Synchronous Coexpression of Epidermal Growth Factor Receptor and Cyclooxygenase-2 in Carcinomas of the Uterine Cervix: A Potential Predictor of Poor Survival Gwi Eon Kim, 1 Yong Bae Kim, 1 Nam Hoon Cho, 3 Hyun-Cheol Chung, 2 Hong Ryull Pyo, 1 Jong Doo Lee, 3 Tchan Kyu Park, 5 Woong Sub Koom, 1 Mison Chun, 6 and Chang Ok Suh 1 Departments of 1 Radiation Oncology, 2 Medical Oncology, Yonsei Cancer Center, 3 Pathology, 4 Nuclear Medicine, 5 Obstetrics and Gynecology, Brain Korea 21 Project for Medical Science, Yonsei University, College of Medicine, Seoul, Korea, and 6 Department of Radiation Oncology, Ajou University, College of Medicine, Suwon, Korea ABSTRACT Purpose: To evaluate the potential of the new prognos- tic information gained by analyzing the coexpression of epidermal growth factor receptor (EGFR) and cyclooxyge- nase-2 (COX-2) in cervical cancer patients. Experimental Design: Sixty-eight patients with Interna- tional Federation of Gynecology and Obstetrics stage IIB squamous cell carcinoma of the uterine cervix, who under- went concurrent chemoradiotherapy between 1993 and 1996, were divided into the following four groups according to their immunoreactivities for EGFR and COX-2 in paraf- fin-embedded sections: (a) the EGFR-negative/COX-2-neg- ative group (n  11); (b) the EGFR-negative/COX-2-positive group (n  8); (c) the EGFR-positive/COX-2-negative group (n  27); and (d) the EGFR-positive/COX-2-positive group (n  22). The clinical features, patterns of treatment failure, and survival data in the four groups were compared. Results: Positive immunoreactivity for EGFR and COX-2 was observed in 49 of 68 (72%) and 19 of 68 (28%), respectively. However, no strong correlation was found be- tween the levels of EGFR and COX-2 immunopositivity (R 2  0.05, P  0.07). Patients in the EGFR-positive/COX- 2-positive group had a higher likelihood of locoregional recurrence than those in the other three groups (P  0.02). Of the patients in the four groups, patients positive for both oncoproteins were found to have the worst prognosis with an overall 5-year disease-free survival rate of 55% compared with 91% for the EGFR-negative/COX-2-negative patients, 88% for the EGFR-negative/COX-2-positive patients, and 69% for the EGFR-positive/COX-2-negative patients (P  0.05, log-rank test). In addition, the synchronous coexpres- sion of the EGFR and COX-2 oncoproteins was found to be an independent prognostic factor by univariate and multi- variate analyses (relative risk  4.0, P  0.03). Conclusions: Given these observations, we conclude that the coexpression of EGFR and COX-2 immunoreactiv- ity may be used as a potent molecular risk factor for pre- dicting the poor survival of patients with the International Federation of Gynecology and Obstetrics stage IIB squa- mous cell carcinoma of the uterine cervix. INTRODUCTION Because the molecular mechanisms of tumor aggressive- ness are usually dependent on the proliferative stimuli induced by various tumor promoters, numerous proto-oncogenes and oncogenes regulating tumor cell growth, differentiation, and motility have been investigated to identify molecular targets that might be used as potential predictors of survival in the manage- ment of cancer (1, 2). Of a number of biological markers, epidermal growth factor receptor (EGFR) has received much attention during the last decades. It is a trans-membrane glyco- protein, which consists of the following three distinct domains: (a) an external ligand-binding domain; (b) a short intramembra- nous segment; and (c) a cytosolic domain with tyrosine kinase activity (2–7). Ligand-induced dimerization and autophospho- rylation of EGFR activates a signal transduction pathway by activating intrinsic protein tyrosine kinase activity and the phos- phorylation of several target proteins, which lead to increased DNA replication and the stimulation of cellular differentiation and proliferation (2). Increased EGFR expression has been observed in many experimental cell lines and human tumors, such as head and neck cancer (3), esophageal cancer (4), gastric cancer (5), and cervical cancer (6 –14). In the case of uterine cervical cancer, the incidence of EGFR overexpression has been variably reported to occur in 6 – 85% of cases according to the detection techniques and methods used previously (7). Although there have been a few contradictory results (14), the majority of reports show that elevated levels of EGFR correlate with a more aggressive biological behavior and are clinically relevant to poor prognosis in cervical cancer patients (7–13). On the other hand, cyclooxygenase (COX)-2, a key en- zyme that catalyzes the conversion of arachidonic acid to pros- taglandins and other eicosanoids, alters several cellular re- sponses involved in cell cycle regulation, the inhibition of apoptosis, extracellular matrix deposition, or pathological an- giogenesis (15–21). It promotes carcinogenesis, tumor prolifer- ation, and the growth and spread of cancer by mediating the pathological processes that affect mitogenesis, cellular adhe- Received 3/24/03; revised 11/13/03; accepted 11/13/03. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Gwi Eon Kim, Department of Radiation Oncol- ogy, Yonsei Cancer Center, Yonsei University, College of Medicine Seodaemoon-Gu, Shinchon-Dong 134 Seoul 120 –752, Korea. Phone: (82)-2-361-7631; Fax: (82)-2-312-9033; E-mail: gekim@yumc.yonsei. ac.kr. 1366 Vol. 10, 1366 –1374, February 15, 2004 Clinical Cancer Research Research. on May 29, 2016. © 2004 American Association for Cancer clincancerres.aacrjournals.org Downloaded from