COMMENTARY Open Access

Roadbook for the implementation of next-generation sequencing in clinical practicein oncology and hemato-oncology inBelgiumEls Van Valckenborgh1* , Aline Hébrant1, Aline Antoniou2, Wannes Van Hoof1, Johan Van Bussel3,Patrick Pauwels4, Roberto Salgado5,6,7, Waltruda Van Doren8, Anouk Waeytens8 and Marc Van den Bulcke1

Abstract

In the field of oncology research, next-generation sequencing has contributed significantly to the discovery of DNAmutations associated with diagnosis and prognosis. It also aids in the development of targeted therapies to specificmutations and the rise of personalized medicine. As part of molecular diagnostics in cancer patients, analysis by next-generation sequencing is becoming part of routine clinical practice. The introduction of this complex technology in ahealthcare system comes with multiple challenges and requires a clear action plan. Such an action plan, as outlinedin this paper, was developed in Belgium and includes steps in ensuring the quality and indications of NGS testing,installing data registration and tackling ethical issues. A final step is to perform a pilot study to control the access,quality, harmonization and expertise in DNA testing. This action plan can serve as a guide for similar initiatives byother countries to facilitate NGS implementation in clinical practice.

Keywords: Next-generation sequencing, Health care, Cancer, Personalized medicine

BackgroundPersonalized medicine, also known as individualized orprecision medicine refers to “a medical model using thecharacteristics of individuals’ phenotypes and genotypes(e.g. molecular profiling, medical imaging, and lifestyledata) for tailoring the right therapeutic strategy for theright person at the right time” [1]. It is complementaryto the ‘one size fits all’ medical approach wherein asingle treatment strategy would fit all patients from acertain tumor type. One of the hallmarks of personalizedmedicine is the development of targeted agents. Thesetargeted agents are designed to specifically interfere withkey molecular events that are involved in the prolifera-tion, survival or spread of cancer cells and aim harmingas little as possible normal cell function. Potential targetsare molecules overexpressed or mutated in tumor cellsor fusion proteins that are newly formed by chromo-somal rearrangements. Monoclonal antibodies and small

molecules are the main types of drugs applied in tar-geted therapies. Examples are the BCR-ABL1 fusionleading to a constitutively active tyrosine kinase activityin chronic myeloid leukemia targetable by imatinib orthe use of vemurafenib in melanoma patients targetingthe BRAFV600E mutation [2, 3].The concept of targeted therapy is driven by molecular

diagnostics that enables the identification of patient pop-ulations most likely to benefit from precision medicine.Molecular diagnostics in oncology comprises a set of bynow standard techniques to analyze cellular biomarkersincluding immunohistochemistry, immune-phenotyping,cytogenetics, polymerase chain reaction, fluorescent insitu hybridization, comparative genomic hybridizationassays, microarrays and Sanger sequencing. Recenttechnical advances and lower cost have paved the intro-duction of next-generation sequencing (NGS) analysis inclinical routine practice. This high-throughput approachwherein millions of sequencing reads are analyzed inparallel allows investigating a large number of genes andsamples simultaneously. Over the past years the cost of

* Correspondence: Els.VanValckenborgh@sciensano.be1Belgian Cancer Centre, Sciensano, Brussels, BelgiumFull list of author information is available at the end of the article

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Van Valckenborgh et al. Archives of Public Health (2018) 76:49 https://doi.org/10.1186/s13690-018-0295-z

NGS tests has dropped significantly making it moreaffordable for reimbursement by the healthcare systems.The cost drivers of this technology are however shiftingfrom the purely analytical phase towards the post-analyt-ical phase such as data-storage, analysis and interpret-ation. NGS enables more precise decision-making forcancer patients by providing detailed information fordiagnosis, prognosis and therapy with targeted drugs orconventional treatment schedules (chemotherapeutics,stem cell transplantation). In order to achieve this preci-sion-decision making, a strict quality assurance and dataregistration to allow downstream data-mining and out-come analysis of stratified medicine usage is required.NGS can be performed on tumor tissue (formalin-fixed,paraffin-embedded (FFPE) samples) as well as on liquidsamples (blood, bone marrow), therefore, allowing thetechnology to be implemented both in oncology andhemato-oncology [4, 5]. Introducing a complex newtechnology in a healthcare system aiming at offering fullaccess to all citizens represents a major challenge whichrequires ahead planning.

