Radiolabeled HER2-targeted molecular probes in breast cancer imaging: current knowledge and future prospective

Breast cancer is the most frequent non-dermatologic malignancy in women. Breast cancer is characterized by the expression of the human epidermal growth factor receptor type 2 (HER2), and the presence or lack of estrogen receptor (ER) and progesterone receptor (PR) expression. HER2 overexpression is reported in about 20 to 25% of breast cancer patients, which is usually linked to cancer progression, metastases, and poor survival. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are the gold standards for determining HER2 status, even though IHC has largely focused on quantifying HER2⁺ status versus "other" HER2 status (including variants with low or no expression). Recent findings regarding the beneficial therapeutic effects of anti-HER2 monoclonal antibodies (mAb) in HER2^low metastatic patients lead to changes in the classic definition of advanced breast cancer, and methods for precise assessment of HER2 status are being developed. As a result, various radiolabeled HER-targeted mAbs and antibody fragments have been designed to avoid repeated biopsies with potential bias due to tumor heterogeneity, including single-chain variable fragment (scFv), F(ab')2, affibody, and nanobody. These small targeting radiotracers displayed favorable biodistributions, clearance, and stability, allowing for higher image quality, shorter circulation half-life, and lower immunogenicity. This study aimed to comprehensively review the application of radiolabeled anti-HER2 antibody fragments in breast cancer in vivo imaging and provide a better understanding of targeted HER2 quantification.