Preoperative Serum Tissue Factor Levels Are an Independent Prognostic Factor in Patients With Ovarian Carcinoma Liz Y. Han, Charles N. Landen Jr, Aparna A. Kamat, Adriana Lopez, David P. Bender, Peter Mueller, Rosemarie Schmandt, David M. Gershenson, and Anil K. Sood A B S T R A C T Purpose Tissue factor (TF) is a procoagulant that plays an important part in tumor angiogenesis. We sought to determine the role of preoperative serum TF levels in predicting clinical outcome in patients with ovarian cancer. Materials and Methods TF expression was determined by reverse transcriptase polymerase chain reaction in ovarian cell lines. Using enzyme-linked immunosorbent assay, we assessed preoperative serum TF levels in 98 women with invasive epithelial ovarian carcinoma, 30 with low malignant potential (LMP) tumors, 16 with benign tumors, and a separate validation group of 39 women with adnexal masses. Clinical information was gathered from chart review. Results TF was expressed in four of the five ovarian cancer cell lines, but absent in the nontransformed cells. Ovarian cancer patients had a median preoperative serum TF level of 85.2 pg/mL, which was significantly higher than in those with LMP tumors (12.8 pg/mL; P  .01) and benign adnexal disease (30.7 pg/mL; P  .01). TF  190 pg/mL was significantly associated with decreased patient survival (P  .01). After adjusting for other clinical variables in a multivariate Cox regression model, TF  190 pg/mL was an independent prognostic factor (P  .01). Analysis of serum TF levels from the validation set confirmed that high TF (190 pg/mL) was associated with a 3.4-fold increase in risk of death from disease (P = .02) and shorter survival (P = .01). Conclusion Preoperative serum TF levels are significantly elevated in patients with ovarian carcinoma. Elevated preoperative TF level is an independent prognostic factor for death from disease. J Clin Oncol 24:755-761. © 2006 by American Society of Clinical Oncology INTRODUCTION It is known that approximately 50% of all patients with malignant disease and almost 90% of patients with metastatic lesions have abnormalities in hema- tologic parameters, and as a result, various coagula- tion factors have been evaluated. 1 Furthermore, underlying factors of this intrinsic hypercoagulable state have been shown to play a role in tumor angio- genesis and metastasis. 2 As the main physiologic initiator of the coagu- lation pathway, tissue factor (TF) is a 47-kDa trans- membrane glycoprotein of the cytokine-receptor superfamily that begins the coagulation cascade in normal human physiology. However, there is in- creasing evidence to implicate TF in tumor angio- genesis. 3 Through the clotting-dependent pathway, TF contributes to tumor angiogenesis by generating thrombin, activating platelets, and depositing fibrin, all of which produce more TF, release stored vascu- lar endothelial growth factor (VEGF) and support new blood vessel matrix. 2-4 In addition, TF triggers the clotting-independent pathways by cleaving the protease-activated receptors (PARs) and initiating the transcription of VEGF. 4,5 A significant associa- tion between high TF expression and microvessel density (MVD) has been observed in colorectal, lung, breast, liver and urologic carcinomas. 6-11 Fur- thermore, high levels of TF expression have been found to be an independent prognostic factor for poor survival in patients with solid tumors. 7-10,12,13 In fact, TF expression negativity has been shown to confer a significantly better prognosis. 14 Ovarian carcinoma is the most deadly of the gynecologic malignancies. Therefore, development of novel biomarkers that can sufficiently contribute From the Departments of Gynecologic Oncology, Biostatistics and Applied Mathematics, and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Iowa Hospitals and Clinics, Iowa City, IA. Submitted June 2, 2005; accepted October 5, 2005. Presented in part at the 36th Annual Meeting of the Society of Gyneco- logic Oncologists, Miami Beach, FL, March 19-23, 2005. Funded in part by The University of Texas at M.D. Anderson Cancer Center Specialized Programs of Research Excellence in ovarian cancer (Grant No. 1P50CA83639). Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Address reprint requests to: Anil K. Sood, MD, Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Unit 1362, PO Box 301439, Houston, TX 77230- 1439; e-mail: asood@mdanderson.org. © 2006 by American Society of Clinical Oncology 0732-183X/06/2405-755/$20.00 DOI: 10.1200/JCO.2005.02.9181 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 24  NUMBER 5  FEBRUARY 10 2006 755 Downloaded from ascopubs.org by 34.228.39.121 on June 14, 2022 from 034.228.039.121 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.