prepare a doctoral thesis on an outstanding research topic. Students preparing to qualify in pharmacy or veterinary medicine are eligible for this call. Fig. 4/ Distribution of total funding allocated for translational research training in 2007-2013 4.6% 28.6% Biology= €3.2 M Aetiology= €0.5M Prevention= €0.01 M Early detection, diagnosis, prognosis = €1.8 M Treatment= €2.4 M Scientific models= €0.4 M Table 3/ Results of the Translational Research Training Programme in 2012-2013 Year Funding institutions Objectives Funding Results: Proposals submitted Projects selected Selection rate 2012 2013 Aviesan/ITMO Cancer To promote training of students or young medical, pharmacy and veterinary science graduates in translational research by funding master’s degrees, doctoral theses or post-doctoral research. €2.086 M €1.511 M 36 27 75% 52 25 48% In all, 130 training grants have been awarded for translational research, for a total of €8.3 M, since 2007 (50% success rate), including 11 to postdoctoral candidates and 45 to students preparing theses (Figure 4). INCArapportGB2013.indd 36 38.7% 21.9% 0.1% 6% 2012-2013 Highlights 52 candidates selected for training in translational research, for a €3.5 M funding (Aviesan-ITMO Cancer). 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 1.1.3. THE EUROPEAN TRANSLATIONAL CANCER RESEARCH PROGRAMME The ERA-Net TRANSCAN programme, specific for translational research in oncology, presently involves 19 countries represented by 29 funding institutions and organisations, including INCa. The TRANSCAN programme is aimed at establishing coordination at European level for national translational cancer research programmes, and providing joint funding for research projects selected following the 3 joint calls for proposals planned over the duration of TRANSCAN. 37 INCa is actively involved in drawing up and organising calls for proposals, and funding the research projects selected. INCa is more specifically tasked with coordinating the work package (WP) on training and promotion of multidisciplinarity. With the help of recommendations from TRANSCAN’s Scientific Advisory Board, the members of the network agree annually on the definition of a topic for the next call for proposals to be launched. An overall analysis of funding allocated by the partners to translational cancer research, based on the CSO classification defined by the international ICRP network is planned. Table 4/ ERA-NET on Translational Cancer Research/ERA-NET TRANSCAN Objectives of TRANSCAN To coordinate the national and regional funding organisations’ activities in translational cancer research at European level, with the launch of 3 joint transnational calls for proposals (JTCs). Website: http://www.transcanfp7.eu/transcan/index.php 1- Management and network coordination. 2- Survey and analysis of national cancer research funding for translational research. Sharing of INCa’s experience with the TRANSCAN partners, using the CSO classification system. Definition by INCa and its partners, in 2012, of the topic for the 2nd CFP (JTC 2012). Definition in 2013 of the topic for the 3rd CFP (JTC 2013). Implementation of their review process. 4- Implementation of the 3 joint transnational calls (JTCs). In 2013, INCa is providing secretariat services for the entire process of the 2nd CFP (JTC 2012). 5- Implementation of capacity building and training activities. INCa is the leader of this work package for the 3 calls for proposals. TRANSCAN Work packages 6- Monitoring of activities network and sustainability. Call for proposals (JTCs) INCArapportGB2013.indd 37 3 calls for proposals launched within 3 years Launch dates: end of 2011, 2012 and 2013. 2-stage procedure: pre-proposals + full proposals Publication of results in October of year N + 1 Start of funding in April of year N + 2 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 38 Table 5/ ERA-NET TRANSCAN – Calls for proposals Topic of calls for proposals 1st call for proposals: JTC 2011 “Validation of Biomarkers for Personalised Cancer Medicine”. 2nd call for proposals: JTC 2012 “Translational Research on Primary and Secondary Prevention of Cancer”. 3rd call for proposals: JTC 2013 “Translational Research on Tertiary Prevention of Cancer” Currently being drawn up for launch in December 2013. For the 3 calls for proposals: Within proposals, it is possible to add a specific component related to training (short- or long-term), or to increasing multidisciplinarity. This additional component, which must, however, be related to the research objectives, will be funded only if it receives a favourable review. Funding of calls for proposals Results of calls for proposals 1st call for proposals: JTC 2011 15 funding partners: Germany, Austria, Belgium, Spain, France, Greece, Israel, Italy, Latvia, Luxembourg, Poland, Romania, Slovakia, Slovenia, Turkey. 2nd call for proposals: JTC 2012 15 funding partners: Germany, Austria, Belgium, France, Israel, Italy, Latvia, Luxembourg, Norway, Netherlands, Poland, Portugal, Romania, Slovakia, Turkey. Total budget: €10.6 M (of which €1.3 M from INCa). Provisional total budget: €14.31 M (of which €1.5 M from INCa and €0.3/0.5 M from ARC Foundation). 1st call for proposals: JTC 2011 Number of “pre-proposals” submitted: 117, including 579 teams Number of full proposals: 34 Number of projects selected: 10 2nd call for proposals: JTC 2012 Number of “pre-proposals” submitted: 55, including 257 teams Number of full proposals: 22 Number of projects selected: pending (October 2013) Participation of French teams 60 “pre-proposals,” including 80 teams/18 coordinators. Participation of French teams 22 full projects, including 29 teams/7 coordinators. 28 “pre-proposals,” including 36 teams/7 coordinators. 6 projects selected, including 7 teams/1 coordinator. 13 full projects, including 18 teams/3 coordinators. INCArapportGB2013.indd 38 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 39 Focus on projects funded through JTC 2011 The number of responses to the 1st call for proposals indicates the interest of European teams in working on more advanced phases of biomarker development for clinical application. This also stresses the enthusiasm of researchers for increasing their scientific collaboration at a European level in order to share complementary expertise, to benefit from access to specific technologies and highly qualified platforms, and to create larger patients cohorts or larger sample collections. Of the 10 projects selected for funding by the TRANSCAN partners, over half of funded projects deal with biomarkers aimed at predicting the efficacy or toxicity of treatments administered to patients: • use of nuclear medicine to predict the efficacy of hormone therapy for breast cancer, • invoking DNA repair pathways to predict the efficacy of chemotherapy for colorectal cancer, lung cancer, and breast cancer, • interest of monitoring immunological biomarkers following haematopoietic stem cell transplantation, and during treatment for breast and ovary cancers. This is evidence of the continued efforts devoted to developing personalised medicine in order to tailor therapeutic care to the characteristics of individual patient and his/her tumour. Two projects are specifically devoted to improving diagnosis: one through the use of nuclear medicine in thyroid cancer, and one through the study of genetic changes in leukaemias. Finally, biomarkers for prognosis are the subject of two projects, one of which uses genomic techniques in Ewing’s sarcoma, and the other of which uses detection of circulating tumour cells in prostate cancer. Focus on the JTC 2012 topic “Translational Research on Primary and Secondary Prevention of Cancer” The number of projects submitted under the 2nd TRANSCAN call for proposals (55 vs. 117 for JTC 2011) is evidence of the originality of the topic chosen. Indeed, the TRANSCAN partners, supported by the recommendations of the Scientific Advisory Board, wished to further the contribution of translational research to questions raised by primary and secondary cancer prevention. The methodological complexity of the studies and the need for access to patient cohorts make the establishment of these projects difficult, but their impact is expected to be significant in terms of public health and European research organisation in this field. INCArapportGB2013.indd 39 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 1.1.4. DEVELOPMENT OF SPONTANEOUS TUMOUR MODELS AND ALTERNATIVES TO CLINICAL TRIALS The strategic initiative to support the development of spontaneous tumour models and alternatives to clinical trials, a corollary of the first measure of the Cancer Plan, was launched for the first time in 2011, and renewed in 2012 and 2013 with dedicated calls for proposals. Its objectives are to encourage the various disciplines to work together and incorporate research carried out on spontaneous cancers occurring in animals, particularly dogs, into studies done on a worldwide scale in the areas of biology, diagnosis, prognosis and treatment of cancers that affect humans. Prior to this dedicated call, and from 2009 on, INCa redoubled its efforts to mobilise the different research communities (biologists, clinicians and veterinarians) through specific seminars and meetings. Collaborations were established with European partners, and cooperation put in place with the US Comparative Oncology Trials Consortium. Table 6/ Main features of the Research Programme for Spontaneous Tumours Models Year Funding institutions Objectives Funding Selection rate 2012 2013 Fig. 5/ Spontaneous tumour models 2011-2013: €2.5 M 10 9 8 7 6 5 4 3 2 1 0 2011 2012 Fig. 6/ Spontaneous tumours: funding awarded in 2011-2013 by type of cancer Aviesan /ITMO Cancer To increase collaboration between veterinarians, researchers and clinicians so as to promote the translation of results from cancer research, through support of research projects and development of tools to monitor treatment of spontaneous cancers in animals that are diagnosed and treated in a way to be a potential outlook for humans. €1.45 M €0.57 M 44% 22% 2013 Nb of projects submitted Nb of projects selected 4 projects 1,200,000 1,000,000 Funding in €M 40 800,000 2 projects 600,000 1 project 400,000 200,000 1 project INCArapportGB2013.indd 40 Haematology Melanoma Lung/UADT Breast 0 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT The establishment of a European consortium The European dynamic in comparative oncology initiated by INCa and ITMO Cancer has helped to mobilise veterinarians and clinicians, who have applied to a COST action (European Union). This application is undergoing the final phases of processing, and brings together some ten partner countries around a core group made up of French, British, Danish and Italian teams. This project, entitled ACT (Interdisciplinary Consortium for Accelerated Cancer Translational Research) aims to promote the development of new necessary preclinical models. Spontaneous tumours in dogs show clinical, pathological, immunological, molecular, diagnostic and therapeutic characteristics similar to those that occur in humans. It is to develop innovative therapeutic concepts for cancer from spontaneous animal models. Within this framework, a multidisciplinary network of European experts in human and veterinary medicine will be developed in order to foster discussion, training and dissemination of information, and to expedite translation into clinical practice in comparative oncology. Collaboration with the CLIP² network has been initiated, and a workshop will be held in January 2014. 2012-2013 Highlights New call for proposals, “Spontaneous Tumour Models”, handled jointly by INCa and ITMO Cancer; first edition in 2011. • 8 projects since 2011, €2.5 M 41 1.1.5. RENEWAL OF THE INTEGRATED RESEARCH ACTION PROGRAMME FOR A SPECIFIC TYPE OF TUMOUR In 2007, INCa launched an annual thematic programme devoted to a specific pathology. The programme, entitled, “Integrated Research Action Programme” (PAIR), is aimed at bringing together scientific and medical communities specialising in this pathology. Projects cover all areas of research, such as biology, clinical research, epidemiology, innovative technologies, prevention, screening, diagnosis, treatment and social sciences. This specific programme is organised in two stages. The preparatory work is performed by a scientific organising committee in order to identify the context and define the research areas to be targeted in the call for proposals. A national seminar is organised before launching the call, in order to bring together the scientific and medical communities, and encourage the creation of large consortia. A partnership between the three major funders of cancer research — ARC Foundation, the French National Cancer League and INCa — has been initiated and each of the three partners contributes to funding the projects selected. Following gynaecological cancers in 2012, and before early forms of breast cancer in 2014, the 2013 PAIR is focused on melanomas. The significant increase in the incidence of melanoma in recent years (from 2,210 in 1980 to 9,780 in 2011, according to InVS [French Institute for Public Health Surveillance] estimates), which affects young individuals, together with some recent advances in research on treatment, justifies a strong call for action. (Aviesan-Inserm for ITMO Cancer). • Establishment of a European network for comparative oncology. INCArapportGB2013.indd 41 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT Year Funding institutions Objectives Funding Results: Proposals submitted Projects selected Selection rate 2013 (melanomas) INCa ARC Foundation National Cancer League To increase collaboration between French research teams, and to obtain original insights on questions at the interface between epidemiology, human and social sciences, economics, public health, biology and clinical medicine. It is therefore strongly recommended that collaborative projects involving different disciplines be drawn up in response to this call for proposals. €5.12 M 25 9 (including 2 projects funded by INCa exclusively) 36% Since 2007, 7 Integrated Research Action Programmes have been managed by INCa. Overall, 63 projects have been selected, for a total funding of €33.9 M (Figure 7). Fig. 7/ Trends in the PAIR programme for 2007-2013: number of projects selected and funding awarded 7 16 6 14 12 5 10 4 8 3 6 2 Number of projects Table 7/ Main features of the Integrated Research Action Programme Funding €M 42 4 1 2 0 0 Melanoma Gynecological cancers UADT Prostate Hepatocellular carcinoma Lymphoma Colorectal 2007 2008 2009 2010 2011 2012 2013 Total funding Nb of projects INCArapportGB2013.indd 42 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT Since its implementation in 2007, the Integrated Research Action Programme has covered all areas of research, in line with the programme’s goals (Figure 8). Nearly a third of projects selected since 2007 have studied the development and fine-tuning of strategies for diagnosis and prognosis, and markers of the response to treatment. Fig. 8/ Types of projects funded and investment in PAIR programmes over the 2007-2013 period: €34 M 43 However, it is important to note that the variety of types of research varies with the tumour. The melanoma programme in 2013 covers biology, screening, diagnosis and treatment; the programmes for colorectal cancer and hepatocellular carcinoma cover all categories of research. Fig. 9/ Distribution of PAIR programmes 2007-2013 by CSO category 2013 Melanoma € 3.2M € 2012 Gynaecological cancers (non breast) 0.9M € 6.2M 6.6M Biology Aetiology Prevention Early detection, diagnosis, prognosis Treatment Human and social sciences Scientific models € 2010 Prostate 2009 Hepatocellular Carcinoma 2008 Lymphomas 2007 Colorectal 4.2M € 1.1M € 11.8M 2011 UADT Biology Aetiology Prevention Screening, diagnosis, prognosis Treatment Human and social sciences Scientific models € INCArapportGB2013.indd 43 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 44 1.2. NEW ACTIONS TO STRENGTHEN ORGANISATION AND INFRASTRUCTURES devoted to translational/integrated research This objective has been met by the designation of 8 SIRICs (Integrated Cancer Research Sites) for a 5-year period, following two calls for applications launched in 2010 (2 SIRICs designated in 2011) and in 2011 (6 SIRICs designated in 2012). 1.2.1. Coordination of Integrated Cancer Research Sites (SIRIC) The 2009-2013 Cancer Plan included among its “flagship” objectives, to be achieved in 2013, the designation of multidisciplinary research sites linking the different dimensions of research (basic, clinical, public health, epidemiology, and human and social sciences), by concentrating a critical mass of experts (physicians, researchers, engineers, healthcare workers and patients) working within the constraints — especially competitiveness and quality assurance — of translational research. The SIRICs should become national centres of reference for cancer research, with the two main roles of preparing and conducting integrated research programmes, and establishing programmes for the dissemination of knowledge and new practices. In establishing a competitive policy for the designation of sites, INCa hopes to offer new opportunities for conducting translational cancer research, thus helping to optimise and hasten the production of new knowledge and promote its dissemination and application to cancer care. Each SIRIC is involved in specific programmes, representing the expertise and strategies of the site. The essential assessment criteria used to determine the continued existence of the SIRICs are the achievement of individual objectives, and cooperation between SIRICs on converging objectives. INCArapportGB2013.indd 44 The budget allocated to this programme is €64 M, jointly funded by INCa, Aviesan-ITMO Cancer and the Ministry of Health (DGOS). 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 45 EIGHT INTEGRATED RESEARCH SITE ON CANCER (SIRIC) CERTIFIED BY INCa Fig. 10/ Locations of the 8 SIRICs in France SIRIC Institut Curie CAncer Research and PErsonalized Medicine (CARPEM) Onco Lille - C2RC Stratified Oncology Cell DNA Repair And Tumor immune Elimination (SOCRATE) © INCA - aebk - june 2012 LYon site de recherche intégrée sur le cancer (LYRIC) Bordeaux Recherche Intégrée Oncologie (BRIO) Montpellier Cancer (MC) Pôle régional de référence en cancérologie de PACA-Ouest Guadeloupe Martinique Guyane La Réunion Source: INCa, 2012 Drafted by INCa’s Research Division, 2012 INCArapportGB2013.indd 45 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 46 Establishment of coordination for the SIRICs INCa is particularly committed to the establishment of coordination, to help support and monitor the programme. The priority objectives of SIRIC coordination can be found at three main levels: 1) Framing the interface between SIRICs • To allow sharing of experience and coordinated development of managerial, organisational and institutional aspects (annual meeting of SIRIC managers, the first of which was held in June 2013). • To encourage and facilitate scientific discussion among the SIRICs to stimulate collaboration and optimise the scope of projects. A first interface seminar brought together the 8 SIRICs in February 2013, with the aim of sharing information on their respective research programmes, and identifying areas of complementarity. • To make proposals regarding the development of translational research, i.e., organisation of roles, professional advancement, expertise in proposing recommendations and priority lines of research. Each SIRIC has appointed 2 representatives to form a committee of “translational research” experts that will meet for the first time in autumn 2013. • To develop interface with clinical-biological databases, provide leadership in the development of genomic-led medicine in the development of immunotherapy, integrate the “peripheral” science (mathematics, physics and social and human sciences) and strengthen relationships with their geographic environment to promote clinical research. 2) The choice of the creating and funding SIRICs make them key leading partners for the expansion of national actions, such as: • Integration of mathematics and physics • Expansion of tumour genetics • Promotion of secondary advice through clinical research • Integration of social science and public health. Qualitative analysis of the implementation of the SIRICs will be carried out in collaboration with a team from the Centre for the Sociology of Organisations (CSO, UMR CNRS-Sciences Po) whose scientific interests relate to changing the conditions for public action, particularly in the areas of health research, and the analysis of knowledge production. From the CSO’s perspective, the SIRICs are a particularly interesting example of public policy, since they are aimed at stimulating and improving cooperation and coordination between players. For the present purpose, it involves better coordination of clinical and research activities—including those that come under Human and Social Sciences, an innovation for the biomedical sector. Communication is expected to become faster and better, as is the translation of research knowledge into clinical practice. In short, the SIRICs constitute an original public initiative to promote what is known by health players as “translational research.” For this reason, analysing them will help to contribute to CSO’s cross-sectional area of interest, which is focused in changing the conditions for public action. A second area of cross-sectional reflection for CSO concerns the analysis and production of knowledge, particularly scientific knowledge. Members of the laboratory particularly intend to study the organisation of research, an activity strongly marked by serendipity, as well as the impact of the organisational processes on the type, nature and form of knowledge produced. In this perspective, the relevance of the SIRICs as a subject of research seems obvious. 2012-2013 Highlights Coordination of the activities of the 8 integrated cancer research sites. 3) Developing a qualitative analysis for actions conducted by the SIRICs Analysis of the SIRICs is eagerly anticipated, since they are simultaneously involved in the organisation of research and the production of new knowledge and its translation into clinical practice. INCArapportGB2013.indd 46 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 1.2.2. ORGANISATION OF ENHANCED SCIENTIFIC USE OF THE BIOBANKS, AND FUNDING OF MULTI-CENTRE CLINICAL-BIOLOGICAL DATABASES INCa’s goal of rationalising the storage of biological resources in tumour banks and exploiting them for cancer research, to which it has been committed for several years, has been pursued and strengthened in 2012 and 2013. INCa’s actions and recommendations are still aimed at optimising the organisation of the tumour banks with a view to creating collections linked to databases, both at local level and as part of multi-centre networks. Coordination of tumour banks The tumour banks’ index of scientific contribution, calculated from an analysis of activity reports for 2009, led to a readjustment of the MERRI (French Government’s education, research, information and innovation programme of the Ministry of Health) budget allocated to the tumour banks in 2012. The new procedure for calculation and distribution of MERRI support credits considers the volume of activity declared in activity reports, i.e. inward flow (number of new patient files), outward flow (number of samples used for research projects), and weighting for quality certification. This reassessment has rekindled the interest of the managers of tumour banks in considering the scientific purposes of preparation, storage and availability of biological samples. INCArapportGB2013.indd 47 47 In 2012, the online activity reports for tumour banks - 20102011- was improved in consultation with INCa’s “Biological Resources” working group (representatives from the canceropoles). The online activity report allows comprehensive monitoring of health- and science-related activities by pathology (French CIM 10 for International Statistical Classification of Diseases and Related Health Problems). The assessment of the scientific contributions of the tumour banks is more accurate and specific. Not only do the data collected allow a refinement of the assessment criteria and the index of scientific contribution, they also help improve the visibility to local and national collections, to the quality of organisation of the tumour banks, and to their activities in terms of scientific contribution (specialised networks, research programmes, listing in publications). Selection of data will help in establishing a summary data sheet for every tumour bank, and will allow the main characteristics and collections of the tumour banks to be posted on the INCa website. The wealth of data collected enables INCa to develop a database as a resource for enhanced use and strategic orientation for biological resources. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 48 Fig. 11/ 2010-2011 Scientific contributions from the tumour banks funded by INCa and DGOS Indicators for the scientific contributions of tumour banks, based on 2010-2011 activity reports, and according to the following criteria: - sample flows (incoming and outgoing) - quality certification (NF S 96-900, ISO 9001) Groupement de Coopération Sanitaire - participation in research programs Centre de Refence Regional en Cancerologie - participation in publications Centre hospitalier de Lens CHU de Rouen CHU d'Amiens Paris area Institut Curie AP-HP Hôpital St Louis AP-HP HÔTEL DIEU Hôpital Avicenne AP-HP, Hôpital Bichat APHP, Hôpital Beaujon APHP, Hôpital Foch Hôpital NeckerEnfants Malades AP-HP Ambroise Paré HEGP Hôpital René Huguenin Institut Curie AP-HP GHU Paris Sud Institut Gustave Roussy AP-HP Groupe Hospitalier "CancerEst" APHP, Hôpital Saint Antoine APHP, Groupe hospitalier Pitié Salpêtrière APHP Cochin St Vincent de Paul Institut Mutualiste Montsouris Groupe Hospitalier Henri Mondor CHU de Reims CLCC Institut Jean Godinot CHU de Caen Centre François Baclesse Centre Hospitalier Régional d'Orléans CHU d'Angers Institut Régional du Cancer Nantes-Atlantique CHU de Strasbourg Hôpital de hautepierre CHU de Dijon CHU de Besançon CHRU de Tours 2010-2011 Scientific contribution indicator Centre Paul Strauss CHU de Nancy Hôpitaux de Brabois, Hôpital Central CHU de Rennes CHU de Poitiers CHU de Limoges 540,000 Centre Léon Bérard Centre Jean Perrin Hospices Civils de Lyon Centre Hospitalier de Chambéry CHU de Clermont-Ferrand 200,000 CHU de Saint Etienne Institut Bergonié CHU de Grenoble 100,000 50,000 25,000 10,000 5,000 2,000 1,000 © INCa - aebk - juin 2013 CHU de Brest Hôpital Morvan CHU de Bordeaux Hôpital Haut-Lévêque CHU de Toulouse Institut Claudius Regaud CRLCC Val d'Aurelle Paul Lamarque CHU Montpellier Hôpital Gui de Chauliac pas de données CHU de Nice CH du Pays d'Aix Institut Paoli Calmettes Assistance Publique Höpitaux de Marseille CH de Perpignan Guadeloupe Martinique Guyane La Réunion CHU de Fort de France Hôpital Pierre Zobda-Quitman Source: INCa and DGOS, 2012 Drafted by Research and Innovation Division - INCa - 2013 INCArapportGB2013.indd 48 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT Nationwide clinical-biological databases (French BCBs) The objective of the call for proposals for BCBs initiated in 2011 is to encourage the different players to join forces to create clinical-biological databases linked with biological samples, for a single pathology. These BCBs should enable the collection of information, its inclusion and cross-disciplinary exploitation in different areas of research (epidemiological, basic, translational, and clinical) to be optimised. Table 8/ The clinical-biological database: a strategic research tool Objectives • To perform research in analytical epidemiology and public health. • To perform research in biology and support the development of clinical trials. • To help scientists understand and explain phenomena, from molecular interaction to the entire metabolism of organisms in normal and pathological situations. • To enable identification of potential strategies for the diagnosis and analysis of cancer subtypes. Structure A multi-centre organisation to standardise data collection and sharing with scientific and medical communities. Stored data • Disease history (medical and treatment history). • Administrative (geographical and occupational) and socio-economic data. • Clinical and biological data (results of biomedical and paramedical tests). • Individual and collective behavioural and environmental data. Funding €2.3 M (3 years). INCArapportGB2013.indd 49 49 1) To optimise the compilation of information linked with collections: • by creating (or reorganising) a multi-centre medical and scientific network, enabling work on a national scale, • by developing interoperability among information systems available in the different preexisting databases, • by favouring a national quality approach for the collection, management and exchange of clinical, epidemiological and biological data, • by creating (or optimising) around biological collections an organisation of multi-centre and multidisciplinary networks for the collection of standard data, particularly between cohorts, biobanks, and the different healthcare players. 2) To optimise the exploitation of data: • by promoting the integration, pooling and sharing at national scale of all data useful to a community of scientific experts, • by fostering access for research teams to specialised data, • by facilitating the cataloguing of biological resources and the choices for building strategic collections (biological resources linked to defined clinical and analytical data), • by promoting cross-sectoral epidemiological studies to examine the role of environmental factors in the occurrence of cancer, and the influence of social factors in the occurrence, prevention, detection and care of cancer, • by permitting the production of an annual scorecard to optimise decisions to support research projects. The scorecard summary can if necessary be made available to the public and presented by INCa in communications on its website. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 50 This call for proposals strengthens the organisation of specialised networks, the governance of which INCa will help to organise, in order to develop a “model” for fostering the sharing of data and biological resources for projects conducted on a nationwide scale. 