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

S-1's tegafur is bioactivated to 5-fluorouracil mainly by CYP2A6; decreased-function alleles (4, 7, 9, 48), common in East Asians, reduce this bioactivation.

Retrospective study of 145 patients with pancreatic ductal adenocarcinoma who underwent curative resection and received adjuvant S-1 (78 after neoadjuvant S-1), with germline CYP2A6 genotyping by exome sequencing. Decreased-function genotypes (56.6% of patients, including 4.1% poor metabolisers) were associated with more lymph-node metastases (78.0% vs 52.4%) and shorter recurrence-free survival (median 19.2 vs 32.3 months). In multivariable analysis, poor-metaboliser status was independently associated with overall survival (HR 3.17; 95% CI 1.06-9.46).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A textbook case of germline pharmacogenetics applied to oncology (still pharmacogenetics): a CYP2A6 poor metaboliser bioactivates less tegafur, potentially underexposing to active 5-FU and worsening prognosis. The signal is consistent and independent on multivariable analysis, but the study is retrospective, single-centre and specific to East Asian populations. Prospective validation is essential before using it as a biomarker to adjust S-1 dosing.

Analysis by Dr Thibaut Benquey