title: Impact of tumor angiogenic profile on the outcome of patients with metastatic breast carcinoma treated with weekly docetaxel. A Hellenic Cooperative Oncology Group (HeCOG) study.
abstract: BACKGROUND
  Metronomic taxane administration has putative antiangiogenic properties. Herein, we examined the baseline tumor angiogenic profile of patients with metastatic breast carcinoma (MBC) in a prospective-retrospective translational research study. The interplay between the angiogenic factors expressed in the tumors and their prognostic value in MBC were investigated.
  
  
  METHODS
  Tumor tissues from patients with MBC treated with weekly docetaxel (n=159) were examined by immunohistochemistry for VEGF-A, VEGF-C, VEGFR-1, VEGFR-2, VEGFR-3 and osteopontin (OPN) and by mRNA analysis for expression of VEGF-A, VEGFxxxa, VEGFxxxb, VEGF-C, thrombospondin-1 (THBS-1), hypoxia-inducible factor-1α (HIF-1α) and von Hippel-Lindau (VHL) genes. Associations between these parameters and outcome were statistically analyzed.
  
  
  RESULTS
  Statistically significant correlations were identified between almost all biomarkers examined in continuous form, particularly at the mRNA level: VEGF-A with VEGFxxxa (rho=0.70); VEGF-C with VEGFxxxa, VEGFxxxb and VHL (rho=0.51, 0.60 and 0.44 respectively); HIF-1α with VEGF-C and THBS1 (rho= 0.48 and 0.45). High VEGF-A mRNA was associated with worse survival (p=0.0279) and marginally with progression free survival (PFS). Intratumoral co-expression of VEGFR-1 and VEGFR-2 proteins was associated with more favorable survival (p=0.0337). In multivariate analysis, only high VEGF-A mRNA levels retained their prognostic role for worse PFS and survival (PFS: HR=2.34, 95% CI=1.25-4.40, p=0.0080; survival: HR=3.15, 95% CI=1.48-6.72, p=0.0029).
  
  
  CONCLUSIONS
  In MBC, this study confirms the adverse prognostic effect of high intratumoral VEGF-A mRNA and reveals the combined VEGFR-1/VEGFR-2 protein expression as a potentially favorable prognosticator, which merits further evaluation in larger studies.
authors: Department of Pathology, University Hospital, University of Patras School of Medicine, Rion, Greece. hkourea@yahoo.com.
authors: Helen P
authors: HP
authors: Kourea
authors: Department of Pathology, and Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors: Vassiliki
authors: V
authors: Kotoula
authors: Division of Oncology, Department of Medicine, University Hospital, University of Patras School of Medicine, Patras, Greece.
authors: Angelos
authors: A
authors: Koutras
authors: Health Data Specialists Ltd, Athens, Greece.
authors: Zoi
authors: Z
authors: Alexopoulou
authors: Department of Pathology, Alexandra Hospital, Athens, Greece.
authors: Irene
authors: I
authors: Papaspirou
authors: Second Department of Medical Oncology, "Metropolitan" Hospital, Piraeus, Greece.
authors: Dimosthenis V
authors: DV
authors: Skarlos
authors: Department of Pathology, "Papageorgiou" Hospital, Thessaloniki, Greece.
authors: Ioannis
authors: I
authors: Efstratiou
authors: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors: Mattheos
authors: M
authors: Bobos
authors: Department of Clinical Therapeutics, "Alexandra" Hospital, University of Athens School of Medicine, Athens, Greece.
authors: Flora
authors: F
authors: Zagouri
authors: Department of Medical Oncology, "Hippokration" Hospital, Athens, Greece.
authors: Pavlos
authors: P
authors: Papakostas
authors: Oncology Section, Second Department of Internal Medicine, "Hippokration" Hospital, Athens, Greece.
authors: Dimitrios
authors: D
authors: Pectasides
authors: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors: Sofia
authors: S
authors: Chrisafi
authors: Oncology Department, General Hospital of Chania, Crete, Greece.
authors: Ioannis
authors: I
authors: Varthalitis
authors: Second Department of Medical Oncology, "Agii Anargiri" Cancer Hospital, Athens, Greece.
authors: Gerasimos
authors: G
authors: Aravantinos
authors: Second Department of Medical Oncology, Hygeia Hospital, Athens, Greece.
authors: Paris
authors: P
authors: Kosmidis
authors: First Department of Medical Oncology, "Metropolitan" Hospital, Piraeus, Greece.
authors: Dimitrios
authors: D
authors: Bafaloukos
authors: Department of Pathology, University Hospital, University of Patras School of Medicine, Rion, Greece.
authors: Chrisoula D
authors: CD
authors: Scopa
authors: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, and Department of Medical Oncology, "Papageorgiou" Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors: George
authors: G
authors: Fountzilas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D012189:Retrospective Studies; D043823:Taxoids / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D043823:Taxoids; D000077143:Docetaxel