A high tumor mutational burden (TMB) is only useful for predicting clinical responses to immune checkpoint inhibitors in a subset of cancer types, according to a study recently published in Annals of Oncology (https://www.annalsofoncology.org/article/ S0923-7534 (21) 00123-X / fulltext). TMB, which measures the number of tumor mutations by taking a ‘photograph’ of its molecular alterations, may not be reliable as a biomarker for all solid tumors.
High tumor mutation burden is a leading candidate biomarker for identifying cancer patients who may benefit from immune checkpoint blockade, based on the underlying assumption that increasing the numbers of mutant proteins will create antigenic peptides, which can be recognized as abnormal by the immune system, allowing for enhanced immunogenicity and increased clinical response with anti-PD-1 and anti-PDL-1. Accumulating evidence supports this hypothesis in certain cancers such as lung cancer and melanoma. The aim of the study was to evaluate if this is true for all solid cancers, by analyzing over 10,000 patients across 31 cancer types from The Cancer Genome Atlas of the National Cancer Institute to determine TMB and identify the correlation between predicted neoantigen load and tumor immunogenicity, measured by the infiltration of immune cells (CD8+ T cells) into the tumor.
Results show that TMB status was capable of successfully predicting response to checkpoint blockade in certain cancers, such as melanoma, lung and bladder cancer, while there was no association with outcome in others, including breast, prostate and brain cancers. For cancers with a strong correlation between TMB status and T cell infiltration, patients with a high TMB had a 39.8% overall response rate to checkpoint inhibitors, which was significantly higher than those with a low TMB; in contrast, TMB status was not predictive of outcome in the second class of tumors (without a correlation between TMB and CD8 T cells infiltration), where patients with a high TMB had a 15.3% overall response rate, which was actually lower than the response rate in patients with low TMB.
«Our results do not support applying high TMB status as a universal biomarker for immunotherapy response», the author Daniel J. McGrail said. «While TMB status does show value in predicting response to immune checkpoint blockade in several cancer types, this was not generalizable across all cancers: for those cancer types where a high TMB does not appear to increase immunogenicity, additional prospective studies are needed to determine if TMB status can be an effective clinical biomarker and at what threshold».
