High Tumor Mutation Burden Only Useful Prognosis Predictor for Some Cancers

PD-1 Antibody Targeting Immune Checkpoint Inhibitor
3D rendering of a therapeutic antibody molecule binding to PD-1 protein on a surface of a t cell, which prevents binding to PD-1L on a cancer surface and inhibits immune checkpoint

High tumor mutation burden can predict improved response to immune checkpoint therapy for cancers such as melanoma, lung and bladder cancer, but is less useful at predicting treatment response for other solid tumors, show study results.

The research team, led by scientists from the University of Texas MD Anderson Cancer Center, found that high tumor mutation burden (TMB) was only predictive of response in tumors that had a positive correlation between the production of neoantigens and CD8 T-cell production by the immune system.

“This study represents the most comprehensive analysis to date of TMB as a biomarker for response to immune checkpoint blockade,” said Daniel McGrail, Ph.D., a postdoctoral fellow at the MD Anderson Cancer Center, who was first author of the paper describing the research, which is published in the journal Annals of Oncology.

“Our results do not support applying high TMB status as a universal biomarker for immunotherapy response, suggesting that additional tumor type-specific studies are needed to clarify how best to apply TMB status in cancer types where it does not appear to be associated with outcomes.”

Previously high TMB was proposed as a biomarker to predict how well cancer patients will respond to immune checkpoint inhibitors, as increased tumor mutations are linked with increased production of neoantigens by the immune system making them more ‘visible’ as a drug target.

Indeed, in 2020 the FDA approved the anti-PD-1 checkpoint inhibitor pembrolizumab for treating patients with advanced and refractory cancers with a high TMB. But the study this approval was based on did not test all cancer types.

This led McGrail and colleagues to analyze data from more than 10,000 tumors included as part of The Cancer Genome Atlas to evaluate correlations between neoantigen and CD8 T-cells across 31 different cancer types. Objective response rates and overall survival were used to assess efficacy of immune checkpoint inhibitors.

The researchers found that for cancers such as melanoma, where there is a strong correlation between neoantigen and CD8 T-cell levels, high TMB predicted a better response to immune checkpoint inhibitors. Patients in this group had a 39.8% overall response rate to the therapy, a rate four times higher than those with low TMB.

However, in cancers with no relationship between neoantigen levels and CD8 T-cell levels, such as breast and prostate cancer and glioma, this was not the case. In this group of patients, people with a high TMB only had a 15.3% response rate to immune checkpoint inhibitors, a rate 54% lower than the rate seen in those 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,” explained McGrail.

“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.”

The researchers also looked at methods to assess TMB and found that exome sequencing provided more accurate results than testing a targeted panel of variants. While they acknowledge exome sequencing may not be possible in every case, they call for more cancer-type specific assessment of TMB to improve accuracy and to allow clinicians to make better treatment choices for their patients.

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