@article{2cd8ffbbc07b48789a6b9c6f03415294,
title = "The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies",
abstract = "The whole-genome sequencing of prospectively collected tissue biopsies from 442 patients with metastatic breast cancer reveals that, compared to primary breast cancer, tumor mutational burden doubles, the relative contributions of mutational signatures shift and the mutation frequency of six known driver genes increases in metastatic breast cancer. Significant associations with pretreatment are also observed. The contribution of mutational signature 17 is significantly enriched in patients pretreated with fluorouracil, taxanes, platinum and/or eribulin, whereas the de novo mutational signature I identified in this study is significantly associated with pretreatment containing platinum-based chemotherapy. Clinically relevant subgroups of tumors are identified, exhibiting either homologous recombination deficiency (13%), high tumor mutational burden (11%) or specific alterations (24%) linked to sensitivity to FDA-approved drugs. This study provides insights into the biology of metastatic breast cancer and identifies clinically useful genomic features for the future improvement of patient management.",
keywords = "EVOLUTION, VARIANTS, GERMLINE, PACKAGE, BRCA1",
author = "Lindsay Angus and Marcel Smid and Wilting, {Saskia M.} and {van Riet}, Job and {Van Hoeck}, Arne and {Luan Nguyen} and Serena Nik-Zainal and Steenbruggen, {Tessa G.} and Tjan-Heijnen, {Vivianne C. G.} and Mariette Labots and {van Riel}, {Johanna M. G. H.} and Bloemendal, {Haiko J.} and Neeltje Steeghs and Lolkema, {Martijn P.} and Voest, {Emile E.} and {van de Werken}, {Harmen J. G.} and Agnes Jager and Edwin Cuppen and Stefan Sleijfer and Martens, {John W. M.}",
note = "Funding Information: We thank Barcode for Life and Stichting Hetty Odink (no. R3545) for the financial support of the clinical studies and WGS analyses. This publication and the underlying study have been made possible partly by the data that the Hartwig Medical Foundation and CPCT have made available to the study. We would like to thank all local principal investigators and medical specialists, and the nurses of all contributing centers for their help with patient recruitment. We are particularly grateful to all participating patients and their families. This work was supported in parts by grants from the Pink Ribbon Foundation (no. 204-184) and CZ healthcare insurance (no. CZ-201300460). M.S. was supported by Cancer Genomics Netherlands through a grant from the Netherlands Organization of Scientific Research. H.V.D.W., J.V.R. and the Erasmus MC Cancer Computational Biology Center were financed through a grant from the Daniel den Hoed Foundation. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2019",
month = oct,
doi = "10.1038/s41588-019-0507-7",
language = "English",
volume = "51",
pages = "1450--1458",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "10",
}