More mutations, better response to immunotherapy? What we found in tumors with a very high mutational burden

What tumor mutational burden is

Tumor mutational burden (TMB) is the number of mutations in a tumor's DNA. The more mutations, the more "foreign" the tumor looks to the immune system, and the easier it is for immunotherapy to help the body's defenses recognize it. That is why, above a certain threshold, 10 mutations per million DNA "letters," a high mutational burden is already used to recommend immunotherapy for any type of tumor.

The question

Do tumors with a very high mutational burden, above 20, form a distinct group with even better responses? If so, it would be worth using a higher cutoff to choose treatment.

What we did

We studied 133 patients with advanced tumors and a high mutational burden, across more than 20 different types of cancer, analyzed by broad genetic sequencing. We compared those with a high burden (between 10 and 20) with those with a very high burden (above 20).

What we found

• About one-third of patients had a very high mutational burden.
• These tumors had much more microsatellite instability (MSI), a fault in the DNA "proofreading" system that generates many mutations.
• Response to immunotherapy and survival were similar in both groups. The very-high-burden group lived somewhat longer, but the difference was not large enough to be considered real.

What this means for you

A high number of mutations, on its own, doesn't tell the whole story. When deciding on immunotherapy, it is better to look at mutational burden together with other information about the tumor, such as microsatellite instability and specific genetic changes.

The limitations

This is a single-center study, with a moderate number of patients and a wide variety of tumor types. Larger, multicenter studies are needed to confirm these findings.

For information only. It does not replace an individual medical assessment.