Imaging Diagnostic and Therapeutic Targets: Human Epidermal Growth Factor Receptor 2

Abstract

Since the approval of trastuzumab, a humanized monoclonal antibody against the extracellular domain of human epidermal growth factor receptor 2 (HER2), 3 other HER2-targeting agents have gained regulatory approval: lapatinib, pertuzumab, and trastuzumab-emtansine. These agents have revolutionized the management of HER2-positive breast cancer, highlighting the concept that targeted therapies are successful when patients exhibit tumor-selective expression of a molecular target-in this case, HER2. However, response prediction and innate or acquired resistance remain serious concerns. Predictive biomarkers of a response-which could help in the selection of patients who might benefit from a selected targeted therapy-are currently lacking. Molecular imaging with anti-HER2 probes allows the noninvasive, whole-body assessment of HER2 tumor burden and has the potential to improve patient selection, optimize the dose and schedule, and rationalize assessment of the response to anti-HER2 therapies. Furthermore, unlike biopsy-based HER2 assessment, this approach can reveal inter-or intratumoral heterogeneity as well as variations in HER2 expression over time. This review summarizes the available literature and the current status of molecular imaging as a tool for the assessment of HER2 (target) expression or the prediction of an early treatment response in early and advanced HER2-positive breast cancer. Human epidermal growth factor receptor 2 (HER2) is overexpressed in several cancers, including breast, gastric, ovary, prostate, bladder, and lung cancers, and is a proven therapeutic target in the first 2 tumor types (1,2). In breast cancer (BC), in particular, HER2 overexpression is found in 15%-25% of patients and is associated with a clinically aggressive course. Successful targeting of HER2 with a range of anti-HER2 drugs has resulted in markedly improved patient outcomes in both advanced and early disease settings (3).However, the presence of a target (in this case, HER2) does not always guarantee benefit from matched targeted therapies because downstream signaling resistance or escape can occur. In HER2-overexpressing BC, it has been estimated that about 50% of patients with metastases do not benefit from anti-HER2 therapies (4), and not a single biomarker for identifying nonresponding patients has yet been validated (5).Furthermore, there is increasing evidence of temporal and spatial heterogeneity in BC HER2 overexpression. Patients with negative test results at diagnosis can have positive test results later in the disease course and vice versa, a fact that explains why biopsy of metastatic disease is a strong recommendation of many clinical treatment guidelines (6). Heterogeneity in biomarker expression at metastatic sites is only beginning to be recognized, with growing appreciation for molecular imaging.This article focuses on HER2-positive BC and provides a comprehensive overview of the present and future roles of molecular imaging in improving target mapping, predicting benefit from chemotherapy with or without ...

First In-Human Medical Imaging with a PASylated 89Zr-Labeled Anti-HER2 Fab-Fragment in a Patient with Metastatic Breast Cancer

“…Human epidermal growth factor receptor 2 (HER2) is a cell membrane receptor tyrosine kinase that plays a key role in cell development, proliferation, and differentiation [1]. Moreover, HER2 is overexpressed in a variety of cancers, including bladder; lung; gastric; ovarian; prostate; and, in particular, breast cancer (BCa) [2]. Overexpression of HER2 on tumor cells is associated with a high rate of proliferation and aggressive disease, poor prognosis, and short overall survival [3].…”

Fluorine-18 Labeling of the HER2-Targeting Single-Domain Antibody 2Rs15d Using a Residualizing Label and Preclinical Evaluation

“…This has led to the development of a variety of HER2-targeted therapies including the anti-HER2 antibodies trastuzumab and pertuzumab, T-DM1 (Kadcyla®)—an antibody-drug conjugate derived from trastuzumab and emtansine (DM1), and the tyrosine kinase inhibitor lapatinib [3–5]. Because only a subset of breast cancer patients has HER2-expressing tumors, reliable evaluation of HER2 status is a critical step in selecting patients who might benefit from these HER2-specific treatments.…”

Radioiodination of BODIPY and its application to a nuclear and optical dual functional labeling agent for proteins and peptides

“…Trastuzumab is an antibody against human epidermal growth factor receptor 2 (HER2) that is overexpressed in several cancers, and commonly used as a carrier protein of radioisotopes and fluorescence dyes for the in vivo imaging of cancers 24, 25 . According to the similar method used for the conjugation reaction of BSA, we reacted [ 125 I] 4 with trastuzumab, and purified the reaction mixture with size-exclusion chromatography.…”