title: Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) negatively affect overall survival in carcinoma of the cervix treated with radiotherapy.
abstract: OBJECTIVE
  The purpose of this study was to examine a variety of biomarkers in carcinoma of the cervix to better characterize (1). the natural history of the disease, (2). response to radiotherapy (RT), and (3). potential for new therapeutic strategies.
  
  
  METHODS
  Fifty-five patients with Stage IB-IVA carcinoma of the cervix, treated with definitive intent RT, and on whom tumor tissue blocks were available were included in this study. Charts were reviewed for clinical parameters and disease status. Immunohistochemistry was performed for epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), CD34, topoisomerase II alpha (topo-II), and cyclooxygenase-2 (COX-2). Univariate and multivariate Cox proportional hazards modeling was performed with disease-free survival (DFS) and overall survival (OS) as the end points. Biomarkers were evaluated for correlation between various prognostic factors.
  
  
  RESULTS
  In this series of 55 patients with carcinoma of the cervix treated with definitive RT, only stage was significant on univariate analysis for DFS (p < 0.0001). On univariate analysis, increasing FIGO stage (p < 0.0001) and membranous staining of EGFR (p < 0.037) indicated diminished OS. On multivariate analysis for DFS, COX-2, VEGF, and stage were significant (p = 0.012, p = 0.014, and p = 0.03, respectively), with increased expression indicating a worse prognosis. For OS, multivariate analysis revealed that VEGF, EGFR, and FIGO stage were significant (p = 0.005, p = 0.011, and p < 0.0001, respectively). Significant direct correlations were identified between VEGF and CD34 (p = 0.04), COX-2 and topo-II (p = 0.04), COX-2 and grade (p = 0.04), and tumor size and clinical stage (p = 0.04).
  
  
  CONCLUSIONS
  Multivariate analysis revealed that increased staining for VEGF and COX-2 indicated diminished DFS, and VEGF and EGFR identified patients at increased risk of death. A significant direct correlation between VEGF and CD34 implicates the process of angiogenesis. Topo-II is a proliferative marker and it correlated directly with COX-2, indicating that expression of COX-2 may be greater in more proliferative tumors. Increased expression of EGFR, VEGF, and COX-2 has identified patients with a worse prognosis in cancer of the cervix. These data support the investigation of therapeutics that target these proteins in carcinoma of the cervix.
authors.affiliation: Department of Radiation Oncology, University of Utah, Salt Lake City, UT 84132, USA. david.k.gaffney@hsc.utah.edu
authors.forename: David K
authors.initials: DK
authors.lastname: Gaffney
authors.forename: Derek
authors.initials: D
authors.lastname: Haslam
authors.forename: Alexander
authors.initials: A
authors.lastname: Tsodikov
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hammond
authors.forename: James
authors.initials: J
authors.lastname: Seaman
authors.forename: Joseph
authors.initials: J
authors.lastname: Holden
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Lee
authors.forename: Karen
authors.initials: K
authors.lastname: Zempolich
authors.forename: Mark
authors.initials: M
authors.lastname: Dodson
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D051546:Cyclooxygenase 2; D018572:Disease-Free Survival; D016228:Endothelial Growth Factors / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism*; D008565:Membrane Proteins; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012189:Retrospective Studies; D015996:Survival Rate; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D014408:Biomarkers, Tumor; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008222:Lymphokines; D008565:Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D066246:ErbB Receptors