title: Angiogenesis- and Hypoxia-Associated Proteins as Early Indicators of the Outcome in Patients with Metastatic Breast Cancer Given First-Line Bevacizumab-Based Therapy.
abstract: OBJECTIVE
  We examined whether pretreatment levels of angiogenesis- or hypoxia-related proteins and their changes after one cycle of first-line bevacizumab-based therapy were associated with response, PFS, or OS in patients with metastatic breast cancer.
  
  
  METHODS
  We included 181 patients enrolled in the phase II ATX trial evaluating first-line paclitaxel and bevacizumab without or with capecitabine (NTR1348). Plasma samples were analyzed for VEGF-A, soluble VEGFR2 (sVEGFR2), angiopoietin 2 (ANG2), soluble TIE2 (sTIE2), IL6, IL8, and carbonic anhydrase 9 (CA9). Baseline serum CA15-3 was documented. HR was adjusted for confounding factors. Where appropriate, an optimal cut-off value defining a high and a low group was determined with Martingale residuals.
  
  
  RESULTS
  At baseline, multiple proteins were significantly associated with PFS (ANG2, IL6, IL8, CA9, CA15-3) and OS (ANG2, sTIE2, IL6, IL8, CA9, CA15-3). After one cycle, VEGF-A, ANG2, sTIE2, and IL8 significantly decreased, while sVEGFR2 and CA9 significantly increased. The relative change in sVEGFR2 (P= 0.01) and IL8 (P= 0.001) was associated with response. Defining optimal cut-off, patients with a high CA9 rise (>2.9%) had better PFS (HR 0.45) and OS (HR 0.54) than those with low/no rise.
  
  
  CONCLUSIONS
  Multiple angiogenesis- or hypoxia-related proteins were prognostic for PFS and OS. Molecular agents targeting these proteins might be beneficial in patients with high levels. Changes in IL8 or sVEGFR2 levels at second cycle appear predictive for response. Changes in CA9 levels during bevacizumab-based therapy for prediction of PFS and OS merit further study.
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Siu W
authors.initials: SW
authors.lastname: Lam
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Nienke M
authors.initials: NM
authors.lastname: Nota
authors.affiliation: Erasmus Medical Center-Daniel den Hoed Cancer Center, Rotterdam, the Netherlands.
authors.forename: Agnes
authors.initials: A
authors.lastname: Jager
authors.affiliation: Reinier de Graaf Hospital, Delft, the Netherlands.
authors.forename: Monique M E M
authors.initials: MM
authors.lastname: Bos
authors.affiliation: Albert Schweitzer Hospital, Dordrecht, the Netherlands.
authors.forename: Joan
authors.initials: J
authors.lastname: van den Bosch
authors.affiliation: Tergooi Hospitals, Hilversum, the Netherlands.
authors.forename: Ankie M T
authors.initials: AM
authors.lastname: van der Velden
authors.affiliation: Haga Hospital, The Hague, the Netherlands.
authors.forename: Johanneke E A
authors.initials: JE
authors.lastname: Portielje
authors.affiliation: Isala Clinics, Zwolle, the Netherlands.
authors.forename: Aafke H
authors.initials: AH
authors.lastname: Honkoop
authors.affiliation: The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
authors.forename: Harm
authors.initials: H
authors.lastname: van Tinteren
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands. e.boven@vumc.nl.
authors.forename: Epie
authors.initials: E
authors.lastname: Boven
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068258:Bevacizumab / Q000008:administration & dosage; D015415:Biomarkers; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000860:Hypoxia / Q000097:blood*; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000097:blood*; D011379:Prognosis; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D000068258:Bevacizumab