Abstract PS1-12-04: Development and characterization of patient-derived xenografts of HR+/HER2- breast cancer following progression on CDK4/6 inhibitor-based therapy

Abstract A limitation in the field of research around HR+/HER2- breast cancer is the lack of models that represent meaningful features of the disease. On the NCT04526587 clinical study, standard of care tumor tissues were collected to develop patient-derived xenografts (PDX) from patients that had progressed on CDK4/6 inhibitor-based therapy. As of September 2025 a total of 11 models have been developed. In general, there was a greater success in establishing models from solid tissue biopsies relative to liquid collections, such as ascites or effusion. The models expressed variable levels of the estrogen receptor and were molecularly characterized by whole-exome sequencing and gene expression analyses. The PDX models were highly represented by ESR1 mutations as well as PIK3CA and other common genetic lesions in metastatic HR+/HER2- breast cancer. All models fell into the Luminal B or HER2 subtypes of breast cancer based on absolute assignment of breast cancer intrinsic subtypes. The subtype of each model remained relatively static with passaging in NSG mice supplemented with estrogen pellets. Assessment of therapeutic sensitivity illustrated a general resistance to CDK4/6 inhibitors relative to established xenograft models (e.g. MCF7 xenografts). However, combination treatment with CDK4/6 and CDK2 inhibitors was highly effective in halting proliferation. Combined treatment resulted in potent arrested and generated in vivo gene expression changes indicative of therapy-induced senescence. In select cases, PDX tumors failed to proliferate following the cessation of treatment, supporting the potency of this therapeutic regimen. Pilot studies have used cell culture of select PDX models to define unique mechanisms of resistance and vulnerabilities. Together this work is providing new resources and insights upon which to combat therapeutic resistance in metastatic HR+/HER2- breast cancer. Citation Format: A. Witkiewicz, S. Tzetzo, E. Schultz, E. Bailey, R. Kyne, T. O'Connor, E. Knudsen. Development and characterization of patient-derived xenografts of HR+/HER2- breast cancer following progression on CDK4/6 inhibitor-based therapy [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 PS1-12-04.