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Nat Commun. 2016 Aug 9;7:12498. doi: 10.1038/ncomms12498.

Aromatase inhibition remodels the clonal architecture of estrogen-receptor-positive breast cancers.

Author information

1
McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA.
2
Department of Medicine, Division of Genomics and Bioinformatics, Washington University School of Medicine, St Louis, Missouri 63108, USA.
3
Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63108, USA.
4
Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri 63108, USA.
5
Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63108, USA.
6
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63108, USA.
7
Department of Breast Surgery, MD Anderson Cancer Center, Houston, Texas 77030, USA.
8
Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota 55905, USA.
9
Department of Surgery, Division of Public Health, St Louis Breast Tissue Registry, Washington University School of Medicine, St Louis, Missouri 63108, USA.
10
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.

Abstract

Resistance to oestrogen-deprivation therapy is common in oestrogen-receptor-positive (ER+) breast cancer. To better understand the contributions of tumour heterogeneity and evolution to resistance, here we perform comprehensive genomic characterization of 22 primary tumours sampled before and after 4 months of neoadjuvant aromatase inhibitor (NAI) treatment. Comparing whole-genome sequencing of tumour/normal pairs from the two time points, with coincident tumour RNA sequencing, reveals widespread spatial and temporal heterogeneity, with marked remodelling of the clonal landscape in response to NAI. Two cases have genomic evidence of two independent tumours, most obviously an ER- 'collision tumour', which was only detected after NAI treatment of baseline ER+ disease. Many mutations are newly detected or enriched post treatment, including two ligand-binding domain mutations in ESR1. The observed clonal complexity of the ER+ breast cancer genome suggests that precision medicine approaches based on genomic analysis of a single specimen are likely insufficient to capture all clinically significant information.

PMID:
27502118
PMCID:
PMC4980485
DOI:
10.1038/ncomms12498
[Indexed for MEDLINE]
Free PMC Article

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