Efficacy of immune checkpoint blockade in MUTYH -associated hereditary colorectal cancer

SummaryColorectal carcinomas (CRCs) caused by hereditary biallelicMUTYH gene mutations are characterized by elevated mutation load and high lymphocyte infiltration. Given that these tumor features are associated with the response to immune checkpoint inhibitors, we administered nivolumab to a CRC patient who carried two inactiveMUTYH alleles (p.Y179C and p.G396D) and previously experienced failure of chemotherapy. This experimental treatment resulted in a pronounced tumor response. We further compared tumor lymphocyte infiltration inMUTYH-associated (n = 3), high-level microsatellite instability (MSI-H,n = 8) and microsatellite stable (MSS,n = 6) CRCs. BothMUTYH-driven and MSI-H CRCs showed noticeably higher lymphocyte densities than those of microsatellite stable tumors; this difference reached the level of statistical significance for the comparison of central areas of the tumors (p = 0.02 and 0.03, respectively) but not for the invasive tumor margins. AlthoughMUTYH-associated tumors are exceptionally rare among unselected CRC cases, their share in CRC patients with somaticKRAS p.G12C substitution approaches 5 –25%. These observations provide a rationale for further evaluation of the efficacy of the immune checkpoint blockade inMUTYH-driven CRC.
Source: Investigational New Drugs - Category: Drugs & Pharmacology Source Type: research