1.2.3. SUPPORT FOR “LIFE SCIENCES TECHNOLOGICAL PLATFORMS”: THE IBiSA PROGRAMME INCa, in collaboration with Aviesan-ITMO Cancer, is involved in the organisation and support of technological research platforms coordinated by GIS IBiSA (Scientific Interest Group for Biology, Healthcare and Agronomics Infrastructures). The 2012 BCB call for proposals resulted in the submission of 14 applications, 4 of which were selected for a 3-year funding. Nine BCBs are thus currently supported by INCa, and the 3rd call was launched in March 2013. Figure 12 shows all platforms designated by GIS IBiSA, and Figure 13 shows the different platforms that have received support for cancer research since 2008, i.e. over €9 M in total. This support represents over half of the investment made in these platforms at national level. Initial impacts • After 10 years of a national policy led by the Ministries of Health and Research, entrusted to INCa in 2005, France now has a genuine organisation allowing the scientific goals of the tumour banks to be consolidated. • A refine activity report and national monitoring of the tumour banks’ activities, according to parameters indicating their contribution to research. • Provision of support funding according to measured contributions, which strengthens those tumour banks that become involved in local and national networks. • An organisational approach to upgrading biological resource collections into networks, by providing support through a call for the creation of clinical-biological databases. INCArapportGB2013.indd 50 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 51 Fig. 12/ The IBiSA-designated life sciences platforms and infrastructures Paris Villeneuve-d'Ascq Lille Fontenay-aux-Roses Mont-St-Aignan Reims Caen Brest Gif-sur-Yvette Type of research carried out at the platform Orléans Angers Nouzilly Surgères Clermont Ferrand Lyon Bordeaux Structural biology, biophysics Bioinformatics Sreening and chemical banks New therapies, vectorisation, stem cells Herbal treatment research Animal house, functional exploration Others Guadeloupe Illkirch Orsay Proteomics Genomics, Transcriptomics Metabolomics In vivo imaging Cellular imaging Martinique Strasbourg Evry Rennes Nantes Vandoeuvre les-Nancy Versailles Villeurbanne Bron La Tronche Grenoble Cestas Montpellier Toulouse Castanet-Tolosan Guyane St-Paul les-Durance Rousset Nice Antibes (Sophia Antipolis) Marseille La Réunion St-Pierre Source: INCa and GIS-IBiSA, 2012 Drafted by: Research and Innovation Division - INCa – 2013 INCArapportGB2013.indd 51 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 52 Fig. 13/ IBiSA-designated life sciences platforms and infrastructures for cancer research: €9 M in support provided since 2008 Guadeloupe Guyane Martinique La Réunion Paris Villeneuve d'Ascq Reims Caen Orsay Strasbourg Gif-sur-Yvette Rennes Illkirch Evry Angers Share of funding for cancer research (INCa/Inserm) Lyon La Tronche Funding for cancer research (in euros) 600,000 Grenoble Toulouse 400,000 200,000 Montpellier © INCa - aebk - juin 2013 Orléans Nantes Nice 100,000 60,000 Type of research carried out at the platform Proteomics Genomics, transcriptomics In vivo imaging Cellular imaging Structural biology, biophysics Screening and chemical banks New therapies, vectorisation, stem cells Animal house, functional exploration Others INCArapportGB2013.indd 52 Marseille Source: INCa and GIS-IBiSA, 2012 Drafted by Research and Innovation Division – INCa – 2013 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 53 As a priority, INCa and Avisean-ITMO Cancer provide support for platforms conducting activities partly or fully focused on cancer research. Support is provided for a wide range of technological specialities. However, for the 2008-2012 period, particular efforts have been made in the following areas: • in vivo imaging (5 platforms, €1.4 M) and cellular imaging (8 platforms, €2 M), • proteomics (6 platforms: €1.4 M in total), • genomics and transcriptomics (4 platforms, €1 M), • screening and chemical libraries (4 platforms, €0.7 M), • screening and combinatorial libraries (4 platforms, €0.7 M). From 2011, INCa began to redefine national priorities in terms of the support provided for technological platforms for the specific requirements of each area of cancer research, taking into account the “investments for the future” provided by the State to laboratories of excellence and “large” equipment (See INCa Scientific Report 2010-2011, Part 3, Chapter 1.5). INCArapportGB2013.indd 53 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 54 2 INCREASED SUPPORT FOR CLINICAL RESEARCH AND DEVELOPMENT of early phase trials for innovative molecules 2.1. THE CLINICAL CANCER RESEARCH PROGRAMMES In France, academic clinical research on cancer is organised through 2 annual calls for proposals managed by INCa, and funded by DGOS (Ministry of Health). Table 9/ Main features of the Hospital Clinical Research Programme (PHRC) for cancer Year Funding institutions Objectives 2.1.1. THE NATIONAL HOSPITAL CLINICAL RESEARCH PROGRAMME (PHRC) FOR CANCER The PHRC Cancer allows a competitive selection of the best clinical research projects. The strategic plan defined by INCa and the Ministry of Health is designed to elicit: • large therapeutic studies in the form of cooperative multicentre trials, to establish international clinical practice standards, • trials for clinical validation of innovative techniques in the areas of treatment and diagnosis. Practical clinical objectives and the simplification of trials for patient recruitment are important assessment criteria during project selection. In 2013, of 240 letters of intent submitted to the PHRC Cancer, 109 projects were short-listed for final review in November 2013. INCArapportGB2013.indd 54 2012 2013 Ministry of Health • To validate new medical or scientific knowledge in the clinical field. • To improve quality of care by evaluating new diagnostic and therapeutic. Funding Proposals submitted Projects selected Selection rate €20.25 M 21 (projected) 226 54 23.9% 240 - Table 10/ Types of projects selected at the letter of intent stage of the Hospital Clinical Research Programme (PHRC) for cancer in 2013 Nb of projects Systemic treatments 46 Local treatments 23 Combined local and systemic treatments 11 Early detection, diagnosis and prognosis 18 Chemoprevention, vaccines 3 Other 8 Total 109 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT Nearly 75% of letters of intent short-listed were for projects involving therapeutic studies: • over half (57.5%) of these therapeutic study projects involved systemic treatments, • surgery, radiotherapy and combined treatments including at least one of the latter treatment modes accounted for the remaining (42.5%) projects involving therapeutic studies. Fig. 15/ Distribution of total funding allocated to the PHRC cancer in 2007-2012 7% Early detection, diagnosis, prognosis = €26.2 M Treatment = €73 M Research outcomes, QoL = €7.5 M Early detection, diagnosis or prognosis was the objective of 16.5% of letters of intent selected. Fig. 14/ Trends in selection and funding of the Hospital Clinical Research Programme cancer (PHRC) 80 25 60 50 15 40 10 30 Nb of projects Funding €M 25% 68% 70 20 55 20 5 10 0 0 2007 2008 2009 2010 2011 2012 Note: the “early detection, diagnosis, prognosis” category includes early phase trials (see the CSO classification in appendix) 2013 Highlights Collaboration between INCa and the Ministry of Health regarding the Hospital Clinical Research Programme on cancer. 240 letters of intent submitted, 109 projects pre-selected for final review; projected budget €21 M. Total funding Nb of projects INCArapportGB2013.indd 55 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 56 2.1.2. THE NATIONAL PROGRAMME FOR MEDICOECONOMIC RESEARCH ON CANCER (PRME-K) In 2013, the Ministry of Health wished to replace the Programme for Supporting Innovative and Costly Techniques (STIC in French) with the PRME on cancer. In addition to the strand for the assessment of innovative technologies, this programme also includes a strand for the assessment of cancer care plans that include health technologies. All innovative health technologies, including drugs, are eligible. The PRME-K is aimed at health technologies, for diagnostic, therapeutic or screening purposes, which have already been validated in a clinical trial. This programme might potentially improve the present care system. Studies should therefore include medical and economic assessment of the innovative technology or the care plan that incorporates it. Table 11/ Main features of the STIC (2012) and PRME-K (2013) programmes Year Funding institutions Objectives Funding Results: Proposals submitted Projects selected Selection rate 2012 (STIC) 2013 (PRME-K) 2013 Highlights Collaboration between INCa and the Ministry of Health: the Programme for Supporting Innovative and Costly Techniques (STIC) on Cancer has been replaced by the Programme for Medico-Economic Research on Cancer (PRME-K), with a strand that assesses innovative health technologies for diagnosis, treatment or screening, and a strand that assesses care plans incorporating these technologies. 2.1.3. SUCCESS OF THE NEW CALL FOR PROPOSALS FOR EARLY PHASE CLINICAL TRIALS: 9 innovative molecules from public-private partnerships The previous collaboration set up with NCI CTEP since 2009 (See Table 12), and the creation of the early phase clinical trial centres network in 2010, are the two key elements that paved the way for this new national initiative. Ministry of Health (DGOS) To effect significant change in the health system via the use of technologies for diagnosis or treatment that have been validated in a preliminary clinical research phase. Projects are based on medical and financial assessment of the innovation. €0.5 M 2 (projected) 12 3 25% 16 - In 2013, of 16 letters of intent submitted to the PRME-K, 9 projects were short-listed for final review in November 2013, for a projected budget of €2 M. INCArapportGB2013.indd 56 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 57 Table 12/ Milestones in the cooperation between the US NCI and INCa 2010 Cooperation US NCI/INCa • Signature of an agreement to facilitate access to new drugs for patients in France. • INCa is the only European Institution involved in the cooperation with NCI for these early-phase academic trials. 2011-2012 2013 • February: proof of concept established • CHONDROG trial: draft publication. for the CHONDROG trial (inhibitor of • AKTIL study: 22 patients recruited to the hedgehog signalling pathway tested date (51 patients planned). in advanced stage chondrosarcomas): recruitment complete (45 patients) and initial results presented at the ASCO meeting in 2012. • November: AKTIL trial (diffuse large B-cell lymphomas) open for recruitment. At present, international pharmaceutical companies have agreed to provide molecules undergoing development for calls for proposals from INCa for projects intended for the designated early clinical phase trial centres (CLIP²). The CLIP² present proposals for academic clinical trials designed to test drugs for indications or pathologies different to those intended in the companies’ development plans. After signing collaboration agreements with different pharmaceutical companies, INCa has launched calls for proposals on 9 innovative molecules since 2011 (see trends in Figure 16). Fig. 16/ Innovative drugs and public-private partnerships: performance indicators 18 16 14 12 10 8 6 4 2 0 17 13 9 6 2 2011 2012 2013 2014 2015 Table 13/ Establishment of a collaboration between INCa and the pharmaceutical companies 2010 Collaboration with pharmaceutical companies • Several meetings organised to discuss a direct collaboration between INCa and the pharmaceutical companies. 2011-2012 2013 • Implementation of the process. • 3 new calls for proposals launched. • June: positive opinion from the Ethics • 5 clinical trials due to be initiated. Committee. • November 2011: 1st call for proposals launched by INCa. • End of 2012: 6 calls for proposals launched: 1st trial opened for recruitment: PIK ORL for cancer of the head and neck. To launch these calls for proposals for early phase clinical trials, 5 steps are necessary from the identification of the molecule to the beginning of the trial. INCArapportGB2013.indd 57 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 58 12 weeks 6 weeks Fig. 17/ Scheme for organisation of public-private partnerships Competitive call for proposals 14 weeks 6 weeks Projects evaluation Study start 1 2 3 4 5 Molecules identification • Meetings INCa and pharma companies • Input from CLIP2 experts about the molecule • Agreement INCa/pharma • Independent experts • Transfer to pharma Definitive selection • Answer from pharma • 2 projects at maximum chosen by INCa Study launch Table 14/ Molecules offered to the early phase clinical trials programme Objective Date of launch of CFP • To facilitate access to new molecules for patients. A maximum of 2 projects funded for each molecule. Funding is provided by INCa and ARC Foundation. Innovative Molecules Proposals presented Projects selected Nov 2011 PI3K/mTor inhibitor PI3K inhibitor 18 4 1 (Kaposi’s sarcoma) 1 (cancer of the head and neck) April 2012 PI3K/mTor inhibitor Anti CDK 4/6 13 7 1 (myeloid leukaemia and myelodysplasia) 2 (GIST/metastatic melanoma) July 2012 p70/AKT inhibitor 20 2 (solid tumours/ breast cancer) August 2013 Anti-EGFR monoclonal antibody 14 Suspended 2013 Oncolytic virus CFP in progress 2013 p38 MAPK inhibitor CFP in progress 2013 Anti HER3 CFP expected 2013 Several contacts in progress with other companies Table 14 shows the different collaborations established to date. 2013 Highlights Partnerships have been created between INCa and the pharmaceutical companies in relation to 9 innovative molecules that are currently being tested or due for testing in the context of early phase clinical trials following independent assessment. These studies are being conducted via the CLIP2 organisation. • Agreements pharma/CLIP2 and INCa/CLIP2 • Supply of the drug INCArapportGB2013.indd 58 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 2.2. ORGANISATION OF CLINICAL RESEARCH, AND STRENGTHENING OF STRUCTURES AND INFRASTRUCTURES The main objectives are as follows: • to provide support for the development of early phase clinical research projects through measures that facilitate coordination and organisation, one such measure being the designation of the CLIP2 clinical trial centres, • to increase cooperation between the cooperative groups, • to increase research capacity by coordinating clinical research staff members and providing support to the data processing centres, • to publicise ongoing clinical research projects, and increase recruitment to trials. 2.2.1. INITIATIVE: CLIP² NETWORK OF EARLY PHASE CLINICAL TRIAL CENTRES Enabling access to innovative drugs is an objective of the 20092013 Cancer Plan. This access is mostly through collaborations arranged by INCa with the pharmaceutical companies, which agree to make their molecules available to a structured network of centres designated by INCa. 59 Table 15/ The INCa-designated early-phase clinical trial centres – 16 CLIP² centres designated in 2010 Funding €9 M over more than four years Partnership • ARC Foundation • French National Centre for Management of Trials on Health Industry Products, or CeNGEPS (a Public Interest Group) • Lilly Foundation Objectives It is hoped, by means of the CLIP²: • to obtain better therapeutic outcomes for cancer patients, • to improve access to innovation for cancer patients, • to test drugs for indications that fall outside the development plans of the pharmaceutical companies, • to increase the quality and number of early phase clinical trials, • to cover all cancer pathologies (including haematological, paediatric, rare cancers, etc.), • to increase the visibility and attractiveness of French academic clinical research to industry, • to propose a framework for coordination between the public and private sectors to stimulate drug development through academic research. Initial impacts INCa has become recognised as a pioneering institution in Europe, capable of establishing a coordinated procedure. An increase in the number of patients recruited in early phase clinical trials (nearly 300% within three years). Leadership among clinical research investigators: oral presentations at major international conferences, more and more proposals for industry-sponsored phase I trials in the CLIP² centres. A growing number of requests from pharmaceutical companies to participate in this programme. INCArapportGB2013.indd 59 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 60 CENTRES LABELLISÉS INCa D’ESSAIS CLINIQUES DE PHASE PRÉCOCE (CLIP2) Fig. 18/ Map of CLIP2 centres ParisCHU AP-HP CHU AP-HP HEGP Saint Louis Institut Curie Villejuif Institut Gustave-Roussy Centre François-Baclesse Caen CHU de Nantes Nantes Institut de cancérologie de l'Ouest Dijon Centre Georges-François Leclerc Clermont Ferrand CLCC CHU CHU de Bordeaux Institut Bergonié Lyon CHU Lyon Sud Centre Jean-Perrin Centre Léon-Bérard Bordeaux Institut Claudius Regaud Montpellier Toulouse Centre Val d'Aurelle Paul-Lamarque Guadeloupe Martinique Guyane Marseille Institut Paoli-Calmettes La Réunion Source: INCa, 2011 Drafted by Research Division – INCa – 2011 INCArapportGB2013.indd 60 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT Tables 16 to 18 show the number of clinical trials by phase (I, I/II and II) conducted by CLIP², by sponsor type and number of patients recruited since 2009. The number of clinical trials in each phase has increased since 2010. Table 18/ Percentage of early-phase clinical trials conducted by CLIP² by type of sponsor 2010 Table 16/ Number of early-phase clinical trials opened in the CLIP² 61 Total Academic sponsor Industrial sponsor 43.5% 56.5% 2011 46% 54% 39.6% 60.4% 2009 2010 2011 2012 2012 Phase I 41 35 43 56 2010 18% 82% Phase I/II 30 16 20 25 2011 20% 80% Phase II 159 102 103 106 2012 17.8% 82.2% Total 230 153 166 187 2010 28% 72% 2011 31% 69% 2012 44% 56% 2010 53.5% 46.5% 2011 57% 43% 2012 50% 50% Nb of clinical trials The number of patients recruited to early phase clinical trials has also increased each year. Table 17/ Number of patients recruited to early-phase clinical trials conducted by the CLIP² Nb of patients 2009 2010 2011 2012 Phase I 186 394 551 802 Phase I/II 117 131 115 222 Phase II 687 1,044 1,122 1,784 Total 990 1,569 1,788 2,808 In early-phase clinical trials, a large part of sponsorship is provided by pharmaceutical companies, especially for phase I. The increasing number of trials initiated in 2012 in the 16 CLIP² also shows increased investment in early phase clinical research by companies in France. This willingness of the companies to develop their molecules on the territory may be attributed to the fact that the CLIP² offer a pledge of quality and know-how on early-phase clinical trials. INCArapportGB2013.indd 61 Phase I Phase I/II Phase II These initiatives facilitate access to innovative molecules for patients in France. The agreement between the US NCI and INCa and the process implemented between INCa and the pharmaceutical companies, are new in Europe. This type of public-private partnership serves as a pilot scheme within the EPAAC programme. It offers a model for coordination between European countries. Indeed, cooperation in Europe will help to save time on recruitment to early phase trials, most especially where rare cancers are concerned, by combining scientific progress with quality, and will have a positive impact on health. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 62 2.2.2. NEW INITIATIVE: DESIGNATION OF NEW COOPERATIVE INTERGROUPS Following its designation of 16 CLIP2 (early-phase cancer clinical trial centres) in 2010, and of 8 SIRICs (integrated cancer research sites) in 2011 and 2012, INCa organised a competitive evaluation aimed at designating cooperative intergroups. The goals of this action are twofold: to invigorate clinical research and to improve resources for multidisciplinary research. This action is conducted in accordance with the objectives in Measures 1 and 4 of the 2009-2013 Cancer Plan. Table 19/ Designation of cooperative inter-groups Funding Objectives €0.3 M in 2013 • To increase cooperation between cooperative groups. • To involve cancer cooperative groups in the implementation of clinical research actions from the 2009-2013 Cancer Plan. • To increase the number of patients recruited to cancer clinical trials. The following cooperative intergroups were designated in 2012: • the French Intergroup for Thoracic Oncology (IFCT), • the LYSA-LYSARC lymphoma research intergroup (LYSA, the Lymphoma Study Association, created by merging GELA [Adult Lymphoma Study Group], and GOELAMS [East-west Group for Acute Leukaemias and Other Blood Diseases]), • the French Myeloma Intergroup (IFM), • the ORL (ENT) Intergroup, comprising GORTEC (Oncology and Radiotherapy Group for Head and Neck Cancer), GETTEC (French Study Group for Tumours of the Head and Neck) and GERCOR (Multidisciplinary Cooperative Cancer Research Group), • the Digestive Tumours Intergroup, which brings together FFCD (French Federation of Digestive Cancer) and GERCOR, • the ARCAGY-GINECO Intergroup (Gynaecological Cancer Research Association and National Investigators Group for the Study of Ovarian and Breast Cancers). Two new cooperative intergroups should be designated in 2013. In 2012 and 2013, cooperative intergroups were designated via two calls for applications. The first call for applications was launched in March 2012, and applications assessed by an international review committee in July 2012. The second call for applications was launched in March 2013, and applications assessed by an international review committee in June 2013. These calls for applications followed a two-year process, initiated by recommendations from INCa’s International Scientific Advisory Board and continued at the wishes of INCa’s advisory committees (Committee of Patients, Friends and Family and Users and committees of Health professionals) to mobilise the cooperative groups. INCArapportGB2013.indd 62 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 2.2.3. CREATION OF A NETWORK OF CLINICAL RESEARCH TEAMS TO CONTRIBUTE TO CANCER PATIENT RECRUITMENT FOR CLINICAL TRIALS Since 2006, INCa and the French Ministry of Health have established 26 Mobile Clinical Research Teams (French acronym EMRC). The objective is to create conditions that encourage researchers in hospitals (public and private) to participate in clinical trials. Approximately 70 FTEs (clinical research assistants and clinical trial technicians) have been funded, based in over 160 different hospitals throughout France. Table 20/ Network of clinical teams designed to foster patient recruitment Funding Initial impacts The number of patients recruited to clinical trials doubled between 2007 and 2012. In 2012, 160 hospitals reported actual patient recruitment through the network of clinical teams (at the time of implementation, over 220 hospitals declared their interest in receiving assistance from one of these teams). Thanks to the positive assessment of this programme, the Ministry of Health increased its funding to €3.4 M (13%) in 2012. €3 M per annum, recurrent since September 2007, granted by the Ministry of Health. Objectives • To promote participation in clinical trials by hospital researchers. • To ensure equal access to clinical trials for patients in all types of hospitals in France. • To ensure the good quality of data collected during clinical trials. Results • Reliable quantitative indicators: number of patients recruited to clinical trials by FTE. • Qualitative assessment, performed by an ad-hoc committee, based on comprehensive reports on the organisation and management of teams. INCArapportGB2013.indd 63 63 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 64 2.2.4. NETWORK OF DATA PROCESSING CENTRES In order to guarantee the quality of data from clinical trials, INCa has been supporting 11 Data Processing Centres (DPCs) for the last 6 years. CENTRES DE TRAITEMENT DES DONNÉES DES ÉTUDES CLINIQUES EN CANCÉROLOGIE Fig. 19/ Map of data processing centres Paris Lille St Cloud CTD centre René Huguenin Caen CTD SLS (APHP) CTD GERCOR CTD Institut Curie Villejuif CTD IGR CTD du Cancéropôle Nord-Ouest (CTD CNO) CTD FFCD Dijon CLCC Lyon CHU CTD PARCC-ARA CTD GELARC CTD Essais cliniques cancer Bordeaux Bordeaux Montpellier Marseille CTD Montpellier CTD IPC Guadeloupe Martinique Guyane Cancéropôle PACA La Réunion Source: INCa et DGOS, 2011 Drafted by Research Division – INCa – 2011 INCArapportGB2013.indd 64 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT Table 21/ Network of Data Processing Centres Funding Objectives Results • Pilot phase in 2008 (€1 M provided by INCa), recurrent funding provided by the Minsitry of health (DGOS) since 2009. In addition, DPCs receive funding from other sources for research projects management. • To provide logistical assistance with data processing in order to guarantee the quality of data collected (up to date and quality controlled): support in designing the investigation report form, data entry and data entry control, data traceability and security specifications, freezing of databases and longterm monitoring of patient data. • To contribute to project management expertise by providing randomisation, coordination of data collection, and data verification and correction. • To provide methodological expertise for the design of protocols, investigation report forms and data formats, and statistical expertise for the analysis of results and drafting of publications. • Annual activity reports. • Agreements signed between DPCs and INCa for a formal assessment process. 65 Table 22/ DPCs’ activities Extreme values Headcount (number of full-time equivalents) 2011 2010 2.0 – 48.5 3.0 – 57.7 Nb of biomedical research projects • Including phase I to III clinical trials (%) • Including international projects (%) 10 – 138 10 – 139 28.6 – 100 0 – 58.3 31.6 – 100 0 - 70 Nb of patients recruited to projects 239 – 2,923 310 – 1,291 Nb of patients recruited to projects since the creation of the DPCs* 605 – 11,611 716 – 10,512 Projects with academic sponsors 72.9 – 100 72.7 – 100 Projects analysed over the course of the year (intermediate or final analysis) 0 – 53 3 – 14 Nb of publications per year 0 – 77 0 – 50 3 5 8 7 8 8 Nb of DPCs providing methodological support Nb of DPCs which carried out their own methodological projects Nb of DPCs which funded research projects *Some facilities already existed before being designated as DPCs in 2007. Initial impacts Collaborations in clinical epidemiology and application to investigator-driven calls for proposals in research in human and social sciences, epidemiology, and public health. Some, in particular, manage no more than 10 studies a year, whereas others can manage up to 139 studies a year. In addition, they differ in their ability to provide biostatistical support to research projects and to conduct their own methodological studies. The above table 22 summarizes the spectrum of DTC’s heterogeneous activities. DPCs’ HUB initiative in biostatistical methodology for phase I clinical trials, especially with regard to training the CLIP2. DATECAN project: Common assessment criteria for clinical trials (breast, digestive, urogenital, sarcoma). INCArapportGB2013.indd 65 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 66 2.2.5. RECRUITMENT OF PATIENTS TO CLINICAL TRIALS: A 72% INCREASE FROM 2008 TO 2012 The annual survey carried out by INCa with healthcare organisations in receipt of funding under the Cancer Plans allowed an evaluation of clinical cancer research activities carried out in 2012. All of the organisations took part in the survey. In France, a definite increase was observed in the number of patients enrolled in clinical trials: a 72% increase from 2008 (base year) to 2012, + 90% for patients participating in academic trials and + 24% for patients participating in industrial trials during the same period. Fig. 21/ Recruitment to cancer clinical trials according to the type of care provider in 2012 (INCa survey) 11% Community Centres (private) University Hospitals Cancer Care Centres Community Centres (public) Figure 20 describes the progression of patient recruitment recorded in INCa’s annual survey, and Figure 21 shows the distribution of this recruitment among the different types of care facilities. 37,492 35,000 Nb of patients 30,000 25,000 24,043 26,003 40% 43% Fig. 20/ Patient recruitment to cancer clinical trials in France in 2012 (INCa survey) 40,000 6% From 2008, patient recruitment to trials carried out in Cancer Care Centres (CLCCs) increased by 78%, and by 27% in University hospitals (CHUs). The ratio of recruitment to academic vs. industrial trials is 82/18. 28,167 20,000 15,000 10,000 5,000 0 2004 2005 2006 2007 2008 2009 2010 2011 2012 Nb of patients enrolled - academic trials Nb of patients enrolled - industry-sponsored trials All INCArapportGB2013.indd 66 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 2.2.6. INCa’s CANCER RESEARCH CLINICAL TRIALS REGISTRY Since 2007, INCa’s cancer clinical trials registry has allowed easy access to cancer clinical trials conducted in France. It is freely accessible on INCa’s website, and enables provision of quality and regularly updated information to patients, health professionals and the general public. Table 23/ The cancer clinical trials registry Objectives Created in 2007 to provide high quality information on clinical trials conducted in France. Results • 1,546 clinical trials advertised on INCa’s website in May 2013: • 506 recruiting trials, sponsored by more than 212 industrial and academic bodies, • 60% of trials registered are sponsored by academic bodies. 67 Fig 22/ Number of clinical trials advertised on 15 May 2013 Apr.07 Jul.07 Academic trials Industry trials All open trials Dec.07 Jul.08 Dec.08 Jul.09 Dec.09 Jul.10 Dec.10 June 11 Initial impacts Regular increase in the number of visitors to the clinical trials registry. Development of direct and interactive access for physicians during multidisciplinary meetings. Dec.11 June 12 Dec.12 May 13 0 100 200 300 400 500 600 700 800 900 1,000 Since its creation, the INCa cancer clinical trials registry has been evolving, in an effort to provide information accessible to the general public, and by facilitating the search and the selection of clinical trials. Since the beginning of 2012, visitors to the clinical trials registry can, with the help of a multi-criteria search engine, more accurately target their search using different selection criteria, such as the sponsor or target organ, and can also apply the geographic criterion using the geolocation module included in the registry. Since the new web portal was implemented in 2012 between 40,000 and 70,000 visits/month (new operating system) have been recorded. INCArapportGB2013.indd 67 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 68 3 INCREASED SUPPORT FOR RESEARCH IN BIOLOGY, GENOMICS AND CANCER SCIENCES 3.1. DEDICATED RESEARCH PROGRAMMES Table 24/ Features of the research programme for cancer biology and sciences Research focused on cancer biology helps to increase the basic knowledge of oncogenesis, and of the development and progression of cancer. The understanding of biological mechanisms opens up new prospects for advances in treatment, inhibition of resistance mechanisms and the development of tools through the establishment of projects involving physics, mathematics or information technology. Year In order to promote and support this progress in the long term, INCa launches a recurrent call for proposals, focused on cancer biology and sciences, and linked to other organisations funding research, in order to strengthen the new areas of research. Moreover, INCa participates actively in the International Cancer Genomics Consortium (ICGC). 3.1.1. CANCER BIOLOGY AND SCIENCES: THE MOST IMPORTANT INVESTIGATOR-DRIVEN PROGRAMME AND BUDGET MANAGED BY INCa Since 2005, INCa has offered the French scientific community an investigator-driven call for proposals for the funding of original and promising projects in different areas and disciplines of cognitive research in oncology. Leaving the initiative to the creativity of the researchers, this annual call for proposals represents 25-30% of the Institute’s total expenditure on investigator-driven calls for proposals every year. INCArapportGB2013.indd 68 2012 Funding institutions Objectives Funding Proposals submitted Projects selected Selection rate 2013 INCa • This call aims at acquiring new knowledge and developing new tools to open new therapeutic perspectives. • Open to all areas of cognitive research and to scientific disciplines involved in tumour biology research, this call has been launched to: - enable the achievement of original projects, - strengthen multidisciplinary collaborations, - develop research in emerging areas. €15.9 M €15.1 M 191 32 16.7% 208 33 15.8% In 2013, 33 projects were selected from the 208 proposals submitted. At approximately 16%, the selection rate is consistent with the recommendations of the INCa’s International Scientific Advisory Board and international standards, in order to maintain a competitive assessment. Overall funding for the 33 selected projects is €15.1 M. To comply with the objectives of the call, nearly 87% of the projects funded aim to study the biological mechanisms of cell transformation and disease progression, according to the CSO classification (Figure 23). 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT Fig. 23/ Distribution of funding awarded to projects selected in 2013 for the cancer biology and sciences programme Fig. 24/ Detailed analysis of the distribution of projects selected in 2013 by type of study (CSO categories) 8% 1.1 Normal Functioning 1.2 Cancer Initiation: Alterations in Chromosomes Biology 5% Biology €13.2 M Aetiology €0.7 M Treatment €1.2 M The second area of interest in the CSO classification deals with treatment. Thus 8% of projects study either mechanisms of response and resistance to treatments, or identification of new therapeutic targets. It is interesting to note that in 2013, nearly 5% of the projects aim to identify and study exogenous factors associated with the origins and causes of cancer — environmental factors, bacterial and viral infectious agents, or lifestyle — and the interactions between these factors and proteins involved in cell regulation. 3% 21% 9% 54% 1.4 Cancer Progression and Metastasis Aetiology A more detailed analysis (Figure 24) shows that over 50% of the biology projects are focused on processes linked to the development of cancer and its interaction with the tumour microenvironment (metabolic adaptations, immunological microenvironment, invasion, metastasis or angiogenesis). Approximately 21% of the projects specifically concern mechanisms of DNA repair and epigenetic regulation of gene expression, whereas 10% of them study oncogenes and tumour suppressor genes. Finally, 3% of the selected projects are on the subject of normal cell function. 1.3 Cancer Initiation: Oncogenes and Tumor Suppressor Genes 2.1 Exogenous Factors in the Origin and Cause of Cancer Treatment 87% 69 5.3 Systemic Therapies Discovery and Development 5% 8% Since 2007, 235 projects have been selected from 1,436 proposals submitted to the cancer biology research programme, for a total budget of nearly €108 M. The number of letters of intent (LI) submitted in 2013 remains very high. This programme is the Institute’s most attractive in number of applications. These observations lead to two conclusions: • this programme is fulfilling its goals, namely by supporting research in a number of diverse areas, • INCa is consolidating its position as a first-rate funding agency for cancer-related research programmes, alongside the French National Research Agency (ANR), which funds untargeted upstream research (cancer excluded). This observation demonstrates that the impact of the environment on specific cancers is becoming increasingly important in basic research. INCArapportGB2013.indd 69 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 70 Table 25/ Trends in selection and funding of the research programme in Cancer Biology and Sciences Year Proposals submitted Projects selected Funding €M Selection rate 2007 106 40 14.4 37.70% 2008 145 30 13.5 20.70% 2009 342 27 13.5 7.90% 2010 241 43 20.8 17.80% 2011 203 30 14.9 17.78% 2012 191 32 15.9 16.75% 2013 208 33 15.1 15.80% Total 1,436 235 108.1 16.36% There has been a change in the distribution of projects among the various sub-categories in biology. We note an increase in the proportion of projects focusing on genetic and epigenetic regulation of gene expression, especially DNA repair mechanisms. This trend can be linked to the proliferation of tools available for carrying out this type of research. Studies related to the development and progression of cancer based on interactions with the tumour microenvironment (mainly on the regulation of processes in metastasis and angiogenesis) also remain strongly represented. Projects related to cancer aetiology have increased slightly since 2012. The number of projects focusing on early cancer detection has decreased steadily since the Institute launched a call for proposals for translational research. No project of this type was funded in 2013. 3.1.2. SUCCESS OF THE PROGRAMME FOR RESEARCH IN PHYSICS, MATHEMATICS AND ENGINEERING SCIENCES RELATED TO CANCER Following the success of the first call in 2011, the “Physics and Cancer” call for proposals was renewed in 2012 and 2013, with a significant increase in the budget for the 2nd and 3rd editions (+70%). Among the 54 proposals examined this year, 19 were selected. The selection rate is comparable to that of 2012 (37%), as is the overall multi-year budget (€4 M). This call for proposals is handled by Aviesan for ITMO Cancer as part of the actions of the Cancer Plan. It is managed in close collaboration with INCa. Since the launch of this initiative, a total of 57 research projects (€10 M) has been undertaken at the interface of biology, mathematics and physics in the area of cancer. Table 26/ Features of the programme Year 2011 Funding institutions Objectives Funding Results: Proposals submitted Projects selected Selection rate 2012 2013 Aviesan - ITMO Cancer To attract physicists, mathematicians and engineers toward cancer research in order to improve the understanding, diagnosis or therapeutic management of cancer. €2.6 M 64 17 26% €4.1 M €4 M 63, 57 eligible 55, 54 eligible 21 19 37% 35% Of the 54 proposals examined in 2013, 13 had been submitted in previous years. Innovative and daring projects proposed by young consortia were selected. The number of projects focusing on treatment has remained stable, and these projects are specifically directed at understanding mechanisms of action and resistance, the characterisation of molecular signatures indicating response to treatment, and the identification of new targets for treatment. INCArapportGB2013.indd 70 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT Fig. 25/ Physics, mathematics, engineering sciences and cancer 71 Fig. 26/ Physics, mathematics and engineering sciences in cancer 2011-2013 (€10.8 M) 2013 2012 2011 Dosimetry Non-nuclear imaging 4.1M € Projects with non specific type of cancer Projects with specific type of cancer Nuclear imaging 6.7M € Instrumentation Radiotherapy Among the types of cancer targeted by the development of new approaches for diagnosis and prognosis, bronchial cancer and cancers of the central nervous system are the two most featured types of cancer in projects funded. Mathematical models 0 Dosimetry Non-nuclear imaging Nuclear imaging Instrumentation Radiotherapy Mathematical models 1 2 3 4 5 6 7 8 Nb of projects selected 2011 2012 2013 2 3 5 8 1 5 1 2 3 5 2 5 2 5 2 3 In the 2011-2013 period, over 60% of the total budget has been allocated to projects which do not concern any specific type of cancer, but the development of technologies or models. INCArapportGB2013.indd 71 For the 2011-2013 period, we have 10 studies for the development of mathematical models. These projects involve a total of 25 teams from different research organisations and distributed throughout the territory. These models incorporate the multifactorial processes involved in tumorigenesis (genetic alterations, microenvironment, etc.) resulting from complex interactions (immunological, inflammatory, etc.), and recapitulate invasive properties (progression of tumour growth), as well as properties conferring resistance to treatment (chemotherapy and radiotherapy). The models include drug pharmacokinetics, the dynamics of tumour growth, individual variability, response to treatment, prediction of treatment efficacy in terms of survival, and Darwinian evolution of malignancy. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 72 These models offer computer simulations aimed at: • mimicking the biomechanical effect exerted by the stroma or ionic composition and cell volume on the tumour, • replacing measures of radiotherapy treatment planning systems (TPS) by a model mimicking respiratory movements, in order to achieve automated quality control and increase radioprotection, • identifying the best in silico protocols for administering two drugs (antiangiogenic and chemotherapy) for the treatment of colorectal cancer, • describing the relations between the appearance/ disappearance kinetics of nuclear DNA repair foci; chromatin condensation/decondensation, and making immunofluorescence a reliable predictive tool, • proposing “simulated clinical trials” of survival as a function of time taken for tumour growth, • optimising parameters for predicting the radiation doses to apply in hadron therapy. 2013 Highlights New call for proposals, “Physics and Cancer” handled jointly by Aviesan-ITMO Cancer and INCa; first edition in 2011. 19 projects selected and funded, €4 M (Aviesan-ITMO Cancer). Last, projects aimed at perfecting new local treatments have accounted for nearly 50% of investment committed since 2011. 3.1.3. RENEWAL OF THE INITIATIVE TO SUPPORT RESEARCH IN SYSTEMS BIOLOGY FOR CANCER Support for systems biology is a priority set out in the 2009-2013 Cancer Plan, and a first call for proposals was implemented in 2012, managed by Aviesan for ITMO Cancer in close collaboration with INCa. The main objectives are to support upstream multidisciplinary research (mathematics, physics, chemistry, information technology, biology etc.), in order to progress to the modelling of complex processes or integral biology in the area of cancer. Fig. 27/ Distribution of funding awarded to the physics, mathematics and engineering sciences in cancer programme 2011-2013 by CSO category This new call for proposals in France led to over 20 proposals per call. 8 systems biology projects have been selected since 2012, for a total amount of €3.6 M. € 1.8M € 1.1M 0.2M € 2.5M € Biology Aetiology Screening, diagnosis, prognosis Treatment Scientific models 5.2M € INCArapportGB2013.indd 72 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT Fig. 28/ Overview of proposals submitted and projects selected through Aviesan-ITMO Cancer managed calls for proposal, under the cancer plan 2011-2013 73 3.2. THE GENOMICS PROGRAMME AND THE EPIGENOMICS PROGRAMME Genomics combines a set of analyses to enable study of an individual’s genome, from mapping, identification and sequencing of genes to the study of gene function and control of gene expression. Spontaneous tumour models Some cancers may be associated with hereditary transmission of mutations, known as constitutional mutations; however, in the majority of cases, the process of tumour development is associated with the acquisition of somatic mutations. Physics, maths, engineering sciences Submitted 2011 Selected 2011 Submitted 2012 Selected 2012 Submitted 2013 Selected 2013 Cancer and environment Systems biology and cancer 0 10 20 30 Spontaneous Physics, tumour models mathematics, engineering sciences Submitted 2011 Selected 2011 Submitted 2012 Selected 2012 Submitted 2013 Selected 2013 40 50 Cancer and environment 60 70 80 Nb of projetcs Systems biology and cancer 9 64 2 17 9 57 23 21 4 21 9 4 6 54 22 22 2 19 7 4 Thanks to the arrival of new genotyping and high-throughput sequencing techniques, it is now possible to identify somatic alterations characteristic of a tumour. 3.2.1. THE INTERNATIONAL CANCER GENOMICS CONSORTIUM The International Cancer Genomics Consortium (ICGC) was created in 2008, with the following objectives: • to identify genetic alterations responsible for cancers, • to identify new therapeutic targets, • to select active drugs based on tumour genomics. In order to attain these objectives, the ICGC consortium has set itself the goal of obtaining a comprehensive description of the genomic, transcriptomic and epigenomic variations present in 50 different types and/or subtypes of tumours which are of clinical and societal importance across the globe. The minimum sample number defined for these analyses is 500 per tumour type/subtype. The International Cancer Genome Consortium is one of the most ambitious biomedical research projects since the Human Genome Project. This consortium assists the coordination of large-scale projects, and sharing of generated information. This will boost the development of effective tools for prevention, diagnosis and treatment of several types of cancers. As of September 30, ICGC has received commitments from funding organisations for 64 project teams in about 15 countries (Asia, Australia, Europe and North America) to study the genomes of over 24,000 tumours. Other countries and organisations have planned to join ICGC. INCArapportGB2013.indd 73 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 74 Table 27/ Main objectives of ICGC and initial results To collect approximately 500 tumour/normal pairs from each of the 50 main cancer types. To perform comprehensive genome analysis of each concerned tissue (constitutional and somatic): genome, transcriptome and methylome. To make the data available to the scientific community and public. Initial results 7th ICGC Scientific Workshop in Heidelberg, Germany (9-11 December 2012) 64 projects are underway, covering all the main tumour types. 22,670 adults and 2,000 paediatric cases are being analysed. A new system for data submission has been developed. A new data portal is expected. The format for clinical data will be revised. Highlights of the 7th ICGC Workshop: • Quality of sequences obtained from paraffin-embedded tumours appears satisfactory. • Preliminary data suggest that RNA sequencing could also be performed on tumours that embedded with good conditions. • Analysis of sequencing data has also been done in 20 laboratories worldwide, showing that from the same database, laboratories identify between 500 to 2,500 mutations, depending on what filters are applied in the laboratories. • This is leading to a harmonisation of data handling processes. ICGC programme: initial results A status report on projects in progress was presented at the 6th ICGC Scientific Workshop, organised by INCa in Cannes in March 2012, and at the 7th Scientific Workshop in December 2012 in Heidelberg: over 22,000 tumour samples have already been sequenced from around the world, and the initial results published on the ICGC site. Initial results on liver cancer demonstrate 4 new genes frequently mutated in hepatic tumours, which are implicated in the initiation of hepatocellular carcinomas (Guichard et al., Nature Genetics, 2012, 694-698). Study of the physiological role of proteins expressed by these genes and signalling pathways is underway. Teams participating in the breast cancer genomics programme, including teams from France, have been able to monitor tumour development in 21 breast cancers through an extremely detailed and unequalled analysis of sequencing results for the complete repertoire of these tumours. These new algorithms, developed specifically, shed light on the complexity of events leading to oncogenesis, and help to analyse their potential association with intratumoural heterogeneity (Nik-Zainal et al., Cell, 2012, 979-993 and 994-1007). Results from programmes for liver and breast cancers have very strong implications for improving the understanding of tumour development, and open up new prospects for targeted treatment. INCArapportGB2013.indd 74 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 75 Table 28/ Genetic data produced by the ICGC consortium Total samples in progress Total samples submitted to Data Coordination Centre Tumours Controls Tumours Controls Consenting donors 19,339 9,470 334 332 Samples for which the project confirmed diagnosis 16,737 8,830 334 332 Pathology/annotation (primary tumour) 16,685 2,315 216 210 Clinical annotation (donor) 8,173 2,190 321 319 Exome 3,336 3,707 254 254 Whole genome 1,098 1,062 95 93 Copy Number Variation 7,001 5,820 50 52 Structural rearrangements 315 285 8 8 Transcriptome (RNA-Seq) 2,610 207 17 0 Transcriptome (Arrays) 3,042 182 1,915 4 miRNA 5,750 343 945 1 Methylation (Array) 4,204 851 1,470 0 Methylation (NGS) 49 14 70 0 A Global Alliance has been created on the fringes of this international programme, to promote the sharing of genomic and clinical data. Its main objective is to hasten medical advances, by encouraging widespread access to genomic and clinical data through the definition of a common framework of technical, operational and ethical standards, in order to ensure the secure and responsible interoperability of genomic research platforms. INCa is a founding member. INCArapportGB2013.indd 75 3.2.2. ICGC DATA PORTAL In 2012, ICGC published genetic data from a series of studies on different types of cancer. The data can now be used by researchers worldwide, to help drive forward their own research projects. The latest version of data from the consortium includes the initial results from the study on myelodysplastic syndrome in the UK, together with work on liver cancer in France, and a project on paediatric brain tumours in Germany. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 76 3.2.3. OUTCOME OF FRENCH PARTICIPATION IN THE INTERNATIONAL ICGC CONSORTIUM The ICGC programme is an opportunity in the area of genomics research which has been seized by INCa and AviesanITMO cancer. From the coordination of biological resources to investment in high-throughput sequencing platforms, all stages of genomic analysis are brought into play, with major qualitative and quantitative challenges. Liver cancer genome programme (Jessica Zucman, UMRS U674) Work conducted by Jessica Zucman-Rossi’s team (Inserm Unit 674, “Functional Genomics of Solid Tumours”) has identified 4 genes and signalling pathways, which had not been previously described in liver tumours (ARID1A, RPS6KA3, IRF2 et NFE2L2, Guichard et al., 2012, Nature Genetics, Vol 44,6,694-700). The dissemination of data should help researchers around the world to acquire new knowledge on mechanisms of cancer development, and open new avenues for research on therapeutic targets. Furthermore, since there are important genetic and lifestyle differences between patients, project data will be compared. In 2013, 4 projects for functional validation were launched for a period of one year: • endoplasmic reticulum/oxidative stress signalling in hepatocellular carcinoma: contribution of misfolded secreted protein load, • activation of the Wnt/-catenin pathway in hepatocellular carcinomas not mutated in the CTNNB1 gene, • role of chromatin remodelling in hepatic carcinogenesis, • role of RSK2 protein function loss in hepatocellular carcinomas. This is the case, for example, with the French project, which will compare cases of prostate cancers in patients in France and the French West Indies, or projects on breast cancer in the UK, France and the US. INCArapportGB2013.indd 76 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT Breast cancer genome programme (Gilles Thomas, Synergie Lyon Foundation) The objective, by May 2014, is to get a whole genome analysis (whole genome, epigenome, RNA) of 75 HER2+ cancers (15% of breast cancers). Comparative analysis of multiple tumours of the same tumour type shall lead to the identification of recurrent mutations, which may have been the source of clonal selection (driver mutations), and identified altered metabolic pathways. In parallel, a study of the constitutional genome on nearly 8,000 samples of breast cancer, including 3,000 HER2+ cancers is to begin in 2013 and aims to identify risk factors specific to this tumour with poor prognosis. Prostate cancer genome programme (Olivier Cussenot, Hôpital Tenon) January 2011 saw the launch of the prostate cancer genome project “Molecular dissection of Aggressive Prostate Cancer according to microenvironment and genetic background.” This study should show whether aggressiveness-specific molecular events (progression and metastasis, resistance to castration, etc.) are early implemented in disease evolution. 77 Ewing’s sarcoma genome programme (Olivier Delattre, Institut Curie) The goal of this project is to identify genomic events involved in the development of Ewing’s sarcoma. There are plans to perform whole genome sequencing as well as RNA sequencing on a series of 100 Ewing’s sarcomas, comparing metastatic cases with cases that were localised at diagnosis and little evolutive. The first 15 samples were sequenced at the Centre for Genomic Analysis (CNAG) in Barcelona, and 85 others are in progress. Rare tumour genome programme The last programme will concern the sequencing of several types of rare tumours. The first project, which has just been defined, involves retinoblastoma. Two other projects are being considered, on uterine carcinosarcomas and leiomyosarcomas. The project plans to include 100 tumour specimens from aggressive prostate cancer (high grade) collected at prostatectomy; to sequence whole genome and validate the identified events. The programme is being done in collaboration with the National Centre for Genomic Analysis (CNAG) in Barcelona. The first step involves the sequencing of DNA from 15 matched tumour/normal pairs from Caucasian patients and from 15 matched tumour/normal pairs from patients of Caribbean origin, whose forms of prostate cancer are more aggressive. INCArapportGB2013.indd 77 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 78 4 INCREASED SUPPORT FOR RESEARCH IN SOCIAL SCIENCES, EPIDEMIOLOGY AND PUBLIC HEALTH One of INCa’s goals is to bring social sciences and public health research applied to oncology in France up to the best international standards. In line with the Cancer Plan, particular efforts are being devoted to increasing basic and health intervention research in order to reduce social inequalities related to cancer, and increase the impact of cancer prevention measures, participation in screening and access to care. Fig. 29/ RISP call for proposals: themes of projects submitted since 2010 11% To achieve this goal, INCa has established links with other national organisations in order to combine experience and know-how in deciding how to modify our approach to environmental and behavioural risk factors. INCa’s action complements exceptional support provided nationally to large cohorts under the National “Investment for the Future” programme. 4.1. THE RESEARCH PROGRAMMES 4.1.1. HEALTH INTERVENTION RESEARCH IN POPULATION: 2013, A YEAR OF CONSOLIDATION In 2013, INCa continued to support health intervention research in population (RISP), via a dedicated call for proposals existing since 2010. Figure 29 indicates the distribution of the themes for proposals submitted (N=76); 11 projects were selected of all calls for proposals. INCArapportGB2013.indd 78 3% Primary prevention Secondary prevention Care Post-cancer Others 20% 21% 45% The three 2013 projects concern: • preventing smoking among young people (“peer” education), • reducing in exposure of farmers to pesticides, • reducing in inequalities regarding the burden carried by caregivers of elderly people with cancer. This call for proposals in health intervention research will be replaced in 2014 by the enlisting of all players involved in prevention and organise a joint call with IReSP (French Public Health Research Institute) for research proposals in primary prevention. The other funding partners are ANRS (French National Agency for Research on AIDS and Viral Hepatitis), CNAMTS (French National Health Insurance Fund for Salaried Workers), CNSA (National Solidarity Fund for Autonomy), DGS (French Directorate General for Health), ARC Foundation, INPES (French National Institute for Prevention and Health 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT Education), MILDT (Inter-ministerial Mission for the Fight against Drugs and Drug Addiction), and RSI (Independent Workers’ Health Insurance). Finally, INCa’s contribution to different working groups in relation to health intervention research in population has revealed the important need for decision-makers and public health researchers to work more closely (to produce conclusive data; to select effective interventions, etc.). 4.1.2. THE RECURRENT PROGRAMME FOR SOCIAL AND HUMAN SCIENCES, EPIDEMIOLOGY AND PUBLIC HEALTH RESEARCH A major objective of the 2009-2013 Cancer Plan is to bring together the community of researchers in social sciences, epidemiology and public health so that they undertake a larger number of research projects in these disciplines. Beyond coordination carried out with the canceropoles in order to increase the size and quality of projects, and efforts made to communicate with the community through INCa colloquia, this support is provided through a recurrent call for proposals. These “investigator-driven” calls are nonetheless led by the Cancer Plan to draw the attention of researchers to important or poorly explored questions. Of 54 investigator-driven research projects submitted, 20 were selected (35%), for a total amount of €4.81 M (average: €240,000 per project), i.e a significant increase from 2012. Research themes: • psycho-oncology (perceived health, caregivers, quality of life, neurology), • sociology (social inequalities, care plans, post-cancer, re- entering the workforce, informing relatives at risk, elderly patients), • economics (prevention, general practitioner, caregivers for elderly patients), • physical activity, genetics and ethics, care plans and trajectories, • risk factors (nutrition, reproduction, occupational and environmental exposures), tertiary prevention (adjuvant treatment), • care trajectories, innovations. A little over half of the projects are clearly multidisciplinary. Fig. 30/ Human and social sciences, epidemiology and public health research programme distributed by CSO category 6% Table 29/ Main features of the recurrent Social and Human Sciences, Epidemiology and Public Health Research programme Year 2012 Funding institutions Objectives Funding Proposals accepted for review Projects selected Selection rate INCArapportGB2013.indd 79 INCa To enlist the research community to work on projects in social and human sciences, epidemiology and public health. €4.81 M 41 16 39% 54 20 37% 17.1% Epidemiology Primary prevention Secondary prevention Tertiary prevention Human and social sciences, economics Biostatistics and methodology 2013 €3.88 M 79 57.7% 8,6% 7% 3.7% 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 80 4.1.3. NEW INITIATIVES DEVELOPED IN COLLABORATION WITH OTHER ORGANISATIONS TO SUPPORT RESEARCH ON ENVIRONMENTAL RISKS Since 2012, a dedicated call has been launched by ITMO Cancer to strengthen support for research in the area of environmental risk factors: 45 proposals have been submitted. Table 31/ Main characteristics of the Research Programme in Employment-Health- Environment Year Funding institutions Table 30/ Effects of Exposure to Environmental Risk Factors for Cancer Year Funding institutions Objectives Funding Projects submitted Projects selected Selection rate 2012 2013 Aviesan - ITMO Cancer To improve the knowledge of delayed effects of exposure of individuals to risk factors associated with the environment, in terms of analysing the risks of cancer occurrence and progression. €2.4 M €2.8 M 23 9 39% 22 7 32% The 2013 call for proposals for the National Research Programme in Employment-Health- Environment saw a 2-fold increase in the number of proposals submitted in the area of assessment and analysis of environmental risks for cancer, indicating a strong motivation of the scientific community to work on these subjects. In 2013, a total of 9 projects from this call were cancerrelated; 6 of these were funded under the Cancer Plan, and the remaining 3 were supported by the Ministry of Labour and ADEME (French Environment and Energy Management Agency). Objectives 2011 2012 2013 ANSES (French Agency for Food, Environmental and Occupational Health Safety) – Aviesan - ITMO Cancer. To evaluate and analyse environmental risks for human health in the general population or at work. From emerging risks to known risks, which can generate complex scientific polemics, and for which a single approach can include concepts, methods and tools from different disciplines. Funding €1.26 M €1.2 M €0.85 M Results: Proposals submitted Proposals short-listed Projects selected Selection rate 31 letters of intent 9 9 29% 20 letters of intent 9 7 35% 44 letters of intent 20 6 14% Studies selected this year included the role of UV exposure in the occurrence of malignant haemopathies, the role of in utero exposure to pesticides in the occurrence of childhood acute leukaemias (AL), the impact of multiple exposures to carcinogenic substances and the search for biomarkers for exposure to mixtures of pollutants or to families of (known or suspected) carcinogenic pollutants, the impact of environmental, occupational and behavioural risk factors in relation to genetic predispositions, models for quantitative assessment of the excess risk for cancer of the respiratory tract from occupational and environmental exposure to certain carcinogenic agents, especially at low doses. 2012-2013 Highlights 36 projects funded in human and social sciences, public health, epidemiology and health intervention research. INCArapportGB2013.indd 80 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 2 TGIR COHORTS E3N Funding for E3N enables the collection of saliva specimens from cohort subjects in order to obtain their DNA. Constances The meeting for the official launch of the cohort took place on 7 March 2013. INCArapportGB2013.indd 81 Objectives Funding institutions Year Funding In recognition of their major role in research in epidemiology and public health, the 2009-2013 Cancer Plan has made support for cohorts a specific action of the measure regarding environmental and behavioural risks (Action 3.5 of the Cancer Plan). INCa has entered into a partnership with IReSP (French Public Health Research Institute) and ITMO Public Health (Multi-organisation Thematic Institute dedicated to Public Health). ITMO Public Health and IReSP have been entrusted by the Ministry of Research with the scientific monitoring of all cohorts supported under the TGIR (Very Large Research Infrastructures) and Investment for the Future schemes (16 cohorts in all). Table 32/ Support provided to Cancer Cohorts Selected projects: 4.2. RESEARCH ORGANIZATION, STRUCTURES AND INFRASTRUCTURES FOR EPIDEMIOLOGY AND PUBLIC HEALTH RESEARCH 81 2009 TGIR 2011 2012 Complement to Grand Emprunt (Great National Loan) To fund structural investment in infrastructure tools for epidemiology and public health: large national cohorts. €2 M E3N, Constances €1 M €1 M 5 Canto, COBLAnCE, Cryostem, E4N, Hope-Epi 2012-2013 INCa/IReSP: Ancillary studies (2012) INCa/IReSP: Research in mathematics and statistics applied to cancer. To fund additionnal studies on tools for large infrastructures. €0.86 M (ancillary studies) €1.3 M (mathematics research). 8 projects selected 9 projects selected. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 82 Table 33/ Main characterictics of the “Investment for the Future” cohorts Funding Objectives Expected results Progress report for 2011-2012 E4N Canto Hope-Epi COBLAnCE Cryosystem €7.95 M €18.8 M €5.6 M €2 M €3.4 M • To analyse family and genetic factors in women recruited to the E3N cohort. • To assess the effects of exposure to certain environmental factors in early life on people’s health as adults. (prospective cohort of young adults). To study the chronic toxicity of cancer treatments in 20,000 patients suffering from localised breast cancer, and identify indicators predicting chronic toxicity. • To identify environmental and genetic risks associated with childhood cancer. • To identify the disparities between treatments, and the short- and long-term side effects. To identify biomarkers to predict bladder cancer progression by monitoring epidemiological, economic, urological, pathological and molecular biology data from 2,000 cancer patients, from 17 clinical centres throughout France, for over 9 years. To characterise graftversus-host disease (transplant rejection) by taking samples of immunological stem cells from transplant patients, in order to understand the pathophysiology of this disease, the predictive factors linked to its occurrence, the response to immunosuppressive agents, and the longterm prognosis. • Discovery of biological and genetic risk factors for certain diseases for the general population. • Implementation of procedures for prevention. Development of new treatments, improvement of quality of life and reduction of health costs. • Optimisation of treatments, and improvement in patient quality of life following treatment. • Several HOPE-Epidemiology partners are directly involved in international research ACCIS, ENCR, IARC, Eurocare, FCSS (PanCare) and CLIC1. Work on more accurate and earlier diagnoses, and possibly on bettertargeted therapies. A reduction in complications associated with bone marrow transplants used to combat blood cancers, and increased success rates as a result. Design, print and mail the questionnaire used to recruit E4N subjects. Initial pilot phase carried out with this questionnaire, 5 technicians hired. Data collection from 209 female patients recruited to the cohort. The total cohort is currently 1,300 female patients. The HOPE-EPI project 55 patients have been comprises 3 strands led recruited in the first recruitment centre. by 3 teams. • 25,000 patients recruited-follow-up of 11,572 patients (5- year survivors). • 1,545 patients recruited with full eCRF from 2004 to 2011, including • 379 patients recruited in 2011. Patient recruitment has recently begun: 4 partner transplant units are operational for this project, and 17 others will open progressively during the 1st half of 2013. 