Annals of Oncology Advance Access originally published online on February 1, 2008
Annals of Oncology 2008 19(5):915-919; doi:10.1093/annonc/mdm599
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gastrointestinal tumors |
Prognostic significance of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase protein expression in colorectal cancer patients treated with or without 5-fluorouracil-based chemotherapy
1 Oncology Research Institute
2 Department of Pathology
3 Department of Community, Occupational and Family Medicine, National University of Singapore
4 Department of Haematology–Oncology, National University Hospital, Singapore
5 School of Surgery and Pathology, The University of Western Australia, Perth
6 Department of Radiation Oncology, Sir Charles Gairdner Hospital, Perth, Australia
7 Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA
* Correspondence to: Dr R. Soong, Oncology Research Institute, Center for Life Sciences #02-14G, 28 Medical Drive, National University of Singapore, 117456 Singapore. Tel: +65-65168055; Fax: +65-68739664; E-mail: nmirs{at}nus.edu.sg
Background: Low tumour expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP) have been linked with improved outcome for colorectal cancer (CRC) patients treated with 5-fluorouracil (5-FU). It is unclear whether this occurs because such tumours have better prognosis or they are more sensitive to 5-FU treatment.
Patients and methods: Associations between TS, DPD and TP levels, determined by tissue microarrays and immunohistochemistry, and survival was evaluated in 945 CRC patients according to treatment status.
Results: Low TS and DPD expression associated with worse prognosis in stage II [hazard ratio (HR) = 1.69, 95% confidence interval (CI) (1.09–2.63) and HR = 1.92 (95% CI 1.23–2.94), respectively] and stage III CRC patients treated by surgery alone [HR = 1.39 (95% CI 0.92–2.13) and HR = 1.49 (95% CI 1.02–2.17), respectively]. Low TS, DPD and TP associated with trends for better outcome in stage III patients treated with 5-FU [HR = 0.81 (95% CI 0.49–1.33), HR = 0.70 (95% CI 0.42–1.15) and HR = 0.66 (95% CI 0.39–1.12), respectively].
Conclusion: Low TS and DPD expression are prognostic for worse outcome in CRC patients treated by surgery alone, whereas low TS, DPD and TP expression are prognostic for better outcome in patients treated with 5-FU chemotherapy. These results provide indirect evidence that low TS, DPD and TP protein expression are predictive of good response to 5-FU chemotherapy.
Key words: colorectal cancer, fluorouracil, predictive, prognostic, thymidylate synthase
Received for publication July 12, 2007. Revision received December 10, 2007. Accepted for publication December 17, 2007.