Clin Transl Oncol. 2026 Jan 21. doi: 10.1007/s12094-025-04214-3. Online ahead of print.

ABSTRACT

Pancreatic cancer (PC), predominantly pancreatic ductal adenocarcinoma, remains one of the most lethal malignancies, largely due to late diagnosis and intrinsic resistance to conventional therapies. In recent years, mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) have emerged as clinically actionable biomarkers in a small but distinct subset of PC, accounting for approximately 1-2% of cases. These tumors display unique molecular characteristics, including a high prevalence of wild-type KRAS and TP53, elevated tumor mutational burden, and recurrent kinase fusions, which together confer enhanced immunogenicity and increased sensitivity to immune checkpoint inhibitors (ICIs). In addition to their therapeutic relevance, dMMR/MSI-H status has important diagnostic implications for the identification of Lynch syndrome-associated pancreatic cancers, informing genetic counseling and familial risk assessment. This review summarizes current understanding of the molecular basis of mismatch repair deficiency and microsatellite instability in PC, evaluates available diagnostic approaches such as immunohistochemistry, polymerase chain reaction, and next-generation sequencing, and discusses the prognostic and predictive significance of dMMR/MSI-H status. Emerging clinical evidence supporting the use of ICIs in selected patients across neoadjuvant, adjuvant, and advanced disease settings is also reviewed, along with challenges related to assay discordance, tumor heterogeneity, and immunotherapy resistance. Finally, future directions are highlighted, emphasizing the need for standardized testing algorithms, integration of multi-omics and spatial profiling technologies, and prospective clinical studies to optimize precision treatment strategies for this rare but clinically meaningful subtype of pancreatic cancer.

PMID:41563663 | DOI:10.1007/s12094-025-04214-3