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Overexpression of FLIP_L Is an Independent Marker of Poor Prognosis in Colorectal Cancer Patients

Authors' Affiliations: ¹ Section of Gastrointestinal Surgery, University Hospital Nottingham and ² Academic Department of Clinical Oncology, Nottingham City Hospital, Nottingham, United Kingdom

Requests for reprints: Lindy Durrant, Department of Clinical Oncology, University Hospital Nottingham, Hucknall Road, Nottingham, United Kingdom. Phone: 44-115-924-9924, ext. 42800; Fax: 44-115-970-9428; E-mail: Lindy.Durrant{at}nottingham.ac.uk.

Purpose: Colorectal cancer is one of the most common cancers. The tumor necrosis factor–related apoptosis inducing ligand (TRAIL) pathway transmits apoptotic signals and anticancer agents that activate this system, which are in clinical development. We sought to determine the prognostic value of the clinically most relevant members of this pathway in colorectal cancer patients.

Experimental Design: We used an arrayed panel of colorectal cancer tissue to assess the protein expression of the functional TRAIL receptors (TRAIL-R1 and TRAIL-R2) and both the long and short forms of FLICE inhibitory protein (FLIP_L and FLIP_S). Disease-free survival was examined by Kaplan-Meier estimates and the log-rank test. Prognostic factors were determined by Cox multivariate analysis.

Results: The TRAIL receptors and FLIP_S were not associated with survival. On univariate analysis, strong FLIP_L expression was associated with a significantly higher survival (P = 0.0082). On multivariate analysis using the Cox proportional hazards model, FLIP_L phenotype was significantly associated with a poor prognosis in this series (hazard ratio, 2.04; 95% confidence interval, 1.18-3.56; P = 0.011).

Conclusions: Overexpression of FLIP_L, but not TRAIL-R1 or TRAIL-R2, provides stage-independent prognostic information in colorectal cancer patients. This may indicate a clinically more aggressive phenotype and a subset of patients for whom more extensive adjuvant treatment would be appropriate.