title: Mutational Profile of Metastatic Breast Cancers: A Retrospective Analysis.
abstract: BACKGROUND
  Major advances have been achieved in the characterization of early breast cancer (eBC) genomic profiles. Metastatic breast cancer (mBC) is associated with poor outcomes, yet limited information is available on the genomic profile of this disease. This study aims to decipher mutational profiles of mBC using next-generation sequencing.
  
  
  RESULTS
  Whole-exome sequencing was performed on 216 tumor-blood pairs from mBC patients who underwent a biopsy in the context of the SAFIR01, SAFIR02, SHIVA, or Molecular Screening for Cancer Treatment Optimization (MOSCATO) prospective trials. Mutational profiles from 772 primary breast tumors from The Cancer Genome Atlas (TCGA) were used as a reference for comparing primary and mBC mutational profiles. Twelve genes (TP53, PIK3CA, GATA3, ESR1, MAP3K1, CDH1, AKT1, MAP2K4, RB1, PTEN, CBFB, and CDKN2A) were identified as significantly mutated in mBC (false discovery rate [FDR] < 0.1). Eight genes (ESR1, FSIP2, FRAS1, OSBPL3, EDC4, PALB2, IGFN1, and AGRN) were more frequently mutated in mBC as compared to eBC (FDR < 0.01). ESR1 was identified both as a driver and as a metastatic gene (n = 22, odds ratio = 29, 95% CI [9-155], p = 1.2e-12) and also presented with focal amplification (n = 9) for a total of 31 mBCs with either ESR1 mutation or amplification, including 27 hormone receptor positive (HR+) and HER2 negative (HER2-) mBCs (19%). HR+/HER2- mBC presented a high prevalence of mutations on genes located on the mechanistic target of rapamycin (mTOR) pathway (TSC1 and TSC2) as compared to HR+/HER2- eBC (respectively 6% and 0.7%, p = 0.0004). Other actionable genes were more frequently mutated in HR+ mBC, including ERBB4 (n = 8), NOTCH3 (n = 7), and ALK (n = 7). Analysis of mutational signatures revealed a significant increase in APOBEC-mediated mutagenesis in HR+/HER2- metastatic tumors as compared to primary TCGA samples (p < 2e-16). The main limitations of this study include the absence of bone metastases and the size of the cohort, which might not have allowed the identification of rare mutations and their effect on survival.
  
  
  CONCLUSIONS
  This work reports the results of the analysis of the first large-scale study on mutation profiles of mBC. This study revealed genomic alterations and mutational signatures involved in the resistance to therapies, including actionable mutations.
authors.affiliation: INSERM Unit U981, Gustave Roussy, Villejuif, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Lefebvre
authors.affiliation: Department of Medical Oncology, Centre Léon Bérard, Inserm U1052, Lyon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachelot
authors.affiliation: Biostatistics Department, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France.
authors.forename: Thomas
authors.identifier: http://orcid.org/0000-0003-0724-0659
authors.initials: T
authors.lastname: Filleron
authors.affiliation: INSERM Unit U981, Gustave Roussy, Villejuif, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Pedrero
authors.affiliation: Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Nantes, France.
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
authors.affiliation: INSERM Unit U981, Gustave Roussy, Villejuif, France.|Department of Medical Oncology, Gustave Roussy, Villejuif, France.|Faculté de Médecine, Université Paris Sud, Kremlin-Bicêtre, France.|Drug Development Department (DITEP), Gustave Roussy, Villejuif, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.affiliation: Drug Development Department (DITEP), Gustave Roussy, Villejuif, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Massard
authors.affiliation: Department of Medical Oncology, Centre François Baclesse, Caen, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Lévy
authors.affiliation: Department of Medical Oncology, Gustave Roussy, Villejuif, France.
authors.forename: Monica
authors.initials: M
authors.lastname: Arnedos
authors.affiliation: INSERM Unit U981, Gustave Roussy, Villejuif, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Lacroix-Triki
authors.affiliation: R&D UNICANCER, Paris, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Garrabey
authors.affiliation: Bioinformatics core facility, Gustave Roussy, Villejuif, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Boursin
authors.affiliation: Bioinformatics core facility, Gustave Roussy, Villejuif, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Deloger
authors.affiliation: INSERM Unit U981, Gustave Roussy, Villejuif, France.
authors.forename: Yu
authors.identifier: http://orcid.org/0000-0002-1497-1794
authors.initials: Y
authors.lastname: Fu
authors.affiliation: INSERM Unit U981, Gustave Roussy, Villejuif, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Commo
authors.affiliation: INSERM Unit U981, Gustave Roussy, Villejuif, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Scott
authors.affiliation: INSERM Unit U981, Gustave Roussy, Villejuif, France.|Department of Medical Biology and Pathology, Translational research laboratory and biobank, Gustave Roussy, Villejuif, France.
authors.forename: Ludovic
authors.identifier: http://orcid.org/0000-0003-2535-1010
authors.initials: L
authors.lastname: Lacroix
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy.|Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
authors.forename: Maria Vittoria
authors.identifier: http://orcid.org/0000-0002-3967-9861
authors.initials: MV
authors.lastname: Dieci
authors.affiliation: Department of Medical Oncology, Institut Curie, Paris & Saint-Cloud, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Kamal
authors.affiliation: Department of Medical Oncology, Institut Curie, Paris & Saint-Cloud, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Diéras
authors.affiliation: Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Gonçalves
authors.affiliation: Department of Clinical Research, Centre Antoine Lacassagne, Nice, France.
authors.forename: Jean-Marc
authors.identifier: http://orcid.org/0000-0003-0069-3743
authors.initials: JM
authors.lastname: Ferrerro
authors.affiliation: Department of Medical Oncology, Institut du Cancer de Montpellier, Montpellier, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Romieu
authors.affiliation: Department of Medical Oncology, Centre Oscar Lambret, Lille, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Vanlemmens
authors.affiliation: Department of Medical Oncology, Centre Jean Perrin, Clermont-Ferrand, France.
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Mouret Reynier
authors.affiliation: Department of Medical Oncology, Centre Henri Becquerel, Rouen, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Théry
authors.affiliation: Department of Medical Oncology, Centre Eugène Marquis, Rennes, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Le Du
authors.affiliation: Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Guiu
authors.affiliation: Department of Medical Oncology, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Dalenc
authors.affiliation: UNICANCER Biobanking Center, Centre Léon Bérard, Lyon, France.
authors.forename: Gilles
authors.identifier: http://orcid.org/0000-0002-5725-519X
authors.initials: G
authors.lastname: Clapisson
authors.affiliation: Department of Medical Oncology, Institut Bergonié, Université de Bordeaux, INSERM U916, Bordeaux, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Bonnefoi
authors.affiliation: R&D UNICANCER, Paris, France.
authors.forename: Marta
authors.initials: M
authors.lastname: Jimenez
authors.affiliation: Department of Medical Oncology, Institut Curie, Paris & Saint-Cloud, France.|EA7285, Versailles-Saint-Quentin-en-Yvelines University, Montigny-le-Bretonneux, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Le Tourneau
authors.affiliation: INSERM Unit U981, Gustave Roussy, Villejuif, France.|Department of Medical Oncology, Gustave Roussy, Villejuif, France.|Faculté de Médecine, Université Paris Sud, Kremlin-Bicêtre, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: André
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D059472:Exome; D005260:Female; D006801:Humans; D009154:Mutation; D009362:Neoplasm Metastasis; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA