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

Purpose: 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. Experimental Design: 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 (WES) or targeted next-generation sequencing (NGS). The tumor microenvironment was evaluated by transcriptomic analysis and multiplex fluorescence immunohistochemistry (IHC). Results: 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; hazard ratio (HR): 6.20, P = 0.002) than those with high TMBs. Among common gene alterations in GI tumors, only PTEN mutations, which were mutually exclusive with a low TMB, were significantly associated with a lower ORRs than wild-type PTEN (21.4 vs 54.8%; odds: 4.45, P = 0.045). Compared to wild-type PTEN, PTEN mutations in the phosphatase domain were associated with significantly lower ORRs (12.5 vs 54.8%, P = 0.049), shorter PFS (2.6 vs 15.6 months; HR: 5.04, P < 0.001), lower intratumoral CD8+ T cell levels, higher intratumoral CD204+ macrophage levels, and PI3K/AKT/mTOR pathway enrichment, while PTEN mutations in the C2 domain were not. Conclusions: Low TMBs and PTEN 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.