Clinical Impact of Mismatch Repair Gene Mutation-Based Alert on Immunotherapy Decision Making Across Patients With...

Despite approval of pembrolizumab and dostarlimab for tumors that are deficient in mismatch repair (MMR) proteins, many patients do not undergo mismatch repair deficiency (dMMR) testing by immunohistochemistry (IHC). We demonstrated that patients with mutations in MMR genes are more likely to have dMMR, and we initiated an automated alert based on mutations in MMR genes to streamline the delivery of information to physicians. This study evaluates the utility of this alert and identifies opportunities for improvement.

An automated alert was implemented within our health database at the MD Anderson Cancer Center triggered by pathogenic variants in any of the four MMR genes. The alert recommended follow-up MMR IHC testing to proceed with clinical guidelines for immunotherapy decision making. We conducted a retrospective review of patients tested using the in-house tissue-based next-generation sequencing (NGS) assay who received this alert over a 1-year period.

Within the 4,778 patients tested using the in-house NGS assay, 225 harbored at least one mutation in one of the MMR genes and 52 (1.1%) triggered the dMMR alert. Among the alerted cases, 22 had documented dMMR IHC testing; however, only two underwent IHC after the alert was issued. The remaining 30 patients were not tested for MMR IHC because of prior immunotherapy initiation (n = 14), alternative clinical indications for immunotherapy (n = 6), or NGS-based reported microsatellite stability-stable status (n = 9). Only one patient (1.9%) underwent alert-driven IHC testing that led to a change in clinical management.

Most alerts did not result in actionable follow-up because of prior testing or established treatment decisions. To enhance clinical utility and reduce alert fatigue, iterations of the alert should be limited to patients without prior MMR IHC or microsatellite instability testing and who have not received immunotherapy.