Abstract 3115: Establishment and characterization of patient-derived breast cancer models for cancer studies

Abstract

Abstract BACKGROUND: Despite the progress and development of targeted agents and Immunotherapeutics, breast cancer is still the leading cause of death among women worldwide. At present, targeted therapy for breast cancers include endocrine blockage therapy for estrogen receptor positive (ER+) tumors and trastuzumab or lapatinib for HER2 positive (HER2+) tumors and CDK inhibitors for HER negative (HER-) tumors as well as PARP inhibitors for BRCA1/2 mutations. There is still a high unmet need for triple negative breast cancer (TNBC) and relapsed breast cancers with specific mutations. Breast cancer is a highly heterogeneous disease and reliable breast cancer models are needed to develop new clinical therapies and better reflect tumor biology. Patient-derived xenograft (PDX) models have been widely used for understanding tumor characteristics and represent human heterogeneity more faithfully and thus are suitable for mouse clinical studies for predicting drug efficacy in the clinic. Here we report the establishment and characterization of a panel of breast cancer (BC) PDX for preclinical research. METHODS: Tumor samples from patients’ breast tumor or metastastic lesion obtained via surgery, biopsy, or pleural effusions/ascites were engrafted subcutaneously in immunodeficient mice to establish PDX models. The models were classified and characterized by histopathology, immunohistochemistry (IHC), and breast cancer specific biomarkers such as estrogen receptor (ER), progesterone receptor (PR) and HER2. Genomic analysis of these models was performed by next generation sequencing (NGS). In these breast cancer models, the effects of estrogen on tumor growth and targeted endocrine therapy such as Fulvestrant were evaluated. The change of tumor volume over time was used to determine the growth rate and response to treatment in mice. RESULTS: A series of BC PDX models derived from primary patient breast tumor or metastatic lesions were successfully established and characterized. Key characteristics of parental tumors, such as histopathology, clinical markers, gene expression and copy number, as well as estrogen dependence was retained. The IHC data indicated various expression levels of ER, PR and HER2 across the panel, with TNBC being the dominant subtype. ESR1 mutation, which may play an important role in BC progression and endocrine therapy resistance, was also identified in an estrogen-independent model. In vivo, these models showed distinct tumor growth rates and different pharmacodynamic responses to standard of care agents. For example, ESR1 mutant model was responsive to Fulvestrant. CONCLUSIONS: The established BC PDX panel represent a range or ER/PR/HER2 expression status from primary and advanced cancer providing a series of preclinical models for breast cancer research and potential for mouse clinical trial enrollment. Citation Format: Leilei Chen, Xueying Yang, Likun Zhang, Xiaobo Chen, Henry Q.X. Li, Jingjing Wang. Establishment and characterization of patient-derived breast cancer models for cancer studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3115.