Abstract 5281: Development of a panel of breast cancer patient-derived xenograft models (PDX) with estrogen independence and/or acquired resistance to endocrine treatment

Abstract

Abstract Eighty five percent of preclinical agents entering oncology clinical trials fail to demonstrate sufficient safety or efficacy to gain regulatory approval (1). This failure rate shows a weak understanding of the complexity of human cancer, the continued limitations of the predictive value of existing preclinical models and the scale at which cancer models are interrogated in the preclinical setting (2). Consequently, there is a need of new experimental models that better replicate the diversity of human tumor biology in a preclinical setting. It is now evidenced that PDXs models recapitulate human tumor biology and predict patient drug response (3) by directly comparing drug responses in patients and their corresponding xenografts. To extend such observations to a greater number of human cancers, we have generated in collaboration with EISAI an extensive collection of breast cancer PDXs. Similar to what is observed in the clinic, 60% of our breast PDX panel is classified as estrogen receptor (ER) positive. Tested compounds which interfere with the ER pathway as anti-estrogens (fulvestrant) or estrogen deprivation (without estrogen supplementation, or ovariectomy), are able to decrease the tumor growth in PDX-bearing mice. However, in clinic, endocrine treatment efficacy is limited by intrinsic and acquired resistance (4). The main mechanisms of resistance to these therapies are lack of expression of ER, deregulation of ER-associated transcription factors, coactivators, activation of receptor tyrosine kinase signaling, and aberrant expression of cell-cycle regulators (5). In order to reconcile this need for relevant preclinical models and to study acquired resistance we developed a panel of breast cancer PDX models either resistant to fulvestrant or able to grow in the complete absence of estrogen (ovariectomy or without estrogen supplementation). Each generated tumor was then analyzed by IHC for their ER/PR expression. Whole exome mutation and gene expression were also analyzed and compared to the parental tumor. 1: Arrowsmith, J. & Miller, P. Trial watch: phase II and phase III attrition rates 2011-2012. Nat. Rev. Drug Discov. 12, 569 (2013). 2: Paul, S.M. et al. How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nat. Rev. Drug Discov. 9, 203-214 (2010). 3: Hidalgo, M. et al. Patient-derived xenograft models: an emerging platform for translational cancer research. Cancer Discov. 4, 998-1013 (2014). 4. Ring, A. & Dowsett, M. Mechanisms of tamoxifen resistance. Endocr Relat Cancer 11:643-58 (2004). 5. Hanny, A. & Abdel-Hafiz. Epigenetic mechanisms of tamoxifen resistance in luminal breast cancer. Diseases Jul 6;5(3) (2017). Citation Format: Marc Hillairet de Boisferon, Ismahene Benzaid, Elodie Marie Dit Chatel, Nicolas Hoffmann, Bruce Littlefield. Development of a panel of breast cancer patient-derived xenograft models (PDX) with estrogen independence and/or acquired resistance to endocrine treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5281.