| Affiliation: | 1. Unit of Pharmacogenomics, Department of Genetics, Institut Curie, Paris, France;2. Translational Research Department, RPPA Platform, Institut Curie Research Center, Paris, France;3. Department of Biopathology, Institut Curie, Paris, France;4. Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie Research Center, Paris, France;5. BioPôle Alfort, National Veterinary School of Alfort, Maison Alfort, France;6. INRA, APEX-PAnTher, Oniris, Nantes, France;7. Translational Research Department, Genomics Platform, Institut Curie Research Center, Paris, France;8. INSERM, U900, Paris, France;9. Unit of Somatic Genomics, Department of Genetics, Institut Curie, Paris, France;10. Rt2 Lab, Institut Curie, Paris, France;11. Genomics of Excellence (ICGex) Platform, Institut Curie Research Center, Paris, France;12. Department of Medical Oncology, Institut Curie, Paris, France |
| Abstract: | Triple-negative breast cancer (TNBC) represents 10% of all breast cancers and is a very heterogeneous disease. Globally, women with TNBC have a poor prognosis, and the development of effective targeted therapies remains a real challenge. Patient-derived xenografts (PDX) are clinically relevant models that have emerged as important tools 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 (n = 61) in order to test targeted therapies and identify biomarkers of response. At the gene expression level, TNBC PDX represent all of the various TNBC subtypes identified by the Lehmann classification except for immunomodulatory subtype, which is underrepresented in PDX. NGS and copy number data showed a similar diversity of significantly mutated gene and somatic copy number alteration in PDX and the Cancer Genome Atlas TNBC patients. The genes most commonly altered were TP53 and oncogenes and tumor suppressors of the PI3K/AKT/mTOR and MAPK pathways. PDX showed similar morphology and immunohistochemistry markers to those of the original tumors. Efficacy experiments with PI3K and MAPK inhibitor monotherapy or combination therapy showed an antitumor activity in PDX carrying genomic mutations of PIK3CA and NRAS genes. TNBC PDX reproduce the molecular heterogeneity of TNBC patients. This large collection of PDX is a clinically relevant platform for drug testing, biomarker discovery and translational research. |
