Molecular characterisation of aromatase inhibitor-resistant advanced breast cancer: the phenotypic effect of ESR1 mutations.
Date
2019-01-22ICR Author
Author
Lopez-Knowles, E
Pearson, A
Schuster, G
Gellert, P
Ribas, R
Yeo, B
Cutts, R
Buus, R
Garcia-Murillas, I
Haynes, B
Martin, L-A
Smith, I
Turner, N
Dowsett, M
Type
Journal Article
Metadata
Show full item recordAbstract
BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: Major genotypic and phenotypic heterogeneity exists between AI-resistant disease. ESR1 mutations appear to drive oestrogen-regulated processes in resistant tumours.
Subject
Breast
Humans
Breast Neoplasms
MAP Kinase Kinase 4
Receptor, erbB-2
Cadherins
Estrogen Receptor alpha
Antigens, CD
Aromatase Inhibitors
Estrogens
Neoplasm Staging
Gene Expression Regulation, Neoplastic
Drug Resistance, Neoplasm
Mutation
Adult
Aged
Aged, 80 and over
Middle Aged
Female
Class I Phosphatidylinositol 3-Kinases
Research team
Endocrine Therapy Resistance
Molecular Oncology
Medicine (RMH Smith Cunningham)
Endocrinology
Language
eng
Date accepted
2018-11-05
License start date
2019-01
Citation
British journal of cancer, 2019, 120 (2), pp. 247 - 255
Publisher
SPRINGERNATURE