Abstract P2-14-29: Image guided surgery for tumor detection in breast cancer using the PH activated micellar tracer ONM-100: The SHINE study
Authors: Steinkamp PJ , Voskuil FJ , Koller M , van der Vegt B , Doff JJ , Zhao T , Hartung J , Jayalakshmi Y , Sumer BD , Gao J , Witjes MJ , van Dam GM 
Published: May 2019

Abstract
Background: Currently, no reliable intra-operative tumor detection and margin assessment technologies during breast conserving surgery are available. Fluorescence-guided surgery (FGS) using tumor specific fluorescent tracers can improve intra-operative tumor detection. However, a major limitation is the lack of broad tumor applicability due to complex oncogenotypes and histologic phenotypes. A strategy to overcome this challenge is targeting metabolic vulnerabilities that are more ubiquitous and regarded as generic hallmarks of cancer. The extracellular environment of tumors is relatively acidic compared to healthy tissue due to aerobic glycolysis, the so-called Warburg effect. ONM-100, a micellar polymer tracer labeled with the fluorescent imaging dye Indocyanine Green (ICG), has an exquisitely pH-sensitive binary on/off mechanism. The micelles dissociate in acidic environments causing the unquenching and fluorescent activation of the ICG dye. As most solid cancer types are acidotic, ONM-100 acts as a generic tracer targeting a broad range of tumors. This proof of concept, first in-human study, investigates the safety and feasibility of ONM-100 as an intra-operative fluorescent tracer in breast cancer (BC) patients.
Methods: In this phase 1 study, the pH-activated fluorescent tracer ONM-100 was administered 24±8h prior to surgery in a dose escalation scheme ranging from 0.1 mg/kg to 0.8 mg/kg in groups of 3 patients each. Patients with biopsy proven BC were included. Patients that had undergone neoadjuvant therapy were excluded. Blood was drawn up to day 10 to assess safety and pharmacokinetic data. Intra-operative images were collected of the tumor before and after excision and of the wound bed. Immediately after excision ex vivo fluorescence images were obtained from the serially sliced specimen and the formalin fixated paraffin embedded tissue blocks. Fluorescence images were correlated with histopathological assessment on Hematoxylin and Eosin (H/E) stained sections.
Results: In this ongoing clinical trial, 4 patients with BC were enrolled between March and May 2018. No tracer related (serious) adverse events were observed. A strong and sharply demarcated fluorescent signal in tumor tissue was observed in all 4 patients with in- and ex vivo imaging (median Contrast to Noise Ratio 6.5; IQR 7.25), which correlated with areas of tumor involvement on histopathology. In one BC patient, an intra-operatively unnoticed tumor positive margin was detected using fluorescence imaging. Additionally, a BC satellite lesion was detected, which was otherwise missed by the pathologist.
Conclusion: Preliminary results of this ongoing first in-human study with the pH-activated tracer ONM-100 shows that ONM-100 is well tolerated and safe and allows fluorescent tumor visualization both in- and ex vivo. Here, we provide the first data that this pH-sensitive optical tracer can be used as a tracer for FGS and for margin detection. Further analysis on microscopic biodistribution of ONM-100 is currently being performed and possibilities for metastatic lymph node detection will be explored.
Citation Format: Steinkamp PJ, Voskuil FJ, Koller M, van der Vegt B, Doff JJ, Zhao T, Hartung J, Jayalakshmi Y, Sumer BD, Gao J, Witjes MJ, van Dam GM. Image guided surgery for tumor detection in breast cancer using the PH activated micellar tracer ONM-100: The SHINE study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-14-29.