Original Title: État des connaissances : profilage moléculaire des tumeurs solides adultes - Focus Panel (illumina) - analyse de 52 biomarqueurs 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 network in the field of molecular diagnostics and personalized medicine, particularly in the areas of rare disease diagnosis and cancer. To this end, the RQDM, with the support of the Ministère de la Santé et des Services sociaux (MSSS), has undertaken a project to enhance technology, develop and repatriate analyses performed by next-generation sequencing (NGS). The deployment of this vast project undoubtedly entails opportunities and risks for the overall service offering and requires that a reflection be carried out in this sense. At the request of the MSSS, the Institut national d'excellence en santé et en services sociaux (INESSS) conducted a rapid assessment of the relevance, issues and, when appropriate, optimal implementation modalities associated with the analyses developed or to be technologically enhanced by RQDM, from a global perspective of the Quebec health system. The information related to each analysis that has been captured by INESSS is consolidated in individual self-supporting documents such as this one. This report deals with the molecular profiling of adult solid tumors and more specifically, with the commercial AmpliSeq kit for the Focus PanelTM (IlluminaTM) which allows for the analysis of 52 biomarkers by NGS. Also at the request of the MSSS, the optimal implementation modalities as well as the best practices for stratifying and standardizing the information generated by the multigene panels for the analysis of several somatic biomarkers are the subject of an independent report by INESSS. The document is available on the INESSS website.

Authors' results and conclusions: RESULTS: (1: Clinical contexts and Proposed analyses): The requester is proposing the deployment of a service offering that consists of replacing several individually performed analyses with a panel of 52 solid tumor-associated genes analyzed by NGS. NGS methodologies and comprehensiveness of oncology panels could vary between the designated laboratories. Specifically, the requester plans to use this analysis for molecular profiling of the following cancers: lung cancer, colorectal cancer, gastrointestinal stromal tumors, melanoma, thyroid cancer, bladder cancer/urothelial carcinoma. The assessment of the added value and issues associated with the implementation of the analysis is primarily focused on lung cancers, as the requester did not provide an algorithm for the other tumor sites. (2: Clinical validity): Since this is a commercial panel, the 52 genes were selected by the manufacturer based on their clinical relevance as described in the published scientific literature, relevant clinical trials, and recommendations from learned societies in somatic oncology. The requester proposes to report only 18 of these genes, representing more specifically 11 for lung cancer, 4 for colorectal cancer, 7 for gastrointestinal stromal tumors, 3 for melanoma, 5 for thyroid cancers and 2 for urothelial carcinomas. This kit simultaneously analyzes regions of recurrent somatic alterations (hot spots) in DNA and RNA isolated from fresh, frozen or formalin-fixed, paraffin-embedded tumor tissue. The commercial kit can identify SNV (single nucleotide variation), indels (insertions-deletions), gene fusions and CNV (copy number variation) variants at an allelic frequency greater than 5%. It should be noted that in the context of this work, INESSS does not have the mandate to rule on the clinical validity of this analysis. (3. Clinical utility): The use of the Focus PanelTM could replace 10 medical biology analyses currently in the Repository that are predominantly used to determine eligibility for certain targeted therapies, especially EGFR, ALK, ROS1, RAS, BRAF and KIT. The use of multi-gene panels per NGS, as opposed to sequential gene-by-gene analyses, is generally favored by the majority of organizations listed for the requester's targeted cancers. The panel also includes genes that may have clinical utility in the future. The use of NGS in lung cancer offers significant advantages, including the ability to determine the status of several recognized relevant biomarkers from a limited amount of biological material. This has the potential to improve services for patients with advanced or metastatic lung cancer, notably an anticipated reduction in testing time and cost, as new relevant targets may be added in the near term. While the Focus PanelTM can assess the mutational status of diagnostic and prognostic biomarkers, the clinical relevance of this analysis in the context of solid tumors is primarily due to its ability to identify therapeutic targets. Therefore, the assessment of the anticipated added value of molecular profiling of advanced cancers by NGS panel should take into account various perspectives, notably those of the Canadian regulatory authorities and the Quebec public paying agent. (4. Implementation considerations): General issues The experts consulted had mixed views on the need to report gene alterations for all genes included in the Focus PanelTM for all solid cancers targeted by the requester. Some would prefer that only variations that predict alteration of clinically actionable targets in the Quebec context be reported from the outset, while others believe that pathogenic variations and variants of uncertain significance for all genes in the panel should be reported to prescribers for all tumour sites. Various practices are used to override access criteria for therapeutic agents that are not included on the Quebec List of medications. It has been reported that some laboratories are under pressure to perform tests associated with drugs that are commercially available in Canada but not reimbursed in Quebec. Issues specific to the cancers targeted by the requester Some of the biomarkers proposed by the requester for lung cancer are currently associated with treatments not covered by the Quebec public drug insurance plan, notably because of a lack of recognition of therapeutic value, or never evaluated by INESSS or not approved for this type of tumor. Some experts believe that only KRAS, NRAS and BRAF are important in colorectal cancer for predicting response to anti-EGFR drugs or for prognosis. A delay of 10 days or less with the Focus PanelTM for RAS and BRAF gene analyses would represent a regression compared to the current situation with the PCR method. In practice, oncologists prefer to use immunotherapies that are effective for both mutated and wild-type KIT patients. KIT gene mutation status is still reported at this time, but its usefulness is questionable. (5. Economic analysis): A rapid review of the scientific literature and a critical analysis of the relevant publications were conducted. The studies identified did not allow INESSS, due to difficulties in generalizing the results to the Quebec context, to accurately evaluate and rule on the efficiency of the Focus PanelTM for the molecular profiling of solid tumours. It should be noted that, given the nature of the mandate granted to INESSS by the MSSS, no modelling was carried out. CONCLUSION: In this exercise, several important concerns were revealed that encourage caution in deploying such an analysis for all solid tumors. The use of a multi-gene panel to profile advanced or metastatic NSCLC has the potential to reduce the delays and costs related to the analyses of established or clinically investigated therapeutic targets in a setting where biological material is often limited and the time required to initiate treatment is critical. As a result, positive impacts on the quality of care offered to these patients are anticipated. Despite several sources of uncertainty, there may be additional costs associated with the use of the Focus PanelTM, but cost savings may be anticipated, should the need arise to detect new actionable biomarkers with clinical relevance. The appropriateness of molecular profiling using a multi-gene panel as an alternative to the techniques currently used for other types of tumor should be further evaluated in terms of clinical and economic issues. Similarly, access criteria, diagnostic and clinical algorithms, and targets to be reported should be established in a consensual manner among all stakeholders involved and based on the best available scientific evidence.

Authors' methods: 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 Quebec experts. Only documents presenting synthesis data or recommendations related to the use of an NGS test to clarify the diagnosis, stratify the prognosis and select the treatment of an adult patient with one of the solid tumours targeted by the requester were retained. INESSS established an advisory committee where members were invited to express their views on the various issues associated with the implementation of the proposed test. The final findings are based on the triangulation of scientific data, the positions taken by the main learned societies consulted, and the contextual data and experiential knowledge collected.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/en/publications/publications/publication/profilage-moleculaire-des-tumeurs-solides-adultes-focus-panelmc-illuminamc-analyse-de-52-biomarqueurs-somatiques.html

Year Published: 2022

URL for published report: https://www.inesss.qc.ca/en/publications/publications/publication/profilage-moleculaire-des-tumeurs-solides-adultes-focus-panelmc-illuminamc-analyse-de-52-biomarqueurs-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: Gouvernment du Québec