[State of knowledge: virtual genes panels of pediatric cancers by NGS of somatic exome and transcriptome - evaluation report of an analysis developed by the RQDM]

Zaoui K, Gravel C, Rousseau A
Record ID 32018004909
Original Title: État des connaissances - Panels des cancers pédiatriques par SNG de l’exome et du transcriptome somatiques
Authors' objectives: The mandate of the Réseau québécois de diagnostic moléculaire (RQDM), of which the Centre québécois de génomique clinique (CQGC) is a part, is to meet the current and future needs of the health and social services system in the field of molecular diagnostics and personalized medicine, particularly with regard to the diagnosis of rare diseases and cancer. To this end, the RQDM, with the support of the Ministère de la Santé et des Services sociaux (MSSS), has undertaken a vast project to upgrade technology and develop and repatriate next-generation sequencing (NGS) tests. The deployment of this project undoubtedly entails opportunities and risks for the overall offer of NGS services. At the MSSS’s request, the Institut national d'excellence en santé et en services sociaux (INESSS) carried out a rapid assessment of the relevance and challenges of the tests developed by the RQDM and, where applicable, how best to implement them from the overall perspective of the Quebec healthcare system. The information on each test gathered by INESSS is consolidated in individual reports like this one. This report deals with somatic exome and transcriptome sequencing for the molecular diagnosis of pediatric cancers.
Authors' results and conclusions: RESULTS (#1 CLINICAL CONTEXTS AND PROPOSED TESTS ): According to the requester, a large proportion of the genetic alterations found in pediatric cancers are not covered by conventional molecular tests. Consequently, for the vast majority of these cancers, NGS tests are performed outside Québec in the context of clinical trials or locally in the context of research projects funded, among others, by philanthropy. To offer better care and services to the patients concerned, the RQDM is proposing the clinical implementation of virtual panels of genes associated with pediatric cancers, which would be analyzed from somatic exome (DNA) and transcriptome (RNA) sequencing data. For the exome, this would involve a subtractive comparative sequencing approach in which the somatic exome sequencing data would be compared with germline exome data.(#2 CLINICAL VALIDITY): The lists of genes included in the different panels were mainly determined on the basis of recommendations from national and international organizations whose mandate is to guide the practice of medical oncology and molecular pathology according to the available evidence. Among these organizations are the Association for Molecular Pathology (AMP), the American Society of Clinical Oncology (ASCO), the College of American Pathologists (CAP), the National Comprehensive Cancer Network (NCCN), the Children's Oncology Group (COG), the World Health Organization (WHO), the National Cancer Institute (NCI) and the European Leukemia Net (ELN). Concurrent germline and tumour exome analysis using a bioinformatics “subtraction" approach enables one to definitively distinguish between somatic and germline variants. (#3 CLINICAL UTILITY): According to a systematic review that compiled the results from 1408 patients who participated in 21 clinical and observational studies in pediatric oncology, therapeutic targets were identified in 46% of the patients, of whom only 27% received a targeted therapy. According to the authors, the inaccessibility of targeted therapies is a major obstacle. An objective response was observed in approximately 42% of these patients, or 5.2% of the 1,408 patients. Health benefits that are sometime contradictory are reported. In addition to access to clinical studies and personalized therapies, a change or refinement in the diagnosis was reported in 2% to 22% of the cases in which exome and transcriptome sequencing was performed. The highest rate, 22%, was reported by the TRICEPS program at the CHU Sainte-Justine in a cohort of 54 children and adolescents with refractory or relapsed cancer. In this study, refinement of prognostic stratification was also reported in 2% of patients. (#4 RECOMMENDATIONS AND POSITIONS OF LEARNED SOCIETIES AND HEALTH AUTHORITIES): Assessing the feasibility of the clinical implementation of genome sequencing for pediatric cancers is one of the pilot projects in the Plan France Médecine Génomique 2025. Depending on the clinical preindications, all pediatric cancers and leukemias will be eligible for diagnosis. The test is currently available for patients with neuroblastoma and will soon be extended to patients with certain difficult-to-diagnose brain tumours, leukemia, and other pediatric cancers. Pediatric cancers and leukemias where