COX-2 expression in rectal cancer is of prognostic significance in patients receiving preoperative radiotherapy

To determine the impact of cyclooxygenase-2 (COX-2) expression on clinical behavior in irradiated and non-irradiated rectal carcinomas. Tumor samples were collected from 1231 patients of the Dutch TME trial in which rectal cancer patients were treated with standardized surgery, and randomized for pre-operative short-term (5 times 5Gy) radiotherapy or no pre-operative radiotherapy. Tissue micro arrays were constructed from primary tumor material and COX-2 expression was assessed by immunohistochemistry. Tumor cell apoptosis was determined by M30 immunostaining. A high level of COX-2 expression after radiotherapy was associated with low levels of tumor cell apoptosis (p=0.001). COX-2 expression had no significant impact on patient survival or tumor recurrence in non-irradiated tumors. However, in patients receiving preoperative radiotherapy, high level of COX-2 expression was associated with higher incidence of distant recurrences (p=0.003, HR: 1.7, CI: 1.2-2.5), and shorter disease free survival (p=0.002, HR: 1.5 CI: 1.2-2.0) and overall survival (p=0.009, HR: 1.5, C.I.: 1.1-2.0), independent of patient age, tumor stage, tumor location or the presence of tumor cells in the circumferential resection margin. A high level of COX-2 expression following preoperative radiotherapy in resection specimens is associated with apoptosis resistance, high distant recurrence rates and a poor prognosis in rectal cancer.