title: Aromatase inhibition remodels the clonal architecture of estrogen-receptor-positive breast cancers.
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.
authors: McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA.|Department of Medicine, Division of Genomics and Bioinformatics, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors: Christopher A
authors: 0000-0003-4266-6700
authors: CA
authors: Miller
authors: McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors: Yevgeniy
authors: Y
authors: Gindin
authors: McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors: Charles
authors: C
authors: Lu
authors: McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA.|Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors: Obi L
authors: 0000-0002-0843-4271
authors: OL
authors: Griffith
authors: McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri 63108, USA.|Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors: Malachi
authors: 0000-0002-6388-446X
authors: M
authors: Griffith
authors: McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors: Dong
authors: D
authors: Shen
authors: Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors: Jeremy
authors: J
authors: Hoog
authors: McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors: Tiandao
authors: 0000-0003-1650-0555
authors: T
authors: Li
authors: McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA.|Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors: David E
authors: 0000-0001-7934-5906
authors: DE
authors: Larson
authors: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors: Mark
authors: M
authors: Watson
authors: Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors: Sherri R
authors: SR
authors: Davies
authors: Department of Breast Surgery, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Kelly
authors: K
authors: Hunt
authors: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors: Vera J
authors: VJ
authors: Suman
authors: Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors: Jacqueline
authors: J
authors: Snider
authors: Department of Surgery, Division of Public Health, St Louis Breast Tissue Registry, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors: Thomas
authors: T
authors: Walsh
authors: Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri 63108, USA.|Department of Surgery, Division of Public Health, St Louis Breast Tissue Registry, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors: Graham A
authors: GA
authors: Colditz
authors: Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63108, USA.|Department of Surgery, Division of Public Health, St Louis Breast Tissue Registry, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors: Katherine
authors: K
authors: DeSchryver
authors: McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA.|Department of Medicine, Division of Genomics and Bioinformatics, Washington University School of Medicine, St Louis, Missouri 63108, USA.|Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri 63108, USA.|Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors: Richard K
authors: RK
authors: Wilson
authors: McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA.|Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri 63108, USA.|Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors: Elaine R
authors: ER
authors: Mardis
authors: McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA.|Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63108, USA.|Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors: Matthew J
authors: MJ
authors: Ellis
mesh_terms: D000483:Alleles; D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002999:Clone Cells; D005260:Female; D015894:Genome, Human; D006801:Humans; D009154:Mutation / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism*
chemical_list: D047072:Aromatase Inhibitors; D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen; D001141:Aromatase