Abstract 3823: Triple negative breast cancer (TNBC) PDX models for preclinical investigation of novel therapies

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Abstract Breast cancer (BC) is a heterogeneous and complex disease, with varying prognosis. Patient-derived xenograft models (PDX) are able to reflect this heterogeneity and can therefore be used to support the development of novel therapeutic strategies against BC. Preclinical experiments with larger cohorts of BC PDX can be employed to experimentally model a clinical phase II study with new drugs or drug combinations. The predictive value of these preclinical trials was shown earlier in co-clinical trials, where treatment efficacies were compared between patients and their corresponding PDX. Here, we present experimental preclinical data of a cohort of triple negative BC PDX models (TNBC; ER-/PR-/Her2-). Within the scope of different research projects, we established PDX models by collecting breast cancer tissue samples from surgery and engrafting them subcutaneously on immunodeficient mice. In total, 39 PDXs have been successfully engrafted. They were phenotypically characterized and screened for their dug sensitivity to standard of care and targeted drugs (e.g. docetaxel, paclitaxel, bevacizumab, everolimus). The immunohistochemical stainings for estrogen/progesterone/androgen/Her2 receptors, Ki-67, and CK5/6 of the original tumor and the PDX were comparable. The breast cancer PDX models were further analyzed for their mutational and HLA status and were tested for orthotopic growth as well as their potential to form metastases. In our hands, 16 out of 39 PDX models were classified as TNBC subtype (41%). This cohort showed heterogeneous in vivo tumor growth and various chemosensitivity (60% taxane responders, 20% anti VEGF/Her2 responders). The RNAseq analyses detected different genetic alterations (TP53/HDR/BRAF/BRCA mutations, PTEN loss). 7 out of 16 TNBC PDX were implanted orthotopically into the mammary fad pad of NOG mice and metastasized into liver, lung and spleen. Macroscopic metastases were found in the same organs after intravenous injection of tumor cell suspensions from the PDX. To evaluate sensitivity to immune therapy, selected TNBC PDX were used for efficacy studies in HLA matched humanized mice. These models were treated with nivolumab and pembrolizumab, to evaluate response to these check point inhibitors. In summary, our extensively characterized cohort of TNBC PDX reflects the clinical disease situation and can been successfully applied as translational tool for the assessment of determinants for metastasis, tumor progression and drug responsiveness or resistance. Furthermore, TNBC PDX models are applicable for immune-therapeutic testing including combination settings to evaluate novel therapies for TNBC. Citation Format: Diana Behrens, Verena Kiver, Theresia Scheller, Mathias Dahlmann, Bernadette Brzezicha, Britta Buettner, Wolfgang Walther, Jens Hoffmann. Triple negative breast cancer (TNBC) PDX models for preclinical investigation of novel therapies [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 3823.

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