Breast Cancer Research and Treatment

, Volume 172, Issue 1, pp 93–104 | Cite as

The clinical relevance of serum vascular endothelial growth factor (VEGF) in correlation to circulating tumor cells and other serum biomarkers in patients with metastatic breast cancer

  • Malgorzata Banys-Paluchowski
  • Isabell Witzel
  • Sabine Riethdorf
  • Klaus Pantel
  • Brigitte Rack
  • Wolfgang Janni
  • Peter A. Fasching
  • Bahriye Aktas
  • Sabine Kasimir-Bauer
  • Andreas Hartkopf
  • Erich-Franz Solomayer
  • Tanja Fehm
  • Volkmar MüllerEmail author
Clinical trial



VEGF is one of the most important angiogenesis-stimulating cytokines and has been previously shown to be overexpressed in several solid cancers. The aim of the present study was to assess the clinical relevance of serum VEGF (sVEGF) in a large cohort of metastatic breast cancer patients and to explore the relationship between sVEGF and other blood-based biomarkers.


Two hundred fifty-three patients with metastatic breast cancer were enrolled in this prospective, multicentre study. Blood samples were collected before start of first-line or later-line treatment. sVEGF was quantified by a commercially available ELISA. Circulating tumor cells (CTCs) were detected using CellSearch and other biomarkers (EGFR, HER2, RAS p21, TIMP1, CAIX) by ELISA.


Levels of sVEGF were determined in all patients, with a median concentration of 231 pg/ml. After a median follow-up of 19 months, median overall survival (OS) was 10.2 months in patients with sVEGF levels above the upper quartile (i.e. 367 pg/ml), while median OS has not been reached in patients with sVEGF < 367 pg/ml (p < 0.001). Median progression-free survival (PFS) was 4.8 months for patients with sVEGF ≥ 367 pg/ml versus 9.1 months with sVEGF levels < 367 pg/ml (p < 0.001). Patients with sVEGF levels ≥ 367 pg/ml and ≥ 5 CTCs had the shortest OS, while those with sVEGF < 367 pg/ml and non-elevated CTCs had the longest OS. CTCs, grading, line of therapy and RAS p21 were independent predictors of OS. sVEGF, line of therapy and CTCs were independent predictors of PFS in the multivariate analysis.


Metastatic breast cancer patients with elevated levels of sVEGF have significantly worse clinical outcome. This finding supports the biological role of VEGF in breast cancer. Trial registration: Current Controlled Trials ISRCTN59722891 (DETECT).


Breast cancer VEGF Circulating tumor cell Survival Biomarker 


Author contributions

TF, WJ, BA, PAF, SKB, KP, BR, SR, EFS, AH and VM designed and conducted the study. MBP analyzed and interpreted the data, performed statistical analysis and prepared the manuscript. TF, IW, PAF and VM analyzed and interpreted the data and were major contributors in writing the manuscript. All authors read and approved the final manuscript.


The DETECT study was supported by a research grant from Roche Pharma AG, Germany and by Adnagen AG, Germany. ELISA kits were provided at no cost by Oncogene Science. The funding agencies had no role in study design or collection, analysis and interpretation of data or in the writing of the manuscript.

Compliance with Ethical Standards

Conflict of interest

Wolfgang Janni received a research grant from Roche. Bahriye Aktas has served as a consultant/advisor for Roche, Pfizer and Novartis. Klaus Pantel has served as a consultant/advisor for Agena Bioscience. Sabine Kasimir-Bauer has served as a consultant/advisor for Qiagen. Peter A. Fasching has served as a consultant/advisor for Amgen, Novartis, Roche, Pfizer, Teva and Puma Celgene and received a research grant from Novartis. Brigitte Rack has received honoraria or research grants from Novartis, Roche, Pfizer, Janssen Diagnostics, Astra Zeneca, Novartis, Lilly, Chugai and Sanofi. Malgorzata Banys-Paluchowski, Isabell Witzel, Sabine Riethdorf, Andreas Hartkopf, Erich-Franz Solomayer, Tanja Fehm and Volkmar Müller declare that they have no conflicts of interest.

Ethical approval

All procedures performed in this study were in accordance with the ethical standard of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the local ethical committees of participation institutions.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

10549_2018_4882_MOESM1_ESM.docx (16 kb)
Supplementary material 1 (DOCX 15 KB)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Malgorzata Banys-Paluchowski
    • 1
  • Isabell Witzel
    • 2
  • Sabine Riethdorf
    • 3
  • Klaus Pantel
    • 3
  • Brigitte Rack
    • 4
  • Wolfgang Janni
    • 4
  • Peter A. Fasching
    • 5
  • Bahriye Aktas
    • 6
  • Sabine Kasimir-Bauer
    • 7
  • Andreas Hartkopf
    • 8
  • Erich-Franz Solomayer
    • 9
  • Tanja Fehm
    • 10
  • Volkmar Müller
    • 2
    Email author
  1. 1.Department of Gynecology and ObstetricsMarienkrankenhaus HamburgHamburgGermany
  2. 2.Department of GynecologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  3. 3.Department of Tumour BiologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  4. 4.Department of Gynecology and ObstetricsUniversity Hospital UlmUlmGermany
  5. 5.Department of Gynecology and ObstetricsUniversity Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-NurembergErlangenGermany
  6. 6.Department of GynecologyUniversity Hospital LeipzigLeipzigGermany
  7. 7.Department of Obstetrics and Gynecology, University Hospital EssenUniversity of Duisburg-EssenEssenGermany
  8. 8.Department of Obstetrics and Gynecology, University Hospital TübingenUniversity of TübingenTübingenGermany
  9. 9.Department of Gynecology and ObstetricsSaarland University HospitalHomburg/SaarGermany
  10. 10.Department of Obstetrics and GynecologyHeinrich-Heine-University DüsseldorfDüsseldorfGermany

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