Targeted therapeutic strategies in rare subtypes of pancreatic cancer: Histology, molecular profiles, and emerging opportunities.

Pancreatic cancer remains one of the deadliest malignancies, with a 5-year survival below 13% and limited response to standard therapies. Conventional pancreatic ductal adenocarcinoma (PDAC), which accounts for over 90% of cases, dominates the landscape. Yet rare subsets of histological and molecular variants - such as medullary, colloid, intraductal papillary mucinous neoplasm-associated, and acinar cell carcinomas - have distinct biology and actionable alterations. These tumors are more frequently KRAS wild-type and are enriched for homologous recombination deficiency, DNA mismatch repair defects, microsatellite instability-high status, and, notably, recurrent gene fusions, unveiling promising opportunities for precision-guided therapies in a disease that has long been resistant to standard approaches. These molecular features identify subgroups more likely to benefit from platinum-based chemotherapy, PARP inhibition, immune checkpoint blockade, or targeted agent approaches with limited activity in unselected, conventional PDAC. Emerging stratifications, including MAPK pathway status and age at diagnosis, further refine the identification of actionable subgroups. Although limited, clinical evidence, including basket trials and real-world observations, demonstrates that biomarker-guided interventions can yield meaningful and durable responses, with improved progression-free and overall survival. Incorporating a structured diagnostic algorithm that recognizes rare subtypes and integrating comprehensive genomic profiling into routine practice represents a paradigm shift from non-stratified to mechanism-driven therapy in pancreatic cancer. This narrative review summarizes the clinicopathological characteristics, molecular landscapes, and therapeutic opportunities of rare PDAC subtypes, highlighting how precision medicine can reshape prognosis and treatment in a historically hard-to-treat disease.