Tumor mutation burden as biomarker only effective in certain cancers

High tumor mutation burden can predict immunotherapy response only in subset of cancers

March 16, 2021
Mel J. Yeates
Tumor mutation burden as biomarker only effective in certain cancers

HOUSTON—According to a new study led by researchers from The University of Texas MD Anderson Cancer Center, high tumor mutation burden (TMB) is only useful for predicting clinical responses to immune checkpoint inhibitors in a subset of cancer types. 

The findings, which have been published in Annals of Oncology, suggest that TMB status cannot be reliably used as a universal biomarker for predicting immunotherapy response. While TMB status was capable of successfully predicting response to checkpoint blockade therapy in cancers like melanoma, lung, and bladder cancer, there was no association with improved outcomes in others — including breast, prostate, and brain cancers.

“This study represents the most comprehensive analysis to date of TMB as a biomarker for response to immune checkpoint blockade,” said Dr. Daniel J. McGrail, postdoctoral fellow in Systems Biology, and lead author of the study. “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.”

Last year, the FDA approved the anti-PD-1 therapy pembrolizumab for treating patients with advanced and refractory cancers with a high TMB, as indicated by a defined threshold level of mutations. The approval was based on results from the Phase 2 KEYNOTE-158 study, which found improved overall responses in patients with a high TMB. But the trial failed to include several cancer types — like breast, prostate, and brain cancers — which haven’t typically responded to immune checkpoint blockade therapy.

“The FDA approval of pembrolizumab for patients with high TMB certainly provides an important option for many patients. However, we felt that it was important to look more closely at TMB status in a broader group of cancer types and establish approaches to harmonize TMB across various assays to enable clinicians to best utilize the recent FDA approval,” added Dr. Shiaw-Yih Lin, professor of Systems Biology, and senior author of the study.

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 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. But 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 lower than the response rate for patients with low TMB.

“While TMB-H [high tumor mutation burden] demonstrates promise as a predictive biomarker for patient selection for ICB [immune checkpoint blockade] treatment, our analysis fails to support the hypothesis that a single TMB threshold can identify patients in a pan-cancer fashion who may benefit from ICB,” notes the article. “In particular, we find that TMB-H, compared to TMB-L [low tumor mutation burden], indicates neither an improved response rate nor a response rate exceeding 20% for certain cancer types which do not demonstrate a correlation between neoantigen load and CD8 T-cell infiltration, such as breast and prostate cancers.” 

“While this study is limited by retrospective analyses across various DNA sequencing approaches (with minimal data using F1CDx directly), variations in immune checkpoint inhibitors utilized, and many cohorts only consisting of objective response data instead of OS [overall survival] outcomes, the preponderance of the evidence fails to support universal treatment of TMB-H cancers with ICB,” the article continues. “In order to better implement TMB-H as a robust clinical biomarker, critical challenges focused on both accurately determining TMB in a given cancer type and then determining an optimal TMB threshold (if one exists) must be addressed.”

The researchers also found that evaluating TMB status by sequencing a targeted panel of cancer-related genes may overestimate TMB when compared to whole exome sequencing, which offers an unbiased approach. While whole exome sequencing isn’t feasible in a clinical setting, McGrail pointed out that the threshold for defining high TMB status may need to be evaluated in a cancer type-specific manner.

“We found that cancer types that show no correlation between neoantigen load and CD8 T-cell infiltration not only fail to achieve a 20% response rate to ICB in TMB-H tumors, but TMB-H tumors may even demonstrate a worse response rate to ICB than TMB-L tumors. A potential explanation is that ICB sensitivity is largely driven by the presence of pre-existing CD8 T cells, and that the predictive accuracy of TMB-H in certain cohorts is predominately a reflection of high basal immune cell infiltration,” concludes the article. “As using correlation between neoantigen load and CD8 T-cell levels to identify tumor types where TMB-H may serve as a predictive biomarker for ICB response is likely suboptimal, future studies further exploring which TMB-H tumor types predict response to ICB are warranted.”

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