A Heavy Tumor Mutation Burden Predicts Immunotherapy Response: A Survey

According to a study done by researchers from The University of Texas MD Anderson Cancer Center, a high rate of mutations in the genome within a tumor, dubbed high tumor mutation burden (TMB), was just beneficial for predicting clinical reactions to the checkpoint of the immune system inhibitors in a subset of cancer types.

A Heavy Tumor Mutation Burden Predicts Immunotherapy Response: A Survey

The results published in the Journal of Oncology indicate that TMB status might not be a reliable predictor of immunotherapy response. Although TMB status could predict response to the point of delay blockade in some cancers, like melanoma, lung, and bladder cancer, there wasn’t any connection between TMB status and better results in others, such as cancers of the breast, uterus, and brain.

Lead author Daniel J. McGrail, PhD, a postdoctoral fellow in Systems Biology, said, “This research represents the most detailed review of TMB as a biomarker for reaction to self-protective checkpoint blockade to date.”Gene mutations in tumors result in the development of mutated proteins known as neo-antigens, which the system of protection may identify as abnormal. As a result, tumors with a high TMB are more immunogenic, and the TMB status emerged as the front-runner bio-marker for anticipating immunotherapy response, according to McGrail.

The researchers looked at over 10,000 tumors from The Cancer Genome Atlas (TCGA) across 31 cancer types to see whether there was a correlation between TMB status and tumor immunogenicity, which was assessed by the penetration of immune cells (CD8+ T cells) into the tumor.

They discovered two types of tumors: those with a clear association between TMB status and T cell infiltration and those without. TMB status will not be able to estimate reaction in these two classes fairly, according to the authors. Previously conducted trials and MD Anderson patient cohorts were used to test this.

Patients with a high TMB had more substantial clinical results in tumors where there was a clear association between TMB and T cell infiltration. Patients with a high TMB had a 39.8% average checkpoint inhibitor response score, which was slightly greater than patients with a low TMB for all cancer forms in the group.

In the second type of tumors, however, TMB status was not associated with prognosis. Patients with a high TMB had a response rate of 15.3 percent overall, which was better than patients with a low TMB.

“While TMB status does show utility in predicting response to immune checkpoint blockade in a variety of cancer types,” McGrail said, “this was not generalizable to all cancer types. “Additional prospective trials are expected to decide whether TMB status may be an appropriate clinical bio-marker and at what threshold for those cancer types where a high TMB does not seem to improve immunogenicity.” 

Furthermore, the researchers discovered that assessing TMB status by sequencing a targeted panel of linked cancer genes can overestimate TMB compared to the whole sequence of exomes, which is a more unbiased method.

Although entire exome sequencing is not practical in a clinical setting, McGrail states that the threshold for determining high TMB status will need to be determined in a cancer type-specific manner.

The authors point out those retrospective studies of various DNA equating methods, as well as differences in immune checkpoint inhibitors and clinical results recorded among the multiple cohorts used, restrict this analysis.