Detection of mutations in EGFR in circulating lung-cancer cells

被引:1332
作者
Maheswaran, Shyamala [1 ,3 ]
Sequist, Lecia V. [1 ,4 ]
Nagrath, Sunitha [2 ,3 ]
Ulkus, Lindsey [1 ]
Brannigan, Brian [1 ]
Collura, Chey V. [2 ]
Inserra, Elizabeth [1 ]
Diederichs, Sven [1 ]
Iafrate, A. John [5 ]
Bell, Daphne W. [1 ]
Digumarthy, Subba [1 ,6 ]
Muzikansky, Alona [1 ,7 ]
Irimia, Daniel [2 ,3 ]
Settleman, Jeffrey [1 ]
Tompkins, Ronald G. [2 ,3 ,8 ]
Lynch, Thomas J. [1 ,4 ]
Toner, Mehmet [2 ,3 ,8 ]
Haber, Daniel A. [1 ,4 ,9 ]
机构
[1] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA
[2] Massachusetts Gen Hosp, Biomicroelectromech Syst Resource Ctr, Boston, MA 02114 USA
[3] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA
[4] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA
[5] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA
[6] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA
[7] Massachusetts Gen Hosp, Biostat Unit, Boston, MA 02114 USA
[8] Shriners Hosp Children, Boston, MA USA
[9] Howard Hughes Med Inst, Boston, MA 02115 USA
关键词
D O I
10.1056/NEJMoa0800668
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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收藏
页码:366 / 377
页数:12
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