Organ-sparing strategies in patients with MSI/dMMR tumors including Lynch syndrome: Current state of the art and future perspectives for clinical decision-making

Abstract

Deficiency in DNA mismatch repair (dMMR) is a common pathway of carcinogenesis across different tumor types and confers a characteristic microsatellite instability-high (MSI-H) molecular phenotype. The MSI-H/dMMR phenotype may arise from an inherited pathogenic variant in the context of Lynch syndrome and is most frequently observed in endometrial, colorectal, and gastric cancers. MSI-H/dMMR is a major predictive biomarker for the efficacy of immune-checkpoint inhibitors (ICIs). Following the approval of ICIs for metastatic disease, these drugs are now being evaluated in localized disease settings. In this review, we provide an overview of current knowledge regarding the use of ICIs as neoadjuvant therapy and as a part of immuno-ablative, surgery-sparing strategies, with a focus on Lynch-related cancers. Finally, we address the diagnosis, monitoring, and prevention challenges raised by these de-escalation strategies.