Immune checkpoint inhibitors have revolutionized cancer treatment, but only a minority of patients respond to monotherapy and immune-related adverse events remain a major concern. Therefore, the search for biomarkers that can more accurately predict efficacy before starting treatment is intensifying. Tumor mutational burden (TMB) has emerged as one of the leading candidates, as it reflects the number of tumor mutations that can generate neoantigens that can trigger antitumor immune responses. But that enthusiasm is tempered by practical issues. Different sample types, sequencing panels, thresholds, bioinformatics pipelines, and reporting styles can all yield different answers. Because of these challenges and the fact that TMB values vary widely between cancer types, deeper research and more standardized clinical guidance are urgently needed.
Developed by the Yangtze River Delta Lung Cancer Cooperation Group (East China LUngcaNcer Group) Youth Committee and published at (DOI: 10.20892/j.issn.2095-3941.2025.0351). Cancer biology and medicinethis expert consensus outlines how TMB should be defined, tested, standardized, and clinically interpreted to improve its use in actual cancer immunotherapy practice in China.
The central message of this document is that TMB should be treated as a carefully controlled clinical measurement rather than as an ambiguous biomarker. Experts recommend prioritizing recently prepared paraffin-embedded tumor tissue, ensuring adequate tumor cell content, and using validated DNA extraction and quality control procedures before beginning sequencing. When it comes to detection, consensus recognizes whole exome sequencing to be the gold standard, but targeted panel sequencing is recognized as a more practical clinical option when properly validated against whole exome results. To improve reliability, the group recommends panel coverage of at least 1.0 Mb, sequencing depth of at least 200x, and standardized bioinformatics pipelines that can accurately remove germline variants and reduce platform-related bias. The paper also emphasizes the importance of panel design. A panel that is too small can skew TMB estimates, whereas a wider panel can more accurately reproduce whole exome results. Equally important, the authors argue that thresholds should not be universal. TMB values vary widely depending on tumor type, and clinically useful cutoffs need to be related to actual immunotherapy outcomes rather than arbitrary statistical divisions. The consensus thus moves the field away from a simple “high versus low” model and toward a more nuanced framework in which assay design, cancer type, and treatment context all shape meaning.
“TMB is no longer just a research concept,” the expert consensus effectively suggests. “Its value now depends on clinicians and laboratories being able to measure it consistently, interpret it correctly, and place it in the appropriate treatment context.” By emphasizing sample quality, assay harmonization, cancer-specific thresholds, and multidisciplinary interpretation, this paper presents TMB not as a stand-alone answer, but as a decision support tool that is most powerful when used judiciously and combined with broader molecular and clinical evidence.
The impact is practical and immediate. For oncologists, this consensus provides a clearer path to determining when TMB testing can help expand access to immunotherapy, especially in patients with advanced solid tumors where treatment options are limited. For laboratories, it provides a framework to standardize workflows from specimen handling to reporting language. The broader field highlights the maturation stage of precision oncology. Success now depends not only on the discovery of biomarkers, but also on making them reproducible, comparable, and clinically interpretable. If widely adopted, this roadmap could help move TMB from a promising but heterogeneous biomarker to a more reliable part of personalized cancer treatment.
sauce:
Chinese Academy of Sciences
Reference magazines:
https://doi.org/10.20892/j.issn.2095-3941.2025.0351
