A Low Tumor Mutational Burden and <i>PTEN</i> Mutations Are Predictors of a Negative Response to PD-1 Blockade in MSI-H/dMMR Gastrointestinal Tumors.

Abstract

This study performed a comprehensive molecular characterization of microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) gastrointestinal (GI) tumors to elucidate predictors of response to PD-1 blockade. Forty-five patients with MSI-H/dMMR GI tumors, including gastric cancer, colorectal cancer, cholangiocarcinoma, small intestine cancer, pancreatic cancer, and duodenal cancer, receiving PD-1 blockade were analyzed. We conducted the genomic profiling of GI tumors by whole-exome sequencing or targeted next-generation sequencing. The tumor microenvironment was evaluated by transcriptomic analysis and multiplex fluorescence IHC. Patients with low tumor mutational burdens (TMBs) had lower objective response rates (ORRs; 0% vs. 48.8%) and a significantly shorter progression-free survival (PFS; 2.3 vs. 15.6 months; HR, 6.20; <i>P</i> = 0.002) than those with high TMBs. Among common gene alterations in GI tumors, only <i>PTEN</i> mutations, which were mutually exclusive with a low TMB, were significantly associated with a lower ORRs than wild-type <i>PTEN</i> (21.4 vs. 54.8%; odds, 4.45; <i>P</i> = 0.045). Compared with wild-type <i>PTEN, PTEN</i> mutations in the phosphatase domain were associated with significantly lower ORRs (12.5 vs. 54.8%; <i>P</i> = 0.049), shorter PFS (2.6 vs. 15.6 months; HR, 5.04; <i>P</i> < 0.001), lower intratumoral CD8⁺ T-cell levels, higher intratumoral CD204⁺ macrophage levels, and PI3K/AKT/mTOR pathway enrichment, whereas <i>PTEN</i> mutations in the C2 domain were not. Low TMBs and <i>PTEN</i> mutations, especially mutations in the phosphatase domain associated with an immunosuppressive environment, were mutually exclusive and might be negative predictors of PD-1 blockade responses in patients with MSI-H/dMMR GI tumors.