Abstract P4-01-01: Phase II in-human dose escalation study of the optical molecular imaging tracer bevacizumab-800cw for molecular fluorescence guided surgery in primary breast cancer patients
Authors: van Dam GM , Koller M , Qiu SQ , Linssen MD , de Vries J , Jansen L , Kelder W , de Jong JS , Jorritsma-Smit A , van der Vegt B , Robinson DJ , Nagengast WB 
Published: March 2017

Introduction

Molecular Fluorescence Guided Surgery (MFGS) might be used for intraoperative detection of positive resection margins in breast conserving surgery (BCS) for the treatment of breast cancer. Currently, the presence of tumor positive resection margins can only be assessed ex vivo by histopathological analysis of the excised tissue, which takes up to 5 working days. The current study defined the optimal dose of the near-infrared (NIR) optical imaging tracer bevacizumab-800CW to enable intraoperative detection and image-guided pathology of tumor positive resection margins in breast cancer patients.

Methods

Molecular Fluorescence Guided Surgery during BCS was performed in subjects treated for primary breast cancer. The NIR optical imaging tracer bevacizumab-800CW targeting vascular endothelial growth factor A was administered intravenously three days prior to surgery in four escalating dose groups (4.5mg, 10mg, 25mg and 50mg). NIR fluorescent signals were detected real-time using an intraoperative fluorescence camera system (SurgVision BV). Standardized ex vivo analyses of tumor-to-normal ratios (TNR) were performed to define the optimal tracer dose using a BlackBox imaging system (SurgVision BV) for imaging fresh bread loaf slices, a NIR fluorescence flatbed scanner (Odyssey, Li-Cor) for imaging 10µm slices of formalin-fixed paraffin-embedded (FFPE) blocks, NIR Confocal Laser Endomicroscopy (CLE, Mauna Kea Technologies) and multi-diameter single fiber reflectance and single fiber fluorescence (MDSFR/SFF) spectroscopy quantification to enable correction for the influence of tissue optical properties on fluorescence in tumor and normal breast tissue.

Results

Currently, 12 subjects have been included and analyzed in four dosing groups. All tumors showed specific tracer uptake at macroscopic and microscopic level during ex vivo analyses, confirmed by histopathology. Quantification of NIR fluorescent signals showed higher TNRs by increasing doses up to 25mg. No further increase in TNR was seen in the 50mg dose group. CLE showed the feasibility of visualization of the tracer accumulation in tumor tissue compared to normal tissue at a microscopic level. MDSFR/SFF spectroscopy objectively confirmed the dose dependency up to 25mg.

Conclusion and future perspective

Intravenous administration of bevacizumab-800CW in doses up to 50mg is safe and highly tumor specific, showing a plateau of TNR at 25mg and 50mg. Further expansion of the dosing cohorts of 10mg and 25mg with additional seven patients per group will be performed to establish the optimal dose for MFGS during BCS for an upcoming phase III multicenter randomized controlled trial. By enabling MFGS during BCS the surgical treatment of primary breast cancer patients might be optimized by a reduced need for re-excision surgery and thereby reducing the risk of co-morbidity, psychological burden, poor cosmesis and healthcare costs.

Citation Format: van Dam GM, Koller M, Qiu SQ, Linssen MD, de Vries J, Jansen L, Kelder W, de Jong JS, Jorritsma-Smit A, van der Vegt B, Robinson DJ, Nagengast WB. Phase II in-human dose escalation study of the optical molecular imaging tracer bevacizumab-800cw for molecular fluorescence guided surgery in primary breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-01-01.