title: Tumor-Specific Uptake of Fluorescent Bevacizumab-IRDye800CW Microdosing in Patients with Primary Breast Cancer: A Phase I Feasibility Study.
abstract: Purpose:To provide proof of principle of safety, breast tumor-specific uptake, and positive tumor margin assessment of the systemically administered near-infrared fluorescent tracer bevacizumab-IRDye800CW targeting VEGF-A in patients with breast cancer.Experimental Design:Twenty patients with primary invasive breast cancer eligible for primary surgery received 4.5 mg bevacizumab-IRDye800CW as intravenous bolus injection. Safety aspects were assessed as well as tracer uptake and tumor delineation during surgery andex vivoin surgical specimens using an optical imaging system.Ex vivomultiplexed histopathology analyses were performed for evaluation of biodistribution of tracer uptake and coregistration of tumor tissue and healthy tissue.Results:None of the patients experienced adverse events. Tracer levels in primary tumor tissue were higher compared with those in the tumor margin (P< 0.05) and healthy tissue (P< 0.0001). VEGF-A tumor levels also correlated with tracer levels (r= 0.63,P< 0.0002). All but one tumor showed specific tracer uptake. Two of 20 surgically excised lumps contained microscopic positive margins detectedex vivoby fluorescent macro- and microscopy and confirmed at the cellular level.Conclusions:Our study shows that systemic administration of the bevacizumab-IRDye800CW tracer is safe for breast cancer guidance and confirms tumor and tumor margin uptake as evaluated by a systematic validation methodology. The findings are a step toward a phase II dose-finding study aimed atin vivomargin assessment and point to a novel drug assessment tool that provides a detailed picture of drug distribution in the tumor tissue.Clin Cancer Res; 23(11); 2730-41. ©2016 AACR.
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Laetitia E
authors.initials: LE
authors.lastname: Lamberts
authors.affiliation: Technische Universität München & Helmholtz Zentrum, München, Germany.
authors.forename: Maximillian
authors.initials: M
authors.lastname: Koch
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
authors.forename: Johannes S
authors.initials: JS
authors.lastname: de Jong
authors.affiliation: Department of Radiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
authors.forename: Arthur L L
authors.initials: ALL
authors.lastname: Adams
authors.affiliation: Technische Universität München & Helmholtz Zentrum, München, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Glatz
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
authors.forename: Mariëtte E G
authors.initials: MEG
authors.lastname: Kranendonk
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.|Hospital and Clinical Pharmacy, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Anton G T
authors.initials: AGT
authors.lastname: Terwisscha van Scheltinga
authors.affiliation: Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Jansen
authors.affiliation: Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Jakob
authors.initials: J
authors.lastname: de Vries
authors.affiliation: Hospital and Clinical Pharmacy, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Marjolijn N
authors.initials: MN
authors.lastname: Lub-de Hooge
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Carolien P
authors.initials: CP
authors.lastname: Schröder
authors.affiliation: Hospital and Clinical Pharmacy, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Annelies
authors.initials: A
authors.lastname: Jorritsma-Smit
authors.affiliation: Hospital and Clinical Pharmacy, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Matthijs D
authors.initials: MD
authors.lastname: Linssen
authors.affiliation: Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: de Boer
authors.affiliation: Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Bert
authors.initials: B
authors.lastname: van der Vegt
authors.affiliation: Department of Gastroenterology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Wouter B
authors.initials: WB
authors.lastname: Nagengast
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
authors.forename: Sjoerd G
authors.initials: SG
authors.lastname: Elias
authors.affiliation: Division of Cell Biology of the Department of Biology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Oliveira
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
authors.forename: Arjen J
authors.initials: AJ
authors.lastname: Witkamp
authors.affiliation: Department of Radiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
authors.forename: Willem P Th M
authors.initials: WPTM
authors.lastname: Mali
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
authors.forename: Elsken
authors.initials: E
authors.lastname: Van der Wall
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Elisabeth G E
authors.initials: EGE
authors.lastname: de Vries
authors.affiliation: Technische Universität München & Helmholtz Zentrum, München, Germany.
authors.forename: Vasilis
authors.initials: V
authors.lastname: Ntziachristos
authors.affiliation: Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. g.m.van.dam@umcg.nl.|Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.|Department of Intensive Care, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Gooitzen M
authors.initials: GM
authors.lastname: van Dam
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D001557:Benzenesulfonates / Q000008:administration & dosage* / Q000009:adverse effects; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D018567:Breast Neoplasms, Male / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D061848:Optical Imaging; D049268:Positron-Emission Tomography; D014018:Tissue Distribution / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D001557:Benzenesulfonates; C562366:IRDye 800CW; D007211:Indoles; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab