Purpose To evaluate safety, human radiation dosimetry and optimal imaging time of [89Zr]trastuzumab in patients with HER2-positive breast cancer. Procedures Twelve women with HER2-positive breast cancer underwent [89Zr]trastuzumab-PET/CT twice within 7 days postinjection. Biodistribution data from whole-torso PET/CT images, and organ time-activity curves were created using data from all patients. Human dosimetry was calculated using OLINDA with the adult female model. Results High-quality images and the greatest tumor-to-nontumor contrast were achieved with images performed 5 ± 1 day postinjection. Increased [89Zr]trastuzumab uptake was seen in at least one known lesion in 10 patients. The liver was the dose-limiting organ (retention of ~12% of the injected dose and average dose of 1.54 mSv/MBq. The effective dose was 0.47 mSv/MBq. No adverse effects of [89Zr]trastuzumab were encountered. Conclusion [89Zr]trastuzumab was safe and optimally imaged at least 4 days post-injection. The liver was the dose-limiting organ.

Since its discovery, the human epidermal growth factor 2 (HER2) has been extensively studied. Presently, there are 2 standard diagnostic techniques to assess HER2 status in biopsies: immunohistochemistry and fluorescence in situ hybridization. While these techniques have played an important role in the treatment of patients with HER2-positive cancer, they both require invasive biopsies for analysis. Moreover, the expression of HER2 is heterogeneous in breast cancer and can change over the course of the disease. Thus, the degree of HER2 expression in the small sample size of biopsied tumors at the time of analysis may not represent the overall status of HER2 expression in the whole tumor and in between tumor foci in the metastatic setting as the disease progresses. Unlike biopsy, molecular imaging using probes against HER2 allows for a noninvasive, whole-body assessment of HER2 status in real time. This technique could potentially select patients who may benefit from HER2-directed therapy and offer alternative treatments to those who may not benefit. Several antibodies and small molecules against HER2 have been labeled with different radioisotopes for nuclear imaging and/or therapy. This review presents the most recent advances in HER2 targeting in nuclear medicine focusing on preclinical and clinical studies.

[Zr]trastuzumab has the potential to characterize the HER2 status of the complete tumor burden in patients with breast cancer, thus obviating repeat or multiple tissue sampling to assess intrapatient heterogeneity of HER2 status.

Radioimmunotherapies with monoclonal antibodies to the B-lymphocyte antigen 20 (CD20) are effective treatments for B-cell lymphomas, but U.S. Food and Drug Administration-approved radioimmunotherapies exclusively use radiolabeled murine antibodies, potentially limiting redosing. The Food and Drug Administration recently approved 2 unlabeled anti-CD20 monoclonal antibodies, obinutuzumab and ofatumumab, termed next generation as they are humanized (obinutuzumab) or fully human (ofatumumab), thus potentially allowing a greater potential for redosing than with previous-generation anti-CD20 antibodies, including rituximab (chimeric) and tositumomab (murine), which contain more murine peptide sequences. We prepared Zr-ofatumumab andZr-obinituzumab and assessed their tumor targeting by PET/CT imaging and their biodistribution in a preclinical mouse model with CD20 xenografts to determine whether these antibodies have potential as theranostics or for radioimmunotherapy. Obinutuzumab, ofatumumab, rituximab, tositumomab, and human IgG (as control) were radiolabeled withZr. Raji Burkitt lymphoma xenografts were established in severe combined immunodeficient mice. Mice with palpable tumors ( = 4-9) were injected with Zr-obinutuzumab,Zr-ofatumumab, Zr-rituximab,Zr-tositumomab, or Zr-IgG, with small-animal PET/CT images acquired at 1, 3, and 7 d after injection, and then sacrificed for biodistribution analyses. At 1, 3, and 7 d after injection, all anti-CD20 antibodies showed clear tumor uptake on PET/CT, with minimal tumor uptake of IgG. Biodistribution data showed significantly ( < 0.005) higher tumor uptake for obinutuzumab (41.4 ± 7.6 percentage injected dose [%ID]/g), ofatumumab (32.6 ± 17.5 %ID/g), rituximab (28.6 ± 7.6 %ID/g), and tositumomab (28.0 ± 6.5 %ID/g) than IgG (7.2 ± 1.2 %ID/g). Tositumomab had much higher splenic uptake (186.4 ± 49.7 %ID/g, < 0.001) than the other antibodies. Zr-labeled obinutuzumab and ofatumumab localized to tumor as well as or better than labeled rituximab and tositumomab, 2 monoclonal antibodies that have been used previously in B-cell lymphoma radioimmunotherapy, and both obinutuzumab and ofatumumab have the potential for repeated dosing.

Background: The success of human epidermal growth factor receptor 2 (HER2)-targeted therapy depends on accurate characterization of HER2 expression, but current methods available have several limitations. This study aims to investigate the feasibility of [ 89 Zr]pertuzumab imaging to monitor early response to Adotrastuzumab emtansine (T-DM1) therapy in mice bearing xenografts of HER2-positive breast cancer (BCa). Materials and Methods: Pertuzumab was conjugated to DFO-Bz-NCS and labeled with 89 Zr. Mice bearing BT-474 tumors were imaged with [ 89 Zr]pertuzumab and [ 18 F]FDG before and after T-DM1 therapy. Results: Pertuzumab was successfully labeled with 89 Zr with a specific activity of 0.740 MBq/lg. Overall [ 18 F]FDG images showed poor delineation of tumors. Using [ 18 F]FDG-PET to measure tumor volume, the volume remained unchanged from 107.6-20.7 mm 3 before treatment to 89.87-66.55 mm 3 after treatment. In contrast, [ 89 Zr]pertuzumab images showed good delineation of HER2-positive tumors, allowing accurate detection of changes in tumor volume (from 243.80-40.91 mm 3 before treatment to 78.4-40.43 mm 3 after treatment). Conclusion: [ 89 Zr]pertuzumab may be an imaging probe for monitoring the response of HER2-positive BCa patients to T-DM1 therapy.