Cyclooxygenase-2 expression is an independent predictor of poor prognosis in colon cancer

Abstract

Purpose: Cyclooxygenase-2 (COX-2; PTGS2) is considered to play an important role in colorectal carcinogenesis and is often up-regulated in colon cancers. However, previous data on the influence of COX-2 expression on patient outcome have been conflicting.

Experimental design: Using 662 colon cancers (stage I-IV) in two independent prospective cohorts (the Nurses' Health Study and the Health Professionals Follow-up Study), we detected COX-2 overexpression in 548 (83%) tumors by immunohistochemistry. Cox proportional hazards models were used to compute hazard ratios (HR) of colon cancer-specific and overall mortalities, adjusted for patient characteristics and related molecular events, including the CpG island methylation phenotype, microsatellite instability, and p53, CIMP, KRAS, and BRAF mutations.

Results: During follow-up of the 662 cases, there were 283 deaths, including 163 colon cancer-specific deaths. Patients with COX-2-positive tumors showed a trend towards an inferior colon cancer-specific mortality [HR, 1.37; 95% confidence interval (95% CI), 0.87-2.14], which became significant after adjusting for tumor stage and other predictors of clinical outcome (multivariate HR, 1.70; 95% CI, 1.06-2.74; P = 0.029). Notably, the prognostic effect of COX-2 expression might differ according to p53 status (Pinteraction = 0.04). Compared with tumors with both COX-2 and p53 negative, COX-2-positive tumors were significantly associated with an increased cancer-specific mortality (multivariate HR, 2.12; 95% CI, 1.23-3.65) regardless of p53 status. A similar trend was observed when overall mortality was used as an outcome.

Conclusion: COX-2 overexpression is associated with worse survival among colon cancer patients. The effect of COX-2 on clinical outcome may be modified by p53 status.

Figure 1. COX-2 Expression in Colon Cancer

A. No COX-2 overexpression in colon cancer (arrow) or normal colonic mucosa (empty arrowheads). B. Weak COX-2 overexpression (COX-2 negative) in colon cancer (arrows). C. D. Strong COX-2 overexpression in colon cancer (arrows).

Figure 2. Kaplan-Meier survival curves in colon cancer according to tumoral COX-2 status

Figure 3. Stratified analysis of colon cancer-specific mortality in COX-2(+) tumors

Log_e(adjusted HR) with 95% CI for COX-2 positive tumors (vs. COX-2 negative tumors) in various strata is shown. Note that log_e(HR) is great than 0 (i.e., HR>1) in most strata [except for p53(+)], indicating that COX-2 is associated with increased mortalities. CI, confidence interval; CIMP, CpG island methylator phenotype; HPFS, Health Professionals Follow-up Study; HR, hazard ratio; MSI, microsatellite instability; NHS, Nurses' Health Study.