PMID- 28027327
OWN - NLM
STAT- MEDLINE
DCOM- 20170523
LR  - 20220414
IS  - 1549-1676 (Electronic)
IS  - 1549-1277 (Print)
IS  - 1549-1277 (Linking)
VI  - 13
IP  - 12
DP  - 2016 Dec
TI  - Mutational Profile of Metastatic Breast Cancers: A Retrospective Analysis.
PG  - e1002201
LID - 10.1371/journal.pmed.1002201 [doi]
LID - e1002201
AB  - 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. METHODS AND FINDINGS: 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.
FAU - Lefebvre, Celine
AU  - Lefebvre C
AD  - INSERM Unit U981, Gustave Roussy, Villejuif, France.
FAU - Bachelot, Thomas
AU  - Bachelot T
AD  - Department of Medical Oncology, Centre Leon Berard, Inserm U1052, Lyon, France.
FAU - Filleron, Thomas
AU  - Filleron T
AUID- ORCID: 0000-0003-0724-0659
AD  - Biostatistics Department, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, 
      France.
FAU - Pedrero, Marion
AU  - Pedrero M
AD  - INSERM Unit U981, Gustave Roussy, Villejuif, France.
FAU - Campone, Mario
AU  - Campone M
AD  - Department of Medical Oncology, Institut de Cancerologie de l'Ouest, Nantes, 
      France.
FAU - Soria, Jean-Charles
AU  - Soria JC
AD  - INSERM Unit U981, Gustave Roussy, Villejuif, France.
AD  - Department of Medical Oncology, Gustave Roussy, Villejuif, France.
AD  - Faculte de Medecine, Universite Paris Sud, Kremlin-Bicetre, France.
AD  - Drug Development Department (DITEP), Gustave Roussy, Villejuif, France.
FAU - Massard, Christophe
AU  - Massard C
AD  - Drug Development Department (DITEP), Gustave Roussy, Villejuif, France.
FAU - Levy, Christelle
AU  - Levy C
AD  - Department of Medical Oncology, Centre Francois Baclesse, Caen, France.
FAU - Arnedos, Monica
AU  - Arnedos M
AD  - Department of Medical Oncology, Gustave Roussy, Villejuif, France.
FAU - Lacroix-Triki, Magali
AU  - Lacroix-Triki M
AD  - INSERM Unit U981, Gustave Roussy, Villejuif, France.
FAU - Garrabey, Julie
AU  - Garrabey J
AD  - R&D UNICANCER, Paris, France.
FAU - Boursin, Yannick
AU  - Boursin Y
AD  - Bioinformatics core facility, Gustave Roussy, Villejuif, France.
FAU - Deloger, Marc
AU  - Deloger M
AD  - Bioinformatics core facility, Gustave Roussy, Villejuif, France.
FAU - Fu, Yu
AU  - Fu Y
AUID- ORCID: 0000-0002-1497-1794
AD  - INSERM Unit U981, Gustave Roussy, Villejuif, France.
FAU - Commo, Frederic
AU  - Commo F
AD  - INSERM Unit U981, Gustave Roussy, Villejuif, France.
FAU - Scott, Veronique
AU  - Scott V
AD  - INSERM Unit U981, Gustave Roussy, Villejuif, France.
FAU - Lacroix, Ludovic
AU  - Lacroix L
AUID- ORCID: 0000-0003-2535-1010
AD  - INSERM Unit U981, Gustave Roussy, Villejuif, France.
AD  - Department of Medical Biology and Pathology, Translational research laboratory 
      and biobank, Gustave Roussy, Villejuif, France.
FAU - Dieci, Maria Vittoria
AU  - Dieci MV
AUID- ORCID: 0000-0002-3967-9861
AD  - Department of Surgery, Oncology and Gastroenterology, University of Padova, 
      Padua, Italy.
AD  - Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
FAU - Kamal, Maud
AU  - Kamal M
AD  - Department of Medical Oncology, Institut Curie, Paris & Saint-Cloud, France.
FAU - Dieras, Veronique
AU  - Dieras V
AD  - Department of Medical Oncology, Institut Curie, Paris & Saint-Cloud, France.
