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Title: Molecular characterisation of aromatase inhibitor-resistant advanced breast cancer: the phenotypic effect of ESR1 mutations.
Austin Authors: Lopez-Knowles, Elena;Pearson, Alex;Schuster, Gene;Gellert, Pascal;Ribas, Ricardo;Yeo, Belinda ;Cutts, Ros;Buus, Richard;Garcia-Murillas, Isaac;Haynes, Ben;Martin, Lesley-Ann;Smith, Ian;Turner, Nick;Dowsett, Mitch
Affiliation: Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, London, UK
The Breast Cancer Now Toby Robins Research Centre at the Institute of Cancer Research, London, UK
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, London, UK
Breast Unit, Royal Marsden Hospital, London, UK
Issue Date: 2019
Date: 2018-12-19
Publication information: British Journal of Cancer 2019; 120(2): 247-255
Abstract: Several thousand breast cancer patients develop resistance to aromatase inhibitors (AIs) each year in the UK. Rational treatment requires an improved molecular characterisation of resistant disease. The mutational landscape of 198 regions in 16 key breast cancer genes and RNA expression of 209 genes covering key pathways was evaluated in paired biopsies before AI treatment and at progression on AI from 48 patients. Validity of findings was assessed in another five ESR1-mutated tumours progressing on AI. Eighty-nine mutations were identified in 41 matched pairs (PIK3CA in 27%; CDH1 in 20%). ESR1 (n = 5), ERBB2 (n = 1) and MAP2K4 (n = 1) had mutations in the secondary sample only. There was very high heterogeneity in gene expression between AI-resistant tumours with few patterns apparent. However, in the ESR1-mutated AI-resistant tumours, expression of four classical oestrogen-regulated genes (ERGs) was sevenfold higher than in ESR1 wild-type tumours, a finding confirmed in the second set of ESR1-mutated tumours. In ESR1 wild-type AI-resistant tumours ERG expression remained suppressed and was uncoupled from the recovery seen in proliferation. Major genotypic and phenotypic heterogeneity exists between AI-resistant disease. ESR1 mutations appear to drive oestrogen-regulated processes in resistant tumours.
DOI: 10.1038/s41416-018-0345-x
ORCID: 0000-0002-9218-9917
Journal: British Journal of Cancer
PubMed URL: 30563991
Type: Journal Article
Appears in Collections:Journal articles

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