title: An Endothelial Gene Signature Score Predicts Poor Outcome in Patients with Endocrine-Treated, Low Genomic Grade Breast Tumors.
abstract: The ability of vascular genes to provide treatment predictive information in breast cancer patients remains unclear. As such, we assessed the expression of genes representative of normal endothelial microvasculature (MV) in relation to treatment-specific patient subgroups.
  
  
  
  We used expression data from 993 breast tumors to assess 57 MV genes (summarized to yield an MV score) as well as the genomic grade index (GGI) and PAM50 signatures. MV score was compared with CD31 staining by correlation and gene ontology (GO) analysis, along with clinicopathologic characteristics and PAM50 subtypes. Uni-, multivariate, and/or t-test analyses were performed in all and treatment-specific subgroups, along with a clinical trial cohort of patients with metastatic breast cancer, seven of whom received antiangiogenic therapy.
  
  
  
  MV score did not correlate with microvessel density (correlation = 0.096), but displayed enrichment for angiogenic GO terms, and was lower in Luminal B tumors. In endocrine-treated patients, a high MV score was associated with decreased risk of metastasis [HR 0.58; 95% confidence interval (CI), 0.38-0.89], even after adjusting for histologic grade, but not GGI or PAM50. Subgroup analysis showed the prognostic strength of the MV score resided in low genomic grade tumors and MV score was significantly increased in metastatic breast tumors after treatment with sunitinib + docetaxel (P = 0.031).
  
  
  
  MV score identifies two groups of better and worse survival in low-risk endocrine-treated breast cancer patients. We also show normalization of tumor vasculature on a transcriptional level in response to an angiogenic inhibitor in human breast cancer samples. Clin Cancer Res; 22(10); 2417-26. ©2016 AACR.
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden. nick.tobin@ki.se.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Tobin
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Kristian
authors.initials: K
authors.lastname: Wennmalm
authors.affiliation: Department of Surgery, University of California at San Francisco (UCSF), San Francisco, California. Department of Biosciences and Nutrition, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Lindström
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Foukakis
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Liqun
authors.initials: L
authors.lastname: He
authors.affiliation: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Guillem
authors.initials: G
authors.lastname: Genové
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Arne
authors.initials: A
authors.lastname: Östman
authors.affiliation: Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Landberg
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden. Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Betsholtz
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Bergh
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D000077143:Docetaxel; D005260:Female; D015870:Gene Expression / Q000187:drug effects* / Q000235:genetics; D023281:Genomics; D006390:Hemangioendothelioma / Q000188:drug therapy / Q000473:pathology; D006728:Hormones / Q000627:therapeutic use*; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D008875:Middle Aged; D011379:Prognosis; D011758:Pyrroles / Q000627:therapeutic use; D000077210:Sunitinib; D043823:Taxoids / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects* / Q000235:genetics*
chemical_list: D020533:Angiogenesis Inhibitors; D006728:Hormones; D007211:Indoles; D011758:Pyrroles; D043823:Taxoids; D000077143:Docetaxel; D000077210:Sunitinib