title: Impact of intratumoral expression levels of fluoropyrimidine-metabolizing enzymes on treatment outcomes of adjuvant S-1 therapy in gastric cancer.
abstract: We analyzed the expression levels of fluoropyrimidine-metabolizing enzymes (thymidylate synthase [TS], dihydropyrimidine dehydrogenase [DPD], thymidine phosphorylase [TP] and orotate phosphoribosyltransferase [OPRT]) to identify potential biomarkers related to treatment outcomes in gastric cancer (GC) patients receiving adjuvant S-1 chemotherapy. In this study, 184 patients who received curative gastrectomy (D2 lymph node dissection) and adjuvant S-1 were included. Immunohistochemistry and quantitative reverse transcription polymerase chain reaction were performed to measure the protein and mRNA levels of TS, DPD, TP, and OPRT in tumor tissue. In univariate analysis, low intratumoral DPD protein expression was related to poorer 5-year disease-free survival (DFS; 78% vs. 88%; P = 0.068). Low intratumoral DPD mRNA expression (1st [lowest] quartile) was also related to poorer DFS (69% vs. 90%; P < 0.001) compared to high intratumoral DPD expression (2nd to 4th quartiles). In multivariate analyses, low intratumoral DPD protein or mRNA expression was related to worse DFS (P < 0.05), irrespective of other clinical variables. TS, TP, and OPRT expression levels were not related to treatment outcomes. Severe non-hematologic toxicities (grade ≥ 3) had a trend towards more frequent development in patients with low intratumoral DPD mRNA expression (29% vs. 16%; P = 0.068). In conclusion, GC patients with high intratumoral DPD expression did not have inferior outcome following adjuvant S-1 therapy compared with those with low DPD expression. Instead, low intratumoral DPD expression was related to poor DFS.
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: Ji-Yeon
authors: JY
authors: Kim
authors: Department of Pathology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: Eun
authors: E
authors: Shin
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: Jin Won
authors: JW
authors: Kim
authors: Department of Pathology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: Hye Seung
authors: HS
authors: Lee
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: Dae-Won
authors: DW
authors: Lee
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: Se-Hyun
authors: SH
authors: Kim
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: Jeong-Ok
authors: JO
authors: Lee
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: Yu Jung
authors: YJ
authors: Kim
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: Jee Hyun
authors: JH
authors: Kim
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: Soo-Mee
authors: SM
authors: Bang
authors: Department of Surgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: Sang-Hoon
authors: SH
authors: Ahn
authors: Department of Surgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: Do Joong
authors: DJ
authors: Park
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: Jong Seok
authors: JS
authors: Lee
authors: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors: Ju-Seog
authors: JS
authors: Lee
authors: Department of Surgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: Hyung-Ho
authors: HH
authors: Kim
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: Keun-Wook
authors: KW
authors: Lee
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D004338:Drug Combinations; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010094:Oxonic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011379:Prognosis; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005641:Tegafur / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid