Majority of -Mutant and -Deficient Colorectal Carcinomas Achieve Clinical Benefit From Immune Checkpoint Inhibitor Therapy and Are Microsatellite Instability-High.

Purpose: Microsatellite instability-high (MSI-H) colorectal carcinomas (CRCs) show high rates of response to immune checkpoint inhibitors (IOs). mutations and protein loss have been proposed as causes of resistance to IOs, yet they are enriched in MSI-H CRC. We aimed to characterize -mutant, IO-naive CRC.

Patients And Methods: All CRCs with results for Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets, a next-generation sequencing assay that interrogates > 400 genes for mutations as well as MSI status, were surveyed for mutations. All -mutant CRCs were assessed for expression of , major histocompatibility complex class I, and programmed death-1 ligand (PD-L1) via immunohistochemistry and average CD3 and CD8 tumor-infiltrating lymphocyte counts against a control group of MSI-H wild-type CRCs.

Results: Fifty-nine (3.4%) of 1,751 patients with CRC harbored mutations, with 84% (77 of 92) of the mutations predicted to be truncating. mutations were significantly enriched in MSI-H CRCs, with 44 (24%) of 182 MSI-H CRCs harboring mutations ( < .001). Thirty-two of 44 -mutant CRCs with available material (73%) had complete loss of expression, whereas all 26 CRCs with wild-type retained expression ( < .001). mutation status was not associated with major histocompatibility complex class I expression, or mutation, tumor-infiltrating lymphocyte level, or PD-L1 expression after adjustment for MSI status. Of 13 patients with -mutant CRC who received programmed death-1 or PD-L1 IOs, 11 (85%) achieved clinical benefit, defined as stable disease or partial response using Response Evaluation Criteria in Solid Tumors criteria.

Conclusion: mutations occur in approximately 24% of MSI-H CRCs and are usually associated with loss of expression. Most patients with -mutant MSI-H CRC with loss of protein expression obtain clinical benefit from IOs.