Abstract B100: Molecular and pharmacological profiling of PDX breast cancer models and their cellular counterparts to identify resistance mechanisms and novel therapeutic options

Abstract Breast cancer (BC) is a heterogeneous disease that likely originates from different cell compartments that co-inhabit the mammary gland, with more than 20 different histology types reported. At molecular level, BCs are classified by immunohistochemistry as luminal if estrogen and/or progesterone receptor (ER and PR) are over-expressed, HER2-positive if they over-express HER2/neu receptor, or triple negative (TN) when ER and PR are not expressed while HER2 is expressed at (sub-)normal levels. The availability of an increasing number of very well molecularly annotated BC human samples allows an unprecedented stratification of this disease, with numerous gene signatures recently published in recent years identifying additional mutational landscapes and/or signaling pathway-based molecular subtypes. Despite this considerable progress in understanding the biology and genetics of breast cancer, the development of effective therapies is hampered by the lack of sufficient experimental models that recapitulate the genetic diversity of this disease. To tackle this issue, over the last 20 years, we have generated a collection of 56 fully characterized breast cancer PDX models that accurately reproduce BC histological and molecular heterogeneity. Our PDX collection comprises 40 TNBC, 8 Luminal A (ER+, PR+/-), 3 Luminal B (ER+, PR+/-, HER2+) and 5 HER2+ models, associated with 12 cellular models derived from a subset of these PDX (PDXDC), representing the diversity of breast cancer. All models (PDX and PDXDC) were characterized at molecular level, including transcriptomic, whole exome sequencing, IHC staining and/or flow cytometry analysis. PDX were characterized pharmacologically for their response to standards of care to study resistance mechanisms underlying breast cancer progression and to mimic the effects observed at the clinical level. In parallel of these characterization, resistant models to SOCs were generated, especially to Enhertu and olaparib. Associated to in vitro cell derivatives, our collection provides a powerful preclinical platform for translational and preclinical research to identify mechanisms underlying acquired resistance to current therapies and develop novel treatment strategies against breast Cancers. Citation Format: Emilie Indersie, Léa Sinayen, Aurore Gorse, Marie Tavernier, Enora Le Ven, Ester Morgado, Jacques Fieschi, Olivier Déas. Molecular and pharmacological profiling of PDX breast cancer models and their cellular counterparts to identify resistance mechanisms and novel therapeutic options [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B100.