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Background: Risk-adjusted cancer screening and prevention is a promising and continuously emerging option for improving cancer prevention. It is driven by increasing knowledge of risk factors and the ability to determine them for individual risk prediction. However, there is a knowledge gap between evidence of increased risk and evidence of the effectiveness and efficiency of clinical preventive interventions based on increased risk. This gap is, in particular, aggravated by the extensive availability of genetic risk factor diagnostics, since the question of appropriate preventive measures immediately arises when an increased risk is identified. However, collecting proof of effective preventive measures, ideally by prospective randomized preventive studies, typically requires very long periods of time, while the knowledge about an increased risk immediately creates a high demand for action. Summary: Therefore, we propose a risk-adjusted prevention concept that is based on the best current evidence making needed and appropriate preventive measures available, and which is constantly evaluated through outcome evaluation, and continuously improved based on these results. We further discuss the structural and procedural requirements as well as legal and socioeconomical aspects relevant for the implementation of this concept.

\(\bf Background:\) Risk-adjusted cancer screening and prevention is a promising and continuously emerging option for improving cancer prevention. It is driven by increasing knowledge of risk factors and the ability to determine them for individual risk prediction. However, there is a knowledge gap between evidence of increased risk and evidence of the effectiveness and efficiency of clinical preventive interventions based on increased risk. This gap is, in particular, aggravated by the extensive availability of genetic risk factor diagnostics, since the question of appropriate preventive measures immediately arises when an increased risk is identified. However, collecting proof of effective preventive measures, ideally by prospective randomized preventive studies, typically requires very long periods of time, while the knowledge about an increased risk immediately creates a high demand for action. \(\bf Summary:\) Therefore, we propose a risk-adjusted prevention concept that is based on the best current evidence making needed and appropriate preventive measures available, and which is constantly evaluated through outcome evaluation, and continuously improved based on these results. We further discuss the structural and procedural requirements as well as legal and socioeconomical aspects relevant for the implementation of this concept.

For most people, being in good health represents the most important factor to wellbeing. While environmental elements such as physical, chemical, biological, social and psychosocial factors in the environment are key for a person’s wellbeing, also the genome of the individual and its interaction with the environment play an important role. In this paper, we will focus on attitudes towards genomics in the field of personalised medicine in oncology. We will document opinions encountered by patients and citizens on sharing health-related information for various purposes (e.g., research, cost-effectiveness, patient support) aiming to maximise the benefits for cancer patients. We will discuss ethical and legal considerations to be taken into account at the Belgian level to provide a secure, transparent framework for the use of genomics in the healthcare system.

The Table 1 (EU declaration signatory and membership status) of the original article published online contained several errors: the IARC was incorrectly listed in the table, which only includes countries, and footnote; Croatia, Lithuania, Poland and Portugal were not listed as full EMBL members; Estonia is now listed as a Prospect Member of EMBL; Hungary, Ireland and Israel were incorrectly listed as BBMRI-ERIC members; Iceland was omitted from the table. Hyphens stand for ‘not applicable’; the table and footnote have been corrected accordingly. These errors have now been corrected online and in print.

