Detection of HER2-Low Lesions Using HER2-Targeted PET Imaging in Patients with Metastatic Breast Cancer: A Paired HER2 PET and Tumor Biopsy Analysis

Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate, demonstrated remarkable efficacy in previously treated patients with HER2-low metastatic breast cancer (mBC), marking a new therapeutic option for this patient population. Prior studies with HER2 PET using ⁸⁹Zr-radiolabeled antibodies were limited by high rates of imaging false positives for HER2-positive malignancy. In this retrospective study, we investigate whether these false positives (HER2-negative on pathology) could be explained by HER2-low lesions. <b>Methods:</b> A retrospective study was conducted of mBC patients who previously enrolled in 2 prospective HER2 PET imaging trials: NCT02286843 using ⁸⁹Zr-trastuzumab and ⁸⁹Zr-pertuzumab and NCT04692831 using ⁸⁹Zr-ss-pertuzumab. Patients were included if paired HER2 PET scan and biopsy were performed within a 2-mo period. Of 56 total patients, 23 patients met the inclusion criteria. Pathology results for biopsied lesions were collected, without repeat interpretation, and lesions were classified as HER2-positive, HER2-low, or HER2-0. SUV_max of biopsied lesions were compared between pathologic classifications to determine whether lesion uptake intensity could differentiate between HER2-positive and HER2-low lesions. <b>Results:</b> All prior false-positive lesions on HER2 PET scans from NCT02286843 were reclassified as HER2-low (instead of HER2-negative). In the ⁸⁹Zr-trastuzumab cohort, 3 lesions were HER2-positive (33%) and 6 were HER2-low (67%); in the ⁸⁹Zr-pertuzumab cohort, 2 were HER2-positive (29%) and 5 were HER2-low (71%). In the ⁸⁹Zr-ss-pertuzumab cohort (NCT04692831), 7 patients underwent recent biopsies of 8 total lesions demonstrating 1 HER2-positive (12%), 5 HER2-low (62%), and 2 HER2-0 lesions (25%). HER2 PET SUV_max of biopsied lesions were compared between HER2-positive and HER2-low lesions for the combination of all 3 radiotracer cohorts. HER2-low lesions had a significantly higher SUV_max (median, 12.7; interquartile range, 8.05) than did HER2-positive lesions (median, 6.4; interquartile range, 1.98; <i>P</i> = 0.01). <b>Conclusion:</b> HER2 PET imaging with ⁸⁹Zr-radiolabeled antibodies detects HER2-low lesions in addition to HER2-positive lesions in patients with mBC, suggesting its ability to visualize the entire spectrum of HER2 expression. All prior false positives on ⁸⁹Zr-trastuzumab and ⁸⁹Zr-pertuzumab PET scans were reclassified as HER2-low. Lesion SUV_max is not reliable in differentiating HER2-positive from HER2-low lesions; however, it may be useful in distinguishing lesions expressing HER2 from HER2-0 lesions.