title: Breast tumor PDXs are genetically plastic and correspond to a subset of aggressive cancers prone to relapse.
abstract: Patient derived xenografts (PDXs) are increasingly appreciated models in cancer research, particularly for preclinical testing, as they reflect the patient's tumor biology more accurately than cancer cell lines. We have established a collection of 20 breast PDXs and characterized their biological and clinical features, as well as their genetic stability. While most PDXs originated from triple negative breast cancers (70%), our collection comprised five ER + cases (25%). Remarkably, the tumors that produced PDXs derived from a subset of aggressive breast cancers with a high proportion of grade 3 tumors and reduced recurrence-free survival. Consistent with this, we found significant differences between the transcriptomic signatures of tumors that produced a PDX (Take) and those that did not (No Take). The PDXs faithfully recapitulate the histological features of their primary tumors, and retain an excellent conservation of molecular classification assignment and Copy Number Change (CNC). Furthermore, the CNC profiles of different PDXs established from the same tumor overlap significantly. However, a small fraction of CNCs in the primary tumor that correspond to oligoclonal events were gradually lost during sequential passaging, suggesting that the PDXs' genetic structure eventually stabilizes around a dominant clone present in the tumor of origin. Finally, de novo occurring genetic events covering up to 9% of the genome were found in only a minority of the PDXs, showing that PDXs have limited genetic instability. These data show that breast cancer PDXs represent a subset of aggressive tumors prone to relapse, and that despite of an excellent conservation of original features, they remain genetically dynamic elements.
authors.affiliation: INSERM U896, F-34298 Montpellier, France; Institut de Recherche en Cancérologie de Montpellier, Université Montpellier 1, F-34298 Montpellier, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: du Manoir
authors.affiliation: INSERM U896, F-34298 Montpellier, France; Institut de Recherche en Cancérologie de Montpellier, Université Montpellier 1, F-34298 Montpellier, France; Institut de Cancérologie de Montpellier, F-34298 Montpellier, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Orsetti
authors.affiliation: INSERM U896, F-34298 Montpellier, France; Institut de Recherche en Cancérologie de Montpellier, Université Montpellier 1, F-34298 Montpellier, France; Institut de Cancérologie de Montpellier, F-34298 Montpellier, France.
authors.forename: Rui
authors.initials: R
authors.lastname: Bras-Gonçalves
authors.affiliation: INSERM U896, F-34298 Montpellier, France; Institut de Recherche en Cancérologie de Montpellier, Université Montpellier 1, F-34298 Montpellier, France.
authors.forename: Tien-Tuan
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: INSERM U896, F-34298 Montpellier, France; Institut de Recherche en Cancérologie de Montpellier, Université Montpellier 1, F-34298 Montpellier, France; Institut de Cancérologie de Montpellier, F-34298 Montpellier, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Lasorsa
authors.affiliation: Department of Pathology, Institut de Cancérologie de Montpellier, F-34298 Montpellier, France; Unité de Recherche Translationnelle, Institut de Cancérologie de Montpellier, 34298 Montpellier, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Boissière
authors.affiliation: Department of Pathology, Institut de Cancérologie de Montpellier, F-34298 Montpellier, France; Unité de Recherche Translationnelle, Institut de Cancérologie de Montpellier, 34298 Montpellier, France.
authors.forename: Blandine
authors.initials: B
authors.lastname: Massemin
authors.affiliation: INSERM U896, F-34298 Montpellier, France; Institut de Recherche en Cancérologie de Montpellier, Université Montpellier 1, F-34298 Montpellier, France; Department of Surgical Oncology, Institut de Cancérologie de Montpellier, F-34298 Montpellier, France.
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Colombo
authors.affiliation: Department of Pathology, Institut de Cancérologie de Montpellier, F-34298 Montpellier, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bibeau
authors.affiliation: INSERM U896, F-34298 Montpellier, France; Institut de Recherche en Cancérologie de Montpellier, Université Montpellier 1, F-34298 Montpellier, France; Department of Medical Oncology, Institut de Cancérologie de Montpellier, F-34298 Montpellier, France.
authors.forename: William
authors.initials: W
authors.lastname: Jacot
authors.affiliation: INSERM U896, F-34298 Montpellier, France; Institut de Recherche en Cancérologie de Montpellier, Université Montpellier 1, F-34298 Montpellier, France; Institut de Cancérologie de Montpellier, F-34298 Montpellier, France. Electronic address: charles.theillet@inserm.fr.
authors.forename: Charles
authors.initials: C
authors.lastname: Theillet
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000145:classification / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D059467:Transcriptome
keywords: Adverse prognosis; Breast cancer; Genetic stability; Patient derived xenografts