HER3 and FOLR1 Expression as Actionable Targets in High-Grade Serous Ovarian Carcinoma: Prognostic and Therapeutic Implications

<i>Background and Objectives</i>: High-grade serous ovarian carcinoma (HGSC) is characterized by aggressive tumor behavior, frequent recurrence, and limited long-term survival. Despite the established clinicopathological prognostic factors, significant heterogeneity in clinical outcomes persists, highlighting the need for biologically relevant molecular biomarkers. HER3 and folate receptor alpha (FOLR1) have promising prognostic biomarkers in ovarian cancer; however, the combined biological and prognostic impact of these two molecules has not yet been clearly demonstrated. <i>Materials and Methods</i>: This retrospective observational study included 66 patients with histopathologically confirmed HGSC. The immunohistochemical expression of HER3 and FOLR1 was evaluated using a standardized immunoreactivity scoring system. Associations with clinicopathological features were analyzed, and survival outcomes were analyzed using Kaplan-Meier analysis and Cox proportional hazards regression models. <i>Results</i>: High HER3 expression was significantly associated with distant metastasis and was identified as an independent adverse prognostic factor for both overall survival (OS) and progression-free survival (PFS). FOLR1 expression was associated with OS in univariate analysis, but did not retain independent prognostic significance in multivariate models. A moderate yet statistically significant positive correlation between HER3 and FOLR1 expression was observed, suggesting a potential association between proliferative signaling and metabolic pathways that may warrant further mechanistic investigation. <i>Conclusions</i>: Our findings demonstrate that HER3 is a robust prognostic biomarker in HGSC and support a biologically relevant HER3-FOLR1 interaction contributing to tumor aggressiveness. These results provide a translational rationale for combined biomarker assessment and for the development of HER3- and FOLR1-targeted therapeutic strategies, particularly antibody-drug conjugates, for HGSC.