Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer
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- 11 November 2015
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 7 (313), 313ra182
- https://doi.org/10.1126/scitranslmed.aac7551
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.Keywords
Funding Information
- Susan G. Komen Foundation
- National Health Service
- NIHR Biomedical Research Centre at The Royal Marsden
- Institute of Cancer Research, Cancer Research UK (C30746/A16642)
- Mary-Jean Mitchell Green Foundation
- Cridlan Trust
This publication has 21 references indexed in Scilit:
- Noninvasive Detection of Activating Estrogen Receptor 1 (ESR1) Mutations in Estrogen Receptor–Positive Metastatic Breast CancerClinical Chemistry, 2015
- Short report: Monitoring ESR1 mutations by circulating tumor DNA in aromatase inhibitor resistant metastatic breast cancerInternational Journal of Cancer, 2015
- Relationship of PIK3CA mutation and pathway activity with antiproliferative response to aromatase inhibitionBreast Cancer Research, 2014
- Biomarker changes associated with the development of resistance to aromatase inhibitors (AIs) in estrogen receptor-positive breast cancerAnnals Of Oncology, 2014
- ESR1 ligand-binding domain mutations in hormone-resistant breast cancerNature Genetics, 2013
- The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancersNature, 2012
- HER2 discordance between primary breast cancer and its paired metastasis: tumor biology or test artefact? Insights through meta-analysisBreast Cancer Research and Treatment, 2011
- The patterns and dynamics of genomic instability in metastatic pancreatic cancerNature, 2010
- Genome remodelling in a basal-like breast cancer metastasis and xenograftNature, 2010
- Preexistence and Clonal Selection of MET Amplification in EGFR Mutant NSCLCCancer Cell, 2010