Genetic and Clinical Characteristics of Patients With Tumor Mutation Burden‐High Unresectable Pancreatic Cancer and the Efficacy of Pembrolizumab Treatment

BACKGROUND: Pembrolizumab is approved for treating patients with advanced solid tumors exhibiting high tumor mutation burden (TMB), including pancreatic cancer. However, owing to the rarity of TMB-high pancreatic cancer, its genetic and clinical characteristics, alongside the therapeutic effectiveness of pembrolizumab, remain unclear. AIMS: To investigate the characteristics and assess the effectiveness of pembrolizumab in this patient population. METHODS AND RESULTS: We retrospectively reviewed data of 293 patients with unresectable or recurrent pancreatic cancer who underwent comprehensive genomic profiling at our hospital between December 2019 and April 2023. TMB-high was observed in 13 cases (4.4%), including four patients with microsatellite instability-high (MSI-H) (1.4%). Two patients exhibited germline BRCA2 mutations: one with adenocarcinoma and the other with acinar cell carcinoma. Germline mutations in MLH1 and MSH6 were each identified in one case, both exhibiting MSI-H plus TMB-high. The frequency of pathogenic mutations in KRAS, TP53, CDKN2A, and SMAD4 was notably high. KRAS mutations were detected in 12 of the 13 patients (92.3%). Pembrolizumab was administered to six patients, yielding an objective response rate of 33.3% and a disease control rate of 66.7%. Among the three patients with MSI-H plus TMB-high, two achieved partial response, and the median progression-free survival for all three patients was 227 days. Among the three microsatellite stable (MSS) plus TMB-high cases, two exhibited stable disease, and the median progression-free survival for all three patients was 90 days. CONCLUSION: The frequency of TMB-high was 4.4%, which is slightly higher than that previously reported. Pembrolizumab demonstrated greater efficacy in patients with MSI-H plus TMB-high while also exhibiting some efficacy in patients with MSS plus TMB-high.