HER2 assessment in urothelial carcinoma: standardization challenges and the path forward

Human epidermal growth factor receptor 2 (HER2) is a crucial oncogenic factor, highly expressing in various cancers, with urothelial carcinoma (UC) showing one of the highest levels of HER2 overexpression. HER2 serves as an ideal therapeutic target in UC. Current HER2-targeted therapies primarily include tyrosine kinase inhibitors, monoclonal antibodies, and antibody-drug conjugates (ADCs). Among these, ADCs combined with immunotherapy have shown outstanding clinical potential, which have changed the treatment landscape in UC. However, the assessment of HER2 status in UC is still facing major challenges. There is no unified consensus on testing methods and the definition of HER2 positivity, accompanied by significant spatiotemporal expression heterogeneity. These challenges significantly making HER2 assessment difficult in UC, hindering the more precise clinical application of HER2-targeted therapies especially ADCs. In this review, we focus on analyzing the current challenges in standardizing HER2 detection and positivity definitions in UC, elaborating on the spatiotemporal heterogeneity of HER2 expression, and systematically summarizing new HER2 testing methods. It is aimed to provide theoretical insights and new perspectives for HER2 testing and assessment in UC. In order to adress the challenges in HER2 assessment in UC, future researches should concentrate on establishing a unified standard for UC-specific HER2 assessment algorithm, and exploring new HER2 testing methods tailored to clinical needs.