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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 and ex vivo in surgical specimens using an optical imaging system. Ex vivo multiplexed 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 detected ex vivo by 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 at in vivo margin assessment and point to a novel drug assessment tool that provides a detailed picture of drug distribution in the tumor tissue. 

Author information​

Lamberts LE1, Koch M2, de Jong JS3, Adams ALL4, Glatz J2, Kranendonk MEG3, Terwisscha van Scheltinga AGT1,5, Jansen L6, de Vries J6, Lub-de Hooge MN5, Schröder CP1, Jorritsma-Smit A5, Linssen MD5, de Boer E6, van der Vegt B7, Nagengast WB8, Elias SG9, Oliveira S10, Witkamp AJ11, Mali WPTM4, Van der Wall E12, van Diest PJ3, de Vries EGE1, Ntziachristos V2, van Dam GM13,14,15.

1 Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

2 Technische Universität München & Helmholtz Zentrum, München, Germany.

3 Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

4 Department of Radiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

5 Hospital and Clinical Pharmacy, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

6 Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

7 Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

8 Department of Gastroenterology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

9 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

10 Division of Cell Biology of the Department of Biology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

11 Department of Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

12 Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

13 Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. g.m.van.dam@umcg.nl.

14 Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

15 Department of Intensive Care, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.