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Cyclooxygenase-2 Expression Is an Independent Predictor of Poor Prognosis in Colon Cancer

Authors' Affiliations: ¹ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School; ² Department of Pathology, Brigham and Women's Hospital, Boston and Harvard Medical School; ³ Department of Epidemiology, Harvard School of Public Health; ⁴ Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; ⁵ Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts and ⁶ Department of Pathology, Kanagawa Cancer Center, Yokohama, Japan

Requests for reprints: Shuji Ogino, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 44 Binney Street, Room JF-215C, Boston, MA 02115. Phone: 617-632-3978; Fax: 617-277-9015; E-mail: shuji_ogino{at}dfci.harvard.edu.

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 (P_interaction = 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.