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Research Article: Association between HER2 expression, genomic characteristics, and tumor immune microenvironment dynamics in epithelial ovarian cancer

Date Published: 2026-07-20

Abstract:
Despite the rapid clinical approval of the HER2-directed antibody-drug conjugate trastuzumab deruxtecan (T-DXd) for patients with HER2-expressing epithelial ovarian cancer (EOC), preclinical mechanistic studies are lacking.The goal of this investigation was to determine the genomic and immunogenic characteristics associated with HER2 expressing EOC in order to better understand the mechanism of treatment response and what subset of patients will benefit most from single agent and combinatorial HER2-directed treatment regimens. 130 EOC patients were retrospectively identified from our institution’s internal clinical genomic database. Selected genomic characteristics were stratified by gastric HER2 score and distributions were analyzed by Fisher’s exact test. A subset of 34 EOC tumors were internally HER2 stained and fluorescent immunohistochemistry analysis of PD-L1, CD4, and CD8 was performed. EOC cell lines were treated with T-DXd and PD-L1 and VEGFA levels were assessed via quantitative PCR. VEGF expression following combinatorial T-DXd and bevacizumab treatment was determined via western blot. Non-significant differences were detected in HRD, CCNE1 amplification, and ARID1A status between HER2 high (n=29) and low (n=101) tumors in an EOC and high grade serous ovarian cancer (HGSOC) sub-cohort (n=98). Although not statistically significant, patients with HER2 high tumors had lower levels of FOLR1 positivity and higher levels of PD-L1 positivity in both EOC and HGSOC cohorts. Intratumoral PD-L1 expression and CD4+ T cell levels were significantly higher (p<0.05) in HER2 high tumors. Finally, T-DXd substantially downregulated PD-L1 and VEGFA expression, and bevacizumab and T-DXd synergistically reduced VEGF expression. HER2 high EOC tumors are more likely to be FOLR1 negative and PD-L1 positive, and treatment with T-DXd downregulates PDL-1 and VEGFA expression. These findings support further examination to determine if immunotherapy and anti-angiogenic treatments synergize with T-DXd in EOC.

Introduction:
Despite the rapid clinical approval of the HER2-directed antibody-drug conjugate trastuzumab deruxtecan (T-DXd) for patients with HER2-expressing epithelial ovarian cancer (EOC), preclinical mechanistic studies are lacking.The goal of this investigation was to determine the genomic and immunogenic characteristics associated with HER2 expressing EOC in order to better understand the mechanism of treatment response and what subset of patients will benefit most from single agent and combinatorial HER2-directed…

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