Robust response to pembrolizumab in temozolomide-associated hypermutated and microsatellite instability-high functional pancreatic neuroendocrine tumor.

Pancreatic neuroendocrine tumors (PanNETs) are typically characterized by low tumor mutational burden and limited responsiveness to immune checkpoint inhibitors. Emerging evidence suggests that prior exposure to alkylating chemotherapeutic agents may be associated with a hypermutated phenotype (along with DNA mismatch repair dysfunction or DNA damage response gene alterations), potentially sensitizing tumors to immunotherapy. We present a case of a 68-year-old woman with metastatic functional PanNET (VIPoma) who developed a treatment-associated hypermutated, microsatellite instability-high phenotype following capecitabine-temozolomide therapy. Treatment with pembrolizumab resulted in a robust clinical, biochemical, and radiographic response. This case highlights dynamic genomic evolution in PanNETs and underscores the importance of serial molecular profiling in guiding therapeutic decisions.