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Thymidylate Synthase Protein Expression in Primary Colorectal Cancer: Lack of Correlation With Outcome and Response to Fluorouracil in Metastatic Disease Sites

From the Cancer Research Centre, Department of Oncology, Queen’s University Belfast, Belfast, Northern Ireland; Clinical Investigations Program, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Eastern Cooperative Oncology Group Statistical Center, Department of Biostatistical Science, Dana-Farber Cancer Institute, Boston, MA; Northwestern Memorial Hospital, Chicago, IL; University of Pennsylvania, Philadelphia, PA; and Medicine Branch, National Cancer Institute, Bethesda, MD.

Address reprint requests to Patrick G. Johnston, MD, PhD, Cancer Research Centre, Department of Oncology, Queen’s University Belfast, University Floor, Belfast City Hospital, 97 Lisburn Road, Belfast BT9 7AB, Northern Ireland; email: oncology{at}qub.ac.uk.

Purpose: The aim of this study was to investigate the utility of quantitating thymidylate synthase (TS) in the primary tumor as a surrogate for metastatic disease sites to predict the likelihood of response and outcome to fluorouracil (FU) treatment in patients with metastatic colorectal cancer.

Methods: TS protein expression was evaluated using the TS 106 antibody and the avidin biotin labeling immunohistochemical technique in primary tumor samples from 219 patients with metastatic colorectal cancer. The patients were a representative sample of those patients enrolled into the Eastern Cooperative Oncology Group E2290 protocol that evaluated five separate FU-containing regimens in patients with metastatic residual or recurrent colorectal carcinoma.

Results: Our retrospective analysis found that the level and extent of TS protein expression in the primary tumor did not correlate with overall survival in patients with metastatic or recurrent colorectal cancer. A trend toward a direct correlation between the level of TS protein expression and response was noted in tumors that expressed high TS levels. This response advantage for patients expressing high TS levels in the primary tumor was apparent regardless of what FU-based treatment the patient received but was most apparent in the subgroup treated with leucovorin, in which the level of TS expression and response to FU and leucovorin reached statistical significance (P = .034). No significant interaction could be detected between the addition of leucovorin to FU and the level of TS expression in the primary tumor.

Conclusion: This study demonstrated that measurement of TS protein levels in the primary tumor tissue does not aid in predicting outcome or response to FU in a metastatic disease site. These assays must be performed on biopsy tissue from the metastatic disease site that is used to radiologically assess response and outcome to treatment.

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