Pan-cancer analysis of the effect of biopsy site on tumor mutational burden observations

Tumor mutational burden (TMB) has been proposed as a predictive biomarker of response to immunotherapy. Efforts to standardize TMB scores for use in the clinic and to identify the factors that could impact TMB scores are of high importance. However, the biopsy collection site has not been assessed as a factor that may influence TMB scores. We examine a real-world cohort comprising 137,771 specimens across 47 tissues in 12 indications profiled by the FoundationOne assay (Foundation Medicine, Cambridge, MA) to assess the prevalence of biopsy sites for each indication and their TMB scores distribution. We observe a wide variety of biopsy sites from which specimens are sent for genomic testing and show that TMB scores differ in a cancer- and tissue-specific manner. For example, brain or adrenal gland specimens from NSCLC patients show higher TMB scores than local lung specimens (mean difference 3.31 mut/Mb; p < 0.01, 3.90 mut/Mb; p < 0.01, respectively), whereas bone specimens show no difference. Our data shed light on the biopsied tissue as a driver of TMB measurement variability in clinical practice. Papillon-Cavanagh et al. evaluate the impact of biopsy site on measurements of tumor mutational burden (TMB) in a large cohort of tumor samples. The authors observe cancer- and tissue-specific patterns in TMB scores, as well as differences in TMB scores between primary and metastatic samples from the same cancer type. The total number of mutations, or changes, found within the DNA of cancer cells in a tumor sample is known as the tumor mutational burden (TMB). TMB scores have been proposed to be a marker of how well a tumor might respond to immunotherapy, a type of treatment that triggers the body’s immune system to target the cancer. Here, we look at whether TMB scores are dependent on the location in the body from which a tumor sample is taken, the biopsy site. We use over 100,000 specimens from 47 tissues for 12 different cancer types and test for associations between TMB scores and biopsy site. We find that the biopsy site has a strong impact on TMB score. These findings might impact on how clinicians interpret the results of genetic testing in patients and how they make decisions on treatment.