Main textA step-wise process has been applied in Belgiumwherein, at first, feasibility was assessed on the use ofNGS in routine clinical diagnostics in oncology andhemato-oncology [6] (Fig. 1). The conclusions of this as-sessment were discussed with and endorsed in 2015 bythe major stakeholders in Belgium, including representa-tives of public bodies active in healthcare, patient associ-ations and health insurance funds. In a second step, theconclusions of the feasibility study were translated into aroadbook that describes the major actions to be taken tointroduce NGS in clinical settings. This roadbook enti-tled “Introduction of Next-Generation Sequencing in

routine diagnostics in oncology and hemato-oncology inBelgium” was officially approved by the Ministry ofSocial Affairs and Health in 2016 (see Table 1). Theroadbook includes 1°) a description of the governancestructure of the intervention, 2°) the major technical andlogistic actions to be undertaken including an allocatedbudget, and 3°) a number of awareness raising initiativesfor health professionals and patient/citizens.

Action 1: Establish a commission: Commission ofPersonalized MedicineThe effective implementation of NGS and, in a broadercontext, also personalized medicine in healthcare,requires support by a multidisciplinary committee of ex-perts, ideally embedded in an international framework.Such committee was created end 2016 and designated asthe ‘Commission of Personalized Medicine’ or ‘Com-PerMed’. The mission of the ComPerMed is to provide,as much as possible, evidence-based advice to policy-makers on the relevance of introducing innovative solu-tions in personalized medicine, with a major focus on‘omics’ technologies. The ComPerMed works closelytogether with another novel advisory body, the so-calledPlatform CDx of the NIHDI. The Platform CDx gatherscompetences of two advisory bodies in the NIHDI: theCommission for Reimbursement of Medicines and theTechnical Medical Council (Fig. 2). While the latterprovides advice on the practices and the tests to be re-imbursed by the healthcare system, the former adviceson the approval of the medicines. In the last two years,the ComPerMed developed guidelines on the technicalrequirements of NGS testing and the clinical utility ofsomatic mutations in cancer patients, and developedclinical diagnostic guidelines. The ComPerMed will alsoin the future assess the conditions for implementing

Fig. 1 Introduction of Next-Generation-Sequencing in routine diagnostics in oncology and hemato-oncology in Belgium: a multistep process.HSE: Health Service Evaluation; HTA: Health Technology Assessment

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other novel ‘omics‘technologies in daily oncology prac-tice such as whole-genome sequencing (WGS), proteo-mics, metabolomics.The ComPerMed is composed of a management board

and a scientific board. The scope of activities performedby the ComPerMed are decided yearly by the manage-ment board which includes representatives of all con-cerned parties and decision bodies in this field: thesickness insurance agency (NIHDI), the Federal Ministryof Public Health, food chain safety and environment, theCollege of oncology, the College of genetics, the Com-mission of anatomic pathology, the Commission Clinical

Biology, the Cancer Registry, the Federal agency of med-icines and health products, the test accreditationorganization (Belac), the Belgian Health Care KnowledgeCentre (KCE) and Sciensano. They define the actionplan of the ComPerMed and validate the final outcomes.The scientific board on the other hand is a broad repre-sentation of the different professionals and experts inthe field of personalized medicine in Belgium, morespecifically, clinicians, pathologists, clinical biologists,molecular biologists, bioinformatics and IT specialists.The scientific board works on a project basis with adhoc working groups with experts in the topic of interest.The ComPerMed is mainly supporting action 2 and 3 ofthe Roadbook but can also be implicated in other actionswhen its members’ expertise is relevant. The CancerCentre of Sciensano is in charge of the secretariat of theComPerMed.

Action 2: Development of guidelines for NGS use inoncology and hemato-oncologyPerforming high quality diagnostic analysis within ahealthcare system using complex tools such as NGS,both at the technical level as on the level of data inter-pretation, requires an overall agreement between thehealth professionals on practices. Guidelines represent amost valuable asset in such respect. Indeed, the NGStechnology is complicated demanding both optimalassay conditions and settings in the “wet bench” partand “dry or bio-informatics” part of the procedure. Inthe case of NGS, the ComPerMed provided in 2016guidelines with concise recommendations on all steps inthe procedure in a generic, sequencing technology

Table 1 Overview of the actions for the stepwise introductionof NGS technology in oncology and hemato-oncology: theBelgian strategy

Actions of the Belgian roadbook for the implementation of next-generation sequencing in clinical practice in oncology andhemato-oncology

ACTION 1 Establish a commission: Commission of PersonalizedMedecine (ComPerMed)

ACTION 2 Development of guidelines for NGS use

ACTION 3 Development of criteria for NGS use

ACTION 4 &5

Develop and organize a benchmarking trial and EQAfor NGS use

ACTION 6 Implement NGS registration, storage and datamanagement

ACTION 7 Provide NGS education and training

ACTION 8 Informed consent, legal and ethical implications ofNGS use molecular diagnostics

ACTION 9 Pilot study ‘NGS use in routine diagnostics’

ACTION 10 Build on hospital networks for NGS use

Fig. 2 Schematic representation of the ComPerMed and its activities as advisory board towards the reimbursement agency specifically thePlatform CDx. This Platform is a mixed working group of the CRM/TMC, Commission for Reimbursement of Medicines/Technical Medical Council,the decision bodies for medicines and diagnostic tests, respectively

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independent way. The guidelines are complementary tothe ISO15189 norm for medical laboratories, supportexisting guidelines such as those of CAP, and are used asa reference by the national accreditation body Belac [7].The NGS guidelines will not only facilitate the imple-mentation of the required NGS-quality metrics for som-atic variant detection in clinical laboratories, but alsoharmonize test validation, verification, clinical interpret-ation and reporting of variants. The guidelines serve inestablishing in-house procedures and modalities forinternal quality control (IQC) and provide the basis forestablishing an external quality assessment system(EQA) to assure and maintain optimal test performance.The 2016 version of the NGS guidelines will be revisedregularly and the ComPerMed intends to develop infuture versions, some critical aspects in more detail in-cluding variant interpretation, bioinformatics handlingand statistical model for the validation process.

Action 3: Development of criteria for NGS use in oncologyand hemato-oncologyIn this action, the scientific board of the ComPerMed hasto determine for which indications NGS testing has an ap-plication in patient care. The process consists of defining1°) the genes and/or gene regions to be analyzed by NGS

for a given cancer based on literature and expert opinions,and 2°) the conditions for which this test should be per-formed for instance localized disease and/or metastaticdisease. The final objective is to maintain only gene alter-ations with clinical utility in diagnosis and/or therapeuticchoice and/or prognosis (patient outcome) in a specificcancer type. To accomplish this selection of genes, threedifferent levels were defined to be able to categorize thegenes according to standard vs. investigational therapeuticimplication (Fig. 3) [8]. Levels linked to clinical guidelines,standard of care, expert’s opinion and approved drugswere determined from 1 to 3 with level 1 the highest levelof therapeutic implication (standard of care andreimbursed drug). These levels are useful for classifyingvariants for NGS testing and molecular tests. Besides this,the agreement on algorithms displaying the work-up of aparticular cancer type is forming the basis to define thespecific conditions for NGS testing. The algorithms repre-sent a sequential of molecular tests to be performed for aparticular cancer, documented in addition with the clinicalutility (diagnosis, prognosis or therapy), test level and abrief description of the molecular test. The purpose is toregularly revise the gene alterations to be analyzed andtheir level as well as to update the algorithms. Thismethodology will facilitate the implementation and

Fig. 3 Definition of levels for diagnostic/prognostic or therapeutic biomarkers and molecular tests, according to the Belgian healthcare system

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standardization of NGS analysis in clinical practice as wellas allow the development of reimbursement criteria forthis test.

Actions 4&5: Develop and organize a benchmarking trialand EQA program for NGS use in oncology andhemato-oncologyApplication of NGS in clinical laboratories, as any otheranalysis, requires external quality assessment. In first in-stance, it was considered important to estimate the base-line performance of the clinical labs for their adequatemanner of using NGS in their routine diagnostics withina benchmarking trial. The performance of NGS testingneed to be evaluated on different aspects and sequen-tially with first, using samples from well-characterizedgenomic DNA from tumor cell lines to assess the qualityof NGS analysis on determining the presence or absenceof somatic variants and their allele frequencies. Sec-ondly, extending these assessments to the pre-analyticalconditions and to clinical interpretation, using FFPE orblood samples as start material and theoretical casestudies for interpretation assessments. Consultation withall concerned parties is recommended for the develop-ment of the evaluation procedures. This action is per-formed together with a department of Sciensano, thedepartment Quality of laboratories. In a final phase, it isessential to establish a national EQA program to moni-tor the quality of NGS testing in clinical practice and topropose corrective actions where needed.

