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

Nat Commun 2016 08 9;7:12498. Epub 2016 Aug 9.

McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA.

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.

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http://dx.doi.org/10.1038/ncomms12498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980485PMC
August 2016
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