HER2 and HER3 expression in ovarian cancer: Evolution across chemotherapy exposure and implications for targeted therapies.

Abstract

5552 Background: HER2 and HER3 are critical members of the ERBB receptor family, playing pivotal roles in tumorigenesis across multiple cancers, including ovarian cancer (OC). While their potential as therapeutic targets is under investigation, the clinical significance of their expression in OC remain understudied. This study investigates the expression patterns of HER2 and HER3 in OC tissues and evaluates the impact of neoadjuvant chemotherapy (NACT) on their expression levels. Methods: Patients with advanced epithelial ovarian cancer were identified and included in this study. Tumor samples were collected at three timepoints: prior to NACT, during interval debulking surgery and at relapse. HER2 and HER3 expressions were assessed using immunohistochemistry and scored with the gastric Herceptest scoring system (1+, 2+ or 3+), where 3+ expression was considered positive. Results: A total of 163 patients were analyzed, of whom 73% had high-grade serous histology and 21% harbored BRCA mutations. Tumor samples were available for analysis at the following timepoints: 110 pre-NACT, 81 post-NACT, and 22 at relapse. HER2 expression was rare, with 2.3% of tumors exhibiting HER2 1+ expression and 3.1% exhibiting HER2 3+ before NACT. HER2 expression remained stable at interval debulking surgery and relapse. In contrast, HER3 expression was more common with 2.7% of samples exhibiting HER3 1+ expression, 1.8% with 2+ expression and 60.9% with 3+ expression. HER3 expression remained consistent across timepoints, with 65.4% at interval debulking and 63.6% at relapse. HER3-positive samples were significantly associated with high-grade serous histology (81.5% vs 65%, p = 0.005), while BRCA mutation rates did not differ significantly between both groups (16.2% vs 28%, p = 0.267). Progression-free survival (PFS) and overall survival (OS) were comparable between HER3-positive and negative groups. Median PFS was 11.1 months versus 11.2 months (p = 0.537) and median OS was 44.9 months versus 44.3 months (p = 0.734). Conclusions: This study confirms that HER2 overexpression is rare in OC and remains stable throughout the treatment timeline. Conversely, HER3 is frequently expressed, with over 60% of tumors exhibiting 3+ HER3 expression. HER3 expression is strongly associated with serous histology, is stable across NACT exposure, and does not appear to impact clinical outcomes. These findings highlight HER3’s potential as a promising therapeutic target in the OC landscape.