Abstract PS1-09-29: A Rapid Digital Patient-Derived Organoid Guiding Therapy After Antibody Drug Conjugates (ADC)s In Patients with Metastatic Breast CancerYY1 YY1The size limit (including title and body) is 3,400 characters; this does not include spaces

Abstract Background: Metastatic breast cancer (MBC) remains incurable despite recent incorporation of immune checkpoint inhibitors (ICI) and antibody drug conjugates (ADCs). Currently FDA-approved ADCs such as trastuzumab deruxtecan (T-DXd) or sacituzumab govitecan (SG) are routinely used in clinical practice, but data on optimal sequencing of these agents for individual patients are lacking. With the fast-paced clinical development of multiple ADCs in the MBC space, lack of trial data or clinical algorithm guiding subsequent therapy following initial ADC resistance, such as another ADC with a different molecular target or different cytotoxic payload, chemotherapy, or their combination with ICI, had emerged as a critical unmet need. The current study aims to develop a clinical diagnostic assay to guide optimal treatment for patients with MBC using digital patient organoid (DPO). The primary objective of this study is to assess the DPO platform’s ability to predict patient treatment response to therapy in a prospective clinical study in patients with MBC receiving or progressed on ADCs (T-DXd or SG), in order to develop a personalized tool to refine treatment strategies in the post ADC resistance setting. Methods: An institutional IRB was established for prospective collection of fresh tumor biopsies in patients with MBC undergoing treatment with either T-DXd or SG. Tumor biopsies were collected to assess DPO drug sensitivity to a dose range of T-DXd or SG and correlate these results with the progression free survival (PFS). DPO was generated immediately upon arrival. DPO was then subjected to ADCs (T-DXd, SG, Dato-DXd) or chemotherapy drug (Gemcitabine; Carboplatin; Eribulin) dosing experiments to determine drug sensitivities (AUC values calculated from CTG readouts) for downstream correlation analyses. Results: Between 09/2024-06/2025, 28 fresh tumor tissues were collected and processed. 11 samples had sufficient viable cells to pass QC for DPO establishment and were successfully assayed and 8 failed QC, giving a DPO establishment success rate of 57.9%. Organoids typically established and expanded within 7-14 days post-biopsy. Liver metastasis core needle biopsies posed the most challenges due to low initial live cell numbers. A total of 90 DPO assays were conducted for ADCs, payloads, and chemotherapy agents testing. Analysis revealed that prior clinical exposure and progression on an ADC correlated with reduced DPO sensitivity to the same agent, consistent with acquired resistance. The platform was capable of delineating between target- versus payload-based resistance. Notably, DPOs from heavily pretreated patients were often resistant to both ADCs but remained responsive to alternative agents, highlighting potential therapeutic opportunities. Conclusion: The DPO platform shows promise in predicting treatment responses and differentiating resistance mechanisms to ADCs in MBC. This approach provides a foundation for rational selection among different ADCs and chemotherapies, especially after acquired resistance to prior ADC treatment, in patients with advanced breast cancer. Citation Format: Y. Yuan, J. Bitar, D. Lin, J. Mota, D. Marino, K. Sargsyan, M. Campbell, M. Tighiouart, Y. Choi, H. Yu, Z. Wang, L. Vanderpool, S. Kawakita, F. Bustamante, Z. Wang, X. Shen. A Rapid Digital Patient-Derived Organoid Guiding Therapy After Antibody Drug Conjugates (ADC)s In Patients with Metastatic Breast CancerYY1 YY1The size limit (including title and body) is 3,400 characters; this does not include spaces abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-09-29.