That high OPRT predicted grade 3–4 AEs as well as affected response can be theoretically understood, and in animal models, oteracil in S-1 was found to inhibit the OPRT by 70% in the small intestine; however, the inhibition was limited to 0–20% in tumor regions without affecting the antitumor activity of 5-FU. Besides, high OPRT/DPD, OPRT/TP, OPRT/TS, OPRT/DPD + TP + TS, OPRT/DPD + TS, OPRT/TP + TS, and OPRT/DPD + TP were all associated with grade 3–4 AEs, among which, high OPRT/DPD exhibited the highest accuracy. Cui et al.  reported lower baseline plasmic DPD correlated with higher grade of toxicities in AGC patients with S-1 plus docetaxel by ELISA. Further studies were warranted to decide whether OPRT or OPRT/DPD better predicts grade 3–4 AEs. The literature shows severe diarrhea was dose-limiting toxicity for S-1 in Caucasians and severe neutropenia in East Asians perhaps due to CYP2A6 gene polymorphism , while this study did not see its relation to severe diarrhea, neutropenia, or total grade 3–4 AEs and no relation of CYP2A6 gene polymorphism to AUC0–24h or Cmax of 5-FU here helped explain.