title: Prognostic Significance of VEGFC and VEGFR1 mRNA Expression According to HER2 Status in Breast Cancer: A Study of Primary Tumors from Patients with High-risk Early Breast Cancer Participating in a Randomized Hellenic Cooperative Oncology Group Trial.
abstract: BACKGROUND
  Vascular endothelial growth factor C (VEGFC) and vascular endothelial growth factor receptor 1 (VEGFR1) mRNA overexpression has recently been shown to have strong predictive and prognostic value in patients with high-risk early breast cancer undergoing adjuvant chemotherapy. The present study evaluated associations of VEGFC and VEGFR1 with human epidermal growth factor receptor 2 (HER2) and their prognostic value dependent on HER2 status.
  
  
  METHODS
  RNA was isolated from 298 formalin-fixed paraffin-embedded tumor tissue samples from the HeCOG 10/97 (HE10/97) trial, evaluating adjuvant dose-dense sequential chemotherapy with epirubicin followed by cyclophosphamide, methotrexate and 5-fluorouracil therapy with or without paclitaxel (E-T-CMF vs. E-CMF). A fully-automated method based on magnetic beads was applied for RNA extraction, followed by one-step quantitative reverse transcription-polymerase chain reaction.
  
  
  RESULTS
  At 13.3 years of median follow-up, 116 patients (38.9%) had experienced relapse and 115 (38.6%) had died. There were strong associations between VEGFC/VEGFR1 mRNA expression and HER2 and estrogen receptor/progesterone receptor status. In multivariate analysis, both VEGFC and VEGFR1 were found to be associated with risk for death or relapse, but such associations depended on HER2 status and treatment group. High VEGFC was a negative prognostic factor for disease-free survival [hazard ratio (HR)=1.79, 95% confidence interval (CI)=1.05-3.05, Wald's p=0.032], with a trend for overall survival (HR=1.80, 95% CI=0.94-3.47, p=0.078) in patients treated with E-CMF adjusted for clinicopathological characteristics, while high VEGFR1 was associated with increased risk for death, yet non significantly in patients with HER2-negative disease (HR=1.51, 95% CI=0.82-2.77, p=0.18), regardless of treatment.
  
  
  CONCLUSIONS
  VEGFC and VEGFR1 mRNA overexpression is of prognostic value, dependent on HER2 status, in patients with high-risk early breast cancer undergoing adjuvant treatment. Among HER2-negative cases, these angiogenic markers could identify more aggressive tumors with worse prognosis. Further studies are warranted to validate VEGFC and VEGFR1 as potential biomarkers in adjuvant therapy and their use in identifying sub-groups that could benefit from anti-VEGF strategies.
authors.affiliation: First Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece elinardou@otenet.gr.
authors.forename: Helena
authors.initials: H
authors.lastname: Linardou
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece.
authors.forename: Konstantine T
authors.initials: KT
authors.lastname: Kalogeras
authors.affiliation: Sividon Diagnostics GmbH, Cologne, Germany Medical Faculty, Heinrich Heine University Dusseldorf, Dusseldorf, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Kronenwett
authors.affiliation: Health Data Specialists, Ltd., Athens, Greece.
authors.forename: Zoi
authors.initials: Z
authors.lastname: Alexopoulou
authors.affiliation: STRATIFYER Molecular Pathology GmbH, Cologne, Germany.
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Wirtz
authors.affiliation: Oncology Section, Department of Clinical Therapeutics, Alexandra Hospital, University of Athens School of Medicine, Athens, Greece.
authors.forename: Flora
authors.initials: F
authors.lastname: Zagouri
authors.affiliation: Department of Pathology, University Hospital, University of Patras Medical School, Patras, Greece.
authors.forename: Chrisoula D
authors.initials: CD
authors.lastname: Scopa
authors.affiliation: First Department of Medicine, Laiko General Hospital, University of Athens School of Medicine, Athens, Greece.
authors.forename: Helen
authors.initials: H
authors.lastname: Gogas
authors.affiliation: Pathology Department, Metropolitan Hospital, Piraeus, Greece.
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Petraki
authors.affiliation: Second Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Christodoulou
authors.affiliation: Pathology Department, University of Athens School of Medicine, Athens, Greece.
authors.forename: Kitty
authors.initials: K
authors.lastname: Pavlakis
authors.affiliation: Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece.
authors.forename: Angelos K
authors.initials: AK
authors.lastname: Koutras
authors.affiliation: Third Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece.
authors.forename: Epaminondas
authors.initials: E
authors.lastname: Samantas
authors.affiliation: Department of Pathology, IASSO General Hospital, Athens, Greece.
authors.forename: Helen
authors.initials: H
authors.lastname: Patsea
authors.affiliation: Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, University of Athens School of Medicine, Athens, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Pectasides
authors.affiliation: First Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Bafaloukos
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Fountzilas
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D017024:Chemotherapy, Adjuvant / Q000379:methods; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics*; D055815:Young Adult
chemical_list: D003520:Cyclophosphamide; D015251:Epirubicin; D005472:Fluorouracil; D008727:Methotrexate; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D042582:Vascular Endothelial Growth Factor C; D040281:Vascular Endothelial Growth Factor Receptor-1; C467486:VEGFC protein, human; C508053:ERBB2 protein, human
keywords: Prognostic/predictive factors; adjuvant chemotherapy; angiogenesis; anti-VEGF therapy; qRT-PCR