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Intratumoral COX-2 Gene Expression Is a Predictive Factor for Colorectal Cancer Response to Fluoropyrimidine-Based Chemotherapy

Authors' Affiliations: ¹ Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan; Departments of ² Biochemistry and Molecular Biology, and ³ Preventive Medicine, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California; and ⁴ Response Genetics, Inc., Los Angeles, California

Requests for reprints: Peter V. Danenberg, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Room 5318, Los Angeles, CA. Phone: 323-865-0518; Fax: 323-865-3578; E-mail: pdanenbe{at}hsc.usc.edu.

Purpose: Cyclooxygenase-2 (COX-2) is generally elevated in tumors compared with normal tissue and apparently has an important role in tumor development. A number of studies have found high expression of COX-2 to be an unfavorable prognostic factor for overall survival in several cancers. However, the influence of COX-2 expression levels on tumor response to chemotherapy has been relatively little studied. The purpose of this study was to ascertain if COX-2 gene expression is associated with tumor response in the clinical treatment of colorectal cancer with the fluoropyrimidine-based therapy S-1.

Experimental Design: Patients with advanced (stage IV) colorectal cancer were treated with S-1 twice daily based on the patient's body surface area (BSA; BSA < 1.25 m², 80 mg/d; 1.25 m² BSA < 1.5 m², 100 mg/d; BSA 1.5 m², 120 mg/d) for 28 days followed by a 2-week period rest. mRNA was isolated from paraffin-embedded pretreatment primary tumor specimens and expression levels of COX-2 relative to ß-actin as the internal reference gene were measured using a quantitative reverse transcription-PCR (Taqman) system.

Results: The overall response rate in a group of 44 patients treated with S-1 was 40.9%. Sufficient tumor tissue was available from 40 of these patients for COX-2 mRNA quantitation. COX-2 gene expression was significantly lower in the responding tumors compared with the nonresponders (P = 0.012, Wilcoxon test). Patients with COX-2 values above the cutoff value of 3.28 x 10^–3 had a significantly shorter survival than those with COX-2 gene expressions below the cutoff value (adjusted P = 0.031).

Conclusions: Intratumoral COX-2 gene expression is associated with likelihood of response to chemotherapy with S-1 and is a prognostic factor for survival of patients after the start of S-1 chemotherapy.

Key Words: COX-2 • flouropyrimidine therapy • Gastrointestinal cancers: colorectal • Molecular diagnosis and prognosis • Drug resistance

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