title: Thymidylate synthase expression in hepatic tumors is a predictor of survival and progression in patients with resectable metastatic colorectal cancer.
abstract: OBJECTIVE
  To investigate the role of thymidylate synthase (TS),p53, and epidermal growth factor receptor (EGF-R) expressions in hepatic tumors in predicting overall survival (OS), progression-free survival (PFS), and hepatic progression-free survival (HPFS) in patients with resectable metastatic colorectal cancer who were randomly assigned to receive either systemic chemotherapy (SYS) alone or systemic and hepatic arterial infusion (HAI+SYS) chemotherapy following liver surgery.
  
  
  METHODS
  Tissues from metastatic tumors were collected during liver resection from 156 patients, and marker expressions were determined using immunohistochemistry on frozen samples. Univariate associations between marker expressions and baseline variables with OS, PFS, and HPFS were examined. Independent predictors of outcome were determined using a multivariate Cox model.
  
  
  RESULTS
  In multivariate analyses, TS overexpression was found to be an independent factor of poor prognosis in OS (P <.01), PFS (P =.06), and HPFS (P <.01). In addition, resection margin was a significant independent factor for all three outcomes. Patients who received HAI+SYS experienced delayed progression in general, and in the liver, specifically. Increased levels of serum alkaline phosphatase correlated with hepatic progression. We also found a significant TS-treatment interaction for OS (P =.01) in multivariate analysis. In particular, TS+ patients receiving HAI+SYS had significantly higher survival than those receiving SYS (64 month sv 21 months; P =.01).
  
  
  CONCLUSIONS
  TS levels in hepatic tumors and resection margin are independent predictors of survival and progression in patients with metastatic colorectal cancer, whereas p53 and EGFR are not independent predictors. Treatment with HAI + SYS significantly improved the survival profile of TS+ patients.
authors.affiliation: Departments of Epidemiology and Biostatistics, Medicine, Surgery, and Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. gonenm@mskcc.org
authors.forename: Mithat
authors.initials: M
authors.lastname: Gonen
authors.forename: Amanda
authors.initials: A
authors.lastname: Hummer
authors.forename: Alice
authors.initials: A
authors.lastname: Zervoudakis
authors.forename: Deidre
authors.initials: D
authors.lastname: Sullivan
authors.forename: Yuman
authors.initials: Y
authors.lastname: Fong
authors.forename: Debabrata
authors.initials: D
authors.lastname: Banerjee
authors.forename: David
authors.initials: D
authors.lastname: Klimstra
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: Joseph
authors.initials: J
authors.lastname: Bertino
authors.forename: Nancy
authors.initials: N
authors.lastname: Kemeny
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D018450:Disease Progression; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000032:analysis / Q000096:biosynthesis; D005260:Female; D005819:Genetic Markers; D006499:Hepatic Artery; D006801:Humans; D007150:Immunohistochemistry; D007261:Infusions, Intra-Arterial; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D013940:Thymidylate Synthase / Q000032:analysis / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000096:biosynthesis
chemical_list: D005819:Genetic Markers; D016159:Tumor Suppressor Protein p53; D013940:Thymidylate Synthase; D066246:ErbB Receptors