Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation.
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Date
2016-11-09Author
Gellert, P
Segal, CV
Gao, Q
López-Knowles, E
Martin, L-A
Dodson, A
Li, T
Miller, CA
Lu, C
Mardis, ER
Gillman, A
Morden, J
Graf, M
Sidhu, K
Evans, A
Shere, M
Holcombe, C
McIntosh, SA
Bundred, N
Skene, A
Maxwell, W
Robertson, J
Bliss, JM
Smith, I
Dowsett, M
POETIC Trial Management Group and Trialists,
Type
Journal Article
Metadata
Show full item recordAbstract
Pre-surgical studies allow study of the relationship between mutations and response of oestrogen receptor-positive (ER+) breast cancer to aromatase inhibitors (AIs) but have been limited to small biopsies. Here in phase I of this study, we perform exome sequencing on baseline, surgical core-cuts and blood from 60 patients (40 AI treated, 20 controls). In poor responders (based on Ki67 change), we find significantly more somatic mutations than good responders. Subclones exclusive to baseline or surgical cores occur in ∼30% of tumours. In phase II, we combine targeted sequencing on another 28 treated patients with phase I. We find six genes frequently mutated: PIK3CA, TP53, CDH1, MLL3, ABCA13 and FLG with 71% concordance between paired cores. TP53 mutations are associated with poor response. We conclude that multiple biopsies are essential for confident mutational profiling of ER+ breast cancer and TP53 mutations are associated with resistance to oestrogen deprivation therapy.
Subject
POETIC Trial Management Group and Trialists
Breast
Humans
Breast Neoplasms
Ki-67 Antigen
Receptors, Estrogen
Antineoplastic Agents
Aromatase Inhibitors
Estrogens
Biopsy
Treatment Outcome
DNA Mutational Analysis
Drug Resistance, Neoplasm
Mutation
Aged
Aged, 80 and over
Middle Aged
Female
Tumor Suppressor Protein p53
Whole Exome Sequencing
Research team
Clinical Trials & Statistics Unit
Medicine (RMH Smith Cunningham)
Endocrinology
Language
eng
Date accepted
2016-09-19
License start date
2016-11-09
Citation
Nature communications, 2016, 7 pp. 13294 - ?
Publisher
NATURE PORTFOLIO