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

Sammanfattning: ' 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<0.001, overall survival, p=0.001), while in the group of patients treated with surgery and 5-FU -based chemotherapy, TS expression was not of prognostic value. Patients with high TS -expressing tumors had a tendency toward improved clinical outcome (not significant), whereas patients whose tumors expressed a low TS level (28% of the patients) had an impaired clinical outcome following adjuvant therapy (overall survival p=0.008). ' A weak but significant association was found between Ki-67 expression and TS expression (low/high) in rectal cancer (p=0.02). There was no significant correlation between TS and Cyclin A expression (p=0.1). The prognostic value of TS expression can be explained only partly by the proliferative activity of the tumor, since ' Conclusions: TS levels, immunohistochemically assessed in colorectal cancer, are a prognostic factor independent of Dukes' stage. Patients with Dukes' C tumors with low TS expression, as determined by immunohistochemistry, will, according to our findings, have an impaired survival if they are treated with surgery and 5-FU -based adjuvant chemotherapy compared with surgery alone. Further studies in new patient material are needed to see whether the results of the present study can be reproduced. If this is the case, 5-FU -based adjuvant treatment is to be recommended only to high TS expressors, but not to low TS expressors.