Survival Outcomes and Drug Response Associated With Germline Mutations in Pancreatic Cancers

초록

Objectives: Pancreatic ductal adenocarcinomas (PDAC) have poor prognosis and limited treatment options. Recent advances in next-generation sequencing (NGS) have identified germline mutations that may influence prognosis and treatment response, though their clinical relevance remains unclear. We conducted this study to understand how specific mutations affect survival and chemotherapy outcomes, aiming to inform risk stratification and personalized treatment strategies. Materials and Methods: We conducted comprehensive NGS-based germline profiling in 150 retrospectively enrolled PDAC patients. We evaluated associations between germline mutations and overall survival (OS), progression-free survival (PFS), and treatment outcomes, focusing on mutations observed in five or more cases. Results: Among the 150 PDAC patients, the top 10 most frequent germline mutations were CFTR (6.6%, chronic pancreatitis–related), BRCA2 (3%, DNA repair), RECQL4 (3%, DNA repair), FANCA (2.8%, DNA repair), FANCI (2.5%, DNA repair), POLE (2.3%, DNA repair), MRE11 (1.6%, DNA repair), RAD50 (1.5%, DNA repair), PALB2 (1.1%, DNA repair), and MSH2 (1%, mismatch repair). POLE mutation was associated with prolonged OS, whereas RNF43, NF1, CHEK2, DDX41, and FANCI mutations predicted poorer survival. Mutations such as PTCH1, RECQL4, BRCA2, and PALB2 were linked to reduced disease control, suggesting intrinsic chemoresistance. Broad subgroup analysis (e.g., MMR and BRCA) showed no significant differences in survival or treatment outcomes, underscoring the importance of individual gene-level analysis over broad mutation categories. Conclusions: Specific germline mutations in PDAC may serve as clinically meaningful prognostic markers and guide personalized therapeutic strategies. Our findings highlight the potential of integrating germline mutation data into risk stratification and treatment decision-making.