Thymidylate synthase expression in hepatic tumors is a predictor of survival and progression in patients with resectable metastatic colorectal cancer.
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.
Gonen
Mithat
M
Departments of Epidemiology and Biostatistics, Medicine, Surgery, and Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. gonenm@mskcc.org
Hummer
Amanda
A
Zervoudakis
Alice
A
Sullivan
Deidre
D
Fong
Yuman
Y
Banerjee
Debabrata
D
Klimstra
David
D
Cordon-Cardo
Carlos
C
Bertino
Joseph
J
Kemeny
Nancy
N
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
D005819:Genetic Markers; D016159:Tumor Suppressor Protein p53; D013940:Thymidylate Synthase; D066246:ErbB Receptors