Abstract 2973: A comprehensive panel of patient-derived xenografts representing the molecular heterogeneity and diversity of triple-negative breast cancer
Authors: Coussy Florence , Bernard Virginie , Lavigne Marion , Boulai Anais , Chateau-Joubert Sophie , Dahmani Ahmed , Montaudon Elodie , Reyes Cécile , Botty Rania El , Pieron Gaëlle , Laurent Cécile , Melaabi Samia , Salomon Anne Vincent , Bièche Ivan , Marangoni Elisabetta 
Published: August 2018

Purpose: Triple-negative breast cancer (TNBC) is a heterogeneous disease. Patients diagnosed with TNBC have a poor prognosis and identification of new biomarkers and therapeutic agents is a high priority. Patient-derived xenografts (PDX) are clinically relevant models that have emerged as important tool for the analysis of drug activity and predictive biomarker discovery. The purpose of this work was to analyze the molecular heterogeneity of a large panel of TNBC PDX with the perspective to test targeted therapy and to identify biomarkers of response.

Experimental Design: PDX of early-stage TNBC established from 2003 to 2016 (N=60) were analyzed by high-resolution array CGH and gene expression profiling (Cytoscan HD and Human Gene 1.1 ST arrays). Subtypes were identified with the tool TNBCtype (Chen et al., 2012) based on transcriptomic data. A targeted next-generation sequencing (NGS) of 100 genes (the top frequently mutated genes in breast cancer) was performed on Illumina HiSeq2500 sequencer. COSMIC, Tumorportal and cBioportal databases were used for the interpretation of genomic variants. Immunohistochemistry (IHC) and morphologic analysis of PDX were performed as compared to the corresponding patients' tumors. PDX carrying targetable genomic alterations in the PI3K/AKT/mTOR and MAPK signaling pathways were treated by specific inhibitors (selumetinib, BAY 80-6946 and PF-04691502).

Results: At the gene expression level, TNBC PDX represent all the different TNBC subtypes identified by the Lehmann classification. The frequency of the different TNBC subtypes was similar to the TGCA TNBC, except for the immunomodulatory subtype, underrepresented in PDX. Somatic pathologic mutations and copy number alterations were similar in PDX and TCGA TNBC patients. Among the top altered genes are TP53 and oncogenes and tumor suppressors of the PI3K/AKT/mTOR and MAPK pathways (including PIK3CA, AKT1, NF1 and NRAS/KRAS). At the histologic level, TNBC PDX were mainly composed of invasive ductal carcinoma of no special type, with some tumors being classified as apocrine or metaplastic carcinomas. Comparison with the original tumors show similar patterns (based on IHC analysis of CK5, CK8/18, CK14 and AR, FOXA1, EGFR and Ki67). In vivo efficacy experiments with PI3K and MAPK pathways inhibitors showed marked antitumor activity in PDX carrying genomic alterations of PIK3CA, AKT1 and NRAS, NF1 genes. Drug combination experiments are currently ongoing in PDX with simultaneous genomic alterations of PI3KCA and MAPK related genes.

Conclusions: TNBC PDX reproduce the molecular heterogeneity and diversity of TNBC patients. This large collection of PDX is a clinically relevant platform for drug testing, biomarker discovery and translational research.

Citation Format: Florence Coussy, Virginie Bernard, Marion Lavigne, Anais Boulai, Sophie Chateau-Joubert, Ahmed Dahmani, Elodie Montaudon, Cécile Reyes, Rania El Botty, Gaëlle Pieron, Cécile Laurent, Samia Melaabi, Anne Vincent Salomon, Ivan Bièche, Elisabetta Marangoni. A comprehensive panel of patient-derived xenografts representing the molecular heterogeneity and diversity of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2973.