DNMT3A mutations predict PD-(L)1 blockade efficacy in NSCLC

Some patients with nonsmall-cell lung cancer (NSCLC) have somatic DNA methyltransferase 3A (DNMT3A) mutations, which are associated with a reduced DNMT3A expression and a favourable immunophenotype, reveals a study.

Furthermore, these mutations can predict improved immune checkpoint inhibitor (ICI) efficacy.

A total of 1,539 patients with advanced NSCLC treated with ICI and comprehensive genomic profiling from several independent cohorts were included in this study. The authors used beta-binomial modelling of sequencing read counts to infer mutation clonality. They used samples from Cancer Genome Atlas Program (TCGA) and NSCLC cell lines from Cancer Cell Lines Encyclopedia for transcriptomic analyses.

Of the patients, 4.7 percent had deleterious DNMT3A mutations. Those with DNMT3A-mutant NSCLC showed improved response rate (41.7 percent vs 21.5 percent; p<0.001), progression-free survival (hazard ratio [HR], 0.61; p<0.001), and overall survival (OS; HR, 0.66; p<0.01) with PD(L)1 blockade than DNMT3A wild-type cases.

Notably, DNMT3A mutations showed no significant effect on OS among patients with advanced NSCLC who were not treated with ICI (HR, 0.88; p=0.41).

“In examining the impact of DNMT3A clonality on immunotherapy outcomes to account for potential clonal hematopoiesis of indeterminate potential contamination, we confirmed that clonal DNMT3A mutations were associated with improved outcomes compared with DNMT3A wild-type cases,” the authors said.

Furthermore, DNMT3A RNA and protein expression were decreased in NSCLC cell lines with pathogenic DNMT3A mutations. In the TCGA, high DNMT3A mutations showed lowered expression of pathways involved in innate and adaptive immune response, such as interferon-γ, major histocompatibility complex-II antigen presentation, tumour necrosis factor-α, and PD-1 signalling.