Abstract 7328: Anti-tumor activity of anti-body drug conjugates in patient-derived xenografts of metastatic breast cancers patients

Abstract Background: Antibody-drug conjugates (ADCs) have emerged as highly effective new therapeutics for metastatic breast cancer (mBC). Sacituzumab govitecan (SG), an anti-TROP2 ADC, has been approved for the treatment of ER+/HER2- and triple negative mBC and trastuzumab deruxtecan (T-DXd), an anti-HER2 ADC, has been approved for HER2-amplified and HER2-low mBC. Despite the significant improvement in patients’ survival, several hurdles remain to overcome, including the development of predictive biomarkers and the optimal sequential strategy. The aim of this study was to evaluate the response to SG and T-DXd ADCs in PDX models established from mBC and to identify potential biomarkers of response and resistance. Material and Method: Biopsies from metastases or breast tumors from stage IV patients progressing on standard of care treatments were engrafted in nude mice. PDX were characterized at the genomic level and by RNAseq. HER2 expression was scored by IHC analysis by a clinical pathologist. The anti-tumor efficacy of T-DXd and SG was tested in vivo on 20 and 8 PDX respectively as compared to standard care treatment (endocrine therapy, CDK4/6 inhibitors, PARP inhibitors and chemotherapy). Results: Forty-two PDXs were established, 33 (79%) from metastases and 9 (21%) from breast tumors of mBC. At the genetic level, PDX exhibited the typical molecular pattern of mBC with frequent alterations in the PIK3CA, AKT1, ESR1 and FGFR1 genes. Both T-DXd and SG treatment resulted in strong anti-tumor activity in multiple PDX, with 70 % and 75% of the models showing partial or complete response, respectively. Most of the models show similar responses to T-DXd and SG, with few PDX showing a different response pattern. Among these, a BRCA1 mutated PDX showing cross resistance to talazoparib, CDK4/6 inhibitor, chemotherapy and T-DXd, was found to be a highly responder to SG treatment. T-DXd and SG were also highly efficient in ESR1 mutated PDX established from patients progressing on aromatase inhibitors, including a model with cross resistance to different SERD. HER2 expression at baseline did not predict response to T-DXd. GSEA analysis identified different gene sets associated with T-DXd resistance, including KRAS signaling, EMT and hypoxia. Pharmacodynamic experiments in PDX responder and resistant to T-DXd and SG are ongoing to identify pharmacodynamic biomarkers. Conclusion and Perspective: In summary, we established PDX of mBC, characterized for HER2 expression, genomic alterations and response to T-DXd and SG. Both ADCs showed high anti-tumor activity in multiple PDX with resistance to standard treatments including CDK4/6 inhibitors, SERD and PARP inhibitors. Response to T-DXD was not correlated with HER2 expression while T-DXd resistance was associated to an enrichment of EMT and hypoxia gene sets. Citation Format: Elodie Montaudon, Rania El Botty, Heloïse Derrien, Ahmed Dahmani, Laura Sourd, Gabriel Champenois, André Nicolas, Didier Meseure, Guillaume Dutertre, Anne Vincent-Salomon, Laura Courtois, Julien Masliah Planchon, Ivan Bièche, Florence Coussy, Luc Cabel, Elisabetta Marangoni. Anti-tumor activity of anti-body drug conjugates in patient-derived xenografts of metastatic breast cancers patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7328.