Abstract PD3-02: Intraoperative tumor detection using a ratiometric activatable fluorescent peptide: A first-in-human phase I study allows tumors to be visualized in the operating room
Authors: Unkart JT , Chen SL , González JE , Harootunian A , Wallace AM 
Published: March 2017

Background:

A continuing challenge in breast cancer surgery is the difficulty with intraoperative lymph node status determination and achieving negative surgical margins. Current techniques such as frozen section, touch prep and intraoperative radiographic imaging are time consuming and vary in accuracy from institution to institution. Our study is a first-in-human study of a novel ratiometric activatable cell penetrating fluorescent peptide dye conjugate that labels breast cancer tumor tissue in vivo.

Methods:

AVB-620 is a substrate for and activated by proteases in the matrix metalloproteinase family. It has two fluorophores moieties linked by a cleavable peptide. Upon cleavage, there is an increase in fluorescence intensity and a change in the predominant wavelength of fluorescence emission. AVB-620 was given preoperatively via intravenous infusion to stage 0-III breast cancer patients. Patients were monitored for safety and AVB-620 pharmacokinetic parameters determined. After 12-20 hours, patients underwent lumpectomy or mastectomy with either sentinel lymph node biopsy (SLNB) or axillary lymph nodes dissection (ALND). Using a customized near-infrared camera system, fluorescence intensity signals at two wavelengths were measured intraoperatively both in vivo and ex vivo of primary tumors, shave margins and lymph nodes. The intensity ratio of these two wavelengths was utilized to distinguish between malignant and non-malignant tissues. Images were correlated to pathology reports.

Results:

Fifteen patients with average age of 59 years were enrolled across 5 dose cohorts without any significant adverse events. All patients underwent definitive breast surgery (12 lumpectomy, 3 mastectomy) and axillary surgery (12 – SLNB, 3- ALND). Four patients that had tumor-positive lymph nodes confirmed pathologically which correlated with increased fluorescence intensity and ratio on imaging. Primary tumor images also demonstrated fluorescence intensity and ratiometric changes that distinguished cancerous and non-cancerous tissues.

Discussion:

The purpose of this phase 1 dose escalation was to determine safety profile and adequate dosing. This study demonstrated a proof of concept of the use of a protease-activatable ratiometric fluorescent peptide dye conjugate to identify malignant tissue intraoperatively. Increased fluorescent ratio correlated and resulted in fluorescent imaging of known tumor in the operating room, with images that directly correlated with position of tumor in the excised tissue. This approach has the potential to quickly and accurately visualize the pathologic status of tumor margins and lymph node intraoperatively. Further studies to optimize dose, timing of administration, and thresholds for ratiometric imaging are underway.

Citation Format: Unkart JT, Chen SL, González JE, Harootunian A, Wallace AM. Intraoperative tumor detection using a ratiometric activatable fluorescent peptide: A first-in-human phase I study allows tumors to be visualized in the operating room [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 PD3-02.