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 
  • PMID: 31118521
  •     55 citations


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.

Metastasis as a systemic disease: molecular insights and clinical implications.
Maša Alečković, Sandra S McAllister, Kornelia Polyak.
Biochim Biophys Acta Rev Cancer, 2019 Jun 17; 1872(1). PMID: 31202687    Free PMC article.
Prediction of Potential miRNA-Disease Associations Through a Novel Unsupervised Deep Learning Framework with Variational Autoencoder.
Li Zhang, Xing Chen, Jun Yin.
Cells, 2019 Sep 07; 8(9). PMID: 31489920    Free PMC article.
5-Fluorouracil treatment induces characteristic T>G mutations in human cancer.
Sharon Christensen, Bastiaan Van der Roest, +8 authors, Arne Van Hoeck.
Nat Commun, 2019 Oct 09; 10(1). PMID: 31594944    Free PMC article.
Breast Cancer Stem Cells as Drivers of Tumor Chemoresistance, Dormancy and Relapse: New Challenges and Therapeutic Opportunities.
Maria Laura De Angelis, Federica Francescangeli, Ann Zeuner.
Cancers (Basel), 2019 Oct 18; 11(10). PMID: 31619007    Free PMC article.
Novel therapeutic avenues in triple-negative breast cancer: PI3K/AKT inhibition, androgen receptor blockade, and beyond.
Jack J Chan, Tira J Y Tan, Rebecca A Dent.
Ther Adv Med Oncol, 2019 Oct 23; 11. PMID: 31636720    Free PMC article.
LncRNA LINRIS stabilizes IGF2BP2 and promotes the aerobic glycolysis in colorectal cancer.
Yun Wang, Jia-Huan Lu, +16 authors, Rui-Hua Xu.
Mol Cancer, 2019 Dec 04; 18(1). PMID: 31791342    Free PMC article.
Efficacy of PI3K inhibitors in advanced breast cancer.
B Verret, J Cortes, +2 authors, M Arnedos.
Ann Oncol, 2019 Dec 21; 30(Suppl_10). PMID: 31859349    Free PMC article.
Long Non-coding RNA LOXL1-AS1 Drives Breast Cancer Invasion and Metastasis by Antagonizing miR-708-5p Expression and Activity.
Hui-Ting Dong, Qun Liu, +8 authors, Peng Xing.
Mol Ther Nucleic Acids, 2020 Jan 17; 19. PMID: 31945728    Free PMC article.
Phase 1 Dose Escalation Study of the Allosteric AKT Inhibitor BAY 1125976 in Advanced Solid Cancer-Lack of Association between Activating AKT Mutation and AKT Inhibition-Derived Efficacy.
Andreas Schneeweiss, Dagmar Hess, +12 authors, Matthias Ocker.
Cancers (Basel), 2019 Dec 15; 11(12). PMID: 31835495    Free PMC article.
Genomic Features and Clinical Characteristics of Adolescents and Young Adults With Cholangiocarcinoma.
Hao Feng, Huan Tong, +3 authors, Jian Wang.
Front Oncol, 2020 Feb 06; 9. PMID: 32010606    Free PMC article.
Implementation and use of whole exome sequencing for metastatic solid cancer.
Manon Réda, Corentin Richard, +22 authors, Francois Ghiringhelli.
EBioMedicine, 2020 Jan 11; 51. PMID: 31923800    Free PMC article.
'Omics Approaches to Explore the Breast Cancer Landscape.
Joseph Parsons, Chiara Francavilla.
Front Cell Dev Biol, 2020 Feb 11; 7. PMID: 32039208    Free PMC article.
The DNA deaminase APOBEC3B interacts with the cell-cycle protein CDK4 and disrupts CDK4-mediated nuclear import of Cyclin D1.
Jennifer L McCann, Madeline M Klein, +4 authors, Reuben S Harris.
J Biol Chem, 2019 Jun 21; 294(32). PMID: 31217276    Free PMC article.
A practical framework and online tool for mutational signature analyses show inter-tissue variation and driver dependencies.
Andrea Degasperi, Tauanne Dias Amarante, +14 authors, Serena Nik-Zainal.
Nat Cancer, 2020 Mar 03; 1(2). PMID: 32118208    Free PMC article.
The KT Jeang Prize 2019: Reuben S. Harris : Romancing the Mutator.
Retrovirology Editorial.
Retrovirology, 2019 Aug 30; 16(1). PMID: 31462326    Free PMC article.
NOTCH and DNA repair pathways are more frequently targeted by genomic alterations in inflammatory than in non-inflammatory breast cancers.
François Bertucci, Charlotte Rypens, +17 authors, Steven Van Laere.
Mol Oncol, 2019 Dec 20; 14(3). PMID: 31854063    Free PMC article.
Pan-cancer molecular analysis of the RB tumor suppressor pathway.
Erik S Knudsen, Ram Nambiar, +3 authors, Agnieszka K Witkiewicz.
Commun Biol, 2020 Apr 04; 3(1). PMID: 32242058    Free PMC article.
Breast Cancer: A Molecularly Heterogenous Disease Needing Subtype-Specific Treatments.
Ugo Testa, Germana Castelli, Elvira Pelosi.
Med Sci (Basel), 2020 Mar 27; 8(1). PMID: 32210163    Free PMC article.
Overcoming Endocrine Resistance in Breast Cancer.
Ariella B Hanker, Dhivya R Sudhan, Carlos L Arteaga.
Cancer Cell, 2020 Apr 15; 37(4). PMID: 32289273    Free PMC article.
ESR1 Mutations Are Not a Common Mechanism of Endocrine Resistance in Patients With Estrogen Receptor-Positive Breast Cancer Treated With Neoadjuvant Aromatase Inhibitor Therapy.
Tomás Reinert, Susana Ramalho, +13 authors, Marcia Silveira Graudenz.
Front Oncol, 2020 Apr 21; 10. PMID: 32309212    Free PMC article.
Integrated analysis of the E2F transcription factors across cancer types.
Haiwei Wang, Xinrui Wang, +2 authors, Hua Cao.
Oncol Rep, 2020 Apr 24; 43(4). PMID: 32323836    Free PMC article.
Assessing Cell Activities rather than Identities to Interpret Intra-Tumor Phenotypic Diversity and Its Dynamics.
Laloé Monteiro, Lydie Da Silva, +4 authors, Pierre Martinez.
iScience, 2020 May 04; 23(5). PMID: 32361272    Free PMC article.
Novel insights into breast cancer copy number genetic heterogeneity revealed by single-cell genome sequencing.
Timour Baslan, Jude Kendall, +22 authors, James Hicks.
Elife, 2020 May 14; 9. PMID: 32401198    Free PMC article.
Morphologic and Genomic Heterogeneity in the Evolution and Progression of Breast Cancer.
Jamie R Kutasovic, Amy E McCart Reed, +2 authors, Peter T Simpson.
Cancers (Basel), 2020 Apr 05; 12(4). PMID: 32244556    Free PMC article.
Targeted Inhibition of the E3 Ligase SCFSkp2/Cks1 Has Antitumor Activity in RB1-Deficient Human and Mouse Small-Cell Lung Cancer.
Hongling Zhao, Niloy J Iqbal, +7 authors, Liang Zhu.
Cancer Res, 2020 Apr 09; 80(11). PMID: 32265224    Free PMC article.
Neurofibromin Is an Estrogen Receptor-α Transcriptional Co-repressor in Breast Cancer.
Ze-Yi Zheng, Meenakshi Anurag, +28 authors, Eric C Chang.
Cancer Cell, 2020 Mar 07; 37(3). PMID: 32142667    Free PMC article.
The genomic landscape of metastasis in treatment-naïve breast cancer models.
Christina Ross, Karol Szczepanek, +4 authors, Kent Hunter.
PLoS Genet, 2020 May 29; 16(5). PMID: 32463822    Free PMC article.
Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases.
Zheng Hu, Zan Li, Zhicheng Ma, Christina Curtis.
Nat Genet, 2020 May 20; 52(7). PMID: 32424352    Free PMC article.
Association of Independent Prognostic Factors and Treatment Modality With Survival and Recurrence Outcomes in Breast Cancer.
Dat Nguyen, John Yu, William C Reinhold, Sherry X Yang.
JAMA Netw Open, 2020 Jul 10; 3(7). PMID: 32644137    Free PMC article.
Characterizations of Cancer Gene Mutations in Chinese Metastatic Breast Cancer Patients.
Zhonghua Tao, Ting Li, +12 authors, Xichun Hu.
Front Oncol, 2020 Jul 23; 10. PMID: 32695676    Free PMC article.
Landscape of circulating tumour DNA in metastatic breast cancer.
Andrew A Davis, Saya Jacob, +10 authors, Massimo Cristofanilli.
EBioMedicine, 2020 Jul 25; 58. PMID: 32707446    Free PMC article.
Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with AKT1 E17K-Mutant, ER-Positive Metastatic Breast Cancer.
Lillian M Smyth, Kenji Tamura, +25 authors, David M Hyman.
Clin Cancer Res, 2020 Apr 22; 26(15). PMID: 32312891    Free PMC article.
Circulating Tumor Cells in Metastatic Breast Cancer: From Genome Instability to Metastasis.
Ekaterina Ivanova, Ambber Ward, Adrian P Wiegmans, Derek John Richard.
Front Mol Biosci, 2020 Aug 09; 7. PMID: 32766277    Free PMC article.
Clinical implications of prospective genomic profiling of metastatic breast cancer patients.
Courtney T van Geelen, Peter Savas, +11 authors, Sherene Loi.
Breast Cancer Res, 2020 Aug 20; 22(1). PMID: 32811538    Free PMC article.
The Clinical Relevance and Function of Krüppel-Like Factor 16 in Breast Cancer.
Soyeon Bang, Junhong Li, +6 authors, Hongwei Zhang.
Cancer Manag Res, 2020 Aug 22; 12. PMID: 32821156    Free PMC article.
Chemotherapy and CDK4/6 Inhibitors: Unexpected Bedfellows.
Patrick J Roberts, Vishnu Kumarasamy, Agnieszka K Witkiewicz, Erik S Knudsen.
Molecular cancer therapeutics, 2020 Jun 18; 19(8). PMID: 32546660    Free PMC article.
Analysis of Circulating Tumor DNA to Predict Neoadjuvant Therapy Effectiveness and Breast Cancer Recurrence.
Shuai Hao, Wuguo Tian, +5 authors, Donglin Luo.
J Breast Cancer, 2020 Sep 11; 23(4). PMID: 32908788    Free PMC article.
A systems biology approach to discovering pathway signaling dysregulation in metastasis.
Robert Clarke, Pavel Kraikivski, +3 authors, Yue Wang.
Cancer Metastasis Rev, 2020 Aug 11; 39(3). PMID: 32776157    Free PMC article.
Identification of Somatically Acquired BRCA1/2 Mutations by cfDNA Analysis in Patients with Metastatic Breast Cancer.
Neelima Vidula, Taronish Dubash, +26 authors, Aditya Bardia.
Clin Cancer Res, 2020 Jun 24; 26(18). PMID: 32571788    Free PMC article.
The Mutator Phenotype: Adapting Microbial Evolution to Cancer Biology.
Federica Natali, Giulia Rancati.
Front Genet, 2019 Aug 27; 10. PMID: 31447882    Free PMC article.
Characterization of circulating breast cancer cells with tumorigenic and metastatic capacity.
Claudia Koch, Andra Kuske, +28 authors, Klaus Pantel.
EMBO Mol Med, 2020 Jul 16; 12(9). PMID: 32667137    Free PMC article.
