Academy of Medical Sciences of I.R. Iran Archives of Iranian Medicine 1029-2977 29 3 2026 03 01 HER2: Biology and Testing in Gastrointestinal, Genitourinary, and Gynecologic Malignancies 183 187 10.34172/aim.35506 EN Wala Ben Kridis https://orcid.org/0000-0002-4956-9551 Afef Khanfir REVIEW 10.34172/aim.35506 2025 11 18 2026 02 15 This article explores the role of HER2 as an oncogenic driver across multiple cancer types, with a specific focus on gastrointestinal, genitourinary, and gynecologic malignancies. HER2, a member of the ErbB receptor family, is implicated in cell growth, survival, and oncogenesis through its activation of downstream signaling pathways such as MAPK and PI3K/AKT. Aberrant HER2 activation, through gene amplification or activating mutations, is a well-established contributor to the aggressive biological behavior of breast and gastric cancers. Recent studies have expanded the relevance of HER2 beyond breast and gastric cancers to include colorectal, urothelial, and gynecologic cancers, making it a valuable therapeutic target in these settings. This review highlights the molecular mechanisms behind HER2 activation, its clinical significance, and current testing methodologies. The article discusses the evolution of HER2 testing, including IHC, ISH, and NGS approaches, and examines their role in guiding personalized therapy. The challenges of implementing standardized HER2 testing across various cancer types are also considered. Finally, the review examines the clinical outcomes associated with HER2-targeted therapies and discusses future directions in HER2 research, including the integration of HER2 with immune checkpoint inhibitors and other novel treatments.