1 - ACCIS [Automated Childhood Cancer Information System], ENCR [European Network of Cancer Registries], IARC [International Agency for Research on Cancer], Eurocare), FCSS (PanCare) and CLIC (Cancer and Leukaemia in Childhood). INCArapportGB2013.indd 82 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 2011 CALL FOR PROPOSALS, “SUPPORT FOR SECONDARY ANALYSIS OF DATA COLLECTED IN THE CONTEXT OF LARGE STUDIES IN CANCER-RELATED EPIDEMIOLOGY” Eight proposals were selected for funding: four 24-month projects, three 12-month projects, and one 7-month project. Seven projects are currently in progress. Of these 7 projects, 4 underwent a mid-term review in December 2012. One project is finished. The concluding seminar for this call (presentation of results) is planned for mid-2014. The cost of chemotherapy Chimiotherapie-2012-CVT (4)_44 pages 22/07/13 11:06 Page1 SOINS Mesure 21 Situation de la chimiothérapie des cancers The total amount spent on hospitalisation for chemotherapy is increasing in France. COLLECTION États des lieux & des connaissances RAPPORT 2012 ANALYSE DES TENDANCES RÉCENTES DE LA PRATIQUE ET DES DÉPENSES DE LA CHIMIOTHÉRAPIE DES CANCERS EN FRANCE As a long –term illness in France cancer expenses is fully covered by the State; during a hospital stay, funding of administrated drugs is included in a flat fee that covers all service of the patient care. However expensive drugs used for innovative therapies (e.g. intravenously administered targeted treatments) are not included in this fee, but entered in a supplementary list (and paid for as long as the prescription is in accordance with the regulatory framework for proper use). CYTOTOXIQUES, AUTRES ANTICANCÉREUX, THÉRAPIES CIBLÉES (INHIBITEURS DE TYROSINES KINASES ET APPARENTÉS, ANTICORPS MONOCLONAUX) ET HORMONOTHÉRAPIES www.e-cancer.fr INCArapportGB2013.indd 83 83 2012 CALL FOR PROPOSALS, “SUPPORT FOR RESEARCH IN MATHEMATICS AND STATISTICS APPLIED TO CANCER” Nine projects were selected for funding. OTHER FUNDING Under the 2012 call for proposals, “Therapeutic Education of the Patient,” one cancer-related project was selected for funding, and will be funded from the Cancer Plan budget. “Development and Evaluation of a Therapeutic Educational Intervention in Relation to the Compliance of Patients Receiving Hormone Therapies as Part of Breast Cancer Treatment.” Total cost of cancer drug in 2011: about €2.8 billion, distributed as follows: • in hospital: chemotherapy regimens from the supplementary list €1.44 billion, and those included in fees, about €70 M, • in the community: €1.3 billion, for orally administered cancer drugs. Expenditure on targeted therapies is increasing (concentrated on relatively few molecules), • in hospital, 5 molecules represent 75% of expenditure on the supplementary list (trastuzumab, rituximab, bevacizumab, pemetrexed and cetuximab), • in the community, approximately 50% of expenditure relates to targeted therapies (such as imatinib, erlotinib, sunitinib, sorafenib and dasatinib). In conclusion, the estimated cost of €2.8 billion in 2011 agrees with data from the ANSM (French Medicine Agency) report “Analyse des ventes de médicaments en France” [Analysies of drugs sales in France], Oct. 2012, which shows sales turnover for the health industries by treatment area. According to the range of anticancer drugs employed, this turnover should be between €2.4 and 3.6 billion. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 84 5 THE CANCEROPOLES Following the assessment process led by the French Evaluation Agency for Research and Higher Education (AERES in French) in 2011, INCa designated the 7 canceropoles for the 2011-2014 period. The end of the designation agreement in June 2014, and the announcement of the third Cancer Plan have provided an opportunity to take stock of the actions carried out by the canceropoles. The creation of the canceropoles was one of the first organisational measures undertaken by the first Cancer Plan in 2003, and represented a major action for strengthening the national research dynamic, based on the enlistment of players at regional and interregional level. After 10 years of existence, the canceropoles have thus acquired a geographical and institutional base which is recognised. This allowed the generation of strong investment from local governments, industries and the ERDF (European Regional Development Fund), which find in the canceropoles a point of contact for oncology research support (regional funding: €10.3 M in 2012, INCa funding: €9.1 M). INCArapportGB2013.indd 84 ASSESSMENT OF THEIR ACTIONS IDENTIFIES THE FOLLOWING ELEMENTS: • the canceropoles have developed an ability to support the organisation and pooling of technology. Among other things, they have established an operational coordination of biological resources around the creation of the Regional Virtual Tumour Banks, aimed at rationalising the creation of collections and harmonising practices employed in the use of biological resources for research, • the canceropoles have also contributed to the optimisation and growing prominence of technological platforms through joint funding of equipment and staff, technological support, training, etc. A number of actions created to meet local objectives have been deployed in an interregional or even national configuration, such as, for example, coordination of the tumour banks, sharing of expertise in experimental histopathology and virtual microscopy, and meeting needs in relation to bioinformatics, • the scientific leadership actions conducted by the canceropoles have enabled support for academic/industrial partnerships, particularly under schemes for funding and maturation of projects, both nationally (MATWIN) or regionally (CLARA PdC*), • through their knowledge of the area, the canceropoles have acquired a strong ability for mobilising teams and a strong ability to respond to emerging and innovative subjects. They have thus developed experience in making research projects emerge and supporting them. As an illustration, from 2008 to 2012, 296 emerging projects were funded by the canceropoles (excluding Ile-de-France), 60% of which subsequently obtained funding from national calls for proposals. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 85 Table 34/ Funding awarded by the Canceropoles to platforms and organisational programmes, 2008-2013 Funding awarded by the canceropoles for the development of platforms, 2008-2013 (in €) Nb of platforms funded by the canceropole Funding awarded by the canceropoles for the establishment of shared resources for use by the scientific community, 2008-2013 (in €) Amounts awarded Platforms funded to platforms by with a designation the canceropole (IBiSA, INCa) Total Resources/ Organisational programmes Tumour banks Histo-pathology CLARA 7 56,000,000* 5 CLARA 1,535,000 PACA 20 2,630,335 12 PACA 2,481,000 114,000 998,000 NO 4 560,000 2 NO 179,045 148,545 30,500 555,000 GSO 9 1,423,000 GSO 2,058,000 1,300,000 GO 6 345,138 5 GO 1,098,525 77,892 GE 3 455,000 2 GE 400,000 200,000 49 61,413,473 26 IDF Total IDF 2,597,342 170,000 Total 10,348,912 2,010,437 180,000 1,763,500 *The CLARA canceropole has enabled funding for heavy equipment (MRI for example) to develop new research activities in an imaging platform. INCArapportGB2013.indd 85 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 86 The assessment of the canceropoles’ actions, together with organisational developments in cancer research, has led INCa to propose a redefinition of the scope of the canceropoles’ mission under the 2014-2018 Cancer Plan, centred on their ability to organise scientific leadership and to help in the development of innovative projects and organisational actions. 3 special scientific leadership roles have been entrusted to the canceropoles to meet these priorities • Support for the development of new projects through Scientific leadership is critical to research, since it allows the mobilisation and bringing together of skills and expertise, in a spirit of institutional, disciplinary and sectoral decompartmentalisation. From their knowledge of the area developed over 10 years, the canceropoles remain well placed to provide this scientific leadership country-wide, by uniting the research players through the various scientific areas and/ or specialised relevant working groups. This scientific leadership will have to be guided by the priorities framing the specific actions of the canceropoles, to suit the regional or interregional context. 7 priorities for the canceropoles • To support the development of new projects and organisational actions. • To increase the scientific multidisciplinarity and complementarity of expert opinions. • To increase the competitiveness of research proposals submitted in response to CFPs. • To increase the detection of innovation and subsequent technology transfer. • To increase support for young researchers. • To seek regional joint funding. • To contribute to development of European projects through forging links with European regional bodies. INCArapportGB2013.indd 86 the establishment of dedicated calls for proposals for each canceropole These calls for proposals will have to especially focus on projects in disruptive technology and multidisciplinary projects, and will preferably be oriented toward young researchers. They will also have to help foster research in key areas in which France is lagging behind (human and social sciences, epidemiology and public health, for example). • Testing organisational actions In order to participate in development of research and pooling of resources, the canceropoles must stimulate the development of new technologies in their area (support to platforms for a limited period of time). Moreover, INCa may support and guide the canceropoles, to create a force for proposing that organisational actions initiated at regional level be deployed nationally. Conversely, the canceropoles may be requested to contribute to the local establishment of new organisational actions led by INCa. • Support for projects Apart from the consolidation phase for preliminary results (emergence), the canceropoles have the ability to support the development of research projects by making specific offers to researchers (support for project management, referral to contacts for adding economic value, preparation of European projects, and specific support for young teams). 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 6 MAIN EVENTS IN 2012-2013 PRIORITY ACTION OF THE 2009-2013 CANCER PLAN: THE 4th INTERNATIONAL R&D DATING The 4th International R&D dating, in 2012, focusing on “Cancer: Research & Innovations” placed under the patronage of the French Prime Minister, was organised in partnership with Aviesan and ARIIS (French Alliance for Research and Innovation in © Agence Fizzy Health Industries). The meeting brought together 28 drug and biotechnology companies and 54 academic researchers, the latter representing the excellence of French research into understanding malignant processes. This meeting provided an opportunity to increase the number of collaborations between researchers and companies attending the event. Collaborations continued after the event; 35 new contacts were made for 13 selected researchers, involving 14 companies. This meeting also helped to formalise existing contacts. The Prime Minister, Mr Jean-Marc Ayrault, made a specific address to this meeting. INCArapportGB2013.indd 87 87 SEMINAR TO PRESENT RESULTS OF PROJECTS ON TRAINING IN TRANSLATIONAL CANCER RESEARCH Over 80 participants attended the seminar on translational research training, organised by INCa on 27 November 2012, to present the results of projects funded under the Cancer Plan, and discuss the challenges and opportunities in France and in Europe. Mr Roger Genet, General-Director of Research and Innovation, introduced this seminar, recalling the support provided by his Ministry to actions deployed by INCa to promote translational cancer research in France. Of the 103 recipients of training grants, 8 presented their research results, and spoke about the impact of their training on their career plans. Begun in 2007 and funded by INCa until 2010, and subsequently by Aviesan’s ITMO Cancer, the recurrent call for applications for support for translational cancer research training has allowed investment of nearly €6.7 M in 103 training projects. This call for applications is intended for physicians, dentists, veterinarians and pharmacists undertaking a post-graduate training and with an interest in research (Master 2, doctorate, post-doctorate in France or abroad). A survey carried out by INCa of 50 grant recipients who had completed their project, and a survey by AERIO (French Association of Residents in Oncology) indicated overall satisfaction among the students in having completed this double training as medical researchers, but also indicated practical difficulties experienced in making a sustained investment in research work, especially during the first years of medical practice. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 88 Roger Genet (DGRI) opened the seminar on translational research training on 27 November 2nd International Forum on prospective in cancer research and treatment In contrast to the many cancer-related meetings held each year to present major advances in both basic and clinical research, the objective of this international forum is to bring together researchers, clinicians and representatives from the pharmaceutical companies to discuss some major areas from many perspectives, and to identify ways of spurring the transformation of discoveries into future treatments. In 2012, a special session was also organised in order to strengthen the coordination of interdisciplinary approaches. The outlook for cancer genomics enabled debate on the “perfect storm” as described by Thomas Hudson (Ontario Institute for Cancer Research), brought about by changes in sequencing technologies, and the need to anticipate a flood of genomic data. To take a small step back from this surge, the debate was joined by, in addition to Dr. Hudson, a philosopher, Barbara Prainsack, from King’s College, London, a physician, Jean-Yves Blay, director of the INCa-designated integrated cancer research site (SIRIC) in Lyon, one of the sites designated by INCa at national level in France, and late David Cox, Vice-President of a large pharmaceutical company (Pfizer). INCArapportGB2013.indd 88 Two main future directions were identified from this discussion, namely the need for a “return to biology,” in order to better understand the processes behind the many genomic alterations observed, and the need for collaboration at all levels, given the explosion in the classification of cancers generated by the molecular characterisation of tumours. The involvement of patients in such projects obviously raises many ethical and social problems (Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease, 2011). According to Dr Prainsack, their resolution will first require empirical research on the real needs and expectations of individuals. And the solutions will not be “politically robust” without additional collaborative work with researchers in social science to guarantee equal access to these new forms of personalised medicine. The final report on a European project dealing with this subject, jointly led by Dr. Prainsack, will soon be published (Personalised Medicine for the European citizen - towards more precise medicine for the diagnosis, treatment and prevention of disease). 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 89 SCIENTIFIC LEADERSHIP BY INCA AND THE CANCEROPOLES IN 2012-2013 When the designation agreement was signed in 2011, INCa and the canceropoles established specialised working groups with pre-defined strategic and operational challenges. Two working groups in Human and Social Sciences, Epidemiology and Public Health, with a focus on Nutrition and social inequalities, are mainly aimed at facilitating the emergence of collaborative research projects in order to boost the production of French research in these areas. 2 colloquia were organised in 2012: • a workshop, by the working group on Nutrition in collaboration with NACRe (French National Cancer Diet Research Network) was organised on the fringes of INCa’s International Colloquium on Nutrition on 20 June 2013, it brought together 110 participants in order to foster the development of research projects in nutrition and cancer, • a workshop organised in June 2012 by the working group on Social Inequalities. Three sessions were organised on this occasion (resumption of work, determinants and care), in order to facilitate discussion on these themes, identify obstacles, and define actions needed to improve research in these different areas. As part of INCa-canceropole collaboration to organise colloquia, a seminar was organised in June 2013 in Lille on an emerging theme, namely the impact of cancers and treatments on cognitive function (see poster). This brought together 105 individuals around measures taken by the main French players. INCArapportGB2013.indd 89 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 90 7 INTERNATIONAL DEVELOPMENTS 7.1. EUROPEAN PROGRAMMES FOR CANCER RESEARCH EPAAC – EUROPEAN PARTNERSHIP FOR ACTIONS AGAINST CANCER The European partnership for actions against cancer (EPAAC) was constituted and started working in 2010, after the communication from the European Commission to the European Parliament, the Council and the European Economic and Social Committee (COM(2009) 291). This communication provided the strategic direction to future European cancer activities. EPAAC’s work package 8 (WP8) was given the goal of developing a concerted approach for coordination of one third of cancer research from all funding sources across Europe by 2013. This goal, however, was deemed extremely ambitious from the outset given the limited duration of the project and the level of resources allocated. The consortium leaded by INCa and ECCO, the European Cancer Organisation, consequently decided to focus their efforts on selected areas/ topics were there was a clear need for coordination. Input from the cancer community was sought as well as from funders to gain crucial knowledge about the mechanisms for decisionmaking, funding and execution of cancer research. Areas of cancer research expected to bear most benefits from European coordination were identified and prioritized for further actions. Important guiding principles for coordination emerged from the intelligence-gathering exercises and stakeholder meetings. Two areas were deemed highly relevant for potential pilot initiatives which could lead as examples of new coordination ways: a) clinical trials aiming at personalised cancer medicine and b) outcomes research. A specific focus on the pilot project which allows patients an accelerated access to new drugs under development, leaded by the INCa in the area of early phase clinical research is made below. This proposed pilot project aims at testing a novel approach to European cancer research coordination by opening to other INCArapportGB2013.indd 90 countries and/or interfacing national coordination programmes that have proven of highest utility. Several reasons contributed to select the area of early clinical studies (e.g studies are now decisive from early phases of clinical development for the more complex trials and targeted populations; large countries have started to structure clinical cancer research activities through coordinated networks and programmes, and subsequent publicprivate partnerships have become critical to both industry strategies and public authorities in meeting this challenge). The patient-centred national programmes are particularly promising in spurring coordination of cancer research at European level, since they usually deliver high quality services and provide access to clinical and scientific expertise through a single portal of entry. Of particular interest in this context, are the French CLIP² and the UK Alliance programmes for early phase therapeutic cancer research. A meeting was hosted by INCa in Paris in October 2012 led to the agreement amongst participants that the suggested pilot coordination should be pursued in a stepwise way, with an initial assessment of the feasibility of linking the UK and French programmes, taking full advantage of their commonalities: • an organizational framework (i.e. a network of designated clinical research centres linked with molecular biology infrastructures), which allow delivering state-of-the-art biomarker-driven early phase trials in a competitive timeframe, • a partnership with the pharmaceutical industry, • scope of phases I/II trials considered for investigational new drugs on indications outside the company main programme. Subsequently, the lead organizations of both the UK and France programmes and a pharmaceutical company met in April 2013 and reviewed their programmes’ steps. It was decided to focus collaboration on conducting trials that each setting cannot perform on its own in rare cancer for example to achieve critical mass of patients or on new therapies/combination for unmet medical needs. The main conclusion of this meeting was that 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT it appears feasible, despite some discrepancies in the respective procedures, to coordinate both programmes and launch joint calls for proposal across the UK and French networks that would lead to transnational multi-centre studies. The next steps were agreed upon and full methodologies for coordination are under development. Exploratory discussions are under way with Netherlands and Italy to expand the pilot project. One essential milestone concerns the definition of common ways for assessing excellence. For pharmaceutical companies, centre designation is indeed key to the company’s decision to give access to its drugs, and has increased visibility and quality of the centres, and Europe attractiveness. Defining a common set of criteria for quality assurance, however, should not result in erasing each centre’s specificities. The value of the network relies also on the complementarities of the centres. As seen in the national examples, the overall quality/scientific level in early phase trials and molecular biology tests is expected to increase globally. TRANSCAN – COORDINATION IN TRANSLATIONAL RESEARCH The TRANSCAN programme which started in 2011 is another example of a coordinated initiative supported by the European commission. The European Commission funds the networking activities, while the joint research activities resulting from the ERA-NET calls are funded through member organizations involved. TRANSCAN links translational cancer research funding programmes in 19 European States. Main achievements under TRANSCAN comprise the rapid setup of the network governance structure, including an international scientific advisory board, allowing the timely preparation and implementation of joint transnational calls. The first call launched in 2011 related to “Validation of biomarkers for personalised cancer medicine” with an earmarked budget of about €14 M. The second call has been launched in 2012 on “Translational research on primary and secondary prevention of cancer”. Review is ongoing. Please refer to paragraph 1.1.3, page 37 for details on the scientific outcomes of the joint calls. INCa is currently entrusted with the task of call secretariat. The TRANSCAN network has enlarged to 29 funding organizations across Europe, after the recent accession of 3 charities. The TRANSCAN consortium has opted for the use of the Common Scientific Outline (CSO) classification system to code projects and programmes of research within the respective member’s portfolio. Midterm evaluation of TRANSCAN will be conducted based on a set of performance indicators and will help plan for the network sustainability and/or its renewal under the next framework, Horizon 2020. 7.2. THAILAND 1st results of the research programme ‘PapilloV’ “HPV infections and associated cervical lesions in HIV+ Thai women”. In Thailand, cervical cancer ranks second as the most frequent cancer among women with an annual incidence of 24.5 cases per 100,000 women-years and 5,216 deaths per year and remains a major threat to HIV-infected women even under treatment. At the end of 2009, an estimated 210,000 women was living with HIV. Thailand provides free access to antiretroviral treatment since 2003. The main objective of the ‘PapilloV’ study2 is to palliate the lack of information concerning HPV ecology and the risk factors of cervical cancer in HIV-infected women in Thailand, by assessing the prevalence, incidence, and clearance rate of HPV cervical infections and associated cervical lesions. The study will also provide the distribution of the HPV genotypes involved and will assess the other risk factors of cervical lesions. A goal is to help design screening algorithms for early detection of cervical cancer based on the identification of HPV-HR and to allow the assessment of a HPV vaccine policy in this specific population. RCN LAS CR-UK ZonMw BMBF NCBiR DLR FWO MMCI SAS FWF NIO INCa IOB MHEST MoH ISS ACC FCT ISCIII MIUR GSRT LR KEELPNO 91 TUBITAK CSO-MOH 2 - Institut de recherche pour le Développement (IRD), Thailand Ministry of Public Health, Faculty of Associated Medical Sciences of Chiang Mai University, Centre National de Référence des Papillomavirus Humains, Pasteur Institute, Institut National d’Etudes Démographiques (INED) INCArapportGB2013.indd 91 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 92 This 3-year study is conducted within the PHPT cohort (HIVinfected women receiving antiretroviral treatment in Thailand) (and will enrol 884 women The follow-up of these women includes Pap-smear and HPV testing every year, with treatment and more intensive follow-up for women with cervical lesions or HR-HPV infection. Enrolment started in February 2012. As of 1st January 2013, a total of 640 women have been enrolled in 25 hospitals throughout Thailand. The median age of women is 40.2 years. Median duration of antiretroviral treatment is 7.3 years. Most women are responding well to their antiretroviral treatment with 96% of them having an undetectable viral load and immune restoration (CD4 > 250 cells/mm3) in 95% of them. A baseline gynaecological visit, including a Pap-smear and HPV testing, was performed in all participants. Preliminary results: • among 614 women indicate an overall prevalence rate of HRHPV at 25% at baseline, • HPV 16 and 18 are respectively present in 2.7% and 1.1% of the women, • the most frequent genotypes are HPV 39 and 52 with 9.2% of the HPV tests positive for one or both of these genotypes, • among the women infected with HR-HPV, 21% have multiple infections, • pap-smear results are currently available for 557 women. Among them, 6.8% have an abnormal result with 24% high grade lesions. The study is funded by INCa, Fondation de France and the Global Fund to Fight AIDS, Tuberculosis and Malaria. 7.3. AFRICA Capacity building in cancer control and new steps towards increased coordination Joint efforts with our sub-Saharan African partners were mostly directed towards enhancing the medical and technical capacity to cancer control and facilitating fellowship exchanges. As confidence increases, research priorities are now being discussed to address relevant cancer control issues in a context of low resource settings. Current topics include the role of human papillomavirus in cervical cancer as well as evaluations of the effectiveness of screening and treatment methods. A step of great importance to expand the cancer control perspective in low and medium income countries is the development of a national cancer control plan. INCa has joined the effort with the PACT programme of the International Atomic Energy Agency in this area and funded the organization of a sub regional meeting in Nouakchott on November 2012, dedicated to the design and implementation of national cancer control plans with the participation of 5 Francophone Western African countries. The selected countries had an imPACT mission. During the three-day meeting, emphasis was placed on the relevance of the National Cancer Control Plan for enhancing the effectiveness of cancer treatment through radiotherapy. In September 2012, a two-day conference entitled “Cancer in Africa: Building transnational research collaborations to alleviate the cancer burden” was jointly organized by Africa Oxford Cancer Foundation (AfrOx), African Organisation for Research and Training in Cancer (AORTIC), National Cancer Institute USA, National Cancer Institute (InCa Brazil) and National Cancer Institute (INCa France) at the British Medical Association in London. The need for locally relevant research was highlighted to support the implementation of effective and affordable cancer control programmes. Several issues related to the importance of cancer research for development in Africa were discussed (e.g. appropriate model to support clinical and translational research to the benefit of African patients). This was considered as a first coordinated milestone to increased global response to cancer in Africa. 3 - PHPT is an International Research Unit of the Institut de Recherche pour le Développement (IRD) in France and the Faculty of Associated Medical Sciences at Chiang Mai University in Thailand INCArapportGB2013.indd 92 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 8 93 OBSERVATORY FOR RESEARCH INVESTMENT IN CANCER, AND REVIEW OF RESEARCH INVESTMENT A mission of evaluation was created within the Research and Innovation Division, as well as a cross-sectional network of focal points for evaluation to help get an overall view to conduct a coherent evaluation of research, care and public health’s actions. The prototype developed for data visualisation shows that: Data related to grants may be redesigned to identify who is supported—the principal investigators as well as individuals from the research teams. These data may be used to describe existing collaborations at the outset of projects. The evaluation mission devoted its activity to the creation of an observatory for research investment. Text data from grants are sufficient to describe what research is being carried out, by summarising terms used in grant applications and publications. Text information may be used to generate specialised research areas and provide another idea on the type of research being carried out. Furthermore, it is possible to draw a comparison for the same thematic areas in other federal agencies such as the US National Institutes of Health. HELIOS is an observatory for documenting investments and outcomes of investments in cancer research. The underlying framework of the study is based on the idea that funding for research influences scientific production through its effects on the creation and dissemination of scientific ideas through the scientific networks. In the long term, the project is aimed at monitoring activities of networks to measure the scientific, social, economic and professional “products” generated as a result of interactions. INSTITUTIONS employ PEOPLE train Fig. 31/ View of the Helios web prototype GRANTS awarded to pay for produce support PRODUCTS use co-author INCArapportGB2013.indd 93 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 94 Links between researchers in receipt of cancer-related funding and researchers in France and other areas, especially in the private sector, can be identified to describe with whom the research is being done, i.e. collaborative scientific networks. These links between researchers or between research centres or research laboratories can be visualised. The data may also be used to describe where the research funded by INCa is being conducted, whether by research institution or by collaborating institutions. Data on investment cover nearly 1,300 research projects and infrastructures. Outcomes in terms of scientific productions are illustrated by a corpus of 100,000 publications, 2/3 of which include as an author a researcher in receipt of research funding for the 2007-2012 period, and 2,000 patents associated with researchers are referenced in HELIOS. This Observatory acts as a proof of concept for the development of similar tools for measuring and visualising investments made in France under different health plans, and thus for providing tangible evidence of the impact of funding committed. The Observatory provides new indicators of relations with the private sector, collaboration, links with international research and INCa’s geographic reach, as well as funding of the Aviesan/ITMO Cancer, and funding of cancerrelated clinical research by DGOS. The most represented topics among projects for the 2007-2012 period Rank Nb of projets 1 152 Pathway mechanism target molecular model team therapeutic identify cellular cancer approach… 2 130 Trial arm patient phase randomized year treatment iii standard survival month rate experimental qual… 3 116 Molecular clinical analysis gene biomarker marker sample genomic profile identify signature prognost… 4 97 Patient month criteria year inclusion treatment secondary evaluation rate primary follow number week… 5 64 Chemotherapy response patient survival advanced treatment metastatic cancer rate gemcitabine cisplat… 6 55 Treatment therapy anti clinical therapeutic therapies agent efficacy targeted drug combination trial… 7 52 Cancer breast women invasive impact colon diagnosis increase determine diagnosed frequent analyze… 8 52 Aml leukemia acute myeloid leukemic cell blast prognosis flt leukaemia patient pim therapeutic lymph… 9 48 Cell immune tlr response responses mechanism effector dendritic system lymphocyte function innate… 10 47 Survival patient prognostic year recurrence free factor prognosis disease stage analysis outcome poo… 11 46 Radiation radiotherapy dose irradiation therapy doses local volume treatment toxicity irradiated ext… 12 43 Pathway kinase activation signaling phosphorylation activated protein akt inhibitor erk tyrosine inh… 13 41 Model human cell vivo vitro mice animal mouse line effect murine xenograft experimental tested nude… 14 41 Endothelial vegf angiogenesis hypoxia angiogenic factor vascular growth anti hif vessel cell effect… INCArapportGB2013.indd 94 Topic 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 95 The most represented topics in publications during the 2000-2011 period Rank Nb of publication 1 4,999 Patient month year median follow range cases age method percent underwent occurred died time twenty… 2 4,965 Binding domain structure protein site terminal interaction peptide residues structural acid complex… 3 4,884 Case diagnosis cases report rare year pancreatic lesion examination duct revealed cyst man biliary w… 4 4,308 Reaction compound derivative acid ring synthesis yield dot synthesized methyl step amino prepared bo… 5 4,116 Expression gene mrna protein expressed level transcription regulation human regulated transcriptiona… 6 3,921 Surgery surgical resection postoperative complication procedure morbidity patient laparoscopic opera… 7 3,891 Pathway kinase activation signaling phosphorylation activated protein akt inhibitor erk tyrosine inh… 8 3,758 Alpha tnf cytokine factor ifn production beta macrophage kappa inflammatory necrosis induced interle… 9 3,719 Sequence gene region genome site element promoter human protein family conserved repeat transcriptio… 10 3,589 Cd cell lymphocyte blood peripheral tcr subset ccr antigen expression expressed surface specific mol… 11 3,380 Cell apoptosis death induced apoptotic caspase fas activation mediated induce effect dependent induc… 12 3,371 HIV infection virus infected viral human viruses immunodeficiency load antiretroviral aid count HHV… 13 3,348 Ratio interval risk age confidence association regression analysis odd factor multivariate hazard ad… Topic This work, conducted over the 2007-2012 period, has permitted the distribution of research investment to be visualised by city of the project coordinator for the 4 investigator-driven research programmes in biology, translational research, clinical research and human and social sciences research. INCArapportGB2013.indd 95 Figure 32 shows that 30-40% of the budget went to projects in research centres and hospitals in Paris and in the Paris region. