Do thymidylate synthase gene promoter polymorphism and the C/G single nucleotide polymorphism predict effectiveness of adjuvant 5-fluorouracil-based chemotherapy in stage III colonic adenocarcinoma?
Since 5-fluorouracil (5-FU)-based chemotherapy has become standard adjuvant treatment for patients with node-positive colonic adenocarcinoma, there has arisen the need for predictive factors. Thymidylate synthase (TS) is a major target of 5-FU's action, and high TS expression in carcinoma cells could reduce its cytostatic effect. Both, a 28-base pair repeat polymorphism and a cytosine vs. guanine single nucleotide polymorphism in the promoter region of the TS gene are known to modulate its expression. All patients with a single, non-metachronous node-positive colonic adenocarcinoma who underwent a potentially curative resection at this institution in the years 1994-2002, and who received adjuvant 5-FU (n=95) were included in this study. Ninety-four of the 95 patients were successfully genotyped: 70 patients were classified as TS gene low-expressors (2R-2R, 2R-3C and 3C-3C), and 24 patients were classified as high-expressors (2R-3G, 3C-3G and 3G-3G). Contrary to the hypothesis, Kaplan-Meier survival analysis did not reveal any differences between the groups (power of 0.8 to detect an absolute survival difference >30%). In a Cox model, venous angioinvasion and the infiltrative pattern of tumour invasion were strong adverse factors. These results argue against a practical role for the TS gene repeat polymorphism or the C/G single nucleotide polymorphism as a predictive factor. However, by careful histopathological examination a high-risk group of node-positive patients can be defined that could be candidates for studies of alternative (more aggressive) adjuvant treatment.
Prall
Friedrich
F
Institute of Pathology, University of Rostock, D-18055 Rostock, Germany. friedrich.prall@med.uni-rostock.de
Ostwald
Christiane
C
Schiffmann
Leif
L
Barten
Malte
M
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012189:Retrospective Studies; D015996:Survival Rate; D013940:Thymidylate Synthase / Q000235:genetics* / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D013940:Thymidylate Synthase; D005472:Fluorouracil