FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

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

	Full Text PDF Supplementary Material Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

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.

Full Text of this Article

This article has been cited by other articles:

• McDermott, U., Settleman, J. (2009). Personalized Cancer Therapy With Selective Kinase Inhibitors: An Emerging Paradigm in Medical Oncology. JCO 27: 5650-5659 [Abstract] [Full Text]  
• Tanaka, F., Yoneda, K., Kondo, N., Hashimoto, M., Takuwa, T., Matsumoto, S., Okumura, Y., Rahman, S., Tsubota, N., Tsujimura, T., Kuribayashi, K., Fukuoka, K., Nakano, T., Hasegawa, S. (2009). Circulating Tumor Cell as a Diagnostic Marker in Primary Lung Cancer. Clin. Cancer Res. 15: 6980-6986 [Abstract] [Full Text]  
• Ray, M., Salgia, R., Vokes, E. E. (2009). The Role of EGFR Inhibition in the Treatment of Non-Small Cell Lung Cancer. The Oncologist 14: 1116-1130 [Abstract] [Full Text]  
• Dotan, E., Cohen, S. J., Alpaugh, K. R., Meropol, N. J. (2009). Circulating Tumor Cells: Evolving Evidence and Future Challenges. The Oncologist 14: 1070-1082 [Abstract] [Full Text]  
• Helzer, K. T., Barnes, H. E., Day, L., Harvey, J., Billings, P. R., Forsyth, A. (2009). Circulating Tumor Cells Are Transcriptionally Similar to the Primary Tumor in a Murine Prostate Model. Cancer Res. 69: 7860-7866 [Abstract] [Full Text]  
• Mok, T. S., Wu, Y.-L., Thongprasert, S., Yang, C.-H., Chu, D.-T., Saijo, N., Sunpaweravong, P., Han, B., Margono, B., Ichinose, Y., Nishiwaki, Y., Ohe, Y., Yang, J.-J., Chewaskulyong, B., Jiang, H., Duffield, E. L., Watkins, C. L., Armour, A. A., Fukuoka, M. (2009). Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma. NEJM 361: 947-957 [Abstract] [Full Text]  
• Bluemke, K., Bilkenroth, U., Meye, A., Fuessel, S., Lautenschlaeger, C., Goebel, S., Melchior, A., Heynemann, H., Fornara, P., Taubert, H. (2009). Detection of Circulating Tumor Cells in Peripheral Blood of Patients with Renal Cell Carcinoma Correlates with Prognosis. Cancer Epidemiol. Biomarkers Prev. 18: 2190-2194 [Abstract] [Full Text]  
• Armstrong, A. J., Febbo, P. G. (2009). Using Surrogate Biomarkers to Predict Clinical Benefit in Men with Castration-Resistant Prostate Cancer: An Update and Review of the Literature. The Oncologist 14: 816-827 [Abstract] [Full Text]  
• De Giorgi, U., Valero, V., Rohren, E., Dawood, S., Ueno, N. T., Miller, M. C., Doyle, G. V., Jackson, S., Andreopoulou, E., Handy, B. C., Reuben, J. M., Fritsche, H. A., Macapinlac, H. A., Hortobagyi, G. N., Cristofanilli, M. (2009). Circulating Tumor Cells and [18F]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography for Outcome Prediction in Metastatic Breast Cancer. JCO 27: 3303-3311 [Abstract] [Full Text]  
• Colice, G. (2009). Lung Cancer Staging and the Home Insurance Building Constructed in 1884-1885. Chest 136: 6-8 [Full Text]  
• Okumura, Y., Tanaka, F., Yoneda, K., Hashimoto, M., Takuwa, T., Kondo, N., Hasegawa, S. (2009). Circulating Tumor Cells in Pulmonary Venous Blood of Primary Lung Cancer Patients.. Ann. Thorac. Surg. 87: 1669-1675 [Abstract] [Full Text]  
