title: Bevacizumab specifically decreases elevated levels of circulating KIT+CD11b+ cells and IL-10 in metastatic breast cancer patients.
abstract: BACKGROUND
  Whether bevacizumab exerts its anti-tumor properties through systemic effects beyond local inhibition of angiogenesis and how these effects can be monitored in patients, remain largely elusive. To address these questions, we investigated bone marrow-derived cells and cytokines in the peripheral blood of metastatic breast cancer patients undergoing therapy with bevacizumab.
  
  
  METHODS
  Circulating endothelial cells (CEC), circulating endothelial progenitor (CEP) and circulating CD11b+ cells in metastatic breast cancer patients before and during therapy with paclitaxel alone (n = 11) or in combination with bevacizumab (n = 10) were characterized using flow cytometry, real time PCR and RNASeq. Circulating factors were measured by ELISA. Aged-matched healthy donors were used as baseline controls (n = 12).
  
  
  RESULTS
  Breast cancer patients had elevated frequencies of CEC, CEP, TIE2+CD11b+ and KIT+CD11b+ cell subsets. CEC decreased during therapy, irrespective of bevacizumab, while TIE2+CD11b+ remained unchanged. KIT+CD11b+ cells decreased in response to paclitaxel with bevacizumab, but not paclitaxel alone. Cancer patients expressed higher mRNA levels of the M2 polarization markers CD163, ARG1 and IL-10 in CD11b+ cells and increased levels of the M2 cytokines IL-10 and CCL20 in plasma. M1 activation markers and cytokines were low or equally expressed in cancer patients compared to healthy donors. Chemotherapy with paclitaxel and bevacizumab, but not with paclitaxel alone, significantly decreased IL-10 mRNA in CD11b+ cells and IL-10 protein in plasma.
  
  
  CONCLUSIONS
  This pilot study provides evidence of systemic immunomodulatory effects of bevacizumab and identified circulating KIT+CD11b+ cells and IL-10 as candidate biomarkers of bevacizumab activity in metastatic breast cancer patients.
authors: Department of Medicine, Faculty of Science, University of Fribourg, CH-1700 Fribourg, Switzerland.
authors: Sarah
authors: S
authors: Cattin
authors: Central Laboratory, HFR Hôpital Cantonal, CH-1700 Fribourg, Switzerland.
authors: Benoît
authors: B
authors: Fellay
authors: Genomic Technologies Facility, Center of Integrative Genomic (CIG), University of Lausanne (UNIL), CH-1015 Lausanne, Switzerland.
authors: Sylvain
authors: S
authors: Pradervand
authors: OnkoZentrum Zürich, CH-8038 Zürich, Switzerland.
authors: Andreas
authors: A
authors: Trojan
authors: Breast Center, Kantonsspital St.Gallen, CH-9000 St.Gallen, Switzerland.
authors: Thomas
authors: T
authors: Ruhstaller
authors: Department of Medicine, Faculty of Science, University of Fribourg, CH-1700 Fribourg, Switzerland.
authors: Curzio
authors: C
authors: Rüegg
authors: Tumor and Breast Center ZeTuP, CH-9006 St.Gallen, Switzerland.
authors: Gregor
authors: G
authors: Fürstenberger
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D039481:CD11b Antigen / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000473:pathology; D017239:Paclitaxel / Q000627:therapeutic use; D010865:Pilot Projects; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology
chemical_list: D020533:Angiogenesis Inhibitors; D039481:CD11b Antigen; C508609:IL10 protein, human; C509295:ITGAM protein, human; D016753:Interleukin-10; D000068258:Bevacizumab; D019009:Proto-Oncogene Proteins c-kit; D017239:Paclitaxel
keywords: IL-10; KIT; angiogenesis; breast cancer; monocytes