Journal Article
. 2019 May;569(7757).
doi: 10.1038/s41586-019-1056-z.

Genomic characterization of metastatic breast cancers

François Bertucci 1 Charlotte K Y Ng 2 Anne Patsouris 3 Nathalie Droin 4 Salvatore Piscuoglio 2 Nadine Carbuccia 1 Jean Charles Soria 5 Alicia Tran Dien 6 Yahia Adnani 6 Maud Kamal 7 Séverine Garnier 1 Guillaume Meurice 6 Marta Jimenez 8 Semih Dogan 9 Benjamin Verret 9 Max Chaffanet 1 Thomas Bachelot 10 Mario Campone 3 Claudia Lefeuvre 11 Herve Bonnefoi 12 Florence Dalenc 13 Alexandra Jacquet 8 Maria R De Filippo 2 Naveen Babbar 14 Daniel Birnbaum 1 Thomas Filleron 13 Christophe Le Tourneau 15 Fabrice André 16 
Affiliations
  • PMID: 31118521
  •     55 citations

Abstract

Metastasis is the main cause of death for patients with breast cancer. Many studies have characterized the genomic landscape of breast cancer during its early stages. However, there is evidence that genomic alterations are acquired during the evolution of cancers from their early to late stages, and that the genomic landscape of early cancers is not representative of that of lethal cancers1-7. Here we investigated the landscape of somatic alterations in 617 metastatic breast cancers. Nine driver genes (TP53, ESR1, GATA3, KMT2C, NCOR1, AKT1, NF1, RIC8A and RB1) were more frequently mutated in metastatic breast cancers that expressed hormone receptors (oestrogen and/or progesterone receptors; HR+) but did not have high levels of HER2 (HER2-; n = 381), when compared to early breast cancers from The Cancer Genome Atlas. In addition, 18 amplicons were more frequently observed in HR+/HER2- metastatic breast cancers. These cancers showed an increase in mutational signatures S2, S3, S10, S13 and S17. Among the gene alterations that were enriched in HR+/HER2- metastatic breast cancers, mutations in TP53, RB1 and NF1, together with S10, S13 and S17, were associated with poor outcome. Metastatic triple-negative breast cancers showed an increase in the frequency of somatic biallelic loss-of-function mutations in genes related to homologous recombination DNA repair, compared to early triple-negative breast cancers (7% versus 2%). Finally, metastatic breast cancers showed an increase in mutational burden and clonal diversity compared to early breast cancers. Thus, the genomic landscape of metastatic breast cancer is enriched in clinically relevant genomic alterations and is more complex than that of early breast cancer. The identification of genomic alterations associated with poor outcome will allow earlier and better selection of patients who require the use of treatments that are still in clinical trials. The genetic complexity observed in advanced breast cancer suggests that such treatments should be introduced as early as possible in the disease course.

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