Panels des cancers héréditaires adultes par séquençage de nouvelle génération / Next generation sequencing hereditary cancer gene panels

MISE EN CONTEXTE ET MANDAT: Les demandes d'autorisation visant des services de biologie médicale non disponibles au Québec concernent majoritairement le séquençage à haut débit de plusieurs gènes en simultané selon une approche dite de nouvelle génération. Or, les laboratoires de la province possèdent la technologie et l'expertise pour effectuer ces analyses. Dans l'optique de réaliser des économies d'échelle et de favoriser une utilisation plus judicieuse des ressources, le ministère de la Santé et des Services sociaux (MSSS) a entrepris, sous la gouvernance du Réseau québécois de diagnostic moléculaire (RQDM), de rapatrier rapidement plusieurs analyses effectuées par séquençage de nouvelle génération (SNG). Le déploiement de ce vaste projet entraîne indubitablement des opportunités et des risques pour l'offre de services globale et nécessite une réflexion en ce sens. À la demande du MSSS, l'Institut national d'excellence en santé et en services sociaux (INESSS)

BACKGROUND AND MANDATE: Requests for authorization for medical laboratory services that are not available in Québec are mainly for high-throughput simultaneous sequencing of multiple genes using the so-called next-generation approach. The province's laboratories have the technology and expertise to perform these tests. With a view to achieving economies of scale and promoting more judicious use of this technology, the Ministère de la Santé et des Services sociaux (MSSS) has undertaken to quickly repatriate several tests performed by next-generation sequencing (NGS), under the governance of the Réseau québécois de diagnostic moléculaire (RQDM). The rollout of this vast project undoubtedly entails opportunities and risks with respect to the overall offer of services and requires reflection along these lines. At MSSS's request, the Institut national d'excellence en santé et en services sociaux (INESSS) is conducting a rapid assessment of the relevance of, the issues surrounding and, when appropriate, the optimal implementation mechanisms for the repatriation of these tests, from the overall perspective of Québec's healthcare system. The present report deals specifically with the analysis of NGS hereditary cancer gene panels. METHOD: The process included a rapid review of the scientific and grey literature for the clinical and economic aspects, a budget impact analysis, and consultations with Québec experts. Only documents containing synthesis data or recommendations concerning the use of an NGS test for the molecular diagnosis of hereditary cancers were selected. INESSS set up an advisory committee, whose members were invited to express their views on the various issues and considerations regarding the repatriation of the proposed tests. The final findings are based on the triangulation of the scientific data, the positions of the main learned societies consulted, and the contextual data and experiential knowledge gathered. CLINICAL CONTEXTS AND PROPOSED TESTS: Cancer is the leading cause of death in Canada. It is estimated that approximately 40% of Canadians will develop cancer in their lifetime and that 25% will die from it. Up to 10% of the most common cancers are hereditary. In other words, they are caused by pathogenic mutations in one or more oncogenes. The purpose of hereditary cancer gene panels analyzed by NGS is to identify or confirm the genetic etiology of a clinical presentation suggestive of a hereditary cancer syndrome. The cancers covered by these panels concern the following anatomical sites: breast, ovary, endometrium, colon/rectum, prostate, pancreas, stomach, and conditions associated with a predisposition to intestinal polyposis. CLINICAL VALIDITY: In hereditary genetics, the clinical validity of a multigene panel analyzed by sequencing is determined, among other things, by the association of the genes in the panel with the targeted disease. Panels should therefore include all the genes for which variants have been clearly identified as being responsible for at least one of the targeted cancers (pathogenic variants). The requester intends to use eight virtual panels of genes associated with hereditary cancers, which will be analyzed using the sequencing data from the 105 genes in the Canadian Inherited Cancer Panel. Of these, a total of 31 genes (overall virtual panel) will be reported based on the clinical presentation and current oncogenetic knowledge. CLINICAL UTILITY: Data from the literature and the expert consultations are in accord that the proposed molecular investigations help improve the health of individuals