Action 6: Implement NGS registration, storage and datamanagementNGS analysis goes along with the generation of largeamounts of data and the management of such informa-tion can represent an important added value for quality,outcome analysis and reimbursement reallocation as wellas for clinical and public health research. The purpose ofthis action is to develop the technical platform for thecentral collection and storage of NGS data generated bylicensed and accredited labs. In Belgium, this part of theNGS implementation is governed by the Healthdata.beservices at Sciensano. The Healthdata.be service has atechnical platform as part of the implementation of thee-Health 2013–2018 Action Plan of Belgium. Healthda-ta.be looks after the daily management and maintenanceof this new technological tool, the objective of which isto bring all the data that is now stored in multiple healthregisters into a single Internet-based platform. Conse-quently, our platform contributes substantially to theprovision of an infrastructural system dedicated to re-search and monitoring in Belgium. Irrespective of thetopic, the data is recorded in Healthdata.be in a uniformand secure manner. This action requires the develop-ment of a data registration format and IT solutions for

NGS data transfer to the Healthdata.be platform throughthe eHealth infrastructure. Also, an automatic link withthe national Cancer Registry is being established. Theultimate goal is that NGS data are collected togetherwith additional test results into a molecular registry im-proving accessibility of data for clinical research as wellas facilitating evaluation and decision making for policymakers.

Action 7: Provide NGS education and trainingNGS is becoming more accessible for clinical labs but isalso accompanied with various challenges. It is thereforenecessary to provide education and training on the useof NGS. Defining the concrete needs in NGS educationand training is done in concert with the healthcare sec-tor, more specifically the College of Oncology, theCollege of Genetics, the Commission of Clinical Biologyand the Commission of anatomic pathology. It is clearthat different aspects can be covered including technical,legal and ethical aspects, as well as clinical applicationsand new evolutions towards third-generation long-rangeDNA sequencing, whole genome/exome sequencing,RNA sequencing, etc. The formats that can be used forpost academic training and education are symposia,workshops, webinars and online courses. A first initiativewas taken by the Molecular Pathology Working Group,where a two-day course was offered to residents in path-ology. Participating on this course is now mandatory forall residents in pathology.

Action 8: Informed consent, legal and ethical implicationsof NGS use in oncology and hemato-oncology moleculardiagnosticsIt is generally recognized that with the use of NGS tech-nology in clinical practice, new legal and ethical pointsof attention emerge [9]. Besides generating useful clinicalinformation, NGS testing can also reveal large numberof data that may be considered disproportionate, al-though useful for research purposes and/or NGS canproduce results that are not directly linked to thecurrent cancer treatment. NGS data may in addition un-cover relevant hereditary information, which leads to awhole new string of ethical issues. Another major issuewith genetic/genomic information is privacy and dataprotection. A clear informed consent is consideredessential when NGS techniques, especially WGS, orsimilar technologies are being applied for clinical use;this can prevent many misconceptions and avoid ethic-ally problematic situations after testing. The aim of thisaction is to provide guidance on how the legal and eth-ical aspects related to the use of NGS can be managed.For this, it is essential to map the attitudes and informa-tion needs of cancer patients whom NGS testing is of-fered. Focus group studies and citizen labs will be

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installed to address preconceptions, doubts, expectationsof the patients and citizens, the role of the healthcareprofessionals, access to information, data sharing, inci-dental findings, and comprehensiveness of NGS testingby patients and relevance for family members.

Action 9: Pilot study ‘NGS use in routine diagnostics’NGS implementation into the clinical routine diagnos-tics is a complex new intervention and will benefit froma transition period where the introduction of NGS test-ing itself is monitored. A real life pilot study can be putin place for this purpose through conventions of partici-pating labs/hospitals with the reimbursement agency. Atthe end of this real life pilot study, an assessment will bemade on the effectiveness of NGS in molecular diagnos-tics in oncology and hemato-oncology, including howthis multi-testing approach can be positioned in thecurrent reimbursement system, taking into account clin-ical utility, alternatives, therapeutic and societal need,quality and costs. The pilot phase will also allow toevaluate how a molecular data registration system canbe best organized to allow documentation of test resultsand their use for later applications in quality control,output analysis and public health research.

Action 10: Build on hospital networks for NGS use inoncology and hemato-oncologyOptimal use of NGS demands investments in infrastruc-ture and technology, in trained laboratory staff and inIT; affecting not only the logistics of the laboratory butpotentially also that of the whole hospital setting. Anadditional challenge for optimal NGS-implementation ina hospital-setting, aside from the logistics, includes pro-viding adequate genomic oncology training to clinicians,pathologists and geneticists to facilitate the dissemin-ation of genomic knowledge fit-for-purpose for patientmanagement. In regions with multiple testing laborator-ies and hospitals, all with different practices on the im-plementation of these genomic tools in their dailypractice and thus potentially with different impact onpatient care, the establishment of a network-infrastruc-ture between those hospitals will most probably be bene-ficial. Establishing infrastructures for these purposesrequires a huge collaborative effort between all thestakeholders involved, namely oncologists, pathologists,organ-specific specialists, geneticists, patients and gen-eral practitioners, as well as healthcare system represen-tatives from the Government in order to align medicalgenomic-driven practice with health care policy. It maytherefore be considered beneficial for patient care toorganize the testing, data analysis and interpretationwithin such a network infrastructure.The development of regional NGS-network infrastruc-