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 96 Fig. 32/ Distribution of funding by research areas and cities Cancer biology and cancer sciences Paris/IDF 2.17% Lille 34.46% Translational research 2007-2012 Paris/IDF Lille 43.6% 5.2% Rouen 5.2% Caen Roscoff Nancy Paris/IDF Rennes Brest Strasbourg Paris/IDF Strasbourg Rennes 9.66% 2.94% Orléans 2.72% € 92 M Angers Nantes Dijon Nantes Dijon € 34.5 M Lyon 6.3% Clermont Ferrand Grenoble Bordeaux €M Funding Lyon Limoges 9.24% 3.37% Besançon 5.9% Grenoble 3.7% Bordeaux 3.38% Toulouse Montpellier 7.83% Nice Marseille Toulouse 4.01% 7.47% 3.6% Nice Montpellier 5.6% Marseille 8.78% Guadeloupe Martinique Guyane Guadeloupe La Réunion Martinique Guyane La Réunion Source: INCa Drafted by: Research and Innovation Division, Assessment Office, INCa 2013 Clinical research 2007-2012 Paris/IDF Lille 40.3% 4.3% Lens Rouen 2.3% Senlis Sources: INCa, DGOS Drafted by: Research and Innovation Division, Assessment Office, INCa 2013 Social sciences, epidemiology and public health 2007-2012 Reims Caen Paris/IDF Rennes Lille Strasbourg Tours € 122 M Nantes Besançon 3.7% 5.8% Limoges Clermont Ferrand 4.38% € 27.4 M Poitiers Lyon Lyon 10.4% Saint-Étienne Grenoble 2.03% 3.4% Toulouse 3.8% Martinique Guyane Grenoble 8,28% Montpellier 2.7% Nice Toulouse Marseille 2.58% 7.1% Guadeloupe La Réunion Sources: INCa, DGOS Drafted by: Research and Innovation Division, Assessment Office, INCa 2013 INCArapportGB2013.indd 96 8.79% Bordeaux Bordeaux Martinique Pointe-à Pitre Guyane more than 30% Dijon Tours 2.80% Saint-Étienne Guadeloupe Strasbourg 3.97% Dijon 15 10 5 2 1 Share of funding Nancy 4.91% Paris/IDF Rennes Angers 2% 50 40,21% Caen Nancy 2.7% 2.94% Nantes Paris/IDF 2.53% 5.07% 2.5% Brest 5.61% 6.0% Nimes Montpellier 4.94% Marseille 5.31% 10 to 20% 5 to 10% 2 to 5% city below 2% La Réunion Source: INCa Drafted by: Research and Innovation Division, Assessment Office, INCa 2013 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 2013 TOTAL FUNDING AND CANCER PLAN 2009-2013-RELATED OVERALL FUNDING For 2013, the new budget allocations for calls for proposals amount to €47.5 M; we can estimate, with the expected funding for clinical research projects (PHRC and PRME-K), a total funding amounting to €70 M. This explains why this year’s project profile shows a 40% funding for projects on cancer biology, and only 21% on treatment. For 2013, and at the time of writing this report (July 2013), we estimate expenditure on cancer-related research at nearly €100 M; this is distributed between the following five categories: • investigator-driven projects (these concern the 4 large research areas, namely biology, clinical, translational, and human and social sciences/public health), • projects targeted on one tumour type (INCa and the nonprofit organisations ARC Foundation and National Cancer League support an integrated research action programme on one tumour type, see page 42), • thematic projects (targeted research programmes, particularly focused on cancer-related inequalities, environmental risks, innovative molecules at the early clinical trial phase, cancer and employment, etc.), • platforms, resources and infrastructures (the SIRICs, CLIP2, cooperative intergroups, cohorts, clinical-biological databases, etc.), • training and young teams of excellence (especially ATIP Avenir teams, and translational research training). INCArapportGB2013.indd 97 97 Of about €100 M spent, nearly €45 M relates to investigatordriven research programmes; this is in accordance with action 5.3 of the 2009-2013 Cancer Plan, (“Maintain the level of research funding for free researcher driven projects, for 4 to 5-year programmes, at the level of 50% of the INCa’s call for research proposals”) Fig. 33/ Funding for cancer research 2013 €47.4 M (Not including clinical research) 9% 3% 21% Biology= €19 M Aetiology= €4.9 M Prevention= €0,4 M Early detection, diagnosis, prognosis= €7 M Treatment= €10 M Human and social sciences, = €4.4 M Scientific models= €1.5 M 15% 40% 1% 11% 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 98 Fig. 34/ Distribution of 2013 cancer funding (INCa, DGOS, Aviesan-ITMO Cancer): €99 M spending 3.54% 18.34% 29.36% Since 2009, we note a strong increase in the budget allocated (trebled between 2009 and 2013) to the research platforms and infrastructures, as well as a steady increase in investment on priority research areas in the Cancer Plan (budget trebled between 2009 and 2013), see Figure 35. Fig. 35/ 2009-2013 Trends in funding per programme 50 40 €M 4.62% 30 20 10 0 44.15% Social sciences, epidemiology, public health Translational 2009 4.45% 7.59% Biology and cancer sciences 15.46% Clinical 16.68% Investigator-driven calls Strategic research programs dedicated to specific types of tumours Strategic research initiatives (thematic calls) Platforms/resources/infrastructures Research training young teams of excellence INCArapportGB2013.indd 98 2010 2011 2012 2013 Investigator-driven projects Projects dedicated to specific type of cancer Projects dedicated to a specific research issue Platforms/resources/infrastructures Research training/young teams of excellence Among the priorities in the Cancer Plan, research on cancer risk factors has been addressed through the development of dedicated programmes, and collaborations with funding agencies such as ANSES (French Agency for Food, Environmental and Occupational Health Safety) and IReSP (French Public Health Research Institute) have been strengthened since 2011; thus the number of projects selected in the area of environmental, behavioural and genetic risk factors has advanced very significantly. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT At the time of writing this report, we can estimate the proportion of the budget allocated for these areas at 13% of allocations for all calls for proposals in 2013; indeed, for a multi-year allocation of €46 M (while awaiting the results for clinical research programmes), €6.2 M is for projects focused on the study of risk factors. The objective of 15% set by the Cancer Plan has therefore been practically achieved. To finish, an analysis was carried out on 1,292 projects selected over the 2007-2013 period (i.e. over 100 calls for proposals and calls for applications for designation of infrastructures). Investment for this period was €469 M, and the distribution over different research categories is shown in Figure 37. Fig. 37/ Cancer research funding 2007-2013 - Projects and infrastructures: €469 M Fig. 36/ Cancer plan priority: research on risk factors 12% 7 6 €M 5 4 3 2 1 31% 0 2009 Behaviour Environment Genetics INCArapportGB2013.indd 99 2010 2011 2012 99 4% 23% Biology= €110 M Aetiology= €39 M Prevention= €16 M Screening, diagnosis, prognosis= €90 M Treatment= €143 M Human and social sciences, = €55 M Scientific models= €16 M 8% 3% 2013 19% 28/10/13 14:13 100 INCArapportGB2013.indd 100 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 101 Part 3. PERSPECTIVES The strategic orientations for cancer research were drafted by INCa and Aviesan – ITMO cancer with the contributions of the SAB members. From this reflection, 5 priority actions are issued for 2013-2014. 1 - To fight tobacco-related cancers with an ambitious multidisciplinary programme of research/treatment/public health actions. 2 - To build a shared biological, clinical and epidemiological database. 3 - To foster closer ties between teaching and research and increase support for interdisciplinary training. 4 - To support ambitious French cancer research to provide the population and patients quick and sizeable benefits. 5 - To face new challenges in cancer control: European and global perspectives. This section presents within each priority action a set of potential actions that could be implemented. INCArapportGB2013.indd 101 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 102 1 STRATEGIC ORIENTATIONS FOR CANCER RESEARCH4 The incidence of cancer in France, which has increased steadily until recently, is currently stabilising. Sustained efforts in primary prevention, along with the development of screening programmes for precancerous or early forms of tumours in the last ten years, have enabled a reduction in incidence rates. Despite a steady decrease in overall mortality, cancer still remains the leading cause of death (nearly 148,000 in 2012). On closer inspection, the figures show that some tumour types are clearly declining or are being much better treated, whereas others, with a poor prognosis, are marked by a significant increase. The impact of cancer on society remains considerable. It is the leading cause of health-related worry among the French. Since 2003, the State has made a special effort to fight cancer in our country with the help of three successive plans, the most recent of which is in preparation, to cover the period 2014-2018. The previous plan, 2009-2013, had set research as a primary objective, with solid support for the continuum of research, from basic principles to transfer to the patient. It encouraged inter-disciplinary collaborations and the arrival of new themes in the cancer field, and emphasised and identified translational and clinical research as priorities for the benefit of patients and citizens. It also enabled advances in organising cancer research through the creation of 8 integrated cancer research sites (SIRIC), and the harmonisation of responsibilities and consistency of work between the French National Cancer Institute (INCa) and the French National Alliance for Life and Health Sciences (Aviesan), who proposed joint strategic orientations for research in 2010. Given the size of the medical, economic and social problem posed by cancer, planning of research to fight tumour diseases continues to aim at reducing the mortality associated with these pathologies, reversing the overall frequency and that of the most serious tumours, and improving survival and quality of life for patients using more effective and less toxic treatments. In view of increasing survival, it requires a wider reflection in order to improve the chances of returning to a normal social life following the treatment phase. ANALYSIS OF CANCER DETERMINANTS AND ACTIONS TO REDUCE THEIR IMPACT REQUIRE: • increasing basic research in the health area (primary, secondary and tertiary prevention) and fostering its transfer, up to intervention, implementation in the population and therapeutic care, • further breaking down of barriers between disciplines, • exploiting the advances made by developments in genomics, while increasing efforts and investments in technology. This document also anticipates the 3rd Cancer Plan announced by the President of France. It is the contribution of those involved in research and the bodies responsible for planning research and innovation. 4 - The following people were involved in the reflection and in the drafting of this document: ITMO Cancer Fabien Calvo (Director of ITMO Cancer), Alain Eychene (Deputy Director of ITMO Cancer), Jean-Paul Borg, Salem Chouaib, Jean Clairambault, Jacqueline Clavel, Catherine Dargemont, Olivier Delattre, Robin Fahraeus, Jean-Jacques Feige, Jacqueline Godet, Sophie Gomez, AnnickHarel-Bellan, Urszula Hibner, Claire Julian Reynier, Claudine Junien, Claude Leclerc, Patrick Mehlen, Patrick Peretti-Watel, Eric Solary, Bertrand Tavitian, Valérie Thibaudeau (scientific affairs coordinator at INCa), Gilles Thomas, Nathalie Varoqueaux. INCArapportGB2013.indd 102 Scientific Advisory Board of the French National Cancer Institute Geneviève Almouzni, Jean-Pierre Bizzari, Jean-Yves Blay, Nancy Davidson, Anne Eichman, Judy Garber, YannGauduel, Denis Hémon, Daniel Louvard, Bernard Malissen, Theresa Marteau, Michel Marty, Jacques Pouyssegur, Jean-Charles Soria, Michael Stratton, Karin Tarte, Bruno Varet, Robert Weinberg, Otmar Wiestler. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 1.1. THE KEY CHALLENGES Scientific challenges As with other pathologies, cancer research covers a vast area of human knowledge, including the study of a cell’s physiological regulatory mechanisms and interactions with its environment, in order to gain an understanding of their pathological dysregulation. The scope of this area of endeavour requires the study of model systems, from the most rudimentary to the most complex, to allow the analysis of tumour growth, development, migration and colonisation, and mechanisms of resistance to treatment. Analysis of cancer determinants and actions aimed at reducing their impact require effort and investment in the area of technology (biotechnologies for health, sequencing and genomics technologies, imaging, robotics, instrumentation, information technology, drugs, etc.) and in the area of public health (epidemiology, screening and prevention) indispensable to the development of clinical, therapeutic and translational research. The big challenge remains the transition from the current precision medicine to a medicine genuinely tailored to each individual. This redefinition of tumour pathologies requires continued development and use of large-scale technologies, the creation of links between these (genomics/proteomics/metabolomics), and integration of all data into our understanding of cancers and their development. Medical and public health challenges The Aviesan Cancer Alliance and INCa hope to prioritise, in addition to indispensable fundamental research, the impact of which cannot be predicted, three strategic areas of research based on population health objectives. These areas will generate exchange and cross-fertilisation of ideas between basic and applied research. INCArapportGB2013.indd 103 103 Areas 1. Research and innovation for a new definition of “cancerous diseases,” tailored to the objectives of early diagnosis and the development of new tools for treatment. This area embodies an objective for the development of personalised medicine over the next five years. It justifies investment in equipment and staff dedicated to the analysis of data, interactivity between data, and sharing of data between scientists on a European and worldwide scale. It extends to research on medication, research on less invasive surgery, and novel approaches to innovative technologies and developments, including the use of ionising radiation. 2. Research on primary prevention, particularly on high-risk behaviour, and analysis and correction of its failures, i.e. identification of patterns of exposure to risk factors, and approaches targeting individuals and populations, particularly the more vulnerable. This research draws on genetics, understanding of addictions, hostenvironment interaction, and proteomic and metabolic studies, and its outcomes have implications for the political, economic, human and social sciences. 3. Research that helps to identify populations exposed to cancer risks and facilitate monitoring by early detection strategies (secondary prevention). This research involves molecular and genetic epidemiology, imaging and technological development around biological markers. It extends into interventions in populations already cured of a cancer with a view to prevention of its recurrence or the occurrence of a new cancer. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 104 1.2. CURRENT SITUATION AND STRENGTHS IN FRANCE The impetus from the cancer plans has been supported by the coordination of activities undertaken by INCa, which provides funding for research programmes, and by AVIESAN, which brings together those carrying out cancer research. The Director of Research at INCa is the Director of AVIESAN’s ITMO (Thematic Multi-Organisation Institute) Cancer. Together, AVIESAN and INCa have defined all of the strategic orientations in this document, the result of reflection by the international scientific board of INCa and experts from ITMO Cancer. The most recent cancer plan has enabled important modifications to the structures dedicated to cancer research, with the creation and designation of 8 integrated cancer research sites (SIRIC) and 16 designated early-phase clinical trial centres (CLIP2). It has enabled better visibility for French research, and a clear improvement in its quality, now ranked third in Europe. This research planning has also allowed increased involvement in this area of health by research teams working in human and social sciences, and in epidemiology, physical sciences and mathematics. A census has been taken of the teams working on cancer in different organisations. Similarly, regionally or nationally based equipment (Biology, Healthcare and Agronomics Infrastructures, “investment for the future”) has been tracked. Some weaknesses are still apparent in the genomics areas with respect to equipment and especially data analysis, and in engineering sciences, as well as in the translation of basic research into patient-oriented applications. French oncology teams have demonstrated their strong attractiveness for international healthcare industries, especially with regard to clinical research, a strongly performing and highly visible area that benefits patients. Developments in upstream research cooperation have also been enabled, with the support of ARIIS (Alliance for Research and Innovation in Health Industries), as manifested at the 4th edition of the international R&D Dating, inaugurated by the French Prime Minister in November 2012. An analysis of over 2,000 patents relating to cancer was made on this occasion. It is advisable to maintain this effort to share this scientific visibility with our fellow citizens, with better communication and information accessible to all. INCArapportGB2013.indd 104 1.3. PROPOSALS 1.3.1. ORGANISATIONAL The efforts at organisation made in recent years, particularly in the context of investment for the future, and the creation of the SIRICs, indicate that these efforts are worth extending by linking the structures to enhance their impact. The continuum between basic research, observation of cancers, translational research, clinical research, and technology transfer must be guaranteed, together with the enrichment provided by the human and social sciences across all areas. Links between disciplines and improved interaction between research organisations (EPST: Public Scientific and Technical Research Establishment) and universities for networking and translational research, Inserm (French National Institute of Health and Medical Research), CNRS (French National Centre for Scientific Research) and INRA (French National Agronomic Research Institute) for metabolism, etc.) are also necessary, and are among the goals of Aviesan Cancer and INCa. Finally, at the level of Alliances, links between the ITMOs for Public Health, Metabolism, Genetics, Haematology, Infection and Immunity with ITMO Cancer are a permanent reality and should support inter-alliance cooperation, especially with ATHENA (French National Alliance for the Humanities and Social Sciences) and AllEnvi (French National Alliance for Environmental Research). For strategic reasons, links must be deepened with schools of engineering, information technology, mathematics and veterinary medicine. 1.3.2. SCIENTIFIC, TECHNOLOGICAL AND MEDICAL: Genomics and personalised medicine The transition toward personalised medicine includes several components, including technological and biological developments. Since 2010, France has undertaken the sequencing of 2,500 tumours within the framework of the International Cancer Genome Consortium (ICGC). This effort must be maintained until completion, and complemented by in vitro and in vivo validation of identified signalling pathways, and the development of relevant animal models useful in diagnosis and treatment. An interface must be created between geneticists and experts in proteomics to further the area of biomarkers. The development of minimally invasive techniques (plasma, puncture, fluids, etc.) must be encouraged, along with detailed analysis of tumour heterogeneity. Finally, it remains crucial to ensure, under proper conditions, the transition from cognitive research on patient cohorts to the clinical level on an individual scale. This transition requires strong involvement from 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT researchers and specialists in bioinformatics to support the clinical biology teams. It is anticipated that analyses of gene panels will be accomplished in two years, and that complete genome sequencing will then be extended in another five years to those patients that justify its use. At the same time, it is essential to prove that these extensive genome analyses have a genuine impact on patients. It is desirable, at least for frequently occurring pathologies, that there be proof that genomics, through its consequences for treatment choices, offers a genuine benefit for patient survival. For this to happen, randomised clinical trials must be carried out quickly. The investment made in recent years in proteomics and new technologies at the sites involved indicate that France has the necessary structures for the analysis of cancer-associated proteins. It seems justifiable to develop quantitative and targeted analysis, using patient serum, plasma, or tissues, in the light of tumour genomics or hypotheses generated by knowledge of pathophysiology. Advances in genomics have allowed the demonstration of a large number of molecular alterations, the consequences of which are very little understood at the level of structure, function and quantity of proteins. The combination of proteomic and genomic data would enable us to rethink our way of diagnosing cancers, to develop a new generation of biomarkers, and to better treat patients. These programmes are accompanied by a growing demand for information technology for the storage, tracking, sharing and rapid flow of information between clinical services, biobanks and researchers and, of course, for data analysis. Despite recent efforts, it remains difficult to maintain the visibility of French resource centres alongside the large North American and British infrastructures. Apart from our own capacity, it therefore seems advisable to incorporate our data into those generated throughout Europe, probably through the EMBL (European Molecular Biology Laboratory). Medication, molecular pharmacology and biomarkers The emergence in recent years of treatments that target specific abnormalities of the tumour cell or its environment has led to the appearance of a new range of treatments acting on molecular targets other than DNA repair or duplication or mitosis. Clinical results have helped to demonstrate that patients not selected on the basis of a target molecular abnormality are primary resistant, and that for patients with a sensitive tumour, the INCArapportGB2013.indd 105 105 development of secondary resistance is frequent. Identifying and overcoming this resistance are recurring problems, which require contributions from fundamental biology, medicinal chemistry and clinical research. Sites capable of making progress on the analysis of proteinprotein interactions now exist in France, and might on the one hand accelerate knowledge of biology of cellular regulation as well as diagnosis, and on the other hand lead innovation in the development of new targeted treatments. It seems necessary to continue the collaborative effort with industries in these fields that are still essentially academic, for better technology transfer from research, and to combine it with strengths in structural biology, medicinal chemistry, mathematical modelling and information technology. The development of a drug sector, from the identification of targets to proof of concept, is desired by researchers and public authorities alike. The obstacles seem essentially associated with a rigidity in research structures that does not facilitate the movement of staff, especially researchers, and with cultural problems. Many obstacles could be removed by freeing engineering, technical and academic staff for work in a valued applied sector. A marked introduction of engineering sciences into research teaching modules is needed for the adaptation of future graduates, together with the creation of links with specialist schools. Metabolism, infection, inflammation, immunology and cancer These problems at the interface of other disciplines concern the genesis, control and escape of tumours, and primary and tertiary prevention, and are a source of great hope for treatment among patients. Taking ownership of them by researchers requires collaboration between the specialised institutes of the Alliance in the various fields of discipline, through the facilitation of cross-disciplinary activities in these areas. They justify a reinvestment in training in disciplines that have been neglected in recent decades, such as biochemistry, physiology and health technologies, together with recruitment of researchers. Many active new drugs have been developed from basic research carried out in France, particularly in the regulation of immune effectors, without any benefit to society or the economy. Other related areas of research, such as proteomics and lipid research, know almost nothing about one another. Finally, as will be seen below, the incorporation of varied approaches into a complex system with the help of mathematicians and physicists will undoubtedly form a basis 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 106 for progress in our understanding of cancers. The development of animal models for the validation of these approaches makes the need for veterinary pathologists even more urgent. Human and social sciences and public health France is one of the countries in Europe where cancerrelated health inequalities associated with social status are the most marked. They are essentially associated with a failure in prevention, poor uptake of screening, and late diagnosis. Studies on prevention, vulnerability in relation to serious illness, social integration through job retention and return to work, life during and after cancer, etc. are a first response to major societal needs. Research efforts in these areas must be continued and expanded, and include detailed technological approaches (geolocation, social epidemiology, territorial cartography, etc.) and multidisciplinarity, including infrequently consulted fields such as ethics and political science. Moreover, in a context of increasing restrictions on public expenses, the efficacy and efficiency of preventive actions must be demonstrated by studies in the areas of prevention economics and innovation. An initial strategic reflection on prevention was conducted by INCa, IReSP (French Public Health Research Institute), ITMO Public Health and ITMO Cancer in 2012, culminating in recommendations for research already being implemented in 2013. These will be the subject of targeted calls for proposals led by a variety of research groups, the creation of university chairs in prevention, and support for basic research and field studies aimed at intervention, and with a policy for implementing interventions found to be positive. At organisational level, better efficiency must be sought by grouping teams of diverse disciplinary origin, especially in the environment of the integrated cancer research sites (SIRICs), allowing the development of common biological and social approaches to risk exposure (exposome, biological and social markers, populations, environment, etc.). Finally, a reduction in inequalities still remains a very considerable challenge in the cancer area, which must be addressed in a general manner by stimulating research into its technological, social and political components, and promoting action for intervention, to be followed by implementation in target populations. Epidemiology, epigenetics and environment Recent efforts made in investment for the future with broadbased cohorts and pathology-specific cohorts must be continued and expanded, with maintenance of funding being a serious preoccupation. It is also hoped that research may be guided by large surveys on attitudes, beliefs and behaviours INCArapportGB2013.indd 106 related to cancer. Finally, there is general agreement that registry and cohort data should be more easily matched with medico-administrative databases of healthcare consumption and hospitalisation. In addition to analysis of the role of the epigenome in tumour development and targeted therapy, improved coordination between specialists in these disciplines is desirable, together with the linking together of epigenomic data and data on exposure to environmental risk, in cohorts, for example. It would be beneficial to analyse these exposures beyond one generation, and include foetal life. Work on coordination within the framework of the new health and environment plans and with the AllEnvi alliance is already underway. Systems biology It enables dynamic modelling of the organisation of tumour cells and tissues, complex by definition, describing their development and the prediction of drug efficacy, enabling progress toward a better understanding and better care of cancers. Systems biology requires interactions between disciplines; it involves physics, bioinformatics, biostatistics, bioimaging, biophysics, biochemistry and biomechanics; mathematics and theoretical information technology share a central position. It is developing in close association with fundamental biology, which helps to validate experimentally the hypotheses that emerge from the building of models. It lays the groundwork for personalised medicine by supplying the methodological foundations (individual characterisations based on systemic response to treatment) for the creation of patient clusters. Systems biology helps to create relevant pathophysiological profiles based on phenotype, and opens up the field of personalised medicine. In the long term, it would be desirable to bring together various specialities, from cancer development to treatment, within a systems biology institute (which may be an institute without walls, i.e. a network). It is necessary to improve the visibility of systems biology as an interdisciplinary crossroads giving rise to new perspectives and, in the longer term, innovative cancer treatments, with the establishment of collaborations and the creation of predictive models with therapeutic applications. Universities must invest in this discipline, and ad hoc assessment committees capable of judging this type of project must be created. