Cyclooxygenase-2 expression and recurrence of colorectal adenomas: effect of aspirin chemoprevention.
BACKGROUND
Low-dose aspirin reduces the incidence of colorectal cancer and recurrence of adenomas. Cyclooxygenase-2 (COX-2), one of its main target enzymes, is reportedly over-expressed in colorectal adenomas.


OBJECTIVE
To assess COX-2 expression, in relation to adenoma recurrence and the protective effect of aspirin, in a large series of colorectal adenomas, recruited from a double-blind randomised controlled trial comparing recurrences after low-dose aspirin or placebo.


METHODS
Follow-up colonoscopies were performed after 1 and 4 years to assess adenoma recurrence. COX-2 expression was assessed by immunohistochemistry for each adenoma obtained at baseline colonoscopy, separately for epithelium, deep stroma and overall. Architecture, grade of dysplasia, K-ras mutation, p53 and cyclin D1 expression were studied.


RESULTS
COX-2 expression could be assessed in 219 adenomas from 136


METHODS
128 adenomas (58%) from 59 patients strongly expressed COX-2. Strong COX-2 expression predominated in adenomas larger than 10 mm (84/129 vs 44/90; p=0.02) and in adenomas showing high-grade dysplasia (22/29 vs 104/188; p=0.04). Deep stromal but not epithelial initial expression of COX-2 predicted adenoma recurrence in the whole population (30/72 patients or 42% strongly expressed deep stromal COX-2 compared with 16/64 or 25% without recurrent adenoma; p=0.04). The protective effect of aspirin was mainly observed in patients in whom COX-2 initial expression was low (RR for recurrence in patients taking aspirin with low COX-2 expression: 0.59; 95% CI 0.39 to 0.90; p=0.02). There was no significant effect of aspirin at the end of the trial.


CONCLUSIONS
Over-expression of COX-2 was frequent and predominated in large and high-grade dysplasia adenomas. Deep stromal but not epithelial initial expression of COX-2 predicted recurrence of adenomas. Aspirin did not act preferentially on patients whose initial adenomas strongly expressed COX-2.
Benamouzig
Robert
R
Department of Gastroenterology, AP-HP, Hôpital Avicenne, 125 route de Stalingrad, Bobigny, France. robert.benamouzig@avc.aphp.fr
Uzzan
Bernard
B
Martin
Antoine
A
Deyra
Jacques
J
Little
Julian
J
Girard
Bernard
B
Chaussade
Stanislas
S
D000236:Adenoma / Q000201:enzymology* / Q000517:prevention & control; D000293:Adolescent; D000328:Adult; D000368:Aged; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D001241:Aspirin / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000517:prevention & control; D019938:Cyclin D1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000201:enzymology* / Q000517:prevention & control; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D055815:Young Adult
D016588:Anticarcinogenic Agents; D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; D016861:Cyclooxygenase Inhibitors; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D001241:Aspirin