HER2 expression and HER2-low status in high-grade serous ovarian carcinoma: clinicopathologic and prognostic implications

Epithelial ovarian cancer (EOC) is the most common histological type of ovarian cancer, and high-grade serous carcinoma (HGSC) is the most prevalent and lethal subtype, underscoring the urgent need for biomarker discovery. To assess the potential of human epidermal growth factor receptor 2 (HER2) as a biomarker for therapeutic strategies, this study evaluated HER2 protein expression, gene amplification, and HER2-low status in HGSC and three other epithelial ovarian cancer subtypes. We evaluated HER2 protein expression by immunohistochemistry (IHC) and HER2 gene amplification by silver in situ hybridization (SISH) in 219 EOC cases, including 184 HGSCs, 11 endometrioid carcinomas, 11 clear cell carcinomas, and 13 mucinous carcinomas. HER2 IHC and SISH results were analyzed by histologic subtype, and their correlation and associations with clinicopathologic characteristics and survival outcomes were evaluated. HER2 alterations differed significantly by histologic subtype. HGSC showed low rates of HER2 IHC 3 + expression and amplification, at 1.1% and 3.3%, respectively, whereas mucinous carcinoma showed the highest rates, at 23.1% and 38.5%, respectively. HER2 IHC 0–1 + and 3 + showed strong concordance with non-amplification and amplification, respectively ( p < 0.001), while equivocal IHC 2 + cases showed variable amplification depending on histologic subtype. In HGSC, approximately 30% of cases were classified as HER2-low. Higher HER2 IHC scores were significantly associated with worse progression-free survival in HGSC ( p = 0.028), but not with overall survival. HER2 amplification status and HER2-zero/low/high grouping showed no significant associations with survival outcomes. HER2 assessment in EOC requires a histologic subtype–specific approach. The presence of a substantial HER2-low subgroup in HGSC suggests potential relevance for future HER2-low–directed therapeutic strategies, warranting further validation and refinement of EOC-specific HER2 assessment criteria.