89Zr-Trastuzumab PET/CT for Detection of Human Epidermal Growth Factor Receptor 2–Positive Metastases in Patients With Human Epidermal Growth Factor Receptor 2–Negative Primary Breast Cancer

Abstract

Purpose To determine if imaging with 89Zr-trastuzumab, a human epidermal growth factor receptor 2 (HER2)-targeting PET tracer can detect HER2-positive metastases in patients with HER2-negative primary breast cancer. Methods As part of an Institutional Review Board (IRB)-approved, prospective clinical trial of 89Zr-trastuzumab PET/CT (ClinicalTrials.gov identifier NCT02286843), a second group of 11 patients with HER2-negative primary breast cancer and known metastatic disease were recruited. Patients with confirmed HER2-negative primary breast cancer underwent 89Zr-trastuzumab PET/CT to screen for 89Zr-trastuzumab-avid lesions suspicious for unsuspected HER2-positive metastases. 89Zr-trastuzumab-avid lesions on PET/CT were biopsied and pathologically examined to determine HER2 status. Results All 11 patients had confirmed HER2-negative primary breast cancer. Four demonstrated suspicious foci on 89Zr-trastuzumab PET/CT. Of these four, one had biopsy-proven HER2-positive metastases. The other three patients with suspicious 89Zr-trastuzumab-avid foci had biopsy demonstrating a metastasis that was HER2-negative, and were considered false-positive 89Zr-trastuzumab PET foci. Combined with a published report of the first 9 patients, there have been a total of 20 HER2-negative primary breast cancer patients, with 3 patients (15%) having pathologically confirmed HER2-positive distant metastases and 6 (30%) with suspicious 89Zr-trastuzumab-avid foci that were HER2-negative on pathology, which were thus considered false-positive 89Zr-trastuzumab findings. Conclusion This second group of patients confirms the proof-of-concept that 89Zr-trastuzumab PET/CT detects unsuspected HER2-positive metastases in a subset of patients with HER2-negtive primary breast cancer. False-positive 89Zr-trastuzumab-avid foci present a challenge to using this tracer.

Development of 64Cu-NOTA-Trastuzumab for HER2 Targeting: A Radiopharmaceutical with Improved Pharmacokinetics for Human Studies

“…Through both genetic and pharmacologic approaches, it was determined that HER2 is both necessary and sufficient for tumor formation and maintenance in models of HER2positive breast cancer (27). Targeting HER2 with monoclonal antibody, such as trastuzumab and pertuzumab, is a well-established therapeutic strategy for HER2-positive breast cancer in neoadjuvant (28), adjuvant (29,30), and metastatic settings (31,32). Especially trastuzumab, a humanized recombinant monoclonal antibody against HER2, is widely used as a standard treatment for HER2expressing breast cancer.…”

“…Detection of HER2-positive metastatic tumors using radiolabeled HER2 antibodies would be valuable to provide safety, treatment economy, and other therapeutic options to HER2-negative tumor-bearing patients. Conversely, Ulaner et al reported that 89 Zr-labeled trastuzumab PET/CT could be applied to detect unsuspected HER2-positive metastases in patients with HER2-negative primary breast cancer as a proof-of-concept clinical study (32). Thus, it is important to evaluate HER2 expression in metastatic and primary tumors to determine whether anti-HER2 therapy is indicated.…”

First-in-Human Human Epidermal Growth Factor Receptor 2–Targeted Imaging Using 89Zr-Pertuzumab PET/CT: Dosimetry and Clinical Application in Patients with Breast Cancer

“…Although there have been successes in HER2-targeted imaging with 89 Zr-trastuzumab, there have also been examples of nonspecific visualization of malignancies that are HER2-negative on pathology (5,6). More specific HER2-targeted agents may be needed for clinical translation of HER2-targeted imaging agents.…”

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

“…Mild diffuse uptakes were also observed in the tumors with a negative expression of HER2. This is because HER2 expression is not all-or-none as determined by the immunohistochemistry methods [5,17]. In other words, even if HER2 expression of the tumor is negative, the SUV max of the tumor increases in proportion to the IHC score of the tumor [5,17].…”

“…This is because HER2 expression is not all-or-none as determined by the immunohistochemistry methods [5,17]. In other words, even if HER2 expression of the tumor is negative, the SUV max of the tumor increases in proportion to the IHC score of the tumor [5,17]. Therefore, it is important to set the cut-off values of SUV max or SUV ratio carefully between tumor and background for determining HER2 expression using 64 Cu-NOTA-trastuzumab PET image.…”