status: published

14 p. ill. Kankerbehandelingen op maat, met geneesmiddelen die zeer doelgericht de kanker aanvallen, bieden vandaag reeds voor een aantal kankers een grote meerwaarde ten opzichte van de klassieke, ‘blinde’ chemotherapie. Voorwaarde is dat men de ‘doelwitten’ in de kankercel op een betrouwbare en efficiënte manier kan opsporen. Dit is de rol van de diagnostische testen, ‘companion diagnostics’ genoemd. Het Kankercentrum van het Wetenschappelijk Instituut Volksgezondheid (WIV) en het Federaal Kenniscentrum voor de Gezondheidszorg (KCE) onderzochten de nieuwe Next Generation Sequencing gene panel testen. Ze kunnen meerdere genen gelijktijdig onderzoeken, en dat zorgt voor een stroomversnelling bij de aanpak van kanker. Het vergoeden van de testen binnen het huidige RIZIV-budget lijkt mogelijk als ze gecentraliseerd worden uitgevoerd in gespecialiseerde laboratoria die een voldoende groot aantal testen uitvoeren. Daarnaast moet het garanderen en controleren van hun kwaliteit de grootste prioriteit krijgen. VOORWOORD 1 -- SAMENVATTING 2 -- 1. INLEIDING 3 -- 1.1. ACHTERGROND 3 -- 1.2. ONDERZOEKSVRAGEN 3 -- 1.3. ALGEMENE AANPAK 4 -- 2. NEXT GENERATION SEQUENCING PANELTESTS 4 -- 2.1. STAPPEN BIJ HET UITVOEREN VAN EEN NGS-PANELTEST 4 -- 2.2. BESCHIKBAARHEID VAN NGS-PANELS 5 -- 2.3. VOORDELEN VAN DE NGS-PANELTESTS VOOR HET LABORATORIUM 7 -- 2.4. AANDACHTSPUNTEN 7 -- 2.5. REGELGEVING, KWALITEITSBEWAKING EN EDUCATIE 8 -- 3. ECONOMISCHE ASPECTEN 9 -- 3.1. IMPACT VAN DE TESTACCURAATHEID OP DE KOSTENEFFECTIVITEIT 9 -- 3.2. FACTURATIECODES EN NGS-BEHOEFTEN VOOR BELGIË 11 -- 4. INVOERING VAN NGS-PANELTESTS 12 -- AANBEVELINGEN 13

