Study indicates that high mutational burden does not predict response to immunotherapy for different type of cancers
The high tumor mutation burden (TMB-H) has been proposed as a predictive biomarker for response to immune checkpoints inhibitors (ICI), largely because of its potential to generate immunogenic neoantigens. Despite the recent approval of the use of ICI for any tumour with TMB-H, its utility has not been fully demonstrated for all cancers
Tumor gene mutations lead to the production of altered proteins, or neoantigens, which can be recognized as abnormal by the immune system. It is believed that a TMB-H would make tumors more immunogenic, which is why TMB status has become a leading candidate biomarker to predict response to immunotherapy.
In June 2020, the Food and Drug Administration (FDA) approved the use of pembrolizumab to patients with advanced, refractory cancers experiencing TMB-H ≥10 mutations/megabase. The approval was based on the results of the phase II KEYNOTE-158 trial, which observed better responses in patients with TMB-H. However, the study did not include several types of cancer, such as breast, prostate and central nervous system, which typically do not respond to ICIs.
Accordingly, data from more than 10,000 patients in 31 cancer types included in TCGA (The Cancer Genome Atlas) were used to determine TMB to identify the correlation between predicted neoantigen burden and the presence of CD8 T cells. The association between TMB and ICI treatment outcomes was analyzed for both objective response rates (ORR, N = 1551) and for overall survival (OS, N = 1936). The authors hypothesized that TMB status would not be able to predict immunotherapy response.
For cancers with a strong correlation between TMB status and T-cell infiltration, patients with TMB-H showed better clinical results. In all cancer types in this category, patients with TMB-H had ORR of 39.8% at ICI, which was significantly higher than those with low TMB (OR = 4.1; P< 2×10-16).
On the other hand, in cancer types that showed no relationship between CD8 T-cell levels and neoantigen load, such as breast cancer, prostate and gliomas, TMB-H tumors failed to reach ORR of 20% (ORR = 15.3%; P = 0.95), even showing a significantly lower ORR compared to tumors with low TMB (OR= 0.46; P = 0.02).
In addition, the investigators found that assessing TMB status by sequencing a targeted panel of cancer-related genes can overestimate the value when compared to whole-exome sequencing (WES), which offers an unbiased approach.
The authors conclude that the application of TMB-H as a biomarker for ICI treatment is faulty, and further tumor-specific studies are needed in order to better determine the value of TMB for each cancer type. The authors observed that this study is limited because it involves retrospective analyses in various DNA sequencing approaches, as well as obtaining clinical outcomes reported in the different included cohorts.
References:
- Dj McGrail, et al. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Annals of Oncology. March 2021. DOI:https://doi.org/10.1016/j.annonc.2021.02.006
