title: Investigation of the prognostic and predictive value of thymidylate synthase, p53, and Ki-67 in patients with locally advanced colon cancer.
abstract: OBJECTIVE
  To evaluate the value of thymidylate synthase (TS), Ki-67, and p53 as prognostic markers in patients with Dukes' B2 and C colon carcinoma.
  
  
  METHODS
  We conducted a retrospective analysis to evaluate the prognostic value of TS, Ki-67, and p53 in 465 patients with Dukes' B2 (220 patients) or Dukes' C (245 patients) colon carcinoma. Patients represent a nonrandom subset obtained from five randomized phase III trials and were treated with either surgery alone (151 patients) or surgery plus fluorouracil-based chemotherapy (314 patients). All three markers were assayed using immunohistochemical techniques.
  
  
  RESULTS
  With a minimum follow-up of 5 years, our retrospective analysis failed to demonstrate a consistent and significant association between TS, Ki-67, or p53 and either disease-free survival or overall survival. Exploratory analyses did not reveal a convincing explanation for these results that are in conflict with the published literature. Notable interactions were observed. In particular, high Ki-67 levels were associated with increased (decreased) survival in patients with low (high) TS intensity. Patients whose tumors stained positively for p53 seemed to benefit substantially from the use of adjuvant chemotherapy compared with those who were not treated (P =.05).
  
  
  CONCLUSIONS
  This retrospective investigation failed to demonstrate a significant association between TS, Ki-67, or p53 staining and clinical outcome.
authors.affiliation: National Cancer Institute, Bethesda, MD, USA.
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Allegra
authors.forename: Allyson L
authors.initials: AL
authors.lastname: Parr
authors.forename: Lester E
authors.initials: LE
authors.lastname: Wold
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Mahoney
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sargent
authors.forename: Patrick
authors.initials: P
authors.lastname: Johnston
authors.forename: Pam
authors.initials: P
authors.lastname: Klein
authors.forename: Katie
authors.initials: K
authors.lastname: Behan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Connell
authors.forename: Ralph
authors.initials: R
authors.lastname: Levitt
authors.forename: John W
authors.initials: JW
authors.lastname: Kugler
authors.forename: Maria
authors.initials: M
authors.lastname: Tria Tirona
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D003082:Colectomy; D003110:Colonic Neoplasms / Q000737:chemistry* / Q000201:enzymology / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D013940:Thymidylate Synthase / Q000032:analysis*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D016159:Tumor Suppressor Protein p53; D013940:Thymidylate Synthase; D005472:Fluorouracil