128 p. ill. SCIENTIFIC REPORT .9 -- 1 INTRODUCTION 9 -- 1.1 BACKGROUND 9 -- 1.2 RESEARCH QUESTIONS .13 -- 1.3 GENERAL APPROACH 14 -- 1.4 EVALUATION OF DIAGNOSTIC TESTS 14 -- 2 TOWARDS NEXT GENERATION SEQUENCING PANEL TESTS IN ONCOLOGY .16 -- 2.1 MOLECULAR DIAGNOSTICS USED IN ONCOLOGY 16 -- 2.2 NEXT GENERATION SEQUENCING, THE TECHNOLOGY 18 -- 2.3 INTRODUCTION TO NEXT GENERATION SEQUENCING PANEL TESTS .20 -- 2.3.1 The sequencing revolution 20 -- 2.3.2 Importance of targeted sequencing for exploratory clinical research in oncology 22 -- 2.3.3 New technologies, more options, new challenges 26 -- 2.4 COMPOSITION OF THE NGS PANELS .26 -- 2.4.1 NGS panels for solid tumours 27 -- 2.4.2 NGS panels for hemato-oncology 28 -- 2.4.3 Other considerations for NGS panel selection 28 -- 3 REGULATORY ASPECTS, QUALITY ASSURANCE AND EDUCATIONAL NEEDS 29 -- 3.1 NEED FOR INFORMED CONSENT AND PRE-TEST COUNSELLING 29 -- 3.2 REGULATORY CONTEXT OF MOLECULAR TESTS FOR SOMATIC MUTATIONS 29 -- 3.2.1 Regulations for diagnostic laboratories in Belgium .29 -- 3.2.2 Regulations for in-house methods and in-vitro diagnostics 30 -- 3.3 EXTERNAL QUALITY ASSURANCE OF MOLECULAR TESTS FOR SOMATIC MUTATIONS 32 -- 3.3.1 EQA schemes for Haematological and Solid Tumours.32 -- 3.3.2 Performance of the participating (Belgian) laboratories 33 -- 3.4 QUALITY ASSURANCE OF NGS PANEL TESTS FOR SOMATIC MUTATIONS 37 -- 3.4.1 General considerations and the importance of quality 37 -- 3.4.2 Quality assurance for the wet and dry lab part of NGS 39 -- 3.5 REPORTING OF NGS DATA 44 -- 3.6 NEEDS FOR EDUCATION AND A MULTIDISCIPLINARY EXPERT COMMITTEES.50 -- 4 IMPACT OF TEST ACCURACY ON INCREMENTAL COST-EFFECTIVENESS RATIOS 52 -- 4.1 INTRODUCTION AND SCOPE 52 -- 4.2 METHODOLOGY 52 -- 4.2.1 Search strategy .52 -- 4.2.2 Selection procedure 53 -- 4.2.3 Selection criteria53 -- 4.3 RESULTS 53 -- 4.4 ILLUSTRATIVE EXAMPLES FOR BELGIUM 54 -- 4.4.1 Data sources 54 -- 4.4.2 Results and discussion .55 -- 4.4.3 The relevance of test specificity when applied to NGS panels .59 -- 5 FINANCING OF COMPANION DIAGNOSTICS AND TARGETED THERAPY .61 -- 5.1 THE DISCONNECTION BETWEEN PHARMACEUTICALS AND COMPANION DIAGNOSTIC 61 -- 5.1.1 The need for a companion diagnostic conflicts with traditional drug development .61 -- 5.1.2 Disconnection between reimbursement of companion diagnostics and drugs in Belgium .62 -- 5.2 BILLING CODES FOR MOLECULAR DIAGNOSTICS IN ONCOLOGY IN BELGIUM 63 -- 5.2.1 Evolution of billing codes, overall expenditures and testing volumes 64 -- 5.2.2 Current issues with billing codes 65 -- 5.3 MOLECULAR TESTS BILLED BY TYPE OF TUMOUR DIAGNOSED IN BELGIUM (2010-2011) .68 -- 5.3.1 Aims and methods of analysis by tumour type .68 -- 5.3.2 Selection of tumour types.68 -- 5.3.3 IMA/AIM data .68 -- 5.3.4 Results 69 -- 5.4 CURRENT COST OF NGS PANEL TESTS 73 -- 6 OPTIONS FOR INTRODUCING NGS PANEL TESTS IN THE BELGIAN HEALTHCARE 76 -- APPENDICES 79 -- APPENDIX 1. GLOSSARY 79 -- APPENDIX 2. COMPOSITION OF NGS PANELS 91 -- APPENDIX 3. SEARCH STRATEGIES - IMPACT OF TEST ACCURACY ON ICERS 110 -- APPENDIX 3.1. PUBMED 110 -- APPENDIX 3.2. EMBASE 110 -- APPENDIX 3.3. ECONLIT 111 -- APPENDIX 3.4. CRD NHS DATABASES 112 -- APPENDIX 4. MOLECULAR TESTS BY PATHOLOGY, WITH BILLING CODES 113 -- APPENDIX 5. SELECTED NOMENCLATURE CODES 119 -- REFERENCES 123

14 p. ill. Les nouveaux traitements ‘sur mesure’ du cancer, qui ciblent des étapes très précises du processus tumoral, présentent certains avantages par rapport à la chimiothérapie classique et ‘aveugle’. Mais il y a une condition préalable : identifier les patients chez qui ils seront efficaces. C’est le rôle des tests appelés ‘diagnostics compagnons’. Le Centre du Cancer de l’Institut scientifique de Santé publique (ISP) et le Centre Fédéral d’Expertise des Soins de santé (KCE) ont examiné les panels de tests dits de Next Generation Sequencing, qui analysent plusieurs gènes à la fois, permettant une accélération dans la prise en charge des cancers. Si ces tests sont effectués dans un laboratoire central spécialisé qui en réalise un nombre suffisant, le remboursement de ces tests semble possible dans le budget actuel de l’INAMI. Mais la garantie et le contrôle de leur qualité reste la grande priorité. PRÉFACE 1 -- RÉSUMÉ 2 -- 1. INTRODUCTION 3 -- 1.1. CONTEXTE 3 -- 1.2. QUESTIONS DE RECHERCHE 3 -- 1.3. APPROCHE GENERALE 3 -- 2. PANELS DE GENES PAR NGS 4 -- 2.1. PHASES D’EXÉCUTION DES TESTS DE PANELS DE GÈNES PAR NGS 4 -- 2.2. DISPONIBILITE DES PANELS NGS 5 -- 2.3. AVANTAGES DES TESTS DE PANEL DE GENES PAR NGS POUR LE LABORATOIRE 7 -- 2.4. POINTS D‘ATTENTION 7 -- 2.5. REGLEMENTATIONS, ASSURANCE QUALITE ET FORMATION 8 -- 3. ASPECTS ÉCONOMIQUES 8 -- 3.1. IMPACT DE LA PRECISION DU TEST SUR LE RAPPORT COUT-EFFICACITE 9 -- 3.2. CODES DE FACTURATION ET BESOINS SNG POUR LA BELGIQUE 11 -- 4. INTRODUIRE DES TESTS DE PANEL DE GENES PAR NGS 12 -- RECOMMANDATIONS 13

Background Cancer care is undergoing an important paradigm shift from a disease-focused management to a patient-centred approach, in which increasingly more attention is paid to psychosocial aspects, quality of life, patients' rights and empowerment and survivorship. In this context, multidisciplinary teams emerge as a practical necessity for optimal coordination among health professionals and clear communication with patients. The European Partnership for Action Against Cancer (EPAAC), an initiative launched by the European Commission in 2009, addressed the multidisciplinary care from a policy perspective in order to define the core elements that all tumour-based multidisciplinary teams (MDTs) should include. To that effect, a working group conference was held in January 2013 within the EPAAC Work Package 7 (on Healthcare) framework. Methods The consensus group consisted of high-level representatives from the following European scientific societies, patient associations and stakeholders: European CanCer Organisation (ECCO), European SocieTy for Radiology & Oncology (ESTRO), European Society for Medical Oncology (ESMO), European Society of Surgical Oncology (ESSO), International Society of Geriatric Oncology (SIOG), European Association for Palliative Care (EAPC), European Oncology Nursing Society (EONS), International Psycho-Oncology Society (IPOS),European Cancer Patient Coalition (ECPC), EuropaColon, Europa Donna - The European Breast Cancer Coalition, Association of European Cancer Leagues (ECL), Organisation of European Cancer Institutes (OECI), EUSOMA - European Society of Breast Cancer Specialists, European Hospital and Healthcare Federation (HOPE) and EPAAC Work Packages 5 (Health promotion and prevention), 7, 8 (Research), 9 (Information systems) and 10 (Cancer plans). A background document with a list of 26 core issues drawn from a systematic review of the literature was used to guide the discussion. Five areas related to MDTs were covered: care objectives, organisation, clinical assessment, patients' rights and empowerment and policy support. Preliminary drafts of the document were widely circulated for consultation and amendments by the working group before final approval. Results The working group unanimously formulated a Policy Statement on Multidisciplinary Cancer Care to define the core elements that should be implemented by all tumour-based MDTs. This document identifies MDTs as the core component in cancer care organisation and sets down the key elements to guide changes across all European health systems. Conclusion MDTs are an essential instrument of effective cancer care policy, and their continued development crucial to providing patients the care they need and deserve. While implementation must remain in local hands, European health systems can still benefit from having a basis for an effective multidisciplinary model of cooperation. This policy statement is intended to serve as a reference for policymakers and healthcare providers who wish to improve the services currently provided to the cancer patients whose lives and well-being depend on their action.

In the European Union nations, and other countries including Japan, Australia and Malaysia, it is a legal requirement that food products containing genetically modified organism (GMO) materials are labelled as such in order that customers may make informed purchasing decisions. For manufacturers and consumers to be confident about these assertions, systems must be in place along the entire food chain which support the co-existence of GM and non GM materials whilst maintaining a strict segregation between the two. This book is an output of a European Union-funded project entitled "Co-Extra: GM and non-GM food and feed supply chains: their Co-Existence and Traceability". The objective of this four year project is to provide practical tools and methods for implementing co-existence that will: enable the co-existence of genetically modified (GM) and non-GM crops enable the segregation and tracing of genetically modified organism (GMO) materials and derived products along the food and feed chains anticipate the future expansion of the use of GMOs The project is designed to foster a robustly science-based debate amongst all of the stakeholders involved in the food and feed chains, and the tools will be assessed not only from a technical point of view but with regard to the economic and legal aspects. It also surveys the GMO-related legal regimes and practices that exist in and beyond the EU. This book examines the practical tools and methods available to implement the co-existence and traceability of GM and non-GM food materials along the entire food and feed chains, as demanded by consumers and by legislation in force in the EU and elsewhere. GM and Non-GM Supply Foods is a source of valuable information for food manufacturers, food research institutions and regulatory bodies internationally.

