title: Vascular endothelial growth factor and DPC4 predict adjuvant therapy outcomes in resected pancreatic cancer.
abstract: Angiogenesis is important for pancreatic cancer progression, but its role in predicting response to therapy is not known. We investigated the association of various angiogenic factors and intratumoral microvessel density (IMD) with adjuvant therapy and survival in resected pancreatic cancer. Tissue cores from a multi-institutional retrospective series of resected patients were used to build a pancreatic cancer tissue microarray. Vascular endothelial growth factor (VEGF), platelet-derived endothelial cell growth factor (PD-ECGF), CD31 (for IMD), and DPC4 expression were determined using immunohistochemistry. Expression of VEGF and PD-ECGF, both proangiogenic factors, was observed in 70 (56%) and 75 (59%) of 124 tumors, respectively. Expression of DPC4, an angiogenesis inhibitor, was observed in 59 of 124 (48%) tumors. VEGF expression correlated significantly with increased IMD (P=.03), as did loss of antiangiogenic DPC4 (P=.05). PD-ECGF expression did not correlate with IMD. Use of adjuvant therapy was associated with increased survival in patients with VEGF-positive tumors (18.8 [treated] versus 11.2 [untreated] months; hazard ratio [HR]=0.38, 95% confidence interval [CI], 0.19-0.76; P=.005), but not in patients with VEGF-negative tumors. Similarly, improved survival was observed in patients with high IMD (16.3 [treated] versus 11.2 [untreated] months; HR=0.44, 95% CI, 0.23-0.87; P=.02) and in patients with loss of DPC4 (20.3 [treated] versus 11.2 [untreated] months; HR=0.31, 95% CI, 0.14-0.67; P=.002), but not in those with low IMD or normal DPC4 expression. VEGF (stimulator) and DPC4 (inhibitor) are important regulators of pancreatic tumor angiogenesis and predictive of benefit from adjuvant therapy. Adjuvant therapy may have both antiangiogenic and cytotoxic effects. Addition of anti-VEGF agents to adjuvant regimens may further improve outcomes.
authors.affiliation: James P. Wilmot Cancer Center and the Department of Medicine, University of Rochester, Rochester, NY 14642, and the National Human Genomics Research Institute, National Institutes of Health, Bethesda, MD, USA. alok_khorana@URMC.rochester.edu
authors.forename: Alok A
authors.initials: AA
authors.lastname: Khorana
authors.forename: Ying Chuan
authors.initials: YC
authors.lastname: Hu
authors.forename: Charlotte K
authors.initials: CK
authors.lastname: Ryan
authors.forename: Richard A
authors.initials: RA
authors.lastname: Komorowski
authors.forename: Galen
authors.initials: G
authors.lastname: Hostetter
authors.forename: Steven A
authors.initials: SA
authors.lastname: Ahrendt
mesh_terms: D000367:Age Factors; D000368:Aged; D043925:Angiogenesis Inducing Agents / Q000032:analysis; D020533:Angiogenesis Inhibitors / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis*; D017024:Chemotherapy, Adjuvant; D005260:Female; D005544:Forecasting; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000648:ultrastructure; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000601:surgery*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D018714:Radiotherapy, Adjuvant; D012189:Retrospective Studies; D012737:Sex Factors; D051901:Smad4 Protein / Q000032:analysis*; D016019:Survival Analysis; D013939:Thymidine Phosphorylase / Q000032:analysis; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis*
chemical_list: D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D042461:Vascular Endothelial Growth Factor A; D013939:Thymidine Phosphorylase