Impact of CYP2A6 Genotype on Survival Outcomes in Patients With Pancreatic Ductal Adenocarcinoma Receiving Perioperative S-1 Therapy

Objective: To evaluate the impact of CYP2A6 genetic polymorphisms on survival outcomes in patients with pancreatic ductal adenocarcinoma (PDAC) receiving perioperative S-1 therapy. Background: S-1, an oral fluoropyrimidine containing tegafur, is widely used for perioperative treatment of PDAC in Japan. Tegafur requires metabolic activation to 5-fluorouracil, primarily by CYP2A6 . Given the high prevalence of reduced-function CYP2A6 variants in East Asian populations, their clinical significance in PDAC remains unclear. Methods: This retrospective study included 145 patients with PDAC who underwent curative resection and received adjuvant S-1, including 78 patients who had received S-1–containing neoadjuvant therapy. Germline CYP2A6 variants were identified using whole-exome sequencing of peripheral blood samples. Decreased-function alleles (*4, *7, *9) and the rare nonsense allele *48 were evaluated. Patients were classified into poor, intermediate, and normal metabolizer groups. Survival outcomes were analyzed using Kaplan-Meier and Cox regression analyses. Results: Decreased-function CYP2A6 genotypes were identified in 82 patients (56.6%), including 6 poor metabolizers (4.1%). These patients had a higher frequency of lymph node metastasis than those with normal genotypes (78.0% vs. 52.4%, P =0.001). Recurrence-free survival (RFS) was significantly shorter (median, 19.2 vs. 32.3 mo; P =0.040), whereas overall survival (OS) was shorter but not statistically significant (47.9 vs. 62.2 mo; P =0.104). In multivariable analysis, CYP2A6 poor metabolizer status was independently associated with OS (HR, 3.17; 95% CI, 1.06–9.46; P =0.039). Among the 78 patients who received S-1–containing neoadjuvant therapy, both OS and RFS were significantly worse in those with decreased-function genotypes. Conclusions: Decreased CYP2A6 functional genotypes were associated with poorer oncological outcomes in patients with PDAC receiving perioperative S-1 therapy, suggesting that the CYP2A6 genotype may serve as a biomarker for optimizing treatment strategies.