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Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer.

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Date
2015-11-11
ICR Author
Garcia-Murillas, Isaac
Pearson, Alex
Lopez Knowles, Elena
Martin, Lesley-Ann
Dowsett, Mitch
Smith, Ian
Turner, Nicholas
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Author
Schiavon, G
Hrebien, S
Garcia-Murillas, I
Cutts, RJ
Pearson, A
Tarazona, N
Fenwick, K
Kozarewa, I
Lopez-Knowles, E
Ribas, R
Nerurkar, A
Osin, P
Chandarlapaty, S
Martin, L-A
Dowsett, M
Smith, IE
Turner, NC
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Type
Journal Article
Metadata
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Abstract
Acquired ESR1 mutations are a major mechanism of resistance to aromatase inhibitors (AIs). We developed ultra high-sensitivity multiplex digital polymerase chain reaction assays for ESR1 mutations in circulating tumor DNA (ctDNA) and investigated the clinical relevance and origin of ESR1 mutations in 171 women with advanced breast cancer. ESR1 mutation status in ctDNA showed high concordance with contemporaneous tumor biopsies and was accurately assessed in samples shipped at room temperature in preservative tubes. ESR1 mutations were found exclusively in estrogen receptor-positive breast cancer patients previously exposed to AI. Patients with ESR1 mutations had a substantially shorter progression-free survival on subsequent AI-based therapy [hazard ratio, 3.1; 95% confidence interval (CI), 1.9 to 23.1; P = 0.0041]. ESR1 mutation prevalence differed markedly between patients who were first exposed to AI during the adjuvant and metastatic settings [5.8% (3 of 52) versus 36.4% (16 of 44), respectively; P = 0.0002]. In an independent cohort, ESR1 mutations were identified in 0% (0 of 32; 95% CI, 0 to 10.9) tumor biopsies taken after progression on adjuvant AI. In a patient with serial sampling, ESR1 mutation was selected during metastatic AI therapy to become the dominant clone in the cancer. ESR1 mutations can be robustly identified with ctDNA analysis and predict for resistance to subsequent AI therapy. ESR1 mutations are rarely acquired during adjuvant AI but are commonly selected by therapy for metastatic disease, providing evidence that mechanisms of resistance to targeted therapy may be substantially different between the treatment of micrometastatic and overt metastatic cancer.
URI
https://repository.icr.ac.uk/handle/internal/5275
DOI
https://doi.org/10.1126/scitranslmed.aac7551
https://doi.org/10.1126/scitranslmed.aac7551
 
Collections
  • Breast Cancer Research
Subject
Antineoplastic Agents
Aromatase Inhibitors
Breast Neoplasms
Estrogen Receptor alpha
Female
Humans
Multiplex Polymerase Chain Reaction
Research team
Molecular Oncology
Endocrinology
Medicine (RMH)
Language
eng
Date accepted
2015-11-11
License start date
2015-11-11
Citation
Science Translational Medicine, 2015, 7 (313), pp. 313ra182 -
Publisher
AMER ASSOC ADVANCEMENT SCIENCE

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