medwireNews: Tumor mutational burden (TMB) could be a cross-tumor predictive biomarker of immunotherapy, say US researchers who found an association between mutational load and survival across a wide range of malignancies treated with immune checkpoint inhibitors.
They used data from 1662 patients who received PD-1, PD-L1, or CTLA-4 inhibitors – either as monotherapy or in combination – mainly for stage IV or metastatic disease and who underwent targeted next-generation sequencing with the MSK-IMPACT assay that detects somatic mutations in a predefined subset of 468 cancer-related genes.
Noting that “the median and range of mutational load have been shown to vary across tumor types,” the investigators stratified patients by TMB decile within histology. They found that a higher number of mutations was significantly associated with improved overall survival (OS) across the entire cohort, regardless of the cutoff chosen to delineate the high-TMB group.
A similar relationship between OS and mutational load was also observed when the top quintile was used to identify patients with high TMB for each cancer type, with the exception of estrogen receptor (ER)-negative breast cancer and glioma, in which a high TMB appeared to predict worse survival.
Luc Morris and colleagues, from the Memorial Sloan Kettering Cancer Center in New York, note that the association between high TMB and OS improvement did not reach statistical significance for all individual cancer types, but they suggest that this could be due to small sample sizes.
Additionally, the team points out that “the TMB cutoff associated with the top 20% of each cancer type varied markedly,” ranging from 4.4 mutations/Mb for ER-negative breast cancer to 52.2 mutations/Mb for colorectal cancer.
“Importantly, this result suggests that there is not likely to be a universal number defining high TMB that is predictive of clinical benefit to [immune checkpoint inhibitor therapy] across all cancer types, and that the optimal cutpoint is likely to vary for different cancers,” write the authors in Nature Genetics.
Of note, there was no significant difference in OS between individuals with high versus low TMB in a group of 5371 patients with metastatic cancers who did not receive immunotherapy and whose tumors were sequenced with the same assay. This suggests that the observed survival difference among checkpoint inhibitor-treated patients is not simply due to “a general prognostic benefit of high mutational load,” they say.
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