Original Title: État des connaissances - Stratégies de classification et de stratification des variants somatiques

Authors' objectives: 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.

Authors' results and conclusions: 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. The Association for Molecular Pathology (AMP), American Society of Clinical Oncology (ASCO), and College of American Pathologists (CAP) (AMP/ASCO/CAP) joint classification strategy for somatic variants involves four tiers based on their level of clinical evidence that also take into account the Food and Drug Administration (FDA)’s regulatory approvals. The European Society of Medical Oncology (ESMO) has created its ESMO Scale for Clinical Actionability1 of molecular Targets (ESCAT), which defines six categories of clinical evidence for molecular targets according to the implications for patient management. The German Cancer Consortium of the National Center for Tumor Diseases (NCTD) proposes a classification of actionable mutations based on eight levels of clinical or preclinical evidence regarding the association between a molecular biomarker, the response to a specific drug and tumour type. In Canada, the University Health Network (UHN) system takes into account the relationship between the level of clinical actionability evidence, the primary site and tumour histology, the variant’s pathogenicity, and its recurrence in the literature to establish a 5-category classification of actionable variants. Lastly, Australia's Therapy Oriented Precision Oncology Guidelines for Recommending Anticancer Pharmaceuticals (TOPOGRAPH) system provides a classification of approved and covered therapies in the Australian context and experimental therapies based on levels of scientific evidence of their relationship with a biomarker in a specific tumour type. Although the recommendations regarding the interpretation of biomarkers and somatic variants are well documented, those regarding the information to be reported to the clinician by the laboratory are limited. Nevertheless, there is a desire to produce clear, concise reports that include all the necessary information that could influence the clinical interpretation of the test results, including limitations and uncertainties. With respect to disclosure of NGS test results to the treating clinician, the AMP/ASCO/CAP recommends reporting their tiers I to III, whereas the ESMO considers that there would be no proven clinical benefit to detecting actionable alterations beyond ESCAT tier I. The ability of NGS multigene panels to produce a large amount of information poses some issues for the laboratory, the treating clinician, the patient, and the healthcare system. It is considered important that the information made available to clinicians be consistent with the organization of care and access to treatments with demonstrated clinical value. In addition, patients must be able to give informed consent regarding the use of multigene panels, which implies that they are aware of their sometimes low clinical relevance and of the potential incidental findings from these panels. 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.

Authors' methods: 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.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/en/publications/publications/publication/strategies-de-classification-et-de-stratification-des-variants-somatiques.html

Year Published: 2022

URL for published report: https://www.inesss.qc.ca/en/publications/publications/publication/strategies-de-classification-et-de-stratification-des-variants-somatiques.html

English language abstract: An English language summary is available

Publication Type: Other

Country: Canada

Province: Quebec

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)