The prognostic significance of thymidylate synthase and dihydropyrimidine dehydrogenase in colorectal cancer of 303 patients adjuvantly treated with 5‐fluorouracil

• Published in: International journal of cancer 2007-02, Vol.120 (3), p.694-701
• Main Authors: Jensen, Søren Astrup, Vainer, Ben, Sørensen, Jens Benn
• Format: Article
• Language: English
• Subjects: Aged; Antimetabolites, Antineoplastic - therapeutic use; Antineoplastic agents; Biological and medical sciences; Chemotherapy; Chemotherapy, Adjuvant; colonic neoplasms; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - enzymology; Colorectal Neoplasms - pathology; dihydrouracil dehydrogenase (NADP); Dihydrouracil Dehydrogenase (NADP) - metabolism; disease‐free survival; Female; fluorouracil; Fluorouracil - therapeutic use; Humans; Immunohistochemistry; Male; Medical sciences; Middle Aged; Multivariate Analysis; Neoplasm Staging; Pharmacology. Drug treatments; predictive value of tests; Prognosis; Survival Analysis; survival rate; thymidylate synthase; Thymidylate Synthase - metabolism; Treatment Outcome; Tumors; tumour markers, biological
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.22318

Cytotoxic effect of 5‐fluorouracil 5‐FU is mediated through inhibition of thymidylate synthase (TS), and 5‐FU is catabolised by dihydropyrimidine dehydrogenase (DPD). Efficacy of 5‐FU may therefore depend on the TS and DPD activity of colorectal cancer. Archival tumour specimens from 303 consecutive patients were analysed for the expression of TS and DPD using immunohistochemistry. All patients were completely resected for colorectal cancer stages II–III and have subsequently received adjuvant treatment with 5‐FU. In a multivariate analysis adjusting for the impact of bowel obstruction and vascular tumour invasion, diffuse TS pattern was significantly associated with increased risk of recurrence (hazard ratio (HR) = 1.9; 95% confidence interval (CI): 1.1–3.2; p = 0.02), but without significant association to death (HR = 1.6; 95% CI: 0.9–2.8; p = 0.08). High TS intensity was not significantly associated with lower risk of recurrence (HR = 0.6; 95% CI: 0.3–1.1; p = 0.07) or death (HR = 0.6; 95% CI: 0.3–1.2; p = 0.2). High DPD intensity was significantly associated with increased risk of recurrence (HR = 1.5; 95% CI: 1.1–2.3; p = 0.03) and death (HR = 1.6; 95% CI: 1.1–2.5; p = 0.02). Patients with a combination of low TS and high DPD intensity were at significantly increased risk of both recurrence (HR = 2.1; 95% CI: 1.0–4.2; p = 0.04) and death (HR = 2.0; 95% CI: 1.0–4.0; p = 0.05). No relationship between tolerability and toxicity of 5‐FU and TS and DPD expression was found. It is concluded that characterizing colorectal carcinomas by TS and DPD expression may disclose subsets of patients with significantly greater risk of disease recurrence and early death. This may be utilized in the selection of patients for treatment approaches and for decision on follow‐up programs. © 2006 Wiley‐Liss, Inc.