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Prognostic Significance of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand and Its Receptors in Adjuvantly Treated Stage III Colon Cancer Patients

Caroline M. van Geelen, Jantine L. Westra, Elisabeth G. de Vries, Wytske Boersma-van Ek, Nynke Zwart, Harry Hollema, H. Marike Boezen, Nanno H. Mulder, John T. Plukker, Steven de Jong, Jan H. Kleibeuker, Jan J. Koornstra

From the Departments of Medical Oncology, Medical Genetics, Gastroenterology and Hepatology, Pathology, Epidemiology, Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

Address reprint requests to Jan J. Koornstra, MD, Department of Gastroenterology and Hepatology, University Medical Center, University of Groningen, PO Box 30001, 9700 RB Groningen, the Netherlands; e-mail: j.j.koornstra{at}int.umcg.nl

Purpose: In preclinical models, there is synergism between chemotherapy and recombinant human tumor necrosis factor (TNF) –related apoptosis-inducing ligand (TRAIL) on apoptosis induction in tumor cells. Therefore, the prognostic relevance was analyzed of the expression of TRAIL and its death receptors DR4 and DR5 on disease-free survival and overall survival in stage III colon cancer patients treated with adjuvant chemotherapy.

Methods: Tissue microarrays were constructed of primary tumor tissue from 376 stage III colon cancer patients treated in a randomized adjuvant chemotherapy study (fluorouracil/levamisole v fluorouracil/levamisole/leucovorin) and stained immunohistochemically for TRAIL, DR4, and DR5. Log-rank tests and Cox proportional hazard analysis, with adjustment for treatment arm, sex, age, N stage, microsatellite instability status, and p53 mutation status, were performed.

Results: The majority of tumors showed high expression of TRAIL (83%), DR4 (92%), and DR5 (87%). Median follow-up was 43 months. High DR4 expression was associated with worse disease-free survival (odds ratio [OR] = 2.19; 95% CI, 1.06 to 4.53; P = .03), worse overall survival (OR = 2.22; 95% CI,1.03 to 4.81; P = .04) and shorter time to recurrence (P = .02) compared with those with low DR4 expression. TRAIL or DR5 expression had no prognostic value.

Conclusion: High DR4 expression is associated with worse disease-free and overall survival in stage III adjuvant-treated colon cancer patients. Evaluation of DR4 expression in stage III colon cancer patients may identify a subset requiring more aggressive adjuvant treatment.

Supported by Grants No. 1998-1660 and 2000-2286 from the Dutch Cancer Society and Grant No. 2001-31 from the Dutch Digestive Diseases Foundation.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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