e17545 Background: Mucinous ovarian cancer (MOC) is a rare epithelial ovarian cancer. There are currently no systematic therapies in clinical use for MOC that reliably improve patient outcome, therefore new approaches are needed. MOC genetic alterations and the resulting proteins are candidates for targeted molecular therapies. About a quarter of MOC carry high-level ERBB2 (HER2) gene amplification, and early case reports were promising for anti-HER2 targeted agents such as trastuzumab. We hypothesized that the ADC trastuzumab deruxtecan (T-DXd) will show efficacy in models of MOC expressing HER2. Methods: HER2 expression was assessed by immunohistochemistry in MOC tumours, organoids, and xenografts. ERBB2 amplification and model fidelity were confirmed using whole genome sequencing and STR profiling. The efficacy of T-DM1 and T-DXd was tested in vitro using organoid models with varied HER2 expression (3+, 2+/1+, 0), cultured in reduced Matrigel to enhance drug penetration. In vivo efficacy of T-DXd is being evaluated in xenograft models (Org49: 3+, Org60: 1+/2+). Results: HER2 expression was heterogeneous across MOC models, with 2 of 12 organoid lines showing strong (3+) IHC staining and 2 displaying moderate expression. Whole genome sequencing confirmed ERBB2 amplification in two organoids line, correlating with high HER2 protein levels. In vitro testing demonstrated greater efficacy of T-DXd compared to T-DM1 in HER2-positive models, with little to no response in HER2-negative controls. Optimizing 3D culture conditions by reducing Matrigel concentration improved ADC penetration and response. In vivo validation using PDX models (Org49, Org60) is currently underway to assess therapeutic potential. Conclusions: HER2 is a promising therapeutic target in a molecularly defined subset of MOC. T-DXd demonstrated strong preclinical activity in HER2-positive MOC models and warrants further investigation in vivo to support future clinical translation.
Irina Gorobets (2026) studied this question.