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT Physics/mathematics and cancer interfaces: fundamental aspects and transfer toward clinical application The contribution of “hard” disciplines and researchers in these areas, physics, mathematics and engineering, must be increased to enable a new outlook on cancer. Traditional themes must be reinforced, especially radiobiology, and should benefit from the input of recent technologies to generate an understanding of the toxicity and benefits of radiation, the effects of low doses (particularly in diagnosis), and very high dose rates, etc. The development of new non-traditional radiation sources (particle acceleration by ultrashort laser pulse, synchrotron and micro- and nanobeam sources, heavy ion beam) should allow the development of innovative research on radiation biology and its applications, and on dosimetry at the subcellular scale. These efforts must be translated into benefits for patients by improving and personalising treatment protocols, in combined cancer treatment (vector delivery of treatment, radiosensitisation, dose control in real time, etc.). The synergies between instrumentation and treatment centres must be facilitated by training (acquisition of various new skills, training in physics/biology, mathematics/medicine, etc.) and by large communal equipment for physics/care, carried by the universities and the Alliances. It appears, moreover, that the interoperability and sharing of data from genomic databases, clinical and biological databases, socioeconomic data and larger databases such as health insurance might be an instrument of progress and a major source of analysis and research. On a larger scale, a worldwide reflection on access to anonymised genomics data, for example, would enable a better understanding of rare variants and exceptional and highly informative clinical situations with regard to cancers and their development. Clinical research The previous cancer plan enabled a considerable development and deployment of clinical research through the designation of early-phase clinical trial centres (CLIP2), the strengthening of the Programme for Hospital Clinical Research, and designation of cooperative intergroups for clinical research. This has been reflected in a trebling of the number of patients enrolled in early phase trials since 2009 and an overall increase in patient participation in clinical research of over 70% in 4 years. New steps could be taken in relation to support for projects directed by cooperative intergroups that were ambitious in terms of demonstration of improved survival. These groups INCArapportGB2013.indd 107 107 can conduct large-scale trials, with creation of clinical and biological databases. These groups, by their size and visibility, are likely to propose large international trials enabling essential questions to be addressed more quickly. Conversely, it seems desirable to propose an attempt to de-escalate treatment of some pathologies in order to limit treatment sequelae. The structures in place and existing means currently allow these advances. Training and technology transfer Many areas of research justify the creation of new training sectors as mentioned in this document. Training in translational research remains a separate objective that should be prioritised. It is likely to benefit patients by improving every stage of their illness, and likely to benefit society by providing answers to questions concerning health and economic value. To continue the development of personalised medicine, it would be advisable to foster innovation, especially in the area of new treatments. Some targets and strategies are not currently monitored by industrial research, and must be energetically supported through substantial funding. This would enable the repositioning of France in the sector in the long term. Society/patient information Special efforts should be made to increase information for patients and users on research in the area of cancer. Much has been done in the last ten years, but our fellow citizens still remain mistrustful about the role of researchers, their independence, and their ability to approach problems that may arise for patients before, during and after their illness. In particular, and often with reason, the problem of post-treatment sequelae seems to them to be completely overlooked. The constant presence of patient representatives, their “advocates” in all matters of discussion, selection of research projects and strategic choices, should probably be expanded. Similarly, the opinion of these representatives must be expressed and recognised in all contents of clinical research projects. The recognition thus obtained may be extended, with patient advocates becoming the most relevant intermediaries in large programmes for prevention, screening or treatment of cancers. All technological advances, especially in genomics, involve acceptance by patients and users, together with ethical consideration of the limits of interpretation and dissemination of results, which will in turn require the participation of public authorities and representatives of the national community. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 108 2 FIVE PRIORITY ACTIONS FOR 2013-2014 2.1. TO FIGHT TOBACCO-RELATED CANCERS WITH AN AMBITIOUS MULTIDISCIPLINARY PROGRAMME OF RESEARCH/TREATMENT/ PUBLIC HEALTH ACTIONS In 2012, tobacco is still the leading preventable cause of cancer in France. The latest estimate of the number of deaths caused by tobacco-related cancer in France is approximately 44,000, not counting cancer induced by second-hand smoke, which can also lead to lung cancer (Hill, 2012) (IARC 2004). In recent years, France has seen a resurgence in the prevalence of smoking, which contrasts with an underlying long-term decline in tobacco use evidenced by a sharp drop in tobacco sales when the 2003-2007 Cancer Plan was launched. In the 15-75 age group, the smoking rate rose from 31.8% in 2005 to 33.6% (2010 data) (Beck, 2011). This increase is most prevalent in three different populations: women (up 6 points from 2005 to 2010), the unemployed (up from 40% in 2000 to 51% in 2010) and young people. The leading indicator of the effects of smoking is death from lung cancer, but tobacco is a significant factor in 16 other types of cancer: mouth, pharyngeal, throat, pancreatic, bladder, kidney, nasal cavity, sinus, oesophagus, stomach, liver, cervical, myelogenous leukaemia, colon, rectum and ovarian. Smoking can also be a cause of breast cancer (IARC 2012). Although the 2009-2013 Cancer Plan is currently the government’s only anti-smoking measure, the objectives on reducing the smoking rate and righting the inequalities in the public health law of August 2004 will not be achieved. The gap is over 7 points for men and 6 points for women. Several reports bear witness to the historical failure of the antismoking policy in France, despite the series of initiatives that have been undertaken5. • The WHO Framework Convention on Tobacco Control (FCTC), ratified by the French Parliament in 2004. • The report from the French Ministry of Labour, Employment and Health by Yves Bur entitled “Propositions pour une nouvelle politique de lutte contre le tabac” [Recommendations on a new anti-smoking policy], February 2012. • The analysis report on anti-smoking policies from the French Controller and Auditor General, December 2012. • The White Paper issued by the Alliance contre le tabac (AntiTobacco Alliance), February 2013. • The information report on the assessment of policies to fight tobacco use presented to the French National Assembly by deputies Denis Jacquat and Jean-Louis Touraine, February 2013. This failure is mainly caused by insufficient prevention in our healthcare system, poor support to help people quit smoking, and regulations lacking inspection for enforcement. Research efforts should be boosted in epidemiology of tobacco use and its health effects as well as social science-related factors and industry’s economy. A recent paper showed that out of all the types of cancer listed, 35% can be attributed to tobacco use. According to a study by EPIC (European Prospective Investigation into Cancer and Nutrition), tobacco can be blamed for nearly one in five cases of cancer. These latest estimates confirm findings published by IARC in 2007. 5 - Countries where the FCTC recommendations have been implemented achieved a dramatic drop in tobacco consumption: England, 21% of adult smokers, United States 15%, Australia 15%, Canada 13%. In France, the tobacco use had begun falling in the 1970s but started rising again in 2005, primarily among women and populations lower on the socio-economic scale, to reach nearly 34% of adults. INCArapportGB2013.indd 108 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT To this end, INCa would like to develop a multidisciplinary programme of initiatives to determine a strategy on reducing tobacco-related cancer. This long-term programme will operate with visionary management aims to: 1. foster research to cover all the strategies that were devised after consulting a wide range of actors. It will culminate in a set of recommendations on establishing new government prevention policies, 2. set priorities for actions to boost prevention. 2.1.1. INITIATE AN AMBITIOUS PROGRAMME FOR RESEARCH AND DISSEMINATION OF GOOD PRACTICES TO FIGHT SMOKING-RELATED CANCERS In an effort to establish the priority actions to revive the antitobacco policy, INCa could develop a partnership programme of multidisciplinary actions to fight against tobacco-related cancers. Key partners include the ministries of Health and Research, Inpes (National Health Prevention and Education Institute), IRESP (Research Institute for Public Health), InVS (French Institute for Public Health Surveillance), MILDT (Interministerial programme to fight drugs and drug addiction), DGS (General Directorate of Health), SFSP (French Public Health Society), national education, anti-smoking associations, etc. There are several objectives: • to determine the priority research themes (working group and international hearings), • to improve evaluation measures for initiatives, • to increase distribution of good practices, • to share the knowledge generated and guarantee the independence of expertise. Furthermore, one of the programme’s main objectives is to accelerate the pace of putting these research findings into practice among decision-makers and practicians. Much like the Centre for Tobacco Control Studies UK, longterm funding6 for the programme and critical mass for projects should make it possible to build scientific teams. In addition, INCa and its partners could set aside a portion of the budgets in their own calls for proposals on research, not to stir up competition among funding agencies, but rather to unite all of our initiatives under one strategic umbrella. 109 POTENTIAL AREAS OF RESEARCH/PUBLIC HEALTH ACTIONS TO DEVELOP FOR THE PROGRAMME Research in epidemiology, human/social sciences and prevention Tobacco as a risk factor of many cancers: research on other types of cancer than lung cancer should be expanded and include multiple exposures and addictions (alcohol and/or environmental/ occupational exposure). Health intervention research7: mainly for preventive interventions in schools with primary and secondary pupils. Promotion of smoking cessation in patients with cancer: definition of awareness strategies for health professionals and patients, definition of intervention strategies, measure of the impact on quality of life, cancer mortality and all-cause mortality. Bio-monitoring: primarily saliva cotinine (or other biological markers) that can provide additional information to environmental monitoring and valuable insight on the various sources of exposure (particularly in children). The benefits of quitting, risks associated with second-hand smoke8. Tobacco substitutes associated risks. Research in political science, economics, the behavioural and cognitive sciences and the neurosciences Taxation and health policy analysis: possible studies could include: • costs of smoking-related morbidity and mortality for the health insurance system and the community as a whole and studies on resistance and protest among stakeholders who rely on the income generated by tobacco, • economic evaluation of the use of a screening programme for tobacco related cancers in target populations, • feasibility of the implementation of a national lung cancer screening programme (low dose CT scanners, training, surgery, methodology…). New public policy strategy9: current talks about the “Tobacco Endgame” strategy ; nudging (influencing choices through incentives10,11): the theory behind nudging is to set up an environment where people make the best decisions for their health without necessarily forcing them to do so. It is based on the premise that despite informing the public, some public health prevention policies do not produce the intended results. Applying these techniques offers a new way of designing health prevention policies. 6 - Funding should be set aside that matches the importance of the public health threat. 7 - Necessary attentiveness to the adverse effects of the interventions introduced. 8 - Hill C, “Les effets sur la santé du tabagisme passif” [The health effects of second-hand smoke]. BEH 2011,20-21 :233-235. 9 - Special edition, Tobacco Control 2013,22. 10 - Marteau T « Judging nudging :can nudging improve population health ? » BMJ 2011,342:d228. 11 - Behaviour change. Report House of Lords. HL Paper 179. INCArapportGB2013.indd 109 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 110 Research in Information and Communications Technologies (e-tools, technological innovation12) The Internet and smartphones are alternatives with strong potential for collecting data that offer numerous options yet to be explored and validated. The convergence of these technological and epidemiological advances is opening new avenues to enhance prevention strategies, improve public health recommendations and ultimately the state of health among populations. Clinical research Effectiveness of nicotine substitutes; Innovation in developing new molecules and/or new treatments; Join the international discussion on reducing the nicotine content in cigarettes13. Biological research • Improve the analysis of biological markers for tobacco and second-hand smoke14. • Expand the knowledge on genetic influences in treating or preventing dependence, for example, the role of monoamine oxidase inhibitors (MAOI)15, nicotine receptors. • Electronic cigarettes should be included in considerations on the programme. This research should be multidisciplinary (noxiousness, cessation support, ethical aspects, etc.) and financially supported to expose the reasons behind this new trend, which is seeing an exponential rise. The programme will also have to provide resources for the following projects: • consumption trajectories, • the social image of smoking, the portrayal of tobacco use, • resistance to prevention efforts, • health inequalities, • quality of life, • the role of health professionals in smoking prevention, • developing metrology to document personal and collective exposure, • social marketing, marketing practices in the tobacco industry16 and their impacts17, marketing to people’s smoking-related attitudes and habits, unmarked packaging, under-the-counter sales. IMPROVE SCIENTIFIC MONITORING AND COMMUNICATION As part of gaining recognition for the programme, evaluations will be completed and collective works will be distributed to help answer a list of questions previously issued by the working group, clarify the political and administrative directors, researchers and people in the field working on smoking-related cancer prevention and screening. 2.1.2. BOOST PREVENTION OF SMOKING-RELATED CANCER OVER THE NEXT FIVE YEARS Measures to fight the onset of smoking and denormalise tobacco Using taxation as a public health objective to reduce tobacco use: international organisations (such as the World Bank, World Health Organization, International Agency for Research on Cancer (IARC)) consider raising the price of tobacco as the most effective and least costly anti-smoking measure. The impact of higher prices is mostly seen among young people who are the most sensitive to price changes18. These efforts must persist. The Haut Conseil de la Santé Publique (High Council for Public Health) recommends steadily and incrementally raising the price by a wide margin, at least by 10% of the total retail price for tobacco products19. Standardised unmarked packs and larger graphic warnings labels: the Framework Convention on Tobacco Control (FCTC) and related guidelines have demonstrated the effectiveness of placing large graphic warnings labels on tobacco products and standardising the use of unmarked packs20. Findings from three studies21,22,23 funded by INCa on the impact of graphic warnings labels and standardised unmarked packs in France confirm the results obtained around the world24: reasonably sized warnings are known to better inform consumers and the people around them. Combined with the introduction of standardised unmarked packs, large graphic warnings labels can “break” the advertising and promotional component of packaging, thereby helping to “denormalise” tobacco consumption. 12 - For example, on its website NCI has an interactive application called NCI QuitPal http://www.cancer.gov/cancertopics/tobacco/smoking/quitting/nciquitpal-app 13 - Benowitz N et al. “Reducing the nicotine content to make cigarettes less addictive.” Tob Control 2013 ;22 :i14-i17. 14 - Avila-Tang, “Assessing second-hand smoke using biological markers,” Tobacco Control 2013 ;22 :164-171. 15 - Reference sheet “Sevrage tabagique et prévention des cancers” [Smoking cessation and cancer prevention], INCa. 16 - In 2008, NCI published a study on tobacco and the media. The same study could be conducted in France. 17 - Centre d’analyse stratégique « Nouvelles approches de la prévention en santé publique » 2010, n°25 [Strategic analysis centre new prevention approaches in public health]. 18 - Effectiveness of Tax and Price Policies for Tobacco Control, International agency for Research on Cancer (IARC), Handbooks of Cancer Prevention, volume 14 (2011). 19 - Opinion on raising tobacco taxes to reduce the prevalence of smoking. 20 - Idem 21 - http://www.who.int/fctc/text_download/fr/index.html - http://www.who.int/fctc/protocol/guidelines/adopted/article_11/fr/index.html 22 - Karine Gallopel Morvan: “Impact des avertissements sanitaires visuels et des paquets de cigarettes génériques sur des français” [The impact of visual health warnings and generic cigarette packs on the French population], report submitted to INCa in August 2010. 23 - CNCT: “Comment mettre en oeuvre les dispositifs de la CCLAT pour parvenir à une dénormalisation de la consommation de tabac” [How to implement the FCTC measures and ultimately denormalise tobacco consumption], report submitted to INCa in June 2009. 24 - CNCT: “Tapaqfi: produits tabac packagings et coût dissuasifs” [The Tapaqfi Project: tobacco products, packaging and dissuasive prices], report submitted to INCa in December 2011. INCArapportGB2013.indd 110 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT Tobacco advertising at the point of sale and during television broadcasts of motor sports: a 2010 study by the Comité National Contre le Tabagisme (French National Anti-Smoking Committee, CNCT) showed that over 80% of tobacconists do not obey current laws regulating tobacco advertisements in retail outlets, i.e. displaying cigarette packs and selling to minors. 111 Measures on quitting tobacco use These measures include: • involvement of health professionals in smoking prevention, • reimbursement of cessation aids by the health insurance system, • identification of people or population groups at a higher risk for cancer to develop plans customised for individuals or groups (people with high exposure, former cancer patients, etc.). Neither is the legislation being followed in terms of: • the image of tobacco in the media. A study conducted by the Ligue Contre le Cancer (French National Cancer League) in 201225 showed that 80% of the most popular French films at the box office from 2005 to 2010 showed an average of 2.4 minutes of footage where smoking was evident, the equivalent of five tobacco ads, • messages about tobacco aimed at the general public and prevention messages for health professionals. Findings from the INPES/INCa Cancer Barometer revealed that although virtually everyone polled was aware of the risk of cancer from smoking, 65% of them thought that smoking is just as bad for your health as breathing city air. INCa is currently working on a campaign to rank the risks of cancer. It is expected to be operational in 2014 and will focus on two objectives: help the public put the risk factors into perspective in terms of how they actually impact the occurrence of cancer and strengthen awareness on the vital role of prevention as a way to deal with cancer. Potential actions 1. Make the prevention of smoking a full-fledged priority in the French Ministry of National Education’s health education policy, mainly by providing resources to develop and monitor health education initiatives in schools and involving youths, the entire education community and parents in the process. 2. Expand prevention and support initiatives that target women, young people and vulnerable populations. 3. Organise regular local campaigns that contain both proactive messages and positive images that show the virtues of being a non-smoker. 25 - https://uwaterloo.ca/applied-health-sciences/news/report-highlights-successtobacco-control - Do larger pictorial health warnings diminish the need for plain packaging of cigarettes? Wakefield M et al. Addiction, 107, 1159–1167, 2012. 26 - Ligue Contre le Cancer: “Tabac et Cinéma: La ligue révèle les résultats édifiants d’une enquête inédite menée depuis 2005 sur 180 films français” [Tobacco and the Cinema: La Ligue issues some eye-opening findings from an unprecedented study of 180 films since 2005]. Ligue contre le cancer and Ipsos, 31 May 2012. 27 - Projet ITC. Second national report ITC France. University of Waterloo, Waterloo, Ontario, Canada; Institut National de Prévention et d’Éducation pour la Santé (National Health Prevention and Education Institute, INPES), Institut National du Cancer (French National Cancer Institute, INCa), Paris, France. October 2011. INCArapportGB2013.indd 111 Provide smoking cessation treatment plans for patients with a tobacco-induced illness or for whom tobacco exacerbated or accelerated the illness. Findings26 from a study by URC Eco d’Ile de France used a probability model to show the strategy of offering full coverage for smoking cessation is, in a vast majority of cases, a better approach than the current lump-sum coverage system. The referring doctor’s role in raising patient awareness on the prevalence and toll of tobacco in causing diseases and the benefits of quitting. France ranks low among countries that participated in the International Tobacco Control study, with only 27.5% of smokers who receive smoking cessation counselling from their doctor during a routine check-up27. The issue related to the inclusion of smoking cessation in the public health goal-related remuneration (ROSP in French) could be discussed. The role of smoking cessation in cancer-related treatment. Scientific studies28 show the multiple benefits of stopping smoking for patients in the short and long terms, such as reducing the risks posed by surgery, reducing side effects and reducing the return of tumours. For example, benefits were observed in subjects in the EPIC cohort (European Prospective Investigation into Cancer and Nutrition) who were long-time ex-smokers. The risk models are the same for smokers who had quit smoking 10 years or more before joining the cohort and people who had never smoked. Many other studies have shown that continuing to smoke after being diagnosed with cancer increases the risk of a relapse while quitting smoking lowers the risk. This was supported by three studies that looked at lung cancer patients (small-cell lung cancer), who had a higher risk of a second primary cancer, especially second primary lung cancer (NSCL)29,30,31. 28 - Licaj I et al, “Impact du tabac sur la mortalité totale et sur la mortalité par cause dans l’étude européenne EPIC (European Prospective Investigation into Cancer and Nutrition) [The role of tobacco consumption on total and cause-specific mortality in the European Prospective Investigation into Cancer and Nutrition (EPIC) study], BEH 2013,20-21:234-238. 29 - Richardson, G.E., et al., Smoking cessation after successful treatment of small-cell lung cancer is associated with fewer smoking-related second primary cancers. Ann Intern Med, 1993. 119(5): p. 383-90. 30 - Tucker, M.A., et al., Second primary cancers related to smoking and treatment of small-cell lung cancer. Lung Cancer Working Cadre. J Natl Cancer Inst, 1997. 89(23): p. 1782-8. 31 - Johnson, B.E., Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst, 1998. 90(18): p. 1335-45. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 112 They also reveal that patients are usually willing to quit whereas oncologists say smoking is often the last pleasure left for the patient going through this ordeal. In English-language literature, a cancer diagnosis appears to motivate the vast majority of patients to quit smoking32,33. Potential actions 1. Include tobacco use in the Cancer Communication Record (DCC). 2. Draft a guide for health professionals about the effects of smoking and the benefits of quitting after a diagnosis of cancer (education, involving the workplace physician, dentists, teaching doctors and nurses, etc.). 3. Raise awareness among cancer patients on quitting smoking (partnership with patient associations, targeted initiatives for teens and young adults who had cancer as a child to prevent the onset of smoking). 2.2. TO BUILD A SHARED BIOLOGICAL, CLINICAL AND EPIDEMIOLOGICAL DATABASE 2.2.1. OBJECTIVES OF DATA SHARING The database will draw data sources from the healthcare system (medical administrative data generated by hospital institutions, like PMSI (Programme for the Medicalisation of Information Systems) or SNIIR-AM (National Inter-Plan Health Insurance Information System) and clinical, biological and epidemiological datasets generated by research. Over the last few years, the massive amount of new data acquired through genomic analysis (particularly high throughput sequencing) has boosted the production of biological data. These genomic analyses now provide unprecedented opportunities for cancer research and treatment. Genomic data can essentially be used to devise a new classification of tumour sub-types resulting in approaches to the tumour development process that have never been studied. Before these genomic data can be used, they must be correlated with clinical, epidemiological and biological data. Furthermore, the complexity and diversity of cancer requires immense datasets in order to conduct relevant clinical comparisons and research for therapeutic purposes. One of the biggest issues to resolve at the local, national and international levels is using these data in an integrated manner to advance the knowledge and understanding of the mechanisms of cancer and its medical care. In addition, the current fragmented or aggregated format of existing databases means they accumulate substantial volumes of data that are not always used. However, these data serve as research potential that methodologists can analyse after the fact. Their skills provide an opportunity to offer treatment and analysis methods and to guide researchers toward new topics. Using these data in research projects requires widening the shared channels (pooling data sources and types and professionally managing databases) and improving how they are analysed (bioinformatics and statistical skills and analysis tools designed to handle extremely large files and massive numbers of variabilities). Correlation studies of the data collected or generated should then make it possible to formulate functional hypotheses or answer new research questions. 2.2.2. STAKES OF DATA SHARING The data that will need to be shared, integrated and used is extremely broad in terms of classification, type and format. The classification is defined by whether the source of the data is public or private, which may ultimately determine its accessibility. Even for data that is public, the concept of “producer” will also need to be considered, who the promoter is, for example, for the clinical trials. In effect, the promoter could claim rights to use the data before making it available to the entire research community. The type of data pertains to how they are collected or generated: • clinical data (medical files and clinical research data), health expenses, • biological diagnostics data (laboratories), • epidemiological data (surveys and/or public health cohorts and/or research groups), • molecular data (genomics, proteomics, transcriptomics, 3D structures), • imaging data (biological/medical imaging, microscopy and cellular imaging in research). In the cancer research field, the current challenge of managing and integrating large volumes of data mainly involves molecular data and more specifically the genomics data related to clinical data. The format of the data is determined by their classification and type (quantitative, textual, raw, metadata, images, etc.) and by nature varies greatly, which necessitates planning for special storage and processing functionalities when designing a shared database. 32 - Demark-Wahnefried, W., et al., Riding the crest of the teachable moment: promoting long-term health after the diagnosis of cancer. J Clin Oncol, 2005. 23(24): p. 5814-30. 33 - McBride, C.M. and J.S. Ostroff, Teachable moments for promoting smoking cessation: the context of cancer care and survivorship. Cancer Control, 2003. 