HER2 in mullerian malignancies: diagnostic challenges and the emerging HER2-low paradigm

The role of human epidermal growth factor receptor 2 (HER2) in gynecological oncology has evolved from a histotype-restricted biomarker to a central component of molecular stratification, particularly within the p53-aberrant subgroup of Müllerian malignancies. HER2 amplification and overexpression are strongly enriched in this molecular class across diverse histologies, including serous carcinoma, carcinosarcoma, and high-grade endometrioid carcinoma. However, accurate assessment remains challenging owing to the presence of distinct basolateral staining patterns and marked intratumoral heterogeneity, both of which differ from canonical breast cancer paradigms and contribute to clinically significant diagnostic discordance. The therapeutic landscape has simultaneously undergone a major transition, moving beyond monoclonal antibodies that require high HER2 expression to antibody-drug conjugates capable of targeting tumors with low-level expression. This shift has established the clinically actionable "HER2-low" category, substantially expanding the population eligible for targeted therapy. More recently, the emerging concept of "HER2-ultralow" expression (defined as immunohistochemistry 0 with faint/incomplete membrane staining in ??0% of tumor cells) has further challenged traditional binary classification systems and may have therapeutic implications. The efficacy of these agents is driven by the bystander effect, which enables their activity in heterogeneous tumors. This review summarizes the current understanding of HER2 biology in Müllerian cancers, outlines the diagnostic pitfalls and scoring challenges, and discusses evolving therapeutic strategies, with emphasis on integrating molecular classification and optimized testing to ensure accurate patient selection.