Effect of Eribulin With or Without Pembrolizumab on Progression-Free Survival for Patients With Hormone Receptor-Positive, ERBB2-Negative Metastatic Breast Cancer: A Randomized Clinical Trial.
Sara M Tolaney, Romualdo Barroso-Sousa, +17 authors, Ian E Krop.
JAMA Oncol, 2020 Sep 04; 6(10). PMID: 32880602    Free PMC article.
Circulating tumour DNA in metastatic breast cancer to guide clinical trial enrolment and precision oncology: A cohort study.
Andjelija Zivanovic Bujak, Chen-Fang Weng, +12 authors, Sarah-Jane Dawson.
PLoS Med, 2020 Oct 02; 17(10). PMID: 33001984    Free PMC article.
Targeted next-generation sequencing assays using triplet samples of normal breast tissue, primary breast cancer, and recurrent/metastatic lesions.
Toshiaki Akahane, Naoki Kanomata, +4 authors, Takuya Moriya.
BMC Cancer, 2020 Oct 03; 20(1). PMID: 33004031    Free PMC article.
Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors.
Michela Piezzo, Stefania Cocco, +8 authors, Michelino De Laurentiis.
Int J Mol Sci, 2020 Sep 10; 21(18). PMID: 32899866    Free PMC article.
The genomic landscape of metastatic histologic special types of invasive breast cancer.
Fresia Pareja, Lorenzo Ferrando, +15 authors, Jorge S Reis-Filho.
NPJ Breast Cancer, 2020 Oct 22; 6. PMID: 33083532    Free PMC article.
Practical classification of triple-negative breast cancer: intratumoral heterogeneity, mechanisms of drug resistance, and novel therapies.
Antonio Marra, Dario Trapani, +2 authors, Giuseppe Curigliano.
NPJ Breast Cancer, 2020 Oct 23; 6. PMID: 33088912    Free PMC article.
Characterization of the mechanism by which the RB/E2F pathway controls expression of the cancer genomic DNA deaminase APOBEC3B.
Pieter A Roelofs, Chai Yeen Goh, +9 authors, Reuben S Harris.
Elife, 2020 Sep 29; 9. PMID: 32985974    Free PMC article.
Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial.
Nicholas C Turner, Belinda Kingston, +25 authors, Alistair Ring.
Lancet Oncol, 2020 Sep 14; 21(10). PMID: 32919527    Free PMC article.
Targeting DNA Damage Response in Prostate and Breast Cancer.
Antje M Wengner, Arne Scholz, Bernard Haendler.
Int J Mol Sci, 2020 Nov 08; 21(21). PMID: 33158305    Free PMC article.
Characterization of the genomic landscape and actionable mutations in Chinese breast cancers by clinical sequencing.
Guan-Tian Lang, Yi-Zhou Jiang, +25 authors, Zhi-Ming Shao.
Nat Commun, 2020 Nov 12; 11(1). PMID: 33173047    Free PMC article.
Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer: a pilot clinical trial.
Miguel Quintela-Fandino, Esther Holgado, +19 authors, Santos Mañes.
Breast Cancer Res, 2020 Nov 13; 22(1). PMID: 33176887    Free PMC article.
Comprehensive analysis and identification of key genes and signaling pathways in the occurrence and metastasis of cutaneous melanoma.
Hanying Dai, Lihuang Guo, +6 authors, Keqian Xu.
PeerJ, 2020 Nov 27; 8. PMID: 33240619    Free PMC article.
Breast Cancer Heterogeneity and Response to Novel Therapeutics.
Mariona Baliu-Piqué, Atanasio Pandiella, Alberto Ocana.
Cancers (Basel), 2020 Nov 11; 12(11). PMID: 33167363    Free PMC article.
Wnt signaling in breast cancer: biological mechanisms, challenges and opportunities.
Xiufang Xu, Miaofeng Zhang, Faying Xu, Shaojie Jiang.
Mol Cancer, 2020 Nov 26; 19(1). PMID: 33234169    Free PMC article.