Clinical Implications of Mismatch Repair Deficiency in Pancreatic Ductal Adenocarcinoma

Pancreatic cancer is a highly aggressive and lethal disease, characterized by a limited response to chemotherapy and overall poor prognosis. Pancreatic cancers with a distinct mismatch repair deficiency, although relatively rare, have been shown to be associated with markedly better outcomes in comparison. Furthermore, whereas pancreatic cancers are generally unresponsive to current immunotherapy, this specific group of tumors has been shown to have a notable susceptibility to immune checkpoint inhibitors.

In this review, we aim to summarize the relevant literature regarding mismatch-repair associated pancreatic cancers, the impacted biological mechanisms, and the resulting vulnerabilities for potential opportunistic immunotherapeutic treatment approaches. We will also review the current clinical studies assessing survival outcomes of mismatch repair deficient pancreatic cancers and ongoing clinical trials in this emerging field.

Patients with dMMR/MSI-H pancreatic cancers harbor a distinct phenotype that has increased immune activation, greater responsiveness to immune checkpoint inhibitor therapy and better overall survival when compared to other pancreatic cancers. Although this molecular subtype makes up a small minority of cases, emerging data suggest immunotherapy may offer benefit to these patients.