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.
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Data availability
The WGS and corresponding clinical data were requested from the Hartwig Medical Foundation and provided under data request no. DR-026. The clinical data provided by the CPCT were locked on 1 June 2018. Both WGS and clinical data are freely available for academic use from the Hartwig Medical Foundation through standardized procedures; request forms can be found at https://www.hartwigmedicalfoundation.nl27.
Code availability
Full code is available at https://github.com/hartwigmedical/ and https://bitbucket.org/ccbc/r2ccbc.
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Acknowledgements
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.
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L.A., M.S., S.M.W., J.W.M.M. and S.S. wrote the manuscript, which all authors reviewed. M.S., J.V.R. and H.J.G.V.D.W. performed the bioinformatics analyses. L.A. and S.S. managed the clinical data assessment. A.V.H., L.N. and E.C. provided the CHORD (HRD) prediction scores. T.G.S., V.C.G.T.H., M.L., J.M.G.H.V.R., H.J.B., N.S., A.J. and S.S. are the main clinical contributors. H.J.B., M.P.L., E.E.V. and S.S. are members of the CPCT-02 study team and/or CPCT board. S.N.Z. provided assistance that allowed the comparisons with the primary breast cancer cohort (BASIS cohort). E.C. coordinated the sequencing of the samples and contributed to the bioinformatics analyses.
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Supplementary information
Supplementary Information
Supplementary Figs. 1–10
Supplementary Table 1
Patient characteristics.
Supplementary Table 2
Cohorts for the comparison of genomic alterations.
Supplementary Table 3
Frequency of affected driver genes (defined by dN/dScv) per breast cancer subtype.
Supplementary Table 4
Frequency of driver genes (93 breast cancer driver genes reported by Nik-Zainal et al.) per breast cancer subtype.
Supplementary Table 5
Gains and losses defined by GISTIC2.0 (v.2.0.23).
Supplementary Table 6
Actionable alterations according to OncoKB (12 July 2018).
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Angus, L., Smid, M., Wilting, S.M. et al. The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies. Nat Genet 51, 1450–1458 (2019). https://doi.org/10.1038/s41588-019-0507-7
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DOI: https://doi.org/10.1038/s41588-019-0507-7
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