Distributional range of tumor mutational burden (TMB) across multiple cancer types emphasizing the importance of different cutoff values in different tumor types for clinical interpretation: A consensus statement from the SEQUOIA consortium.
Authors: Swat Wojciech , Kumar Dibyendu , Boyle Theresa A. , Dalton Emily , Comer Stewart , Solomon James , Golem Shivani , Eyring Kenneth R , Baskovich Brett , Vashisht Ashutosh , Singh Harmanpreet , Ahluwalia Pankaj Kumar , Alptekin Ahmet , Sahajpal Nikhil , Mondal Ashis , Kota Vamsi , Kolhe Ravindra 
Published: June 2023

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Background: The measurement of tumor mutational burden (TMB) is critical to select patients who are expected to respond to immune checkpoint inhibitors or immune-oncology (IO). The majority of the clinical guidelines on the interpretation & utility of TMB values are based on studies performed on lung cancer, setting a cutoff of 10. Laboratories that are using comprehensive genomic profiling (CGP) for tumor testing are reporting TMB values &/or interpretations (high/low) beyond lung cancer. Multiple studies have shown that the TMB signature is not universal, but rather tumor &/or even patient-specific. However, the pan-cancer trial for IO (KEYNOTE-158) failed to consider setting different cutoffs per tumor type. Currently, no major guidelines or consensus statements address the issue of reporting TMB as a biomarker beyond lung cancer. In the current study, the membership of the SEQUOIA (Sequencing & Oncology Informatics Academic Team) Consortium investigates the landscape of TMB values across multiple cancer types. Methods: We investigated TMB values in 11,670 patient samples (M = 6225; F= 5445) across 13 different tumor types & histological subtypes, including cancers with lung, colorectal, gastrointestinal, brain, prostate, pancreatic, biliary, endometrioid, ovarian, skin, hematological (CLL myeloma) & lymphoid origin. All samples were processed by a CGP panel of 523 genes. Multiple specimen types were included in the study consisting of tissue, blood, marrow, & lymph node. Results: The range of TMB values varied significantly across different cancer types & histological subtypes. The colorectal, melanoma & endometrial cancers have a wider range of TMB values (2-400 mutations/MB) relative to prostate, breast, myeloma, & serous cancers (0-30 mutations/MB). Along with the range, the mean, & median TMB values are also significantly varied across these tumor types. We also identified that a subset of patients exhibits high TMB (>30 mutations/MB) values across almost all types of cancer. Conclusions: TMB values & their association with response to immune checkpoint inhibitors are not very well studied in all cancer types, although a TMB cut-off of 10 mutations/MB was defined as TMB-high for FDA-approved IO in patients with unresectable or metastatic solid tumors. The range, mean, median, cut-offs & clinical interpretations of TMB-high & low for IO based therapies for different tumor types has not been well established. Our data confirm the wide range, mean, & median across different tumor types, & thus laboratories & oncologists need to be cautious in the clinical interpretation of TMB values for patient management. Future studies should assess responsiveness to IO in specific tumor types based on TMB value to determine tumor-specific TMB cutoff values.