by identifying those who are genetically predisposed to developing one or more cancers. In fact, targeted and individualized interventions aimed at detecting cancer earlier and preventing its occurrence or recurrence can be carried out in these individuals. The learned societies and experts consulted also agree that priority should be given to using a multigene panel approach instead of a single-gene approach, taking into account a combination of information regarding the clinical presentation, examination and family history. The genes included in the proposed panels and the criteria for accessing the panels are consistent with information found in the literature. IMPLEMENTATION CONSIDERATIONS: In light of the consultations held, standardizing the criteria for accessing genetic tests across the province and creating clinical algorithms to guide the care and services offered to patients are key elements for implementing these panels in the healthcare system. As well, updating mechanisms should be put in place to ensure that patient management is supported by relevant scientific evidence. Having non-medical genetics specialists order the test, manage the results, and do the patient follow-ups could ease the burden on geneticists, but they would have to be supported by specialized training and detailed, up-to-date clinical algorithms. Obtaining patients' informed consent is paramount, regardless of who orders the test. The implementation of hereditary cancer gene panels should be accompanied by consistency in the quality of molecular diagnostic service and in the turnaround time across the province that is comparable to that currently offered by outside laboratories. In addition, some experts expressed concern about the lack of clear policies on the management and disclosure of variants of uncertain significance (VUS). ECONOMIC ANALYSIS: INESSS is not able to rule on the efficiency of the NGS for hereditary cancer panels. In fact, no economic evaluation in the Québec context has been carried out, and the results in the literature are either not available for some cancers, or uncertain or not transposable to the Québec context for others. With regard to the budget impact, based on the assumptions made, including hereditary cancer gene panels in the Répertoire québécois et système de mesure des procédures de biologie médicale could generate savings of close to $600,000 over the first three years in serving patients throughout Québec. According to the sensitivity analyses performed, these savings could range from close to $9.5M to costs of approximately $1.2M for the same period. It should be noted that the extent of these savings depends largely on the cost of implementing this technology, the sequencing throughput of each instrument, and the number of tests performed. In fact, if there were to be a significant increase in the number of tests, as proposed by the experts consulted, the repatriation costs would be greater than those currently generated by sending the tests outside Québec. Lastly, an increase in genetic counselling resources, which was not taken into consideration in the analyses, could generate additional costs and reduce the potential savings. CONCLUSION: The findings and conclusions in this report are based on a rapid review of the scientific and grey literature and on contextual data and experiential knowledge. The approach consists of a rapid risk analysis for guiding the ministerial decision regarding the repatriation of tests for the molecular diagnosis of hereditary cancer in adults. During this exercise, certain issues were raised regarding the rollout of this test. Standardizing access to germline genetic testing for cancer predisposition syndromes across the province is a desire shared by most of the experts consulted. Using algorithms and clinical indications supported by current scientific evidence would contribute to this standardization. The ordering of this test by non-medical genetics specialists should be supervised or reserved for those who are adequately trained and able to manage posttest follow-ups. According to the experts consulted, the service offered for these tests must be comparable to that provided by the outside laboratories, particularly in terms of quality, reliability, speed, and result traceability. A number of experts also stressed the importance of properly planning, or planning for, the genetic counselling and clinical patient follow-up needs and resources at the provincial level. Lastly, a rapid review of the economic literature and a budget impact analysis revealed several uncertainties. They call for caution with respect to these panels' efficiency and the projected potential savings.

