title: Associations between CYP2A6 polymorphisms and outcomes of adjuvant S-1 chemotherapy in patients with curatively resected gastric cancer.
abstract: BACKGROUND
  Oral fluoropyrimidine S-1 contains tegafur, which is metabolized to 5-fluorouracil by cytochrome P450 2A6 (CYP2A6). We here examined associations between CYP2A6 polymorphisms and treatment outcomes of adjuvant S-1 in gastric cancer patients.
  
  
  METHODS
  Patients received adjuvant S-1 (40 mg/m2twice daily, days 1-28, every 6 weeks for eight cycles) after curative surgery for pathological stage II-III gastric cancer. We analyzed the wild-type allele (W) (CYP2A6*1) and four variant alleles (V) (CYP2A6*4, *7, *9, *10) that abolish or reduce this enzyme activity.
  
  
  RESULTS
  Patients (n = 200) were enrolled between November 2007 and July 2013 with the following clinical characteristics: median age, 57 years (range, 32-83 years); 128 men, 72 women. With a median follow-up of 46.4 months, the 3-year relapse-free survival (RFS) and overall survival (OS) rates were 83.1 % (95 % CI, 77.7-88.5 %) and 94.8 % (95 % CI, 91.6-98.0 %), respectively. Genotype distributions were as follows: W/W (n = 49, 24.5 %), W/V (n = 94, 47.0 %), and V/V (n = 57, 28.5 %). Overall toxicity did not differ according to genotype for any grade (p = 0.612) or grade ≥3 (p = 0.143). However, RFS differed significantly according to CYP2A6 genotype. The 3-year RFS rates were 95.9 % for W/W, 83.1 % for W/V, and 72.5 % for V/V (p = 0.032). Carriers of W/V and V/V genotypes had a poorer RFS with a hazard ratio of 3.41 (95 % CI, 1.01-11.52; p = 0.049) and 4.03 (95 % CI, 1.16-13.93; p = 0.028), respectively, compared with the W/W genotype.
  
  
  CONCLUSIONS
  CYP2A6 polymorphisms are not associated with toxicity of S-1 chemotherapy, but correlate with the efficacy of S-1 in the adjuvant setting for gastric cancer.
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea.
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea.
authors.forename: Sook Ryun
authors.initials: SR
authors.lastname: Park
authors.affiliation: Department of Hematology and Oncology, Gangneung Asan Hospital, 38, Bangdong-gil, Sacheon-myeon, Gangneung, Republic of Korea.
authors.forename: Yongchel
authors.initials: Y
authors.lastname: Ahn
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea.
authors.forename: Min-Hee
authors.initials: MH
authors.lastname: Ryu
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea.
authors.forename: Baek-Yeol
authors.initials: BY
authors.lastname: Ryoo
authors.affiliation: Department of Laboratory Medicine, Center for Diagnostic Oncology, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Republic of Korea.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Kong
authors.affiliation: Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Republic of Korea.
authors.forename: Jeong Hwan
authors.initials: JH
authors.lastname: Yook
authors.affiliation: Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Republic of Korea.
authors.forename: Moon-Won
authors.initials: MW
authors.lastname: Yoo
authors.affiliation: Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Republic of Korea.
authors.forename: Beom Su
authors.initials: BS
authors.lastname: Kim
authors.affiliation: Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Republic of Korea.
authors.forename: Byung Sik
authors.initials: BS
authors.lastname: Kim
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea. ykkang@amc.seoul.kr.
authors.forename: Yoon-Koo
authors.initials: YK
authors.lastname: Kang
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D018279:Carcinoma, Signet Ring Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics*; D004338:Drug Combinations; D005260:Female; D005500:Follow-Up Studies; D005743:Gastrectomy; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010094:Oxonic Acid / Q000627:therapeutic use*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D015996:Survival Rate; D005641:Tegafur / Q000627:therapeutic use*
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6
keywords: CYP2A6 polymorphisms; Gastric cancer; S-1