Does having a high mutation burden help Glioma patients live longer on treatment?

Tumor mutation burden (TMB) refers to the number of mutations in a tumor's DNA. In many cancers, a high TMB can make tumors more visible to the immune system and improve response to immunotherapy. However, in glioma, the story is different. Research shows that high TMB in gliomas is not associated with better survival and may even indicate a more aggressive disease that does not respond well to immune checkpoint inhibitors.

What the research says

A large pan-cancer analysis found that in cancer types where CD8 T-cell levels correlate with neoantigen load (like melanoma and lung cancer), high TMB tumors had a 39.8% response rate to immune checkpoint blockade. But in glioma, there was no such correlation, and high TMB tumors failed to achieve even a 20% response rate ⁹. This suggests that the immune microenvironment in glioma does not effectively recognize or attack mutation-rich tumors.

A comprehensive study of over 10,000 gliomas identified two main pathways to hypermutation (very high TMB): a rare de novo pathway linked to inherited DNA repair defects, and a more common post-treatment pathway caused by temozolomide chemotherapy. These post-treatment hypermutated gliomas were characterized by a lack of T cell infiltration, extensive tumor heterogeneity, poor patient survival, and a low rate of response to PD-1 blockade ¹⁰.

Another study classified the immune tumor microenvironment of gliomas into four subtypes. One subtype (delta) was low in immune cells and had poorer outcomes, while others had higher immune activity. This heterogeneity may explain why high TMB alone does not predict benefit in glioma ³.

Overall, the evidence indicates that high mutation burden in glioma is not a favorable prognostic marker and does not improve survival on standard treatments or immunotherapy.

What to ask your doctor

• What is my tumor's mutation burden and how does it affect my prognosis?
• Should I consider immunotherapy, given that high TMB in glioma may not predict a good response?
• If my tumor has a high mutation burden, does that change my treatment options or clinical trial eligibility?
• Could my tumor's mutation burden be related to prior chemotherapy, and what does that mean for future treatment?
• Are there other biomarkers, like IDH mutation or MGMT methylation, that are more relevant for my glioma?