Abstract B048: Clinically relevant implications of human epidermal growth factor receptor 2 expression and associated antibody-drug conjugate targeting in high grade serous ovarian cancer

Background: The recent accelerated approval of tratuzumab deruxtecan (T-Dxd), an antibody-drug conjugate that targets the human epidermal growth factor receptor 2 (HER2) has garnered clinical excitement in the field of gynecologic cancer. Nevertheless, due to the lack of translational endpoint data there is a large gap in knowledge in terms of the heterogenous nature of HER2 expression in high grade serous ovarian cancer (HGSOC), as well as intratumoral adaptations resulting from T-Dxd treatment. Objective: The purpose of this study was to correlate HER2 pathological scores with ovarian tumor immune microenvironment (TIME) factors and characterize tumor-intrinsic adaptations resulting from T-Dxd targeting. Methods: HER2 scoring was performed by a staff pathologist according to gastric criteria in 34 HGSOC patient tumors and fluorescent immunohistochemistry was performed to determine intratumoral levels of CD8+ T cells and PD-L1. qPCR , western blot, and a proteome profiler oncology antibody array was employed to characterize tumorigenic and immunogenic adaptations following T-Dxd treatment in HGSOC cell lines PEA1 and OVCAR8. PEA1 cells were treated with T-Dxd in combination with bevacizumab to assess changes in VEGF via western blot. TIMER 2.0 analysis was performed to examine the association between ERBB2 expression and immune infiltrate in the ovarian cancer TCGA cohort (n=303). Results: Intratumoral PD-L1 mean intensity was significantly (p<0.05) higher in patients with a HER2 score of 2-3 versus 0-1. No significant differences were detected in CD8+ T cell levels, although mean levels were higher in patients with 0-1 HER2 scores. qPCR analysis revealed notable decreases of AREG (2.27- and 1.64-fold), VEGFA (8.01- and 1.79-fold), PD-L1 (2.18- and 1.53-fold), and CXCL8 (2.76- and 1.12-fold) expression following treatment with T-Dxd, compared to IgG-Dxd control in both OVCAR8 and PEA1 cells, respectively. Western blot revealed a decrease in AREG expression at the protein level as well as phospho-ERK following treatment with T-Dxd compared to IgG-Dxd in OVCAR8 and PEA1 cells. Co-treatment with T-Dxd and bevacizumab led to a synergistic reduction in VEGF, compared to mono-treatment alone in PEA1 cells. Interestingly, an oncology array proteome profiler led to an increase in BCL-X (1.72- and 1.67-fold), and vimentin (1.55- and 1.86-fold) expression following treatment with T-Dxd, compared to IgG-Dxd in both OVCAR8 and PEA1 cells, respectively. Finally, TIMER analysis revealed that ERBB2 levels significantly (p<0.05) correlated with macrophages (r=0.425), mast cells (r=0.252), endothelial cells (r=0.240), and CD4+ T cells (r=0.243). Conclusion: These findings suggest that intratumoral HER2 expression is associated with differential TIME dynamics. Furthermore, continuing to characterize adaptations from T-Dxd treatment could inform upon novel combinatorial treatment approaches to test clinically. Future directions include targeting T-Dxd in combination with bevacizumab in HGSOC patient-derived xenograft models. Citation Format: Payton De La Cruz, Julia Salinaro, Julia McAdams, Samantha Buyungo, Angelica Salaverria, Cara Matthews, Kamaljeet Singh, Paul DiSilvestro, Nicole James. Clinically relevant implications of human epidermal growth factor receptor 2 expression and associated antibody-drug conjugate targeting in high grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B048.