ORIGINAL ARTICLE Thymidylate synthase expression in primary colorectal tumours is correlated with its expression in metastases RIYAD BENDARDAF 1,2 , ADAM ELZAGHEID 1,3 , HANAN LAMLUM 1,2 , ANNIKA A ˚ LGARS 1,2 , EIJA KORKEILA 1 , RAIJA RISTAMA ¨ KI 1 , YRJO COLLAN 3 , KARI SYRJA ¨ NEN 1 & SEPPO PYRHO ¨ NEN 1 1 Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland, 2 Medicity Research Laboratory, University of Turku, Turku, Finland, and 3 Department of Pathology, University of Turku, Turku, Finland Abstract Objective. Thymidylate synthase (TS) is the rate-limiting enzyme in the synthesis of pyrimidine nucleotides and as such a critical target for fluoropyrimidines, which are widely used in the treatment of colorectal cancer (CRC). The purpose of this study was to investigate TS expression in the primary tumours (PTs) and their metastases (M) in advanced CRC. Material and methods. TS expression was determined immunohistochemically in paraffin-embedded biopsies of PT-M pairs in 39 CRC patients, as related to the clinical data. Results. There was no difference in the mean TS index of PTs compared with that of M, 1.25 and 1.14, respectively (p  /0.12). TS expression of PTs was above the mean more often than that of M (61.5% and 41.0%, respectively, p  /0.035). High TS expression in PTs was significantly related to high expression in M (the Fisher exact test, p  /0.001). Using the absolute index values, TS expression in PT and M was significantly correlated (Pearson R  /0.501, p  /0.001). In 29/39 (74.3%) pairs, PT and M had concordant expression levels (Cohen’s kappa 0.508, 95% CI 0.260  0.756, p  /0.001; intraclass correlation coefficient (ICC)  /0.679, 95% CI 0.358  0.836, p  /0.0001). No significant association was found between TS expression and any of the clinicopathological variables, disease outcome (DFS, DSS) or its response to treatment in univariate or multivariate analysis. Conclusions. Albeit usually higher, TS expression in PT was closely correlated with TS expression in M. This suggests that measurement of TS in primary CRC accurately predicts TS expression in subsequent metastases, which may help in selecting those patients most likely to respond to 5-FU-based regimens. Key Words: CRC, immunostaining, metastasis, primary, thymidylate synthase Introduction Colorectal cancer (CRC) is the second most fre- quent cancer in Europe in 2004, responsible for 13% (376,400) of all incident cancer cases. It is also the second most frequent cause of cancer mortality in Europe, with 11.9% (203,700) annual deaths [1]. When localized, CRC is often a curable disease, but the overall prognosis is determined by the extent of local, and particularly metastatic, tumour spread. The disease outlook is relatively poor, because advanced disease is a significant cause of world- wide cancer-related mortality. Thus, estimated 5- year survival rates range from nearly 90% in stage I disease (Dukes’ A) to less than 10% in patients with metastatic disease (Dukes’ D) [1]. For the majority of patients, chemotherapy can give substantial improvement in survival. The standard care for some time has been the fluoropyrimidine, 5- fluorouracil (5-FU), modulated by leucovorin and in combination with irinotecan or oxaliplatin. 5-FU interferes with nucleotide synthesis, and hence the synthesis of DNA in dividing cells. The addition of leucovorin enhances the DNA-directed effects of 5- FU and prolongs the duration of action. Fluoropyrimidine metabolites form a covalent complex with thymidylate synthase (TS). Formation of this complex prevents biosynthesis of intracellular Correspondence: Riyad Bendardaf, MD, PhD, Department of Oncology and Radiotherapy, Turku University Hospital, Savitehtaankatu 1, P.B. 52, FIN-20521, Turku, Finland. Tel:  /358 2 3132 800. Fax:  /358 2 3132 809. E-mail: riyben@utu.fi Scandinavian Journal of Gastroenterology, 2007; 42: 471  476 (Received 26 June 2006; accepted 14 August 2006) ISSN 0036-5521 print/ISSN 1502-7708 online # 2007 Taylor & Francis DOI: 10.1080/00365520600960120