• Sequist, L. V., Engelman, J. A., Lynch, T. J. (2009). Toward Noninvasive Genomic Screening of Lung Cancer Patients. JCO 27: 2589-2591 [Full Text]  
• Dubey, S., Powell, C. A. (2009). Update in Lung Cancer 2008. Am. J. Respir. Crit. Care Med. 179: 860-868 [Full Text]  
• Hicks, R. J. (2009). Role of 18F-FDG PET in Assessment of Response in Non-Small Cell Lung Cancer. JNM 50: 31S-42S [Abstract] [Full Text]  
• Kuang, Y., Rogers, A., Yeap, B. Y., Wang, L., Makrigiorgos, M., Vetrand, K., Thiede, S., Distel, R. J., Janne, P. A. (2009). Noninvasive Detection of EGFR T790M in Gefitinib or Erlotinib Resistant Non-Small Cell Lung Cancer. Clin. Cancer Res. 15: 2630-2636 [Abstract] [Full Text]  
• Gow, C.-H., Chang, Y.-L., Hsu, Y.-C., Tsai, M.-F., Wu, C.-T., Yu, C.-J., Yang, C.-H., Lee, Y.-C., Yang, P.-C., Shih, J.-Y. (2009). Comparison of epidermal growth factor receptor mutations between primary and corresponding metastatic tumors in tyrosine kinase inhibitor-naive non-small-cell lung cancer. Ann Oncol 20: 696-702 [Abstract] [Full Text]  
• Li, J., Wang, L., Janne, P. A., Makrigiorgos, G. M. (2009). Coamplification at Lower Denaturation Temperature-PCR Increases Mutation-Detection Selectivity of TaqMan-Based Real-Time PCR. Clin. Chem. 55: 748-756 [Abstract] [Full Text]  
• Kitago, M., Koyanagi, K., Nakamura, T., Goto, Y., Faries, M., O'Day, S. J., Morton, D. L., Ferrone, S., Hoon, D. S.B. (2009). mRNA Expression and BRAF Mutation in Circulating Melanoma Cells Isolated from Peripheral Blood with High Molecular Weight Melanoma-Associated Antigen-Specific Monoclonal Antibody Beads. Clin. Chem. 55: 757-764 [Abstract] [Full Text]  
• Yung, T. K.F., Chan, K.C. A., Mok, T. S.K., Tong, J., To, K.-F., Lo, Y.M. D. (2009). Single-Molecule Detection of Epidermal Growth Factor Receptor Mutations in Plasma by Microfluidics Digital PCR in Non-Small Cell Lung Cancer Patients. Clin. Cancer Res. 15: 2076-2084 [Abstract] [Full Text]  
• Winer, E., Gralow, J., Diller, L., Karlan, B., Loehrer, P., Pierce, L., Demetri, G., Ganz, P., Kramer, B., Kris, M., Markman, M., Mayer, R., Pfister, D., Raghavan, D., Ramsey, S., Reaman, G., Sandler, H., Sawaya, R., Schuchter, L., Sweetenham, J., Vahdat, L., Schilsky, R. L. (2009). Clinical Cancer Advances 2008: Major Research Advances in Cancer Treatment, Prevention, and Screening--A Report From the American Society of Clinical Oncology. JCO 27: 812-826 [Abstract] [Full Text]  
• Schwarzenbach, H., Alix-Panabieres, C., Muller, I., Letang, N., Vendrell, J.-P., Rebillard, X., Pantel, K. (2009). Cell-free Tumor DNA in Blood Plasma As a Marker for Circulating Tumor Cells in Prostate Cancer. Clin. Cancer Res. 15: 1032-1038 [Abstract] [Full Text]  
• Herbst, R. S., Heymach, J. V., Lippman, S. M. (2008). Lung Cancer. NEJM 359: 1367-1380 [Full Text]  
• (2008). Detecting EGFR Mutations in Circulating Lung Cancer Cells. JWatch Oncology and Hematology 2008: 1-1 [Full Text]  
• Sequist, L. V., Settleman, J. E., Ackman, J. B., Iafrate, A. J. (2008). Case 23-2008 -- A 26-Year-Old Man with Back Pain and a Mass in the Lung. NEJM 359: 405-414 [Full Text]  
• Schiller, J. H. (2008). Noninvasive Monitoring of Tumors. NEJM 359: 418-420 [Full Text]