Tumor Uptake of ⁶⁴Cu-DOTA-Trastuzumab in Patients with Metastatic Breast Cancer

Abstract

The goal of this study was to characterize the relationship between tumor uptake of Cu-DOTA-trastuzumab as measured by PET/CT and standard, immunohistochemistry (IHC)-based, histopathologic classification of human epidermal growth factor receptor 2 (HER2) status in women with metastatic breast cancer (MBC). Women with biopsy-confirmed MBC and not given trastuzumab for 2 mo or more underwent complete staging, includingF-FDG PET/CT. Patients were classified as HER2-positive (HER2+) or -negative (HER2-) based on fluorescence in situ hybridization (FISH)-supplemented immunohistochemistry of biopsied tumor tissue. Eighteen patients underwent Cu-DOTA-trastuzumab injection, preceded in 16 cases by trastuzumab infusion (45 mg). PET/CT was performed 21-25 (day 1) and 47-49 (day 2) h afterCu-DOTA-trastuzumab injection. Radiolabel uptake in prominent lesions was measured as SUV Average intrapatient SUV (<SUV>) was compared between HER2+ and HER2- patients. Eleven women were HER2+ (8 immunohistochemistry 3+; 3 immunohistochemistry 2+/FISH amplified), whereas 7 were HER2- (3 immunohistochemistry 2+/FISH nonamplified; 4 immunohistochemistry 1+). Median<SUV> for day 1 and day 2 was 6.6 and 6.8 g/mL for HER 2+ and 3.7 and 4.3 g/mL for HER2- patients ( < 0.005 either day). The distributions of <SUV> overlapped between the 2 groups, and interpatient variability was greater for HER2+ than HER2- disease ( < 0.005 and 0.001, respectively, on days 1 and 2). By 1 d after injection, uptake ofCu-DOTA-trastuzumab in MBC is strongly associated with patient HER2 status and is indicative of binding to HER2. The variability within and among HER2+ patients, as well as the overlap between the HER2+ and HER2- groups, suggests a role for Cu-DOTA-trastuzumab PET/CT in optimizing treatments that include trastuzumab.

A Microdose Clinical Trial to Evaluate 64Cu-NOTA-Trastuzumab as a Positron Emission Tomography Imaging Agent in Patients with Breast Cancer

“…For this reason, it is important to evaluate HER2 expression before HER2-targeted therapy in order to enhance the treatment e cacy of the patients. 64 Cu-DOTA-Trastuzumab PET, one of the methods for evaluating HER2 expression in a non-invasive method, was reported as a feasible modality with clinical trials [5,6,13,14]. Compared to other PET agents, such as 89 Zr and 124 I, which have been used for evaluating HER2 expression, 64 Cu has the bene t of reducing radiation exposure with a relatively short half-life [2], and also has the advantage of being able to perform PET/CT in an outpatient setting.…”

“…The trials were able to demonstrate that they can quantify HER2 expression of lesions in patients with HER2 expressing tumors [9,11,12]. In addition, the use of HER2 targeted PET imaging using 64 Cu-tetra-azacyclododecanetetra-acetic acid (DOTA)-Trastuzumab has been attempted [5,6,11,13,14]. Clinical trials using this agent in the United States and Japan showed effective identi cation of HER2 expression in breast cancer patients [5,6,13,14].…”

Chemical aspects of metal ion chelation in the synthesis and application antibody‐based radiotracers

“…Clinical trials worldwide have reported the efficacy of using 64 Cu-DOTA-trastuzumab to measure expression of the human epidermal growth factor 2 (HER2/neu) in breast cancer patients. [32][33][34] In addition, 64 Cu-labeled cetuximab for imaging epidermal growth factor receptor has been studied extensive in preclinical work with experiments comparing the performance of different chelates including DOTA, 35,36 CB-TE1A1P, and CB-TE1K1P in combination with either tradition amide bond coupling or "copper-free click" methods for rapid bioconjugation. 37 As efforts gather pace to improve access to 67 Cu, 18 identification of new chelates, linkers, and radiolabeling methods to produce 64/67 Cu-mAbs is essential.…”

Understanding the in vivo fate of radioimmunoconjugates for nuclear imaging

“…That said, this has not stopped several laboratories from bringing 64 Cu-labeled immunoPET agents into the clinic. [99][100][101] The in vivo metabolism of both 64 Cu-and 67 Culabeled antibodies has been studied in several preclinical mouse models. [102][103][104] Yet regardless of the antibody or tumor model, the catabolism of the antibody in the tumor was found to be fast and led to the formation of a final product consisting of the radiocopper-chelator complex attached to a short protein trapped within the lysosome.…”