Stratégies de classification et de stratification des variants somatiques / Somatic variant classification and stratification strategies

MISE EN CONTEXTE ET MANDAT: À la demande du ministère de la Santé et des Services sociaux (MSSS), l'Institut national d'excellence en santé et en services sociaux (INESSS) a procédé à une évaluation rapide de la pertinence, des enjeux et des modalités optimales d'implantation de l'AmpliSeqMC pour le Focus Panel d'IlluminaMC (ci-après nommé Focus PanelMC). Il s'agit d'une trousse commerciale par séquençage de nouvelle génération (SNG) qui permet l'analyse simultanée de 52 gènes identifiés comme biomarqueurs diagnostiques, pronostiques ou prédictifs d'une réponse à un traitement dans le contexte des tumeurs solides. Dès l'amorce de ces travaux, des enjeux spécifiques liés à l'utilisation éventuelle de ce panel ont été soulignés, notamment au regard des attentes anticipées relativement à l'accès et au remboursement de thérapies pharmacologiques ciblées. En phase avec son mandat de soutenir les travaux du Réseau québécois de diagnostic moléculaire (RQDM), l'INESSS a produit un état des connaissances qui résume les meilleures pratiques destinées à stratifier et standardiser l'information générée par l'utilisation des panels multigéniques permettant l'analyse simultanée de plusieurs biomarqueurs somatiques de divers types de cancer. MÉTHODOLOGIE: Pour accomplir ce mandat, l'INESSS a réalisé une revue de la littérature afin de repérer des rapports d'évaluation des technologies et des modes d'intervention en santé, des revues systématiques, des lignes directrices et des guides de pratique clinique traitant de l'interprétation, de la divulgation et de la classification des résultats issus du profilage moléculaire des tumeurs solides par SNG. Les stratégies de recherche de l'information ont ciblé principalement les productions d'autorités ou de sociétés savantes qui exercent dans un système de soins et de services de santé comparable à celui du Québec. Seuls les documents publiés en français ou en anglais à partir de 2010 ont été considérés. Une évaluation de la qualité méthodologique des publications retenues a également été effectuée. Le document produit a fait l'objet d'une validation auprès de la coordination scientifique et de la direction responsable de sa production. Il n'a pas été soumis à une lecture externe. RÉSULTATS: Cinq documents provenant de pays d'Europe, de l'Australie, des États-Unis et du Canada ont été repérés sur le sujet. Chacun propose un système de classification des biomarqueurs ou des thérapies par catégories appelées des « tiers ¼. La définition d'un tiers se base généralement sur le niveau de preuve scientifique qui soutient la valeur diagnostique, pronostique ou prédictive d'un biomarqueur dans un type tumoral précis. Les règles de composition des tiers restent hétérogènes, notamment en termes de niveau de preuve, surtout dans les tiers intermédiaires regroupant des cibles thérapeutiques potentielles, en cours d'investigation ou hypothétiques qui permettent généralement l'accès à des essais cliniques. CONCLUSION: Malgré tous les défis et considérations qui accompagnent le déploiement à l'échelle provinciale de panels multigéniques pour plusieurs types de cancer, la médecine personnalisée en oncologie ne cessera de prendre de l'ampleur dans le système de santé. Pour répondre à des demandes d'analyse de plus en plus nombreuses en évitant de créer des disparités dans l'accès aux services ou aux traitements, l'utilisation de l'information générée par ces tests devrait être encadrée comme le proposent plusieurs organisations. L'adoption d'un système de classification des variants ou des thérapies, fondé sur des niveaux de preuve d'actionnabilité des biomarqueurs et adapté au contexte local, constitue une étape importante dans l'implantation judicieuse d'analyses permettant le profilage moléculaire des tumeurs solides.

BACKGROUND AND MANDATE: At the request of the Ministère de la Santé et des Services sociaux (MSSS), the Institut national d'excellence en santé et en services sociaux (INESSS) conducted a rapid assessment of the relevance of, the issues surrounding and the optimal implementation mechanisms for AmpliSeq™ for the Illumina Focus Panel™ (hereafter "Focus Panel™"). This is a commercial next-generation sequencing (NGS) kit for the simultaneous analysis of 52 genes identified as biomarkers that are diagnostic, prognostic or predictive of a therapeutic response in the context of solid tumours. At the outset of this task, specific issues related to the potential use of this panel were raised, particularly with respect to the anticipated expectations regarding access to and coverage of targeted pharmacological therapies. In line with its mandate to support the work of the Réseau québécois de diagnostic moléculaire (RQDM), INESSS has produced a state-of-knowledge report that summarizes the best practices for stratifying and standardizing the information generated by the use of multigene panels for the simultaneous analysis of several somatic biomarkers of various types of cancer. METHODOLOGY: For the purpose of this task, INESSS conducted a literature review to identify health technology assessment reports, systematic reviews, guidance documents and clinical practice guidelines dealing with the interpretation, reporting and classification of results of NGS molecular profiling of solid tumours. The information search strategies targeted mainly the productions from authorities or learned societies that operate in a health care and services system comparable to Québec's. Only items published in French or English after 2010 were consulted. The methodological quality of the selected publications was assessed. The report produced was validated by Scientific Coordination and the management responsible for its production. It was not submitted for external review. RESULTS: Five publications on this topic from Europe, Australia, the United States and Canada were identified. Each proposes a system for classifying biomarkers or therapies into categories called "tiers". The definition of a tier is generally based on the level of scientific evidence that supports the diagnostic, prognostic or predictive value of a biomarker in a specific tumour type. The rules concerning the composition of tiers are heterogeneous, particularly in terms of the level of evidence, especially in the middle tiers grouping together potential or hypothetical therapeutic targets or therapeutic targets under investigation that generally permit access to clinical trials. CONCLUSION: Despite all the challenges and considerations that accompany the province-wide rollout of multigene panels for several types of cancer, personalized medicine in oncology will continue to grow in the healthcare system. To respond to the increasing number of requests for analysis while avoiding creating disparities in access to services or treatments, the use of the information generated by these tests should be regulated, as proposed by several organizations. Adopting a classification system for variants or therapies that is based on levels of evidence for actionability of biomarkers and adapted to the local context is an important step in the appropriate implementation of tests for the molecular profiling of solid tumours.