Validity and utility of HER2/ERBB2 copy number variation assessed in liquid biopsies from breast cancer patients: A systematic review

Addition of HER2-targeted treatment in breast cancer is mainly determined by the HER2-receptor status of primary breast cancer tissue, since longitudinal sampling is burdensome and often not feasible. However, tumor heterogeneity and receptor conversion occur and may lead to improper diagnose as disease progresses. It is however possible that patients with their applied receptor status misjudged may benefit from HER2-targeted therapy. Liquid biopsies provide a useful source of information for receptor status and determine prognosis or evaluate therapy effectiveness. In this review, we give a comprehensive overview of current analytical and clinical validity and clinical utility of liquid biopsies for HER2 assessment. We systematically searched publications in Cochrane, Embase, PubMed and Google Scholar databases until April 2021 reporting on HER2positivity in liquid biopsies and its concordance with tumor tissue, or on prognostic and/or predictive value of HER2-positivity in liquid biopsies. Applying our selection criteria, we identified 57 studies; 43 studies on circulating tumor cells, 13 studies on circulating tumor DNA and 1 study on extracellular vesicles. Most studies showed an association with outcome or treatment response, but used methods differed greatly, lacked a gold standard and evaluated patient groups differently hampering interpretation of results. We conclude that welldesigned studies to determine assay validity and clinical validity and utility of HER2 assessment through liquid biopsies are currently lacking.