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Int J Cancer. 2019 Aug 24. doi: 10.1002/ijc.32638. [Epub ahead of print]

Serum levels of inflammation-related markers and metabolites predict response to neoadjuvant chemotherapy with and without bevacizumab in breast cancers.

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Department of Clinical Molecular Biology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway.
Department of Circulation and Medical Imaging, NTNU - The Norwegian University of Science and Technology, Trondheim, Norway.
Department of Tumour Biology, Institute for Cancer Research, Radium Hospital, Oslo University Hospital, Oslo, Norway.
Institute of Medical Biology, Faculty of Health Sciences, Artic University of Norway - University of Tromsø, Tromsø, Norway.
Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Department of Pathology, Division of Laboratory Medicine, Oslo University Hospital, Oslo, Norway.
Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
K.G. Jebsen - Thrombosis Research and Expertise Center (TREC), Department of Clinical Medicine, University of Tromsø - The Arctic University of Norway, Tromsø, Norway.
Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.


Angiogenesis is necessary for tumor growth and has been targeted in breast cancer, however, it is unclear which patients will respond and benefit from anti-angiogenic therapy. We report non-invasive monitoring of patient response to neoadjuvant chemotherapy given alone or in combination with anti-VEGF (bevacizumab) in a randomized clinical trial. At four time points during neoadjuvant chemotherapy ± bevacizumab of Her2-negative breast cancers, we measured metabolites and inflammation-related markers in patient's serum. We report significant changes in the levels of several molecules induced by bevacizumab, the most prominent being an increase in pentraxin 3 (PTX3) and von Willebrand factor (VWF). Serum levels of AXL, VWF and pulmonary and activation-regulated cytokine (PARC/CCL18) reflected response to chemotherapy alone or in combination with bevacizumab. We further analyzed serum cytokines in relation to tumor characteristics such as gene expression, tumor metabolites and tumor infiltrating leukocytes. We found that VWF and growth-differentiation factor 15 (GDF15) tumor mRNA levels correlated with their respective serum protein levels suggesting that these cytokines may be produced by tumors and outflow to the bloodstream while influencing the tumor microenvironment locally. Finally, we used binomial logistic regression which allowed to predict patient's response using only 10 non-invasive biomarkers. Our study highlights the potential of monitoring circulating levels of cytokines and metabolites during breast cancer therapy. This article is protected by copyright. All rights reserved.


Bevacizumab; Breast cancer; inflammation; metabolism; neoadjuvant therapy


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