Expression of HER2 Ultralow in Endometrial Carcinoma, High-Grade Serous Ovarian Cancer and Their Metastases

Background/Objectives: HER2-directed antibody–drug conjugates have expanded the clinical relevance of low-level HER2 expression. However, the prevalence and clinical significance of HER2-ultralow expression in gynecologic malignancies remain insufficiently defined. This study characterized the full spectrum of HER2 expression in endometrial carcinoma (EC) and high-grade serous ovarian carcinoma (HGSOC), including matched metastatic lesions. Methods: HER2 expression was assessed by immunohistochemistry in tissue microarrays from 117 EC and 52 HGSOC patients. Available matched metastatic lesions were analyzed in 23 EC and 18 HGSOC cases. HER2 expression was categorized as zero, ultralow, 1+, 2+, or 3+. Associations with clinicopathological parameters and progression-free survival were evaluated. Results: HER2-ultralow expression was common in primary tumors, occurring in 49/117 EC cases (41.9%) and 11/52 HGSOC cases (21.2%), whereas HER2 3+ expression was rare (EC: 2/117, 1.7%; HGSOC: 1/52, 1.9%). HER2 expression in primary tumors was associated with progression-free survival in both entities, with HER2-zero tumors showing the longest estimated progression-free survival. HER2 score discordance between matched primary tumors and metastases occurred in 16/23 EC cases (69.6%) and 8/18 HGSOC cases (44.4%). Conclusions: HER2-ultralow expression represents a frequent and previously underrecognized category in EC and HGSOC. While its prognostic impact remains limited, the high prevalence of HER2-ultralow tumors suggests potential relevance for future HER2-targeted therapeutic strategies. Prospective studies are needed to determine whether this subgroup may benefit from a HER2-targeted therapy.