A large collection of integrated genomically characterized patient‐derived xenografts highlighting the heterogeneity of triple‐negative breast cancer

Nom de la revue
International Journal of Cancer
Florence Coussy, Leanne Koning, Marion Lavigne, Virginie Bernard, Berengere Ouine, Anais Boulai, Rania El Botty, Ahmed Dahmani, Elodie Montaudon, Franck Assayag, Ludivine Morisset, Lea Huguet, Laura Sourd, Pierre Painsec, Celine Callens, Sophie Chateau‐Joubert, Jean‐Luc Servely, Thibaut Larcher, Cecile Reyes, Elodie Girard, Gaelle Pierron, Cecile Laurent, Sophie Vacher, Sylvain Baulande, Samia Melaabi, Anne Vincent‐Salomon, David Gentien, Veronique Dieras, Ivan Bieche, Elisabetta Marangoni

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.