Prognostic significance of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase protein expression in colorectal cancer patients treated with or without 5-fluorouracil-based chemotherapy

• Published in: Annals of oncology Vol. 19; no. 5; pp. 915 - 919
• Main Authors: Soong, R., Shah, N., Salto-Tellez, M., Tai, B. C., Soo, R. A., Han, H. C., Ng, S. S., Tan, W. L., Zeps, N., Joseph, D., Diasio, R. B., Iacopetta, B.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-05-2008; Oxford Publishing Limited (England)
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - enzymology; Adenocarcinoma - mortality; Adenocarcinoma - pathology; Adenocarcinoma - surgery; Aged; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Chemotherapy, Adjuvant; colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - enzymology; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Colorectal Neoplasms - surgery; Dihydrouracil Dehydrogenase (NADP) - analysis; Drug Resistance, Neoplasm; Female; fluorouracil; Fluorouracil - administration & dosage; Fluorouracil - pharmacokinetics; Follow-Up Studies; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Leucovorin - administration & dosage; Male; Medical sciences; Middle Aged; Neoplasm Proteins - analysis; Neoplasm Staging; Pharmacology. Drug treatments; predictive; Prognosis; prognostic; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Survival Analysis; Thymidine Phosphorylase - analysis; thymidylate synthase; Thymidylate Synthase - analysis; Tumors; prognostic; predictive; thymidylate synthase; colorectal cancer; fluorouracil; Antineoplastic agent; Rectal disease; Prognosis; Angiogenic factor; Glycosyltransferases; Colorectal cancer; Intestinal disease; Thymidine phosphorylase; Fluorouracil; Human; Enzyme; Fluoropyrimidine derivatives; Transferases; Enzyme inhibitor; ); Malignant tumor; Dihydropyrimidine dehydrogenase (NADP; Gene expression; Thymidylate synthase; Protein; Colonic disease; Chemotherapy; Treatment; Antimetabolic; Methyltransferases; Pyrimidine derivatives; Digestive diseases; Oxidoreductases; Pentosyltransferases; Cancer
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/annonc/mdm599

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.