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

Tumor mutation load (TMB) as a new biomarker, in predicting the efficacy of tumor immunotherapy has been paid more and more attention.
The current detection method of TMB is mainly based on the high-volume sequencing platform's all-external proton sequencing and target Panel sequencing fitting algorithm, but the detection method, threshold and reporting format lack of uniform standards.
addition, TMB values vary significantly among different cancer species, which also make it difficult for the marker to be applied clinically.
November 11, the Chinese Expert Consensus on Tumor Mutation Load Detection and Clinical Application (2020 Edition), jointly compiled by the Molecular Pathology Collaboration Group of the Professional Committee on Oncology Pathology of the Chinese Anti-Cancer Association and the Genetic Tumor Markers Collaboration Group of the Professional Committee on Tumor Markers, was officially published in the Chinese Journal of Cancer Prevention and Control. Focusing on the definition of TMB, clinical significance, standardization of testing and the relationship with other immunomarkers such as PD-L1, dMMR/MSI-H, 8 TMB testing and application consensus recommendations are provided for clinical practice, with a view to improving the accuracy and reliability of immunosuppressant (ICIs) therapeutic efficacy prediction to the maximum possible.
1, TMB definition expert consensus: TMB generally refers to the number of non-synonymic mutations of soda cells in a specific region, usually with how many mutations per megab 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 combined treatment efficacy, has been confirmed as a pan-cancer immunotherapy predictive efficacy marker.
recommends TMB testing for solid tumor patients who have progressed after standard treatment and do not have better alternative therapies, especially those with high TMB, to help expand the population benefiting from immunotherapy.
Chinese the independent predicted value of TMB still requires more forward-looking research validation.
2.2 Expert consensus on the significant correlation between blood TMB and tTMB: 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 principle 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.
expert consensus on Panel design and platform selection for 3.2 TMB testing: 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.
there are currently a number of NGS sequencers approved by the National NMPA for clinical gene testing, different laboratories can choose different sequencing platforms according to the sample size, estrology requirements.
3.3 TMB algorithm standardization requires expert consensus: target sequencing Panel-based TMB detection should be based on WES detection as the gold standard, including the effect of protein coding somcocyte mutations, should ensure that the detection of mutation frequency ≥5% of somogene cells Mutations to ensure the accuracy and stability of TMB detection values, standardized research on genomic ratio 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 exploration 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 TMB report template preliminary recommendations expert consensus: TMB report content in addition to focusing on TMB calculation principles and values, should also be interpreted for the immunotherapy significance of cancer species, but also need to systematically assess the various driving gene mutations detected by Panel, in order to comprehensively solve the patient's tumor biology characteristics, recommended the application of molecular tumor diagnosis and treatment expert group model (MTB) for clinically assisted decision-making.
4, TMB joint application outlook as a new ICIs therapeutic efficacy prediction marker, TMB in clinical application is still in the initial stage, testing technology is still constantly improving, clinical significance is also rich.
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: Genetic Tumor Markers Collaboration Group of the Professional Committee of Cancer Markers of the Chinese Anti-Cancer Association, Molecular Pathology Collaboration Group of the Professional Committee of the Oncology Pathology Committee of the Chinese Anti-Cancer Association. China Expert Consensus on Tumor Mutation Load Detection and Clinical Application (2020 Edition)