10(4): p. 325-33. INCArapportGB2013.indd 112 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT In terms of a purpose, data pooling and data sharing are designed to integrate them to allow analyses and interpretations. However, when organising them it would be wise to differentiate the assembly, integration and usage phases. • Assembly phase: for the centres that generate or collect data (hospitals, research laboratories, institutional databases) it entails making them available in line with scientific or medical objectives. In theory, the only goal of this availability is to make information public that was obtained using taxpayer money. Yet, they should be made available while keeping potentially identifiable information confidential. Data assembly is based on the interoperability of databases from different sources, i.e. the ability of many different data management systems to exchange information. Achieving this interoperability involves technical factors (different software), syntactical factors (exchange format) as well as semantic considerations (determining a common definition of data). • Data integration phase: it relies on a capacity to link different types of data (clinical, biological, medical imaging criteria, genomic or proteomic profiles, etc.) for the same patients. It requires anticipating and organising data traceability (username) and linking these data so they can be used at a later time. • Data usage phase: it should be managed only within a research strategy that will lead to designing and planning correlation studies between the data and pre-defined criteria for each research project. Usage is the scientific reason for sharing and integration and should be conceived to provide answers to the questions raised within the project framework. The professionalization of data sharing, integration and usage Building and using databases should be professionalised and drawn from a chain of disciplines bringing together clinicians, biologists, pathologists, data managers, bio-informatics specialists, epidemiologists, IT specialists and mathematicians. Furthermore, it is beyond the capabilities of outlying institutions and highly-specialised disciplines to organise data sharing and they need concerted interconnected systems built as national infrastructures. Considerations on introducing dedicated data sharing infrastructures will need to account for existing organisations that provide resources for collecting, producing, storing or accessing data as well as new requirements to accommodate the exponential growth of genomic and imaging data. INCArapportGB2013.indd 113 113 Potential organisational models rely on both existing structures and uniting scientific teams around a research strategy. The existing structures will need to be considered for their industry expertise and service capacity, to manage and process data (collection, quality control, storage) and, for their expertise and capacity for analysis (bio-informatics, bio-statistics). Forming scientific consortia with a research strategy is a determining factor in the design and multi-centre organisation of data collection and of designing and using databases in line with a range of scientific questions. The research strategy involves planning for the data collection, integration and usages, not only at the research project level but also, and most importantly, for the multiyear scale of a scientific theme. Optimising the healthcare-research continuum to collect and access the data with a view to sharing it In light of technological, scientific and medical advances, the potential to generate and use data will grow exponentially. We must plan for this growth, by optimising the development of the projected benefits for society and individuals alike and, controlling the quality and use of the data in line with a national code of ethics and laws. This system involves a large number of participants from the scientific, medical and institutional worlds, whose professional interactions will not be evident in terms of objectives and responsibility – as well as resources. This can only be established through societal choices and the introduction of legal constraints and obligations for doctors, scientists and health/research institutions. INCa is perfectly positioned as an institution to organise and even steer the thought process and offer recommendations on behalf of its two regulatory ministries. In following on the work done by ASIP (Health Information Systems Agency) and beyond the scope of the Cancer Communication Record (DCC), INCa is bringing together all the elements to organise and optimise the healthcare-research continuum. From this perspective and in our vision of the legal framework, consideration would have to be given to the concepts of “ownership” and “responsibility” for the data to be able to plan the addressing and access rights tasks, not to mention an obligation on resources to ensure the quality and integrity of the data. If accepted, these concepts would play a major role in organising the healthcare-research continuum. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 114 It will be impossible to compile the individual data without instituting a unique username and password that create a link between all the data generated at healthcare institutions or laboratories. The job of organising access to the patient data for scientific use could be easier if the data were already compiled and the terms of use for scientific purposes pre-defined. The use of data for scientific purposes could be modulated based on the research project’s ultimate objective. It would thus be easier to plan the projects by clarifying or simplifying the no-objection/consent procedure. As far as resources, information and communications technologies (ICT) enable general-purpose 24-hour access from anywhere in the world to all the resources (data, computing power), but also carry with them adverse effects in terms of security and ethics. Therefore, it would be advisable to set up a common framework to organise hospital and healthcare IT systems by defining specifications and requiring the management of traceability, links and access to patient data. 2.2.3. OBTAINING AND INTEGRATING GENOMICS AND CLINICAL DATA Context The challenge in the cancer research field of managing and integrating large volumes of data mainly involves molecular data and more specifically the genomics data. The development of genomics analysis techniques that can decipher molecular mutations linked to cancer has profoundly changed how cancer is classified, diagnosed and treated. Since 2006, INCa and the French ministry in charge with Health have been building a national network of 28 molecular genetic platforms that conduct molecular tests, primarily tests that determine access to targeted therapies for all patients throughout the country. In 2012, 68,000 cancer patients in France were administered molecular predictive tests: 20,000 patients had lung cancer, 17,000 colorectal cancer, 8,000 breast cancer and 4,000 melanoma. Some 17 medications that target specific molecular tumour abnormalities have been developed in the last 10 years and are already available to patients. Current projections for pharmaceutical companies are counting on the introduction of four to five new and original drugs every year that target new molecular pathways. The increased number of molecular abnormalities to unravel on an individual level for an increasing INCArapportGB2013.indd 114 number of patients will require using “all-in-one” approaches that employ high-speed technologies like next-generation sequencing (NGS). This situation is leading to molecular genetics platforms that are incorporating NGS into clinical practice. For the moment, this pertains to “targeted” NGS where a panel of a dozens to a few dozen genes are analysed. However, INCa is now anticipating the development of extensive tumour genome sequencing, which is expected to begin deployment in the next few years. Genomic data will then have to be generated in the healthcare context for a majority of patients as early as 2014. In addition to molecular epidemiological data, there is a unique opportunity to generate new knowledge by collecting these data in terms of patient clinical characteristics and their treatment and monitoring. For example, we could determine the therapeutic effects of some rare mutations or identify subgroups of patients with atypical response profiles. The “France Biomarkers” project, funded by INCa, collected molecular, clinical, treatment and follow-up data from 20,000 lung cancer patients, making it the first pilot study that can help assess strengths and weaknesses of a project of this kind. Methods and conditions INCa will need to work towards: 1. Modifying the functions of the molecular genetics platforms and providing them the means to systematically collect clinical patient data for which it generated genomics data. 2. Supporting the molecular genetics platforms to design a system to integrate and store clinical and genomics data. 3. Continuing and steering the programme to identify and set up clinical biological databases with systematic collection of genomics data. That is why embarking now on the development of a national database that collects these data is a strategic national endeavour. It does, however, carry a number of challenges that have barely been considered until now: 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT Ethical aspects: the goal of developing these sorts of databases and sharing stored information will be to accelerate oncology research. Yet, in most if not all cases, these clinical and genomics data will be collected in a healthcare setting. This dichotomy raises a number of questions in terms of ethics (i.e. identifying a molecular abnormality without a treatment targeting that abnormality), regulations (i.e. storing data outside the country that by national law belongs to the patients, personal data security, etc.), complete and accurate patient information as well as the ability to meet the requirements of French and European regulatory agencies. Data protection, criteria for data access and sharing, determining patient consent methods to use treatment-related data for research projects – there are several issues that will have to be addressed when these databases are introduced. Consideration will also have to be given to the current context, where the 1995 European directive regulating private data is undergoing revisions. Therefore, the implementation of this project will have to: • anticipate questions on the ethics of collecting, compiling, storing and using private data, • account for French and European legal requirements on accessing private data. Technical aspects: in order to facilitate the data sharing component, we would need to develop a database that could be centralised where the information can be accessed. In this context, the different sources generating the data to be integrated, for example molecular genetics platforms and clinical biological databases will have to provide their data to this database. The ‘large data’ community is a large number of stakeholders involved in the data to integrate, and thereby IT tools, software and methodological tools, in the selection of data banks and databases, and the wide variety of data. This sort of community requires extensive planning to make the data accessible and shareable. INCArapportGB2013.indd 115 115 Therefore, we will need to: • make the data management systems interoperable by using software, exchange formats and validating the data itself, • develop and/or use an academic or private centralised infrastructure, perhaps something like the Cloud or a hierarchical system (i.e. the CERN model) to store the data. Data analysis and use: research teams can analyse and the stored data by importing useful data locally or, since the volume of data is so large, it would be more practical to access it from the centralised database directly, perhaps in the cloud, without importing the data locally. In the first case, all or almost all the teams should have not only the right hardware and software to handle big data, but also the skills required to perform these tasks. For example, these teams would have to have skills in bio-informatics as well as technical computer skills to resolve issues with IT technologies that are still unstable. Thus, there is still some concern right now about data transfer speeds and maintaining the integrity of the data being transferred. Some solutions are more practical than others: • developing and/or using the Cloud provides a secure environment (platform) to analyse data and backup findings, with data, administrative and analysis software, analysis models and storage space for off-site findings that can be viewed remotely on demand, • develop and provide access for research teams to a centralised technical support platform comprised of IT specialists and a methodological support platform of bio-informatics experts, • provide support for training in the skills required to develop and sustain the chain that begins with data collection and ends with sharing integrated data, • plan for and encourage an expanding community, for example an academic community, at the national or European level of analysis, calculation and modelling methods (i.e. algorithms), programming, more shared licences and other tools that enhance the large data environment. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 116 Structures contributing to data production Structures Data processing centres (CTDs) Nb 11 Missions Logistics and methodology support for clinical research projects, particularly in data management, quality control and data analysis. Refers to investigators, qualified personnel (working in clinical research, clinical study technicians) to ensure inclusions and data quality. Interfaces Cooperative inter-groups PHRC (clinical cancer research hospital) CLIP2 Cooperative inter-groups PHRC (clinical cancer research hospital) Mobile clinical research teams (EMRCs) 26 Molecular genetic platforms (PFGM) 28 Conducts molecular testing (diagnostics, prognostics) that help determine access to targeted cancer therapies and conduct disease monitoring. SIRIC CLIP² Cooperative inter-groups Rare cancer initiative Constitutional oncogenetic laboratories 25 Conducts molecular tests to identify people with a high risk for cancer. Tumour banks 58 Organises and rationalises biological resources conservation and access for cancer research. SIRIC Data collection CLIP2 Storage and quality Cooperative inter-groups Rare cancer initiative Builds clinical biological databases associated with biological samples around a common pathology. Organise and optimise data collection to integrate and use data in research projects. SIRIC Integration, storage, mining CLIP2 Cooperative inter-groups Rare cancer networks Clinical biological databases 9 Call for proposals in progress Registries Generalists Specialists (qualified) Oversees ongoing exhaustive basic data 12 collection within a geographically defined 16 population for research and public health purposes. Rare cancer programmes INCArapportGB2013.indd 116 Organises and structures treatment and research frameworks. Data Management Storage Processing Data collection Quality Production Data collection: Lung database: Projet Biomarqueurs France (France Biomarker Project) directed by IFCT (Francophone Thoracic Oncology Inter-group) Production Data collection: database of BRCA and MMR gene mutations BCB Tumour banks Screening management facilities Rare cancer networks Data collection, mining Cooperative inter-groups Production, collection, CLIP2 storage, mining 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 2.3. TO FOSTER CLOSER TIES BETWEEN TEACHING AND RESEARCH AND INCREASE SUPPORT FOR INTERDISCIPLINARY TRAINING The landscape of cancer research has changed considerably in recent years, particularly with the 2009-2013 Cancer Plan that allowed research and care centres to work together and forces and skills to concentrate on eight SIRIC sites designated in 2011 and 2012. For the years to come efforts have to be made beyond SIRICs and higher participation from teaching hospitals (University hospitals, CHU, including affiliated Cancer care centers (CLCC)) in oncology research through and in addition to clinical research is to be obtained. This objective is not specific to cancer, but it could be a driving force in a broader discussion. Moreover, actions should be set up to assign accountability and foster independence among young researchers and support training and an interdisciplinary approach. 2.3.1. ENCOURAGE INTERFACES BETWEEN UNIVERSITIES AND HOSPITALS In addition to the recently designated SIRIC (Integrated Cancer Research Sites), a hospital cancer research policy could be established at CHUs and CLCCs not designated as SIRICs. The goal is to promote the scientific quality of these centres, encourage and support research partnerships outside of the actual centres, increase and harmonise the centres’ research activities with national initiatives led by INCa and the Aviesan cancer alliance, and make translational cancer research one of their core activities. The goal is to leverage these centres’ institutional resources that thereby incorporate fundamental, clinical and population health research into a large cross-disciplinary translational programme that is built and carried out with researchers and clinicians working side by side where translational research warrants a work organisation and exchanges that imply a change in practices and methods. INCArapportGB2013.indd 117 117 Potential actions 1. Set up a call for projects aimed at CHUs and CLCCs that demonstrate exemplary research activities linking clinical/population health and prevention to intensify interactions between research and healthcare. 2. The programme could also include targeted support for basic training aimed at oncology clinicians and bring in both local drivers led by hospitals and universities and national actions run by INCa that would enable complementary coordinated financing for M2 Master’s degrees, PhDs, international internships, discharges from hospital activity. 3. Set up the conditions making it easier to hire teaching hospital staffs that meet the needs of both clinics and research. The expectations of centres that would receive this type of funding are to: • be the main centres contributing to exploring the very nature of cancer and developing more effective preventive, diagnostic and treatment approaches, • provide a substantial contribution to the expansion of shared resources for research, • collaborate and coordinate translational research projects with other programmes assigned and directed by INCa and the DGOS. The projected impacts of this process are ultimately better uniformity between programmes led by hospitals, universities and research centres working on cancer, optimised use of the CHU Cancer Platforms and improved training for young oncologists. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 118 2.3.2. BACKING TO CREATE A CHAIR OF EXCELLENCE IN TRANSLATIONAL RESEARCH Oncology is an especially suitable field for deploying translational research given the steady pace of the advances in describing oncogenesis-related molecular and cellular events and the development of new high-speed technologies, which are providing a unique opportunity to translate these discoveries into tangible advantages for patients with the personalised treatment approach. New Chairs of Excellence in translational research would enhance the support mechanisms introduced in the last few years by universities promoting a culture of translational cancer research through educational and research programmes designed to build a continuum with hospital care. The Chairs of Translational Oncology Research would draw recognition to the teaching hospital career path of physicians and pharmacists qualified to do this research, open doors to toppriority fields of cancer research and promote multidisciplinary education that will improve the quality and visibility of this research. The specific objectives are: In education, to develop a shared culture for the translational research process by organising and facilitating an educational programme of seminars and workshops: • seminars led by international scientists who are experts in their field and invited to come and stay to share organisational and scientific experiences as part of the Chair programme, • workshops in methodology (biostatistics, bio-informatics analysis, data management, etc.) and technology (high-speed genomics analysis, imaging, etc.). In research, within a hospital or special institution (SIRIC), to lead a research programme on a specific theme supported by interfaces between fundamental and clinical research, give visibility to an area/field/process of original and/or top-priority research, form European/international working partnerships and enlist the Chair programme in an international network. Priority themes in translational research: • personalised medicine: developing new diagnostic tests and companion tests alongside the marketing of new therapeutic molecules, developing alternatives to clinical trials, • new therapeutic technologies: advancing developments in surgery, radiobiology, interventional imaging, etc., INCArapportGB2013.indd 118 • post-genomic research: functional validation and interpretation of genomic abnormalities identified with high-speed techniques, • integrative biology: integrating data from genomics analyses with clinical and epidemiological data to devise decisional algorithms, developing research programmes on biology resulting from the integration of clinical and epidemiological data (reverse phase). In transfer, to develop interfaces with industry, pharma and biotech, and strengthen and develop ties with national and local promotional entities. Potential actions The first joint INCa-CPU (Conference of University Presidents) call for candidatures could be launched in late 2013 to create three INCa-University chairs in the first year and two in the second year. They would be backed for four years. 2.3.3. ASSIGN ACCOUNTABILITY AND FOSTER INDEPENDENCE AMONG YOUNG RESEARCHERS This is a general topical subject in research and could be furthered in terms of its structures involving medical interfaces. We could envision a few tangible proposals: Processes for gaining independence in France by forming teams, like the ATIP/Avenir model (a five-year version) Holding a competitive selection process to obtain resources to develop an innovative independent research programme is an excellent premise for fuelling the French scientific community. The initiatives conducted during the ATIP/Avenir programme will need to be continued and expanded. Nevertheless, it is obvious that three years with a five-year extension (ATIP +) is not long enough for the international initiatives to, for example, prepare a smooth transition to the next phase. Other programmes in neighbouring countries generally allow for five years with a twoyear extension with guidance, assessment/consulting after three years and then after five years to help prepare for transitions from one facility to another and ensure that skills are actively flowing between the different structures. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 119 Potential actions 2.3.4. SUPPORT TRAINING AND AN INTERDISCIPLINARY APPROACH 1. Propose adding two more years to ATIP/Avenir Advanced hybrid training programmes The significance of multidisciplinary training, like biology/ mathematics, biology/physics, etc. has long been acknowledged. Since 2010, INCa and then since 2011, Aviesan-ITMO Cancer have most notably been supporting the PhD programme “Frontiers in Life Sciences” (Paris 5 and Paris 7) and there are other institutes like Institut Curie partnering with various universities and PhD programmes supporting this type of training. Projects in the current system range from the most fundamental with cellular and developmental studies that include mathematical/IT applications to processing complex biological data (genome and post-genome) and are also developing educational programmes that are more oriented toward “cancer” applications. projects, selected by EPSTs* with their current criteria in the cancer field or a cancer-related field. This would secure a five-year programme and be comparable to the ERC Junior format. 2. Propose two more years, making it seven years following a selective evaluation. 3. Encourage the introduction of a mentoring programme for young groups and tools that could be used for this purpose. 4. Motivate young researchers to lead large national programmes, for example the open programme on biology and cancer sciences research, an open translational research programme. The majority of these programmes is run by high-profile senior researchers, some of whom coordinate or are involved in numerous demands. An incentive policy aimed at programmes run by young oncology researchers would secure the independence of the initiators (reserved budgets or targeted programmes) and thereby continue fuelling innovative programmes. Prior to the junior team phase, discussions in interdisciplinary education and increased independence Associations like the ARC Foundation, French National Cancer League and FRM (French Foundation for Medical Research) support young people getting involved in cancer research through Master’s, PhD and postdoc grants. Translational projects receive dedicated support from INCa and the Aviesan Alliance. These funding help build independence among the younger population. Interdisciplinary projects contribute to the emergence of skills in interfacing, skills that are increasingly needed as the scope of research and cancer medicine expands. Translational projects receive dedicated support from INCa and the Aviesan Alliance. These funding help build independence among the younger population. Interdisciplinary projects Increase the for thesis and/or contribute to support the emergence of skills in Master’s interfacing, skills that scholarships on competitively subjects are increasinglybased needed as the scope selected of research and cancer (selection process could be based on work done by PhD medicine expands. programmes). Potential actions Training future oncologists in biology INCa could step in to support training for doctors interested in biology. A compelling advantage would be actions to incentivize current training programmes in oncology to join forces or work in tandem with institutions that offer major biology programmes by combining students from many different fields in a space that makes room for the international aspect. Translational projects receive dedicated support from INCa and the Aviesan Alliance. These funding help build independence among the younger population. Interdisciplinary projects Consider to special programmes contribute the emergence of that skillsare in original interfacing, skills that and competitiveneeded and include projectofbetween are increasingly as theascope researchtwo and cancer laboratories with different expertise, a bit like the EIPODS medicine expands. programmes between two laboratories at the EMBL. Potential actions * EPST: Établissements Publics à caractère Scientifique et Technologique (Public Scientific and Technical Research Institutes). INCArapportGB2013.indd 119 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 120 2.4. TO SUPPORT AMBITIOUS FRENCH CANCER RESEARCH TO PROVIDE THE POPULATION AND PATIENTS QUICK AND SIZEABLE BENEFITS From a public perspective, the goals of fighting cancer are to prevent both individuals and population groups from contracting cancer, diagnose them early so treatment is short and barely debilitating, cure them and offer them, as far as possible, a quality of life similar to the pre-diagnosis’ one. Major progress has been made in the last decades in the fight against blood diseases, breast cancer and testicular cancer. However, a speeding-up is awaited in a number of cancerrelated pathologies, particularly the types of cancer with grave prognoses like pancreatic or lung cancer, where no conclusive therapeutic advances have been made, or brain tumours. Every year during the 2003-2007 and 2009-2013 Cancer Plans, support was provided for many research projects and infrastructures, tools and competitive research networks were identified or set up. The 2009-2013 Cancer Plan will have given €469 M to support cancer research in all its forms. It stands to reason, then, that French cancer research is equipped to design, bring about and lead ambitious projects with the specific objective to reduce the incidence, mortality and morbidity of cancer. One of the largest contributions is INCa’s recognition of inter-group cooperatives focusing on major cancer-related pathologies that are likely to spearhead wide-scale national projects targeting these objectives. Translational projects receive dedicated support from INCa and the Aviesan Alliance. These funding help build independence among the younger population. Interdisciplinary projects contribute to the emergence of skills in interfacing, skills that are increasingly needed as the scope of research and cancer medicine expands. INCArapportGB2013.indd 120 Potential actions Set aside a portion of the budget for each of INCa’s calls for projects in clinical research, human sciences and public health to support projects designed to significantly reduce the risks and incidence of severe cancer and improve patient quality of life. INCa’s calls for proposals, some of which are led with partners, cover all the anti-cancer disciplines and fields. These calls for proposals are not targeted; the researchers devise the themes themselves. While all of these projects are competitive, the stakes involved in the issues they address are disproportionate. As an example, over a period of 10 years these calls for proposals funded more early-phase clinical trials than phase III clinical trials at a rate of 2.5-3 times more in some years. The timeline researchers set for these projects is not a determining selection criterion, despite the feeling of urgency expressed by the general public, patients and their loved ones. One of the selection criteria should be a capacity for quick inclusion so the studies are completed in a shorter time. We need the participation of ambitious and competitive research teams and infrastructures when solving questions on the severity, duration and toxicity of treatments. In order to motivate research teams, especially the top ones, to design and submit projects that target these aspects, we will have to set aside a considerable part – estimated to 50% - of calls for proposals’ budgets for them. These scientific challenges would be led by collaborative efforts among the most competitive teams or managed by cooperative intergroups. Accordingly, support to studies on low doses irradiation could benefit secondary and tertiary prevention. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 2.4.1. SUPPORT RESEARCH PROJECTS WITH THE SPECIFIC OBJECTIVE OF SUBSTANTIALLY REDUCING THE RISKS AND INCIDENCE OF CANCER. Research projects, primarily in prevention, epidemiology, public health (PH) and health-intervention research will be funded if they convey a stance on helping slow down or reverse a growing curve or accelerate a reduction in incidence. For example, it would entail projects to identify and analyse risk factors for cancers that keep being little known or not yet known, risk factors that significantly contribute to the occurrence of cancer or risk factors that can be modified by health-intervention projects including their estimated effect. This objective requires stepping up INCa’s actions to attract the best research teams in human and social sciences, epidemiology or public health to the field of cancer and foster translational research projects aimed at using fundamental or biological studies to understand epidemiological or public health observations. Preferred actions 1. Identify and provide innovative researchers, methods and tools in human and social sciences, epidemiological, public health and health intervention research. 2. Organise and support collaborative networks of researchers. 3. Increase the calls for proposals budget for translational research and understanding the behavioural and environmental factors. 121 2.4.2. IDENTIFY AND TIGHTLY MONITOR COGNITIVE RESEARCH PROJECTS WHOSE EFFECTS OR APPLICATIONS COULD BE SIGNIFICANT IN THE SHORT OR MEDIUM TERM FOR REDUCING THE INCIDENCE AND MORTALITY RATE AND IMPROVING PATIENT QUALITY OF LIFE Findings from upstream research can provide a wide array of opportunities, ideas, avenues of validation research and clinics applications. A crucial component is far-reaching financial support for technological innovation to apply fundamental advances. Ensure that the potential/expected impacts or applications of ambitious projects in submissions for calls are systematically explained. Make it one of the selection criteria by committee. Identify a significant and dedicated funding to research team projects that support these approaches. Improve INCa’s internal methods on scientific monitoring and guidance for research projects. 2.4.3. SUPPORT TRANSLATIONAL RESEARCH PROJECTS IN HUMAN AND SOCIAL SCIENCES WHOSE OBJECTIVE IS TO SIGNIFICANTLY IMPROVE QUALITY OF LIFE FOR CANCER PATIENTS A key objective of the French Ministry of Health and INCa has been the quality of life of cancer patients, most notably in conducting actions in the 2009-2013 Cancer Plan. It is an area of research in many of the calls for proposals managed by INCa, especially the investigator-driven call for proposals in human and social sciences research, epidemiology and public health and the call for proposals for PHRC Cancer projects. Potential actions 1. Conduct a scientific assessment of the research projects that are funded and focus on the improvement of quality of life. 2. Promote research on the understanding of quality of life and how to measure it in the calls on clinical research. INCArapportGB2013.indd 121 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 122 2.4.4. IDENTIFY, SUPPORT AND MONITOR CLINICAL TRIALS AIMED AT PROACTIVELY IMPROVING THE OVERALL SURVIVAL RATE OF CANCER PATIENTS Major therapeutic advances have been made for a number of cancers in the last few years. Many types of cancer, such as pancreatic cancer, brain tumours, ovarian cancer, lung cancer and bladder cancer are still posing challenges for research. Rare types of cancer are also a scientific challenge, primarily because the clinical trials are difficult to manage. INCa should encourage teams to conceive and submit clinical trials that aim to substantially improve survival and, in some cases, large pragmatic clinical trials that closely reflect treatments and work to standardise good practices and reduce therapeutic risks and lost opportunities. This objective should be supplemented by trials that specifically address therapeutic de-escalation and reducing treatment-related after-effects. The objectives will be achieved with a collaborative teambased approach via cooperative inter-group. INCa-designated cooperative inter-groups are collaborative and competitive international networks capable of quickly managing phase III clinical trials. They have a proven ability to unite research teams, recruit over 25% of the patients enrolled in clinical oncology trials each year in France (nearly 10,000 patients in 2011) and contribute to approximately 80% of the French academic papers in the authoritative international scientific publications. They need to receive more financial and institutional support. INCArapportGB2013.indd 122 Preferred actions 1. Fund a special research call for proposals for understanding, preventing and reducing treatmentrelated after-effects in the short and medium terms. 