The first in the country! In 2020, TMB testing and clinical application expert consensus came out

On November 11th, the Chinese Expert Consensus on Tumor Mutation Load Detection and Clinical Application (2020 Edition), jointly compiled by the Molecular Pathology Collaboration Group of the Cancer Pathology Professional Committee of the Chinese Anti-Cancer Association and the Genetic Tumor Markers Collaboration Group of the Cancer Markers Professional Committee, was officially published in the Chinese Journal of Cancer Prevention and Control. The definition of TMB, clinical significance, standardization of testing and the relationship with other immunomarkers such as PD-L1, dMMR/MSI-H provide 8 TMB testing and application consensus recommendations for clinical practice, with a view to improving the accuracy and reliability of immunosuppressant (ICIs) therapeutic efficacy prediction to the greatest possible.
1, TMB definition Expert consensus: TMB generally refers to the number of non-synonymic mutations of soda cells in a specific region, usually expressed in terms of how many mutations per megablyb base (XX mutations/Mb).
TMB evaluation is influenced by a variety of factors, such as sample quality and quantity, detection of genome size, and raw letter analysis methods, the scope of application of TMB should be understood before clinical application.
TMB obtained by different detection methods should be evaluated systematically to determine whether it is available.
TMB values reflect the potential of new tumor antigens in tumors, are closely related to DNA repair defects, and have higher TMB in patients with dMMR and MSI-H in a variety of tumors.
2, the clinical significance of TMB 2.1 tissue TMB can be used as an independent immunotherapy efficacy prediction biomarker expert consensus: tissue TMB (tTMB) is a new independent ICIs therapeutic efficacy prediction marker, with a variety of tumor types ICIs single drug or two ICIs combination therapy efficacy, has been proven to be a predictive marker of the efficacy of pan-cancer immunotherapy.
recommending TMB testing for solid tumor patients who have progressed and do not have better alternative therapies after standard treatment, especially those with high TMB, can help expand the population benefiting from immunotherapy.
Chinese the independent forecast value of group TMB still needs more forward-looking research validation.
2.2 Significant correlation between blood TMB and tTMB Expert consensus: Current research evidence shows a significant correlation between blood TMB (bTMB) and tTMB in NSCLC, but there is no uniform standard for bTMB testing.
retrospective studies have found a significant correlation between high bTMB and benefit from single-drug ICIs treatment in NSCLC patients, but have not been confirmed by high-level prospective clinical studies.
3, TMB testing standardized 3.1 sample collection, treatment principles Expert consensus: recommended to use the recent paraffin buried tumor tissue samples for tTMB testing, the testing organization should first complete pathological quality control and ensure that the number of malignant tumor cells can meet the detection requirements.
effect of filtration embryo mutation on subsequent tTMB evaluation, patients' exomenemia, saliva, or normal tissue should be taken as a control sample.
recommends giving priority to genomic DNA extraction using NMPA approved nucleic acid extraction kits for genomic DNA extraction, and tTMB testing laboratories should establish appropriate DNA sample quality control standards and operating procedures according to actual needs, and strictly quality control of DNA sample purity, concentration and fragmentation.
tumor primary and distant metastasis tissue can be used for tTMB evaluation.
The Panel Design and Platform Selection Expert Consensus for 3.2 TMB Detection: When using targeted sequencing Panel for TMB evaluation, it is recommended to conduct a consistent evaluation with the TMB evaluated by WES.
target sequencing Panel coverage should not be < 1.0 Mb in principle, and the minimum effective sequencing depth should ≥ 500 ×.
recommends that targeted sequencing of Panel for TMB testing cover as much other molecular genetic information as possible for patients, including drive gene mutations that can guide targeted therapy, positive predictors of immunotherapy associated with gene mutation generation, and possible negative predictors of immunotherapy.
currently has a number of NGS sequencers approved by the National NMPA for clinical genetic testing, different laboratories can choose different sequencing platforms according to sample size, estrology requirements.
3.3 TMB algorithm standardization requirements Expert consensus: target sequencing Panel-based TMB detection should be based on WES detection as the gold standard, including somogenal cell mutations affecting protein coding, should ensure that the detection of mutation frequency ≥5% of the body Cell mutations to ensure the accuracy and stability of TMB detection values, standardized research on genomic comparation and mutation detection algorithms should be carried out on the ICIs efficacy follow-up database, and panel detection areas can affect TMB values and should be corrected by at least 1,000 WES data.
also recommends using a control sample to filter embryo variants.
3.4 TMB threshold and clinical application expert consensus: TMB values in different cancer species there are significant differences, should be based on the clinical efficacy of ICIs to determine the threshold, in order to maximize the likely screening of ICIs treatment potential benefit groups.
it is important to note that TMB thresholds are not common between the TMB detection systems of different targeted sequencing Panels.
3.5 Preliminary recommendations of the TMB report template Expert consensus: In addition to highlighting the principles and values of TMB calculation, the contents of the TMB report should also be interpreted for the immunotherapy significance of cancer species, and the various drive gene mutations detected by Panel should be systematically evaluated in order to comprehensively solve the patient's tumor biology characteristics, and clinically assisted decision-making should be made using molecular tumor diagnosis and treatment expert group model (MTB).
4, TMB joint application outlook as a new ICIs therapeutic efficacy prediction marker, TMB in clinical application is still in its infancy, testing technology is still constantly improving, clinical significance is also enriched.
recent studies have found that TMB may be used in a joint application with other tumor immunotherapy-related markers (e.g. PD-L1, MSI) or to improve the accuracy and accuracy of immunotherapy efficacy predictions, but specific joint strategies need to be further explored.
References: Collaboration Group on Genetic Tumor Markers of the Professional Committee of the Cancer Markers of the Chinese Anti-Cancer Association, Molecular Pathology Collaboration Group of the Professional Committee of the Cancer Pathology Committee of the Chinese Anti-Cancer Association. China Expert Consensus on Tumor Mutation Load Detection and Clinical Application (2020 Edition)