PMID- 25979954
OWN - NLM
STAT- MEDLINE
DCOM- 20151022
LR  - 20240210
IS  - 1530-8561 (Electronic)
IS  - 0009-9147 (Linking)
VI  - 61
IP  - 7
DP  - 2015 Jul
TI  - Noninvasive detection of activating estrogen receptor 1 (ESR1) mutations in 
      estrogen receptor-positive metastatic breast cancer.
PG  - 974-82
LID - 10.1373/clinchem.2015.238717 [doi]
AB  - BACKGROUND: Activating mutations in the estrogen receptor 1 (ESR1) gene are 
      acquired on treatment and can drive resistance to endocrine therapy. Because of 
      the spatial and temporal limitations of needle core biopsies, our goal was to 
      develop a highly sensitive, less invasive method of detecting activating ESR1 
      mutations via circulating cell-free DNA (cfDNA) and tumor cells as a "liquid 
      biopsy." METHODS: We developed a targeted 23-amplicon next-generation sequencing 
      (NGS) panel for detection of hot-spot mutations in ESR1, 
      phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), 
      tumor protein p53 (TP53), fibroblast growth factor receptor 1 (FGFR1), and 
      fibroblast growth factor receptor 2 (FGFR2) in 48 patients with estrogen 
      receptor-alpha-positive metastatic breast cancer who were receiving systemic therapy. 
      Selected mutations were validated using droplet digital PCR (ddPCR). RESULTS: 
      Nine baseline cfDNA samples had an ESR1 mutation. NGS detected 3 activating 
      mutations in ESR1, and 3 hot-spot mutations in PIK3CA, and 3 in TP53 in baseline 
      cfDNA, and the ESR1 p.D538G mutation in 1 matched circulating tumor cell sample. 
      ddPCR analysis was more sensitive than NGS and identified 6 additional baseline 
      cfDNA samples with the ESR1 p.D538G mutation at a frequency of <1%. In serial 
      blood samples from 11 patients, 4 showed changes in cfDNA, 2 with emergence of a 
      mutation in ESR1. We also detected a low frequency ESR1 mutation (1.3%) in cfDNA 
      of 1 primary patient who was thought to have metastatic disease but was clear by 
      scans. CONCLUSIONS: Early identification of ESR1 mutations by liquid biopsy might 
      allow for cessation of ineffective endocrine therapies and switching to other 
      treatments, without the need for tissue biopsy and before the emergence of 
      metastatic disease.
CI  - (c) 2015 American Association for Clinical Chemistry.
FAU - Guttery, David S
AU  - Guttery DS
AD  - Department of Cancer Studies and Cancer Research UK Leicester Centre, University 
      of Leicester, Leicester, UK;
FAU - Page, Karen
AU  - Page K
AD  - Department of Cancer Studies and Cancer Research UK Leicester Centre, University 
      of Leicester, Leicester, UK;
FAU - Hills, Allison
AU  - Hills A
AD  - Imperial College, Department of Surgery and Cancer, Charing Cross Hospital, 
      London, UK;
FAU - Woodley, Laura
AU  - Woodley L
AD  - Experimental Cancer Medicine Centre Network, Imperial College, Charing Cross 
      Hospital, London, UK;
FAU - Marchese, Stephanie D
AU  - Marchese SD
AD  - Imperial College, Department of Surgery and Cancer, Charing Cross Hospital, 
      London, UK;
FAU - Rghebi, Basma
AU  - Rghebi B
AD  - Department of Cancer Studies and Cancer Research UK Leicester Centre, University 
      of Leicester, Leicester, UK;
FAU - Hastings, Robert K
AU  - Hastings RK
AD  - Cancer Research UK Leicester Centre, University of Leicester, Leicester, UK.
FAU - Luo, Jinli
AU  - Luo J
AD  - Cancer Research UK Leicester Centre, University of Leicester, Leicester, UK.
FAU - Pringle, J Howard
AU  - Pringle JH
AD  - Department of Cancer Studies and Cancer Research UK Leicester Centre, University 
      of Leicester, Leicester, UK;
FAU - Stebbing, Justin
AU  - Stebbing J
AD  - Imperial College, Department of Surgery and Cancer, Charing Cross Hospital, 
      London, UK;
FAU - Coombes, R Charles
AU  - Coombes RC
AD  - Imperial College, Department of Surgery and Cancer, Charing Cross Hospital, 
      London, UK;
FAU - Ali, Simak
AU  - Ali S
AD  - Imperial College, Department of Surgery and Cancer, Charing Cross Hospital, 
      London, UK;
FAU - Shaw, Jacqueline A
AU  - Shaw JA
AD  - Department of Cancer Studies and Cancer Research UK Leicester Centre, University 
      of Leicester, Leicester, UK; js39@le.ac.uk.
LA  - eng
GR  - C14315/A13462X/CRUK_/Cancer Research UK/United Kingdom
GR  - 14549/CRUK_/Cancer Research UK/United Kingdom
GR  - 13462/CRUK_/Cancer Research UK/United Kingdom
GR  - G1100425/MRC_/Medical Research Council/United Kingdom
GR  - NIHR-RP-011-053/DH_/Department of Health/United Kingdom
GR  - 2013 RIF - SHAW/PANCREATICCANUK_/Pancreatic Cancer UK/United Kingdom
GR  - 12011/CRUK_/Cancer Research UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150515
PL  - England
TA  - Clin Chem
JT  - Clinical chemistry
JID - 9421549
RN  - 0 (ESR1 protein, human)
RN  - 0 (Estrogen Receptor alpha)
RN  - 0 (TP53 protein, human)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (PIK3CA protein, human)
SB  - IM
MH  - Breast Neoplasms/*genetics/pathology
MH  - Class I Phosphatidylinositol 3-Kinases
MH  - DNA Mutational Analysis/*methods
MH  - Estrogen Receptor alpha/blood/*genetics
MH  - Female
MH  - High-Throughput Nucleotide Sequencing/methods
MH  - Humans
MH  - *Mutation
MH  - *Neoplastic Cells, Circulating/pathology
MH  - Phosphatidylinositol 3-Kinases/genetics
MH  - Reproducibility of Results
MH  - Tumor Suppressor Protein p53/genetics
EDAT- 2015/05/17 06:00
MHDA- 2015/10/23 06:00
CRDT- 2015/05/17 06:00
PHST- 2015/01/19 00:00 [received]
PHST- 2015/04/17 00:00 [accepted]
PHST- 2015/05/17 06:00 [entrez]
PHST- 2015/05/17 06:00 [pubmed]
PHST- 2015/10/23 06:00 [medline]
AID - clinchem.2015.238717 [pii]
AID - 10.1373/clinchem.2015.238717 [doi]
PST - ppublish
SO  - Clin Chem. 2015 Jul;61(7):974-82. doi: 10.1373/clinchem.2015.238717. Epub 2015 
      May 15.