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
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).
KeywordsBreast cancer VEGF Circulating tumor cell Survival Biomarker
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.
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 was obtained from all individual participants included in the study.
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