Thymidylate synthase expression in colorectal cancer : its role as a prognostic factor and a predictive factor in adjuvant 5-fluorouracil-based chemotherapy

* The enzyme thymidylate synthase (TS) plays a central role in DNA synthesis and is therefore an important target for chemotherapeutic treatment. We have studied the prognostic value of immunohistochemically detected TS on slices of formalin-fixed. paraffin embedded stored colorectal tumors using the monoclonal antibody TS 106. * The level of TS staining in 25 primary colorectal cancers, arbitrarily scored in grades of 0, 1,2, and 3, correlated with enzyme activity, as measured by a tritium release method. * TS was homogenously expressed in two thirds of 48 studied primary colorectal tumors. * TS expression, assessed in 70 primary colorectal cancers Dukes' stage A-D, was an independent prognostic factor for time to death in colorectal cancer (p=0.04). Low TS expression (TS grades 0 or 1) correlated with better outcome and high TS expression (TS grades 2 or 3) with worse outcome. * 243 patients with rectal cancer Dukes' stage A-C were retrospectively studied. Multivariate analysis showed that TS expression was an independent marker for loco-regional recurrence (p=0.04), distant metastasis (p=0.01) and overall survival (p=0.02). * The predictive value of TS expression was studied in colorectal cancers of Dukes' stage B and C from 862 patients who all were included in Nordic adjuvant trials evaluating the efficiency of adjuvant 5- fluorouracil (5-FU) -based chemotherapy. No benefit of adjuvant chemotherapy was found in this group of patients, which was a subgroup of the 2191 included in randomized Nordic studies. In our study group, TS expression was an independent factor for disease-free survival (p=0.05) and overall survival (p=0.05). In the group of 442 patients treated with surgery only, TS expression was an independent prognostic factor (disease-free survival, p