treatment has failed will also be eligible, subject to certain conditions. In particular, the patient must be potentially eligible for an investigational treatment or a clinical trial and have a good performance status and a life expectancy of more than three months. In the Netherlands, at the Princess Maxima Center, Europe’s largest center for the fight against childhood cancer, somatic exome and transcriptome sequencing is now part of the standard of clinical care for children with newly diagnosed, relapsed or refractory tumours. (#5 EXPERT PERSPECTIVE AND IMPLEMENTATION CONSIDERATIONS): Most of the experts consulted support the relevance of exome and transcriptome analysis in refining tumour classification and diagnosing patients with pediatric cancer, and in guiding therapeutic strategies, thereby avoiding the toxicity of certain treatments, reducing the risk of relapse and, ultimately, reducing the risk of death. Some experts emphasized the benefit of extending these tests to all pediatric tumours, which sometimes occur in young adults, and in the context of relapses. Nevertheless, some experts expressed doubts about the need to perform genome-wide, somatic and germline tests for every diagnosis or suspicion of pediatric cancer. More targeted preliminary analyses could, in some cases, be potentially faster and more appropriate from a clinical, organizational, and economic standpoint. (#6 ECONOMIC ANALYSIS): No cost-effectiveness studies of exome and transcriptome sequencing for the molecular diagnosis of pediatric cancers were selected. It should be noted that, given the nature of the MSSS’s request to INESSS, no modeling was carried out. The INESSS is therefore not able to rule on the cost-effectiveness of somatic exome and transcriptome NGS for the molecular investigation of pediatric cancers, since the analysis would generate additional costs for the MSSS and since the resulting health benefits are difficult to quantify using currently available data. Although some uncertainties remain, particularly with regard to the organization of services, the budget impact analysis suggests that including a panel of genes associated with pediatric cancers in the Répertoire québécois et système de mesure des procédures de biologie médicale could generate a cost increase of about $3.0 million over the first three years, excluding indirect costs. CONCLUSION: At a time when precision medicine is playing an increasing role, the deployment of the genome-wide tests described in this report testifies to the desire of several authorities to maximize efforts to better understand and treat the diseases that afflict children, particularly cancer. In this regard, most of the experts consulted agree with the proposed offer of service. However, within the limits of the present request, the data gathered by INESSS does not enable us to conclude with certainty that the routine use of genome-wide tests provides a quantifiable benefit for all types of pediatric cancer. Certain important uncertainties need to be considered to ensure an optimal implementation and judicious use. Among other things, data in support of clinical utility are limited and sometimes contradictory. Although potentially actionable targets can be identified, access to certain personalized treatments could be limited.
Authors' methods: The approach included a rapid review of the scientific and grey literature for the clinical and economic aspects, a budget impact analysis, and consultations with Quebec experts. Only items containing synthesis data or recommendations relating to the use of NGS of the somatic exome and transcriptome to diagnose pediatric cancers were selected. INESSS set up an advisory committee whose members were invited to express their views on the various issues associated with the clinical implementation of the proposed tests. The final findings stem from the triangulation of the scientific data, the positions of the main learned societies consulted, and the contextual data and experiential knowledge that was gathered.
Project Status: Completed
Year Published: 2023
English language abstract: An English language summary is available
Publication Type: Other
Country: Canada
Province: Quebec
MeSH Terms
  • Neoplasms
  • Child
  • Exome Sequencing
  • Whole Genome Sequencing
  • Practice Guidelines as Topic
  • High-Throughput Nucleotide Sequencing
  • Genomics
Organisation Name: Institut national d'excellence en sante et en services sociaux
Contact Address: L'Institut national d'excellence en sante et en services sociaux (INESSS) , 2021, avenue Union, bureau 10.083, Montreal, Quebec, Canada, H3A 2S9;Tel: 1+514-873-2563, Fax: 1+514-873-1369
Contact Name: demande@inesss.qc.ca
Contact Email: demande@inesss.qc.ca
Copyright: L'Institut national d'excellence en sante et en services sociaux (INESSS)
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