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Katherine M. Sheehan, MB; Kieran Sheahan, MRCPath; Diarmuid P. O'Donoghue, FRCP; Fergus MacSweeney, MB; Ronan M. Conroy, BA; Desmond J. Fitzgerald, FRCPI; Frank E. Murray, FRCPEd

JAMA. 1999;282:1254-1257.

Context  Epidemiological studies have implicated the inducible form of cyclooxygenase (COX-2) in the pathogenesis of colorectal cancer; however, its role is not fully understood.

Objective  To examine the relationship between the expression of COX-2 in human colorectal cancer and patient survival.

Design  Patients diagnosed as having colorectal cancer were evaluated and followed up for up to 9.4 years (median follow-up, 2.7 years). Tumor sections were stained for COX-2 using a rabbit polyclonal antibody raised against human COX-2. The extent of COX-2 staining was graded by 2 observers blinded to outcome. Preabsorption of the anti–COX-2 antibody with a COX-2 peptide abolished the staining, demonstrating the specificity of the assay.

Setting  Gastrointestinal unit of a large general teaching hospital in Dublin, Ireland.

Participants  Seventy-six patients (median age, 66.5 years) with colorectal cancer (Dukes tumor stage A, n=9; Dukes B, n=30; Dukes C, n=25; Dukes D, n=12) whose diagnosis was made between 1988 and 1991. Fourteen normal colon biopsies were stained for COX-2 as controls.

Main Outcome Measures  Survival in years following diagnosis compared by extent of COX-2 epithelial staining (grade 1, <1%; grade 2, 1%-19%; grade 3, 20%-49%; grade 4, 50%), Dukes stage, tumor size, and lymph mode metastasis.

Results  COX-2 was found in tumor epithelial cells, inflammatory cells, vascular endothelium, and/or fibroblasts. The extent of epithelial staining was heterogeneous, varying markedly among different tumors. Normal tissue adjacent to the tumors also stained weakly for COX-2. No COX-2 was detected in control tissue samples. The Kaplan-Meier survival estimate was 68% in patients who had grade 1 tumor epithelial staining compared with 35% in those with higher grades combined (log-rank ²=5.7; P=.02). Greater expression of COX-2 correlated with more advanced Dukes stage (Kendall -b, 0.22; P=.03) and larger tumor size (Kendall -b, 0.21; P=.02) and was particularly evident in tumors with lymph node involvement (Kendall -b, 0.26; P=.02).

Conclusions  Our data indicate that COX-2 expression in colorectal cancer may be related to survival. These data add to the growing epidemiological and experimental evidence that COX-2 may play a role in colorectal tumorigenesis.

Author Affiliations: Departments of Clinical Pharmacology (Drs Sheehan and Fitzgerald) and Epidemiology (Mr Conroy), Royal College of Surgeons in Ireland, Departments of Pathology (Drs Sheahan and MacSweeney) and Gastroenterology (Dr O'Donoghue), St Vincent's Hospital, and Department of Gastroenterology, Beaumont Hospital (Drs Sheehan and Murray), Dublin, Ireland.

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