Thymidylate synthase expression in colorectal cancer: a prognostic and predictive marker of benefit from adjuvant fluorouracil-based chemotherapy.
OBJECTIVE
We studied the prognostic value of thymidylate synthase (TS) expression in primary colorectal cancer (CRC) and the role of TS expression as a predictor of chemotherapeutic benefit in patients treated with adjuvant chemotherapy.


METHODS
TS expression was immunohistochemically assessed on tumor sections from 862 patients with CRC Dukes' stages B and C enrolled onto randomized trials evaluating fluorouracil (5-FU)-based adjuvant chemotherapy.


RESULTS
TS expression was an independent prognostic factor for disease-free (P =.05) and overall survival (P =.05). In the subgroup treated with surgery alone, TS was an independent prognostic factor for disease-free (P <.001) and overall survival (P =.001), whereas this was not the case in the subgroup of adjuvantly treated patients. Patients whose tumors expressed high TS levels had a tendency to improved outcome after adjuvant therapy (not significant). The group whose tumors expressed the highest TS grade, grade 3 (34% of the patients), had a significantly longer disease-free survival if they were treated with adjuvant therapy compared with surgery alone (multivariate analyses, P =.02), whereas patients whose tumors expressed low TS levels (28% of the patients) had an impaired outcome after adjuvant therapy (multivariate analyses: disease-free survival, P =.01; overall survival, P =.01).


CONCLUSIONS
TS expression predicts for survival independent of Dukes' stage in patients with CRC treated with surgery alone. The study indicates that patients with high TS levels may benefit from adjuvant 5-FU-based chemotherapy. However, patients with low TS levels seem to have a worse outcome when treated with adjuvant chemotherapy.
Edler
David
D
Department of Surgery, South Hospital, Stockholm, Sweden. david.edler@swipnet.se
Glimelius
Bengt
B
Hallström
Marja
M
Jakobsen
Anders
A
Johnston
Patrick G
PG
Magnusson
Inger
I
Ragnhammar
Peter
P
Blomgren
Henric
H
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000368:Aged; D000704:Analysis of Variance; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D002955:Leucovorin / Q000008:administration & dosage; D007978:Levamisole / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D016019:Survival Analysis; D013940:Thymidylate Synthase / Q000097:blood*; D016896:Treatment Outcome
D000276:Adjuvants, Immunologic; D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D007978:Levamisole; D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil