title: Pharmacogenetic Analysis of INT 0144 Trial: Association of Polymorphisms with Survival and Toxicity in Rectal Cancer Patients Treated with 5-FU and Radiation.
abstract: OBJECTIVE
  We tested whether 18 polymorphisms in 16 genes (GSTP1, COX2, IL10, EGFR, EGF, FGFR4, CCDN1, VEGFR2, VEGF, CXCR2, IL8, MMP3, ICAM1, ERCC1, RAD51, and XRCC3) would predict disease-free survival (DFS), overall survival (OS), and toxicity in the INT0144 trial, which was designed to investigate different postoperative regimens of 5-fluorouracil (5-FU)-based chemoradiation (CRT) in locally advanced rectal cancers: Arm 1 consisted of bolus 5-FU followed by 5-FU protracted venous infusion (PVI) with radiotherapy; arm 2 was induction and concomitant PVI 5-FU with radiotherapy and arm 3 was induction and concomitant bolus 5-FU with radiotherapy.
  
  
  METHODS
  DNA from 746 stage II/III rectal patients enrolled in the Southwest Oncology Group (SWOG) S9304 phase III trial was analyzed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumor tissue. The polymorphisms were analyzed using direct DNA-sequencing or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
  
  
  RESULTS
  GSTP1-Ile105Val (rs1695) was significantly associated with DFS and OS and its effect did not vary by treatment arm. The five-year DFS and OS were 53% and 58%, respectively, for G/G, 66% and 72% for G/A, and 57% and 66% for A/A patients. In arm 2, IL8-251A/A genotype (rs4073) was associated with a lower risk of toxicities (P = 0.04). The VEGFR2 H472Q Q/Q genotype (rs1870377) was associated with a higher risk of grade 3-5 proximal upper gastrointestinal tract (PUGIT) mucositis (P = 0.04) in arm 2. However, in arm 1, this genotype was associated with a lower risk of PUGIT mucositis (P = 0.004).
  
  
  CONCLUSIONS
  rs1695 may be prognostic in patients with rectal cancer treated with adjuvant CRT. rs4073 and rs1870377 may exhibit different associations with toxicity, according to the 5-FU schedule.
authors.affiliation: University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bohanes
authors.affiliation: SWOG Statistical Center, Seattle, Washington.
authors.forename: Cathryn J
authors.initials: CJ
authors.lastname: Rankin
authors.affiliation: SWOG Group Chair's Office/Oregon Health & Science University, Portland, Oregon.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Blanke
authors.affiliation: University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Thomas
authors.initials: T
authors.lastname: Winder
authors.affiliation: University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington; and Division of Preventive Oncology at the National Center of Tumor Diseases, Heidelberg, Germany.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
authors.affiliation: Radiology Oncology Center of Olathe, Olathe, Kansas.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Smalley
authors.affiliation: University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Tyvin A
authors.initials: TA
authors.lastname: Rich
authors.affiliation: Mayo Clinic, Rochester, New York.
authors.forename: James A
authors.initials: JA
authors.lastname: Martensen
authors.affiliation: Northwestern University, Chicago, Illinois.
authors.forename: Al B
authors.initials: AB
authors.lastname: Benson
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mayer
authors.affiliation: Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Cripps
authors.affiliation: Liquid Genomics, Inc., Torrance, California.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Danenberg
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Karen W
authors.initials: KW
authors.lastname: Makar
authors.affiliation: University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.affiliation: SWOG Statistical Center, Seattle, Washington.
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Benedetti
authors.affiliation: University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California. lenz@usc.edu.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage; D059248:Chemoradiotherapy; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012004:Rectal Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005472:Fluorouracil