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

Abstract 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 (p0. 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 (p0. 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 (18Suppl): Abstract nr B048.