Abstract
The overexpression of human epidermal growth factor 2 (HER2) in breast cancer (BC) has been associated with a more aggressive tumor subtype, poorer prognosis and shorter overall survival. In this context, the development of HER2-targeted radiotracers is crucial to provide a non-invasive assessment of HER2 expression to select patients for HER2-targeted therapies, monitor response and identify those who become resistant. Antibodies represent ideal candidates for this purpose, as they provide high contrast images for diagnosis and low toxicity in the therapeutic setting. Of those, nanobodies (Nb) are of particular interest considering their favorable kinetics, crossing of relevant biological membranes and intratumoral distribution. The purpose of this review is to highlight the unique characteristics and advantages of Nb-based radiotracers in BC imaging and therapy. Additionally, radiolabeling methods for Nb including direct labeling, indirect labeling via prosthetic group and indirect labeling via complexation will be discussed, reporting advantages and drawbacks. Furthermore, the preclinical to clinical translation of radiolabeled Nbs as promising theranostic agents will be reported.
Highlights
Breast cancer (BC) is the second leading cause of mortality for women worldwide [1].BC harboring overexpression of the receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2) and/or amplification of the HER2/neu gene accounts for about 20% of all BCs [2]
HER2 expression can change during the course of the disease and can be unequally expressed across primary tumor and metastatic lesions
Since only a subset of BC patients has HER2-positive (HER2+) tumors, robust assessment of HER2 expression represents a critical step in selecting patients who might benefit from HER2-targeted therapies
Summary
Breast cancer (BC) is the second leading cause of mortality for women worldwide [1].BC harboring overexpression of the receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2) and/or amplification of the HER2/neu gene accounts for about 20% of all BCs [2]. HER2 status is determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), both requiring invasive procedures for biopsy sample collection [5] These histopathological methods do not address the whole-tumor heterogeneity and are limited by the sampling of a site at a certain time point, producing many times false-negative or false-positive results, which further impact on the proper selection of treatments [6,7]. Molecular imaging techniques using radiopharmaceuticals can be used to reduce this source of incertitude in the evaluation of HER2 expression This non-invasive imaging approach has the potential to provide information about the global status of HER2 in primary and distant metastatic lesions, at the same time [12]. This approach allows us to monitor the response to HER2-targeted therapies and to identify the patients who become resistant [12,13,14]
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