"Persistent" Subset of Tumor Mutations May Predict Immunotherapy Response

Certain tumor mutations may be more persistent than others and therefore more predictive of durable immunotherapy response than overall tumor mutational burden (TMB), according to research published today in Nature Medicine.

TMB, or the total number of mutations in a tumor, has been explored as a marker to predict immunotherapy response, but with varied success. Typically, the mutations factored into overall TMB would be weighted the same, but the study authors aimed to find out whether certain mutations are more relevant than others for immune therapy response.

“There’s a lot of frustration in trying to use tumor mutation burden as a universal predictive biomarker of immunotherapy response across cancers,” senior study author Valsamo Anagnostou, MD, PhD, director of the thoracic oncology biorepository and co-leader of the Johns Hopkins Molecular Tumor Board and the Lung Cancer Precision Medicine Center of Excellence, said in a statement. “Therefore, it’s imperative to identify the most biologically meaningful subset of mutations within the overall TMB. Our study showed that such mutations reside in aneuploid regions (regions with extra or missing genetic material) of the genome.”

The researchers evaluated mutations in 9242 tumors across 31 cancer types in The Cancer Genome Atlas. This included cancer types that respond to immunotherapy, such as melanoma, non–small-cell lung cancer (NSCLC), and mesothelioma. The goal was to identify mutation types that are less likely to be lost and could be included in a measure of persistent tumor mutation burden (pTMB).

Unlike typical cells, which usually have 2 copies of each chromosome, cancer cells may have just 1 copy of some chromosomes or multiple copies. Mutations within genomes that have abnormal chromosome numbers, known as aneuploid genomes, are where the authors expected persistent mutations to be.

“These ‘stubborn,’ or persistent, mutations are always there in cancer cells, and these mutations may render the cancer cells continuously visible to the immune system,” Anagnostou said. “If the cancer cell is seen by the immune system as something foreign, then there is an anti-tumor immune response. In the case of immunotherapy, this response is augmented, and the immune system continues to eliminate cancer cells harboring these persistent mutations over time.”

They found that regions of the cancer genome that have just 1 chromosome copy per cell had a lower rate of mutation losses than regions with 2 copies per cell. When researchers compared the distribution of overall TMB with pTMB in each tumor type, they found that TMB and pTMB were not always aligned. Some tumors were classified differently when assessed for overall TMB versus pTMB.

“In looking at how different persistent mutation is compared to the overall TMB, we found re-classification rates of TMB-high/low to persistent mutation load-high/low tumors up to 53% in individual tumor types, and a median re-classification rate of 33% across tumor types,” first author Noushin Niknafs, PhD, a research associate at the Johns Hopkins Kimmel Cancer Center, said.

In 7 published cohorts of patients with melanoma, NSCLC, or mesothelioma and a new cohort of patients with HPV-negative head and neck cancer all treated with immune checkpoint blockades, the authors explored the relationship between pTMB and TMB. Among these tumors, TMB and pTMB differed, and some tumors showed high overall TMB with low pTMB or vice versa.

In an analysis including 542 patients with melanoma, NSCLC, mesothelioma, and head and neck cancer, high pTMB was more predictive of immune therapy response compared with measures of overall TMB, the number of mutations prone to loss, or tumor aneuploidy. Persistent mutations were found to be 60 times less likely to be lost based on an analysis of samples taken before immunotherapy initiation and samples taken at the time of acquired resistance.

Overall, the authors conclude that persistent mutations that are less likely to be lost during immunotherapy may be key drivers of consistent immunotherapy response. These mutations and pTMB may hold promise as predictors of therapy response in patients cancer.

Reference

Niknafs N, Balan A, Cherry C, et al. Persistent mutation burden drives sustained anti-tumor immune responses in human cancers. Nat Med. Published online January 26, 2023. doi:10.1038/s41591-022-02163-w