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Published at www.nejm.org July 2, 2008 (10.1056/NEJMoa0800668)

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ABSTRACT

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.

Source Information

From the Massachusetts General Hospital Cancer Center (S.M., L.V.S., L.U., B.B., E.I., S. Diederichs, D.W.B., S. Digumarthy, A.M., J.S., T.J.L., D.A.H.), Biomicroelectromechanical Systems Resource Center (S.N., C.V.C., D.I., R.G.T., M.T.), Departments of Surgery (S.M., S.N., D.I., R.G.T., M.T.), Medicine (L.V.S., T.J.L., D.A.H.), Pathology (A.J.I.), Radiology (S. Digumarthy), and Biostatistics Unit (A.M.), Massachusetts General Hospital and Harvard Medical School; Shriners Hospital for Children (R.G.T., M.T.); and the Howard Hughes Medical Institute (D.A.H.) — all in Boston.

Drs. Maheswaran, Sequist, and Nagrath contributed equally to this article.

This article (10.1056/NEJMoa0800668) was published at www.nejm.org on July 2, 2008. It will appear in the July 24 issue of the Journal.

Address reprint requests to Dr. Haber at Massachusetts General Hospital Cancer Center, CNY-7, Bldg. 149, 13th St., Charlestown, MA 02129, or at haber{at}helix.mgh.harvard.edu.

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