A Case of Pancreatic Cancer with High Tumor Mutation Burden Showing a Remarkable Response to Pembrolizumab

Pancreatic cancer (PC) is an aggressive malignancy with limited therapeutic options and generally poor responsiveness to immune checkpoint inhibitors (ICIs). Microsatellite instability-high (MSI-High) and tumor mutation burden-high (TMB-High) phenotypes are rare, each occurring in approximately 1% of PC cases, but may predict improved response to ICIs. We report a case of recurrent PC harboring both MSI-High and markedly elevated TMB, in which pembrolizumab achieved an exceptional and durable response.

A 72-year-old man presented with appetite loss, and contrast-enhanced CT revealed a large pancreatic tail tumor invading the stomach, colon, spleen, and left kidney. Fine-needle biopsy confirmed adenocarcinoma. Despite initial modified FOLFIRINOX therapy showing progressive disease, subsequent gemcitabine plus nab-paclitaxel achieved partial response (PR). However, gastrointestinal bleeding due to gastric invasion necessitated surgery. The patient underwent extensive resection, including distal pancreatectomy with splenectomy, total gastrectomy, partial colectomy, nephrectomy, adrenalectomy, and portal vein resection and reconstruction using the left renal vein. Pathology demonstrated well-differentiated ductal adenocarcinoma with multiorgan invasion and portal vein tumor thrombus (ypT3N1M0, Stage IIB, Evans Grade IIb). Although adjuvant chemotherapy was considered, it could not be initiated because of persistent postoperative diarrhea and delayed recovery of the patient's general condition. Four months after surgery, recurrence was detected in the para-aortic lymph nodes, with suspected peritoneal dissemination causing right hydronephrosis, accompanied by elevated carbohydrate antigen 19-9 (CA19-9). Comprehensive genomic profiling using the surgically resected tumor specimen revealed MSI-High status and extremely high TMB (75 mutations/Mb), and genomic alterations in MSH2, MSH3, KRAS, TP53, ARID1A, ATR, and SMAD2. Pembrolizumab was initiated, leading to rapid normalization of CA19-9 and continuous tumor shrinkage. The best overall response was classified as PR, and this PR has been maintained. At 26 months after surgery, the patient remains on pembrolizumab with sustained clinical benefit and no significant immune-related adverse events.

This case highlights the potential for exceptional and durable response to pembrolizumab in PC characterized by concurrent MSI-High and markedly elevated TMB. Given the rarity of these biomarkers and the typically poor prognosis of PCs, early genomic profiling may facilitate personalized treatment strategies and improve outcomes in selected patients.