TMB Status Might Not Effectively Predict Immunotherapy Response in all Cancers

High tumor mutation burden (TMB) may be only useful for predicting clinical responses to immune checkpoint inhibitors in a subset of cancer types, according to a new study led by researchers from The University of Texas. The findings, published today in Annals of Oncology, suggest that TMB status may not be reliably used as a universal biomarker for predicting immunotherapy response. 

The researchers analyzed over 10,000 tumors across 31 cancer types from The Cancer Genome Atlas to study the relationship between TMB status and tumor immunogenicity, measured by the infiltration of immune cells (CD8+ T cells) into the tumor. They identified two classes of tumors— those with and without a strong correlation between TMB status and T cell infiltration. The authors predicted that TMB status would not be able to predict immunotherapy response equally in these two groups. They evaluated this using previously published studies and MD Anderson patient cohorts.

For cancers with a strong correlation between TMB status and T cell infiltration, patients with a high TMB had improved clinical outcomes. Across all cancer types in this category, 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. Within this category, patients with a high TMB had a 15.3% overall response rate, which was actually lower than the response rate for patients with low TMB.

"While TMB status does show value in predicting response to immune checkpoint blockade in several cancer types, this was not generalizable across all cancers," lead author Daniel McGrail said. "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."