FAU - Goncalves, Anthony
AU  - Goncalves A
AD  - Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France.
FAU - Ferrerro, Jean-Marc
AU  - Ferrerro JM
AUID- ORCID: 0000-0003-0069-3743
AD  - Department of Clinical Research, Centre Antoine Lacassagne, Nice, France.
FAU - Romieu, Gilles
AU  - Romieu G
AD  - Department of Medical Oncology, Institut du Cancer de Montpellier, Montpellier, 
      France.
FAU - Vanlemmens, Laurence
AU  - Vanlemmens L
AD  - Department of Medical Oncology, Centre Oscar Lambret, Lille, France.
FAU - Mouret Reynier, Marie-Ange
AU  - Mouret Reynier MA
AD  - Department of Medical Oncology, Centre Jean Perrin, Clermont-Ferrand, France.
FAU - Thery, Jean-Christophe
AU  - Thery JC
AD  - Department of Medical Oncology, Centre Henri Becquerel, Rouen, France.
FAU - Le Du, Fanny
AU  - Le Du F
AD  - Department of Medical Oncology, Centre Eugene Marquis, Rennes, France.
FAU - Guiu, Severine
AU  - Guiu S
AD  - Department of Medical Oncology, Centre Georges-Francois Leclerc, Dijon, France.
FAU - Dalenc, Florence
AU  - Dalenc F
AD  - Department of Medical Oncology, Institut Claudius Regaud, IUCT-Oncopole, 
      Toulouse, France.
FAU - Clapisson, Gilles
AU  - Clapisson G
AUID- ORCID: 0000-0002-5725-519X
AD  - UNICANCER Biobanking Center, Centre Leon Berard, Lyon, France.
FAU - Bonnefoi, Herve
AU  - Bonnefoi H
AD  - Department of Medical Oncology, Institut Bergonie, Universite de Bordeaux, INSERM 
      U916, Bordeaux, France.
FAU - Jimenez, Marta
AU  - Jimenez M
AD  - R&D UNICANCER, Paris, France.
FAU - Le Tourneau, Christophe
AU  - Le Tourneau C
AD  - Department of Medical Oncology, Institut Curie, Paris & Saint-Cloud, France.
AD  - EA7285, Versailles-Saint-Quentin-en-Yvelines University, Montigny-le-Bretonneux, 
      France.
FAU - Andre, Fabrice
AU  - Andre F
AD  - INSERM Unit U981, Gustave Roussy, Villejuif, France.
AD  - Department of Medical Oncology, Gustave Roussy, Villejuif, France.
AD  - Faculte de Medecine, Universite Paris Sud, Kremlin-Bicetre, France.
LA  - eng
PT  - Journal Article
DEP - 20161227
PL  - United States
TA  - PLoS Med
JT  - PLoS medicine
JID - 101231360
SB  - IM
MH  - Breast Neoplasms/*genetics/*pathology
MH  - *Exome
MH  - Female
MH  - Humans
MH  - *Mutation
MH  - Neoplasm Metastasis
MH  - Retrospective Studies
MH  - Sequence Analysis, DNA
PMC - PMC5189935
COIS- I have read the journal's policy and the authors of this manuscript have the 
      following competing interests: TB is a board member for Roche, Novartis, Pfizer, 
      and AstraZeneca, and received non-financial support from Roche, Novartis, and 
      AstraZeneca. TB also received grants from Roche and Novartis.
EDAT- 2016/12/28 06:00
MHDA- 2017/05/24 06:00
PMCR- 2016/12/27
CRDT- 2016/12/28 06:00
PHST- 2016/10/04 00:00 [received]
PHST- 2016/11/11 00:00 [accepted]
PHST- 2016/12/28 06:00 [entrez]
PHST- 2016/12/28 06:00 [pubmed]
PHST- 2017/05/24 06:00 [medline]
PHST- 2016/12/27 00:00 [pmc-release]
AID - PMEDICINE-D-16-03211 [pii]
AID - 10.1371/journal.pmed.1002201 [doi]
PST - epublish
SO  - PLoS Med. 2016 Dec 27;13(12):e1002201. doi: 10.1371/journal.pmed.1002201. 
      eCollection 2016 Dec.