Following the judgment of 06 September 2011 on GM honey by the European Court of Justice (legal case C-442-09), the European Union Reference Laboratory for Genetically Modified Food and Feed (EU-RL GMFF) established by Regulation (EC) No 1829/2003, performed an in-house study to test the extraction and PCR analysis of genomic DNA from genetically modified pollen in honey. The present report documents on an extraction method for isolation and analysis of pollen DNA present in honey, including the isolation and analysis of isolated genomic pollen DNA using real-time PCR on commercial honey samples and honey samples spiked with various levels of GM MON 810 pollen., JRC.I.3-Molecular Biology and Genomics

The recently adopted Commission Regulation (EU) No 619/2011 lays down the methods for sampling and analysis for the official control of food as regards to presence of genetically modified material for which an authorisation procedure is pending or the authorisation of which is has expired (the so-called LLP, Low Level presence Regulation). The requirements of this Regulation are technically demanding because they set a non-compliance limit of 0.1% GMO (mass fraction). The European Union Reference Laboratory for Genetically Modified Food and Feed (EU-RL GMFF) plays a crucial role in the implementation of this regulation because only methods validated by the EU-RL that show a RSDr value of maximum 25% at the level of 0.1% related to mass fraction of GM material can be used on falling under that regulation. The aim of this document is to explain how this Regulation will affect the process of validation and how laboratories need to operate under that Regulation., JRC.I.3-Molecular Biology and Genomics

Unauthorised GMOs (UGM) and derived materials are not uncommon in products found on the European market. At present there is zero tolerance for UGM in the EU. In most documented cases, the UGM concentration relative to the product in which the UGM material is found, was low. Low level presence will always represent a challenge to analytically based detection, in particular if the UGM is obscured by other GM material. Analytical ad hoc implementation of the zero tolerance for particular UGMs in feed is described in Regulation (EU) No 619/2011. In Europe, GM detection is predominantly achieved with polymerase chain reaction (PCR) derived methods targeting the transgenic construct and insertion site DNA sequences. The increase in number and divergence of GMOs developed and commercialised has gradually forced the GM detection laboratories to rationalise their analytical work, and most laboratories now apply initial PCR based screenings followed by (when appropriate) more specific PCR based identification and quantification. The detection of any GM is dependent on availability of suitable detection method(s) and control materials to verify the performance of the method(s). Other information, e.g. describing the novel trait, introduced genetic elements, etc. may also facilitate detection, verification and identification of the GM. For UGM, this is a major challenge, and the GMOs are therefore classified into four knowledge groups in the present document. This classification may facilitate stakeholder communication and decision making in analytical laboratories. A decision tree is presented, summarising the recommended principles of GM and UGM detection. Notably, the state-of-the-art of GMO analysis is not static, and it is expected that the guidelines and recommendations presented in this document will have to be modified on a regular basis. Finally, the document highlights a number of R&D priorities and points out the need for reinforced information sharing at the global level.

Unauthorised GMOs (UGM) and derived materials are not uncommon in products found on the European market. At present there is zero tolerance for UGM in the EU. In most documented cases, the UGM concentration relative to the product in which the UGM material is found, was low. Low level presence will always represent a challenge to analytically based detection, in particular if the UGM is obscured by other GM material. Analytical ad hoc implementation of the zero tolerance for particular UGMs in feed is described in Regulation (EU) No 619/2011. In Europe, GM detection is predominantly achieved with polymerase chain reaction (PCR) derived methods targeting the transgenic construct and insertion site DNA sequences. The increase in number and divergence of GMOs developed and commercialised has gradually forced the GM detection laboratories to rationalise their analytical work, and most laboratories now apply initial PCR based screenings followed by (when appropriate) more specific PCR based identification and quantification. The detection of any GM is dependent on availability of suitable detection method(s) and control materials to verify the performance of the method(s). Other information, e.g. describing the novel trait, introduced genetic elements, etc. may also facilitate detection, verification and identification of the GM. For UGM, this is a major challenge, and the GMOs are therefore classified into four knowledge groups in the present document. This classification may facilitate stakeholder communication and decision making in analytical laboratories. A decision tree is presented, summarising the recommended principles of GM and UGM detection. Notably, the state-of-the-art of GMO analysis is not static, and it is expected that the guidelines and recommendations presented in this document will have to be modified on a regular basis. Finally, the document highlights a number of R&D priorities and points out the need for reinforced information sharing at the global level., JRC.I.3-Molecular Biology and Genomics

Unauthorised GMOs (UGM) and derived materials are not uncommon in products found on the European market. At present there is zero tolerance for UGM in the EU. In most documented cases, the UGM concentration relative to the product in which the UGM material is found, was low. Low level presence will always represent a challenge to analytically based detection, in particular if the UGM is obscured by other GM material. Analytical ad hoc implementation of the zero tolerance for particular UGMs in feed is described in Regulation (EU) No 619/2011. In Europe, GM detection is predominantly achieved with polymerase chain reaction (PCR) derived methods targeting the transgenic construct and insertion site DNA sequences. The increase in number and divergence of GMOs developed and commercialised has gradually forced the GM detection laboratories to rationalise their analytical work, and most laboratories now apply initial PCR based screenings followed by (when appropriate) more specific PCR based identification and quantification. The detection of any GM is dependent on availability of suitable detection method(s) and control materials to verify the performance of the method(s). Other information, e.g. describing the novel trait, introduced genetic elements, etc. may also facilitate detection, verification and identification of the GM. For UGM, this is a major challenge, and the GMOs are therefore classified into four knowledge groups in the present document. This classification may facilitate stakeholder communication and decision making in analytical laboratories. A decision tree is presented, summarising the recommended principles of GM and UGM detection. Notably, the state-of-the-art of GMO analysis is not static, and it is expected that the guidelines and recommendations presented in this document will have to be modified on a regular basis. Finally, the document highlights a number of R&D priorities and points out the need for reinforced information sharing at the global level.

BackgroundPatients with cancer, especially hematological cancer, are at increased risk for breakthrough COVID-19 infection. So far, a predictive biomarker that can assess compromised vaccine-induced anti-SARS-CoV-2 immunity in cancer patients has not been proposed. MethodsWe employed machine learning approaches to identify a biomarker signature based on blood cytokines, chemokines, and immune- and non-immune-related growth factors linked to vaccine immunogenicity in 199 cancer patients receiving the BNT162b2 vaccine. ResultsC-reactive protein (general marker of inflammation), interleukin (IL)-15 (a pro-inflammatory cytokine), IL-18 (interferon-gamma inducing factor), and placental growth factor (an angiogenic cytokine) correctly classified patients with a diminished vaccine response assessed at day 49 with >80% accuracy. Amongst these, CRP showed the highest predictive value for poor response to vaccine administration. Importantly, this unique signature of vaccine response was present at different studied timepoints both before and after vaccination and was not majorly affected by different anti-cancer treatments. ConclusionWe propose a blood-based signature of cytokines and growth factors that can be employed in identifying cancer patients at persistent high risk of COVID-19 despite vaccination with BNT162b2. Our data also suggest that such a signature may reflect the inherent immunological constitution of some cancer patients who are refractive to immunotherapy. This work was supported by the Belgian Government through Sciensano [grant numbers COVID-19_SC004, COVID19_SC059, COVID-19_SC061], ORCHESTRA project, which has received funding from the European Union’s Horizon 2020 research and innovation program [grant agreement number 101016167] and University of Antwerp-GOA grant [s30729].