tures should be supported by a thorough documentation

of all quality-measures needed to establish optimalgenomic-driven patient care. This includes documentationof the needed expertise of laboratory staff, documentationon how to ensure optimal interpretation of NGS-variantsfor daily practice, documentation on how to aim for opti-mal inclusion of patients in clinical trials, etc.….The additional benefits of network-infrastructures for

optimal NGS-use are 1°) to expand and link to existingnational genomic medicine implementation initiatives;2°) to develop new collaborative projects in diversesettings and populations within a region or between re-gions; 3°) to contribute in a more efficient way to evi-dence based use of genomic information for clinicalcare; 4°) to define, share and disseminate the best prac-tices of genomic medicine implementation, diffusion andsustainability in diverse settings within a region and 5°)to more efficiently contribute to the development of anationwide database containing specific genomic infor-mation in various histological types of cancer.

ConclusionsPrecision medicine has offered new opportunities in can-cer care with biomarker testing playing a major con-tributive role in this process. As a consequence, targetedNGS is gradually introduced in molecular diagnostics indaily practice. It offers the advantage to obtain more in-formation with less material, thereby replacing sequen-tial biomarker testing. NGS raises a number ofchallenges concerning standardization, sample quality,use of different platforms, variant interpretation, report-ing, data storage, reimbursement, and ethics. A roadmapoutlining a number of actions to tackle these challengesis described in this paper. The actions include the devel-opment of guidelines and criteria for NGS by experts,quality assessments for NGS testing, installation of dataregistration, NGS education and training. Finally theseactions need to be implemented in a real life pilot studythat includes the formation of NGS networks. InBelgium, this roadmap is running and resulted intechnical guidelines for NGS [7], in a document that islinked to the reimbursement of the NGS test, describingthe genes and regions to be analyzed for specific cancers,and in a tool for data registration. Benchmarking studiesto evaluate the quality of NGS testing in Belgian labora-tories were performed, one for solid tumors and one forhematological myeloid cancers. NGS education andtraining is ongoing for pathologists and will be extendedto other disciplines. In addition, cancer patients andcitizens are involved in ethical debates and recommen-dations for policy makers and healthcare professionalswill follow soon. The pilot study of 3 years will start inthe near future and will facilitate the determinationwhether NGS and precision medicine improve patienthealthcare and outcome. Furthermore, collecting the

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NGS-metrics for each Belgian NGS-reference center willenable us to benchmark the results of each laboratorywith existing international benchmarks, like Cosmic orMy Cancer Genome. Using this infrastructure will alsoenable us to centralize the collection of NGS data andallow us to participate in international data-gatheringresources like GENIE. Finally, this program will enablethe most optimal identification and integration ofpatients into clinical trials, as the percentage of variantsencountered for a particular tumor type across thewhole nation will be known.In conclusion, this action plan can serve as a guide for

similar initiatives by other countries to facilitate the im-plementation of NGS in clinical practice in oncologyand hemato-oncology.

AbbreviationsCAP: College of American Pathologists; ComPerMed: Commission ofPersonalized Medicine; ctDNA: Circulating tumor DNA; EQA: External qualityassessments; FFPE: Formalin-fixed, paraffin-embedded; HTA: Healthtechnology assessment; IQC: Internal quality control; NGS: Next-generationsequencing; NIHDI: National Institute for Health and Disability Insurance

AcknowledgementsThe authors would like to acknowledge all parties that participated in thefeasibility study and the development of the roadbook.

Authors’ contributionsAll authors contributed in writing the manuscript. All authors read and approvedthe final manuscript.

Ethics approval and consent to participateNot applicable.

Consent for publicationNot applicable.

Competing interestsThe authors declare that they have no competing interests.

Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.

Author details1Belgian Cancer Centre, Sciensano, Brussels, Belgium. 2Quality of Laboratories,Sciensano, Brussels, Belgium. 3Healthdata.be, Sciensano, Brussels, Belgium.4Pathology Department, University Hospital of Antwerp, Antwerp, Belgium.5Department of Pathology, GZA Hospitals Antwerp, Antwerp, Belgium.6Division of Research, Peter Mac Callum Cancer Center, Melbourne, Australia.7Breast Cancer Translational Research Laboratory, Jules Bordet Institute,Brussels, Belgium. 8Health Care Department, National Institute for Health andDisability Insurance, Brussels, Belgium.

Received: 27 February 2018 Accepted: 10 July 2018

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