Abstract P4-06-03: An annotated collection of pre- and post-therapy breast cancer patient-derived xenograft models built from fine needle aspiration samples aligned with ongoing clinical trials documenting response to treatment

Abstract

Abstract BACKGROUND: Patient-derived xenograft (PDX) models of breast cancer replicate the diverse histologic and molecular features of patient tumors and provide a renewable source of human tumor tissue; however collection of tissue by core needle biopsy is problematic due to patient discomfort, bleeding risk and the limited number of passes a patient can tolerate. In addition, FDA guidelines caution that multiple core needle biopsies could lead to an overestimation of the true pCR rate in neoadjuvant trials. METHODS: To support the neoadjuvant molecular diagnostic and drug development program in TNBC, a pilot study was conducted to determine if fine needle aspiration (FNA) could be used for building PDX models. Prior to engraftment, FNA samples were analysed for cell number and viability. RESULTS: Six PDX models were successfully generated from eight individual tumor samples. These models retain histologic and molecular features of the original patient tumors as determined by immunohistochemistry, RNA expression profiling, and deep whole-exome and targeted gene sequencing. In addition, the tested PDX models recapitulate the responses to therapies across multiple chemotherapeutic agents. Based on this success, we have standardized the use of FNAs to generate PDX models both pre- and post-therapy in two ongoing neoadjuvant clinical trials: 1. MDACC 2014-0185 (PI Stacy Moulder, 360 patients), 'Improving outcomes in TNBC using molecular triaging and diagnostic imaging to guide neoadjuvant therapy' 2. MDACC 2014-0045 (PI Jennifer Litton, 20+ patients), 'A pilot study of BMN673 as a neoadjuvant study in patients with a diagnosis of invasive breast cancer and a deleterious BRCA mutation' FNA cells (x10^4)Cell viability (%)Total viable cells (x10^4)Study entry biopsy (n=67)144.5050.6544.14Post treatment biopsy (n=16)47.0732.5428.38 To date, treatment-naïve primary tumor samples from 67 patients enrolled onto these neoadjuvant trials, and 16 matched non-responsive post treatment tumor samples have been analysed for cell count and viability (table below) prior to being engrafted into the humanized mammary fat pads of NOD/SCID mice. CONCLUSION: We have demonstrated success in using FNAs to build PDX models that recapitulate the biology and clinical course of the original tumor. In our pilot study, we successfully generated six PDX models using FNA for TNBC, including some harboring deleterious BRCA1/2 mutations. Because of the high concordance in histologic, genomic, and clinical attributes, we are now using this approach to develop a rich resource of pre- and post-treatment PDX models for the investigation of therapeutic resistance. Citation Format: Echeverria GV, Chang JT, Cai S, Tu Y, McCoy A, Lau R, Redwood A, Kaffiabasabadi S, Rauch GM, Adrada BE, Jennifer L, Moulder SL, Symmans WF, Piwnica-Worms H. An annotated collection of pre- and post-therapy breast cancer patient-derived xenograft models built from fine needle aspiration samples aligned with ongoing clinical trials documenting response to treatment [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-06-03.