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Thymidylate Synthase Expression in Hepatic Tumors Is a Predictor of Survival and Progression in Patients With Resectable Metastatic Colorectal Cancer

Mithat Gonen, Amanda Hummer, Alice Zervoudakis, Deidre Sullivan, Yuman Fong, Debabrata Banerjee, David Klimstra, Carlos Cordon-Cardo, Joseph Bertino, Nancy Kemeny

From the Departments of Epidemiology and Biostatistics, Medicine, Surgery, and Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY; Department of Medicine, the Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ.

Address reprint requests to Mithat Gonen, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Box 44, New York, NY 10021; email: gonenm{at}mskcc.org.

Purpose: 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.

Patients and 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, TSoverexpression 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 monthsv 21 months; P = .01).

Conclusion: TSlevels in hepatic tumors and resection margin are independent predictors of survival and progression in patients with metastatic colorectal cancer, whereasp53and EGFRare not independent predictors. Treatment with HAI+SYS significantly improved the survival profile of TS+ patients.

Supported by NCI grant 5R01CA61524-7.

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