2. Shift the funding ratio of early-stage clinical trials to phase III clinical trials through a call for proposals managed by INCa and set aside a large part of the PHRC Cancer budget for large-scale clinical trials focused on improving the overall patient survival rate and therapeutic de-escalation. 3. Enlist the cooperative inter-groups designated by INCa to head large phase III clinical trials aimed at improving the survival rate by reserving competitive funding for them (50% of the PHRC). 4. Interactively join the talks with the DGOS on identifying, recognising and supporting clinical investigation networks. 5. Intensify the designation programme for cooperative inter-groups by bringing in new cooperative groups and delineating the cooperative inter-groups. 6. Put in place public-private partnerships to manage the phase III clinical trials and develop a European cooperation policy on these trials. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 2.4.5. NARROW THE GAP BETWEEN RESEARCH AND PRACTICE Implement the use of findings from research in clinical practice to narrow the gap between research and practice and reduce the rate of lost opportunities Despite recommendations from health authorities, it is still a complex process to transfer research findings over to practice for the benefit of populations and patients in many types of cancer. There are economic, organisational and cultural factors involved caused by the separation between research environments and places where medicine is practised. This gap between research and practice can lead to delays, digressions and even bad practices. INCa must interact with its partners to propose and set up actions that provide support for projects designed to narrow the gap between research and practice. Potential actions 1. Support research projects that aim to identify and analyse the factors and conditions of transferring research findings to practice, incorporating them in the political decision-making process and having them assimilated by the general public. 2. Propose the positioning of INCa’s health-intervention research call for proposals to the Ministry of Health as tools to aid the government decision-making process on public health issues. 123 In clinical research, the management of therapeutic trials, most importantly in healthcare institutions, is still perceived by healthcare professionals, hospital administrators, patients and their loved ones as an extra-clinical activity in the sense that they do not seem like an alternative to medical management but rather as an “experiment” whereby day-to-day healthcare practices can occur. For many cancer patients, therapeutic trials may be the only remedial treatment solution available. Thus, for example, it may be useful to propose. Potential actions Liaise with the DGOS (MoH) to experiment in a handful of healthcare facilities on integrating clinical trials aimed at improving overall survival, quality of life, therapeutic de-escalation and the reduction of therapeutic aftereffects into day-to-day cancer care practices. More generally, the transfer of innovations in practices would naturally be a priority insofar as in this instance these innovations contributed to achieving the goal of reducing cancer-related incidence, mortality and morbidity. Potential actions Accelerate the introduction of the INCa programme to detect, bring about, guide and disseminate innovations. INCArapportGB2013.indd 123 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 124 Use research to ensure the findings observed in practice comply with and compare to the research findings The gap between research and practice can also lead to obtaining results in practice that are considerably lower (effect size) than in research. To optimise the results from research for the benefit of populations and patients, INCa could expressly support research projects with objectives to understand the mechanisms, strategies and conditions for reproducing the effect size obtained by research in public health and clinical practices. Optimise research findings in preventive, screening and treatment practices Once the factors and mechanisms limiting the reproducibility of research findings in practice and their effect size have been identified, it must be associated with support for research designed to reduce them. Many calls managed by INCa could be used to this effect. The health intervention research call and those on the quality of care would thereby help, for example, finance projects that aim to deal with these factors and mechanisms to optimise the reproduction of the effect size seen in research findings in practice. Similarly, some rare tumours or tumours for whom therapeutic drifts were experienced should be treated exclusively in specialised centres. Potential actions 1. Support research projects whose objective is to identify and reduce the factors limiting the effect size in practice compared to the effect size observed in research. 2. Interact with the DGOS to have the wording changed in the “Treatment track” section of the call for proposals for PRME-K (Medical Economic Cancer Research Programme) to allow research teams to submit projects aimed at reproducing the optimum conditions for duplicating the research results in practices. INCArapportGB2013.indd 124 2.5. NEW CHALLENGES IN CANCER CONTROL: EUROPEAN AND GLOBAL PERSPECTIVES 2.5.1. EUROPEAN COLLABORATIONS Beyond the European partnership against cancer EPAAC – Continuation and expansion of cancer research coordination in early phase clinical studies. Horizon 2020 perspectives and potential synergies with IMI2 (the innovative medicine initiative 2) Early clinical trials should well be considered as the first milestone to the implementation of personalised/precision medicine and should be pursued through concerted actions and strategic public-private partnerships. As explained under chapter 7 above, EPAAC WP8 was instrumental in the development of an embryonic European coordination scheme in early-phase therapeutic cancer research. We view the renewal of the Innovative Medicine Initiative under the frame Horizon 2020 as an opportunity to expand further this embryonic action and reach to a pan European organizational framework using the public-private scheme of IMI2. Two targeted areas in the field of early phase clinical trials clearly emerged from intelligence-gathering exercises carried out within WP8: i) Early phase clinical trials based on molecular diagnosis, ii) Early phase clinical trials for targeted drug combination. Advances in the molecular profiling of tumour tissues have opened up an era of precision cancer treatment. Molecular profile of individual tumour now guides therapy and has become a decisive factor. Market approval of targeted drugs makes molecular testing mandatory and commands the development of subsequent organizational framework to ensure a fair access to tumour molecular profiling for all patients. Stateof-the-art biomarker-driven early phase trials are important components of the whole framework. They are essential to evaluate the efficacy and safety of new drugs, new therapeutic strategies or administration routes, and make optimal choices about dosages and durations of treatment. They entail public/ private coordination of resources to explore all the potential indications and develop new adequate designs of clinical trials. The Innovative Medicine Initiative is certainly an appropriate place to reach the level of collective think tank needed between the pharmaceutical industries and academic representatives regarding these new types of trials. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT Targeted therapies have also shown some limitations. Chief among these is the potential for cells to develop resistance. Combination of targeted therapies, either with other targeted therapies or with more traditional therapies is a promising way, as it may overcome resistance, synergize the effects of the drugs and increase the efficacy of the treatment. The high number of targeted drugs offers large opportunities to improve treatments. Collaboration between companies would facilitate access to multiple combination and drug association and would spur collaboration with academic groups. Again IMI seems to offer a platform of choice to initiate discussions and conduct this type of study. Promote the new European concerted and support action in the area of personalised medicine (CSA PerMed) The implementation of personalised medicine is a major challenge in Europe and beyond. It calls for appropriate governance strategies at the European level as it defies the way in which healthcare systems are set up. It requires strategic rearrangements in academic and industrial research to support these organizational changes. A consortium of 28 public and private agencies, government bodies, health care professionals, private enterprises, regulatory bodies and leading charities, representing 14 countries, has joined forces to accelerate the development and uptake of personalised medicine in Europe, and submitted a proposal for a “Concerted and Support Action” entitled: Personalised Medicine 2020 and beyond – Preparing Europe for leading the global way (PerMed). This proposal, coordinated by the Federal Ministry of Education and Research of Germany, was successfully evaluated by the European Commission and is expected to start by the end of 2013. It sets the work plan towards the development of a shared vision and a technology roadmap to promote the development and uptake of personalised medicine in Europe. The consortium will first assess the available research and innovation resources, identify leading organizations, gaps and needs, and will point towards possible mechanism to help deploy common activities under Horizon2020, including future alignment of research policies. A technology roadmap will set the long-term objectives and provide a tentative framework to help plan and coordinate technology and system developments. Thematic areas will be identified during 2 workshops to be attended by people representing a wide range of stakeholders (medical companies, charities, health care representatives, clinicians and researchers from across a number of disciplines, and representatives of public sector bodies). The roadmap will capture the range of views expressed by this broad group of stakeholders. INCArapportGB2013.indd 125 125 The INCa will contribute to workpackage 1 “Inventory of activities, key players and identification of gaps and needs” and workpackage 3 “Recommendations for strategic development (Research Agenda)”. The duration of the project is 24 months (2013-2015). Develop a new joint action to reach out the aims of the European cancer partnership set out in the Commission Communication COM(2009)291 of 24 June 2009 The objective of this new joint action, called “CANCON” is to develop a European guide on quality improvement in comprehensive cancer control. The guide will address various aspects of coordinated and integrated cancer control, aiming at improved quality of cancer screening programmes, better integration of cancer care through models for comprehensive cancer care networks, promotion of community-based primary level cancer care approaches and concerted efforts in all aspects of survivorship and rehabilitation, including supportive and palliative care. Other key activity is the organization of a platform, providing Member States with the opportunity to debate and share information and knowledge in topical areas, as the guide develops. This action will contribute to reaching the aims of the European cancer partnership set out in the Commission Communication COM(2009)291 of 24 June 2009 on Actions against cancer: European Partnership (EPAAC), and will build on its achievements and on the outcomes of previous EU actions on cancer. CANCON currently combines 26 associated partners from across Europe. The expected benefits are combined European interdisciplinary knowledge, innovative interventions, future guidelines to improve cancer care and quality of life of cancer patients, and overall decreased inequalities across Member States. The INCa will lead the workpackage 8 on “Survivorship and rehabilitation”, which addresses the life of cancer survivors as they transition from treatment to recovery and beyond. WP8 features content on the role of general practitioners and specialists in providing follow-up care to cancer survivors, the management of late and long-term medical and psychosocial effects of cancer and its treatments, work-related aspects of survivorship for both patients and society and the importance of survivorship care planning. The INCa will also contribute to the workpackage 6 “integrated cancer control” which aims at expanding further the concept of comprehensive cancer centre towards comprehensive cancer care network, that reach out to the patients. Specific 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 126 objectives of WP6 include, within the network organizational framework, the uptake of clinical recommendations and advanced technologies by the network, access to clinical trials, management of rare tumour, development of common infrastructures and professional coordination, integration of research and care. The INCa will finally contribute to the workpackage 9 on “Screening”, which overall purpose is to create further guidance to members States, based on the best available evidence, to implement or improve the implementation of populationbased cancer screening programmes. The duration of the Joint Action is 36 months (2014 – 2017). 2.5.2. GLOBAL CANCER CONTROL While non-communicable diseases are currently seen as true epidemics that have to be fought using strategies modelled after those used to counteract infectious diseases, it makes sense to use the networks and infrastructures developed to fight HIV. This type of coordination is needed to quickly attain international standards and organise patient care. Our cooperation strategy with low and middle income countries is part of a global context where the human cost of cancer seems to be endlessly mounting. This effort inevitably encompasses the training-research-public health continuum. A coordinated effort was set up with international agencies like the IAEA, local partners and health authorities in these countries, of course, as well as French agencies and institutions that had installed infrastructures abroad. Training courses for healthcare teams were organised and research projects launched to build capacity in the countries and while the actions were coordinated with local forces and were part of a national action plan, they remain isolated and difficult to assemble because they mobilise scarce available human resources. Therefore, the objective is to put together some transnational actions and further intensify our coordination efforts with French partners gathered in Aviesan Sud, operators developing a global strategy like the US NCI and networks like AORTIC to deepen the potential impact and introduce programmes that would encourage investigators in low and middle income countries to rely on research and its discipline as they address public health issues. INCArapportGB2013.indd 126 The pressing need to collect epidemiological data with appropriate population-based registries is regularly reasserted by cancer professionals in low and medium income countries (LMICs). Reliable data are needed to guide cancer control interventions, evaluate the requisite resources, convince policymakers in Ministries of Health and other governmental bodies and monitor the outcomes. The Global Initiative for Cancer Registry Development in Low- and Middle-Income Countries (GICR) convened by the International Agency for Research on Cancer (IARC) with the backing of several organizations worldwide addresses the complex problems facing cancer registries in LMICs (staff availability and qualifications, inadequate information technology support, verification of data, etc) in a systemic way. GICR is implemented through “hubs” –regional resource centres capable of providing developmental support towards cancer registries. The INCa intends to collaborate closely with IARC, in particular with the regional network hub for sub-Saharan Africa to help develop cancer registration as a foundation for cancer control. Possible involvements of INCa include the support of training activities and the development of tailored training material to improve the technical and managerial capacity of cancer data professionals, with a particular attention to French-speaking countries. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT INCArapportGB2013.indd 127 127 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 128 CONCLUSION The launch of a new cancer plan was proposed by the President Francois Hollande in December 2012, to start in 2014. He focused its objectives on five directions and priorities: 1 - Prevention, in particular towards primary prevention to strongly reduce cancers which are avoidable, and secondary prevention to reinforce early diagnostic and reduce sequelae and mortality, 2 - Research with the aims to develop a better understanding of the disease and access to better therapies through more personalised treatments, 3 - Better training of professionals involved in cancer care and research including general practitioners (GPs) and clinical nurses, 4 - Increase the quality of care through coordination and interaction of clinical centres with GPs, 5 - Improve the quality of life of patients during their disease and after, through facilitation of the return to work, insurance access, and for children continuity in their school life. The president has commissioned Prof. Jean-Paul Vernant to make proposals for the future who released a report to the ministries in charge of Health and Research in September 2013. This report will be the frame of a series of measures and actions for the future plan, currently being drafted by representatives of the ministries, INCa, scientific and medical experts, public and patients’ advocates. The future plan should be made public in early 2014 and will line the roadmap for the next 5 coming years. Major outcomes for research have been addressed in the present report to the International Scientific Advisory Board of INCa. They represent the contribution of the research community and INCa to the joint reflection to decreasing the burden of cancer in our country. INCArapportGB2013.indd 128 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 129 This year has seen profound changes in the INCa organization and instances. A large number of the members of its International Scientific Advisory Board have been renewed, including its Chair. A broad range of disciplines involved in cancer research is represented with the international recognition of these members. This will help our strategic decisions not only in research but also in quality of care, innovation and public health orientations. The deontology committee has been changed to an ethical and deontology committee since we are facing important decisions about screening strategies, active prevention, and access to new therapies through individual genomics and relationships with pharmaceutical industry through research. Our relations with professionals working in the cancer field, patients and public representatives have been clarified through a unique institutional committee, COMUP, with the aim to bring experience and outlook of the healthcare users and providers to constantly improve the quality, the relevance and the value of the strategies developed by INCa and to sustain its legitimacy and its ownership by everybody. These priorities and changes are the INCa 2014 action plan blueprint. Prof. Agnès Buzyn Chairwoman of the National Cancer Institute INCArapportGB2013.indd 129 28/10/13 14:13 130 INCArapportGB2013.indd 130 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 131 Appendices INCArapportGB2013.indd 131 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 132 1. TUMOUR BANKS Monitoring of activity Recommendations INCa’s Strategic initiatives National and international collaborations 2005-2007 2006: first activity report on the tumour banks. 2007: audit of policy for organisation. • 2005: initial recommendation from INCa (ethics charter, indications for cryopreservation as part of care). • 2007: national recommendations (system for management and quality control of a biological resource collection). 2008-2011 Annual activity reports • INCa recommendations for local 2010: declaration form organisation: governance and available online. operating costs incurred Production of activity report. in facilitating partnerships. • INCa recommendations for organisation at local and network scale: governance and scientific priorities for national collections. • 2008: call for proposals for “Genomic • European BBMRI project: active particiand Scientific added value of Biological pation by INCa. • BIOBANQUES (National infrastrucResources.” (8 projects selected, €5.3 M) ture): INCa is a member of both the management committee • 2011: first call for proposals on specific multi-centre multidisciplinary and the scientific advisory board. databases: tumours and biological collections. (5 projects selected, €2.8 M). 2012-2013 • 2012: implementation of • 2012: written notification of health the online activity report. facilities of the new terms of support Comprehensive monitoring for the scientific contributions of of health- and science-rela- tumour banks, to be based on ted activities by pathology. an index calculated from activity data. Better evaluation of the implementation of INCa’s recommendations from 2011. INCArapportGB2013.indd 132 • 2012: 2nd call for proposals on BCBs • 2013: launch of a 3rd call for proposals (4 projects selected, €2.6 M). on clinical-biological databases, in coo• 2013: development of a national dataperation with Aviesan (BIOBANQUES). base (tumour collections and related expertise) as a resource for enhanced use and strategic orientation. • 2013: development of a new index of scientific contribution, which favours tumour banks that implement INCa’s recommendations from 2011. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 133 2. IBISA PLATFORMS Type of Platform Name of Centre City Proteomics MaP, (Marseille Protéomique) Pole Protéome de Montpellier-LR (Montpellier Proteome Hub) Plate-forme protéomique Paris 5 (Paris 5 Proteomics Platform) Pasteur Proteomics Biogenouest Proteomics Core Facility Plateforme de Protéomique Lille IFR 147 (Lille IFR 147 Proteomics Platform) MARSEILLE MONTPELLIER PARIS PARIS RENNES VILLENEUVE D’ASCQ Novel Therapies, Vectorisation, Stem Cells Plate-forme anticorps monoclonaux-PADAM (PADAM Monoclonal Antibody Platform) ANGERS In vivo Imaging CYCERON Imagerie Sciences du Vivant - In vivo (Life-Sciences Imaging – In vivo) PRIME Imagerie Petit Animal Paris Descartes (Paris Descartes Small Animal Imaging) Plateforme d’imagerie in vivo (In vivo Imaging Platform) CAEN GRENOBLE ORSAY PARIS STRASBOURG Cellular Imaging Imagerie Sciences du Vivant-in vitro (Life-Sciences Imaging – In vitro) Type of Platform Montpellier RIO Imaging Cochin Imagerie (Cochin Imaging Platform) ImagoSeine PICT-IBiSA Institut Curie Cell and Tissue Imaging Toulouse RIO Imaging MICA: Microscopie Imagerie Côte d’Azur (French Riviera Imaging Microscopy) LA TRONCHE MONTPELLIER PARIS PARIS PARIS REIMS TOULOUSE NICE Genomics, Transcriptomics IGBMC Microarray and Sequencing Platform Transcriptomic Genomic Marseille-Luminy MGX - Montpellier GenomiX Plateforme Puce à ADN BioGenOuest (BioGenOuest DNA Microarray Platform) ILLKIRCH MARSEILLE MONTPELLIER NANTES Screening and Chemical Libraries Plateforme ARN interférence (PARi) (RNA Interference Platform) Plate-forme G5C (G5C Platform) PCBIS CDithem GIF SUR YVETTE GRENOBLE ILLKIRCH PARIS Structural Biology, Biophysics Structural Biology and Genomics Platform – Strasbourg PICT ILLKIRCH TOULOUSE Animal Facilities, Functional Exploration AniRA Fonctions du système immunitaire (Immune System Function) CARDIEX (THERASSAY) INTRAGENE-TAAM LYON MARSEILLE NANTES ORLEANS Others TILLING Immunomonitoring en Cancérologie (Oncology Immunomonitoring) The C. elegans functional genomics platform Pharmacology-Screening-Interactome High Throughput MAb Development EVRY MARSEILLE MARSEILLE MONTPELLIER MONTPELLIER INCArapportGB2013.indd 133 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 134 3. CLINICAL TRIALS REGISTRY Milestones in managing the INCa research clinical trials registry. National collaborations International collaborations Figures 2007-2008 Initiation of dialogue with ANSM (French Medicine Agency, formerly AFSSAPS) Collaboration with the US NCI: direct relaying of data from French clinical trials for entry into the NCI PDQ registry. • 100 trials advertised from 50 academic sponsors. • 2008: advertisement of clinical trials conducted by industry. Due to modifications made by NCI to the trials registration process, end of direct INCa submissions to the NCI PDQ registry. Over 1,000 clinical trials advertised in the registry. 2009-2010 • 2009: Agreement concluded between INCa and ANSM for relaying of information on clinical trials of drugs authorised by ANSM. • 2010: operational collaboration with ANSM • Several meetings with ASIP santé (French Shared Health Information Systems Agency) to develop access to the registry for physicians during multidisciplinary patient consultations 2011-2012 • A total of 325 trials were relayed by ANSM (From September 2010); 174 trials were registered in the INCa registry. • Discussion with ANSM with regard to relaying information on nondrug trials. • Collaboration with the 3 main national public health insurers: posting the link to the INCa registry on their websites. Most visited INCa’s web page: over 200,000 visits in May 2011. 2013 • Initiation of reflection with the Santor and Springer companies for the development of a mobile application, “Clinical Trials Registry,” available to practising oncologists. • Initiation of a collaboration with the National Cancer League to make the patient committees aware of clinical research and how to use the clinical trials registry. INCArapportGB2013.indd 134 Over 1,500 clinical trials advertised in the registry. 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 135 Distribution of clinical trials registered according to several criteria on 15 May 2013. Total Open 1,546 506 Academic 948 393 Industrial 598 113 ANATOMIC CLASSIFICATION* Total Open INTERVENTION* Total Open Breast 235 68 Drug** 1,156 433 Prostate 89 36 Radiotherapy 166 57 Respiratory system 164 45 Imaging 91 36 Colon and rectum 127 43 Surgery 88 49 Upper aerodigestive tract (UADT) and ENT 77 28 Transplant 51 16 Liver and bile ducts 68 22 Pharmacology – Translational Research 138 62 Total Urinary system 61 16 Female genital organs 87 29 Digestive system (other than colon or rectum) 88 26 PHASE Total Open Skin – Melanomas 56 15 I 134 46 Blood – Haematology 332 105 I-II 106 36 Nervous system 79 25 II 553 156 Sarcomas 51 22 II-III 25 8 Male genital organs 7 - III 432 138 Endocrine system 22 6 IV 28 4 Metastases 64 19 None 268 118 Others 142 42 **Also includes vaccines. TYPE OF FUNDING*** Total Open ***Only for non-industry-sponsored trials. Public 288 171 Industrial 266 77 *The sum may be greater than the total, since some trials belong to several categories. INCArapportGB2013.indd 135 Mixed 70 24 Not specified 324 121 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 136 4. HEALTH INTERVENTION RESEARCH IN POPULATION (FRENCH ACRONYM: RISP) Main features of the 2013 programme. Year Funding institution Objectives Funding Results: Letters of intent submitted Letters of intent selected Full project received Projects selected Selection rate INCArapportGB2013.indd 136 2013 INCa • To mobilise the research community involved in exploring these research methods in order to develop multidisciplinary research combining biology (genetics, immunology, carcinogenesis, etc.), environment, epidemiology, public health and economic, social, cultural and psychological dimensions. • To implement interventions to assess public health actions in the field. • To analyse, through research, the impact of these policies or the obstacles encountered. • To promote health intervention research that tests the effects of changes to the environment, individual behaviours (e.g. diet, drugs, vaccinations and sporting activities) and collective behaviours (e.g. work organisation). • To extend measures with proven impact to the population. €708,000 10 4 3 3 33% 28/10/13 14:13 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 137 5. CSO • Complementary and Alternative Prevention Approaches • Resources and Infrastructure Related to Prevention The Common Scientific Outline, or CSO, is a classification system organized around seven broad areas of scientific interest in cancer research: • Biology • Etiology (causes of cancer) • Prevention • Early Detection, Diagnosis, and Prognosis • Treatment • Cancer Control, Survivorship, and Outcomes Research • Scientific Model Systems CSO 4 Early Detection, Diagnosis, and Prognosis • Technology Development and/or Marker Discovery • Technology and/or Marker Evaluation with Respect to Fundamental Parameters of Method • Technology and/or Marker Testing in a Clinical Setting • Resources and Infrastructure Related to Detection, Diagnosis, or Prognosis The development of the CSO is laying a framework to improve coordination among research organizations, making it possible to compare and contrast the research portfolios of public, non-profit, and governmental research agencies. The types of research projects funded by INCa, Ministry of Health and Inserm that are presented in this report are based on this CSO classification. The different categories CSO include: CSO 5 Treatment • Localized Therapies - Discovery and Development • Localized Therapies - Clinical Applications • Systemic Therapies - Discovery and Development • Systemic Therapies - Clinical Applications • Combinations of Localized and Systemic Therapies • Complementary and Alternative Treatment Approaches • Resources and Infrastructure Related to Treatment CSO 1 Biology • Normal Functioning • Cancer Initiation: Alterations in Chromosomes • Cancer Initiation: Oncogenes and Tumour Suppressor Genes • Cancer Progression and Metastasis • Resources and Infrastructure CSO 6 Cancer Control, Survivorship, and Outcomes Research • Patient Care and Survivorship Issues • Surveillance • Behavior • Cost Analyses and Health Care Delivery • Education and Communication • End-of-Life Care • Ethics and Confidentiality in Cancer Research • Complementary and Alternative Approaches for Supportive Care of Patients and Survivors • Resources and Infrastructure Related to Cancer Control, Survivorship, and Outcomes Researc CSO 2 Etiology • Exogenous Factors in the Origin and Cause of Cancer • Endogenous Factors in the Origin and Cause of Cancer • Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors • Resources and Infrastructure Related to Etiology CSO 3 Prevention • Interventions to Prevent Cancer: Personal Behaviors that Affect Cancer Risk • Nutritional Science in Cancer Prevention • Chemoprevention • Vaccines INCArapportGB2013.indd 137 CSO 7 Scientific Model Systems • Development and Characterization of Model Systems • Application of Model Systems • Resources and Infrastructure Related to Scientific Model Systems 28/10/13 14:13 138 INCArapportGB2013.indd 138 FRENCH NATIONAL CANCER INSTITUTE 2012-2013 SCIENTIFIC REPORT 28/10/13 14:13 Published by the French National Cancer Institute All rights reserved – Siren 185 512 777 ISSN 1964-5961 OCTOBER 2013 INCArapportGB2013.indd 139 28/10/13 14:13 For more information RAPCSANG13 www.e-cancer.fr Institut National du Cancer 52, avenue André Morizet 92100 Boulogne-Billancourt France Tel. +33 (1) 41 10 50 00 Fax +33 (1) 41 10 50 20 [email protected] www.e-cancer.fr INCArapportGB2013.indd 140 28/10/13 14:13