PMID- 18596266
OWN - NLM
STAT- MEDLINE
DCOM- 20080729
LR  - 20220408
IS  - 1533-4406 (Electronic)
IS  - 0028-4793 (Print)
IS  - 0028-4793 (Linking)
VI  - 359
IP  - 4
DP  - 2008 Jul 24
TI  - Detection of mutations in EGFR in circulating lung-cancer cells.
PG  - 366-77
LID - 10.1056/NEJMoa0800668 [doi]
AB  - BACKGROUND: The use of tyrosine kinase inhibitors to target the epidermal growth 
      factor receptor gene (EGFR) in patients with non-small-cell lung cancer is 
      effective but limited by the emergence of drug-resistance mutations. Molecular 
      characterization of circulating tumor cells may provide a strategy for 
      noninvasive serial monitoring of tumor genotypes during treatment. METHODS: We 
      captured highly purified circulating tumor cells from the blood of patients with 
      non-small-cell lung cancer using a microfluidic device containing microposts 
      coated with antibodies against epithelial cells. We performed EGFR mutational 
      analysis on DNA recovered from circulating tumor cells using allele-specific 
      polymerase-chain-reaction amplification and compared the results with those from 
      concurrently isolated free plasma DNA and from the original tumor-biopsy 
      specimens. RESULTS: We isolated circulating tumor cells from 27 patients with 
      metastatic non-small-cell lung cancer (median number, 74 cells per milliliter). 
      We identified the expected EGFR activating mutation in circulating tumor cells 
      from 11 of 12 patients (92%) and in matched free plasma DNA from 4 of 12 patients 
      (33%) (P=0.009). We detected the T790M mutation, which confers drug resistance, 
      in circulating tumor cells collected from patients with EGFR mutations who had 
      received tyrosine kinase inhibitors. When T790M was detectable in pretreatment 
      tumor-biopsy specimens, the presence of the mutation correlated with reduced 
      progression-free survival (7.7 months vs. 16.5 months, P<0.001). Serial analysis 
      of circulating tumor cells showed that a reduction in the number of captured 
      cells was associated with a radiographic tumor response; an increase in the 
      number of cells was associated with tumor progression, with the emergence of 
      additional EGFR mutations in some cases. CONCLUSIONS: Molecular analysis of 
      circulating tumor cells from the blood of patients with lung cancer offers the 
      possibility of monitoring changes in epithelial tumor genotypes during the course 
      of treatment.
CI  - 2008 Massachusetts Medical Society
FAU - Maheswaran, Shyamala
AU  - Maheswaran S
AD  - Massachusetts General Hospital Cancer Center, Boston 02129, USA.
FAU - Sequist, Lecia V
AU  - Sequist LV
FAU - Nagrath, Sunitha
AU  - Nagrath S
FAU - Ulkus, Lindsey
AU  - Ulkus L
FAU - Brannigan, Brian
AU  - Brannigan B
FAU - Collura, Chey V
AU  - Collura CV
FAU - Inserra, Elizabeth
AU  - Inserra E
FAU - Diederichs, Sven
AU  - Diederichs S
FAU - Iafrate, A John
AU  - Iafrate AJ
FAU - Bell, Daphne W
AU  - Bell DW
FAU - Digumarthy, Subba
AU  - Digumarthy S
FAU - Muzikansky, Alona
AU  - Muzikansky A
FAU - Irimia, Daniel
AU  - Irimia D
FAU - Settleman, Jeffrey
AU  - Settleman J
FAU - Tompkins, Ronald G
AU  - Tompkins RG
FAU - Lynch, Thomas J
AU  - Lynch TJ
FAU - Toner, Mehmet
AU  - Toner M
FAU - Haber, Daniel A
AU  - Haber DA
LA  - eng
GR  - HHMI/Howard Hughes Medical Institute/United States
GR  - P41 EB002503/EB/NIBIB NIH HHS/United States
GR  - R01 CA129933/CA/NCI NIH HHS/United States
GR  - R01 CA129933-01A1/CA/NCI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20080702
PL  - United States
TA  - N Engl J Med
JT  - The New England journal of medicine
JID - 0255562
RN  - 0 (DNA, Neoplasm)
RN  - 0 (Genetic Markers)
RN  - 0 (Protein Kinase Inhibitors)
SB  - IM
CIN - N Engl J Med. 2008 Jul 24;359(4):418-20. doi: 10.1056/NEJMe0804521. PMID: 
      18596267
MH  - Adult
MH  - Aged
MH  - Carcinoma, Non-Small-Cell Lung/drug therapy/*genetics/pathology
MH  - DNA Mutational Analysis/methods
MH  - DNA, Neoplasm/*analysis
MH  - Disease Progression
MH  - Drug Monitoring/*methods
MH  - Female
MH  - *Genes, erbB-1
MH  - Genetic Markers
MH  - Genotype
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - Lung Neoplasms/drug therapy/*genetics/pathology
MH  - Male
MH  - Microfluidic Analytical Techniques
MH  - Middle Aged
MH  - *Mutation
MH  - *Neoplastic Cells, Circulating
MH  - Nucleic Acid Amplification Techniques
MH  - Proportional Hazards Models
MH  - Protein Kinase Inhibitors/therapeutic use
PMC - PMC3551471
MID - NIHMS420480
COIS- No other potential conflict of interest relevant to this article was reported.
EDAT- 2008/07/04 09:00
MHDA- 2008/07/30 09:00
PMCR- 2013/01/22
CRDT- 2008/07/04 09:00
PHST- 2008/07/04 09:00 [pubmed]
PHST- 2008/07/30 09:00 [medline]
PHST- 2008/07/04 09:00 [entrez]
PHST- 2013/01/22 00:00 [pmc-release]
AID - NEJMoa0800668 [pii]
AID - 10.1056/NEJMoa0800668 [doi]
PST - ppublish
SO  - N Engl J Med. 2008 Jul 24;359(4):366-77. doi: 10.1056/NEJMoa0800668. Epub 2008 
      Jul 2.