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. 2008 Massachusetts Medical Society
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. 2008 Massachusetts Medical Society
Authors: Daphne W Bell; Thomas J Lynch; Sara M Haserlat; Patricia L Harris; Ross A Okimoto; Brian W Brannigan; Dennis C Sgroi; Beth Muir; Markus J Riemenschneider; Renee Bailey Iacona; Annetta D Krebs; David H Johnson; Giuseppe Giaccone; Roy S Herbst; Christian Manegold; Masahiro Fukuoka; Mark G Kris; José Baselga; Judith S Ochs; Daniel A Haber Journal: J Clin Oncol Date: 2005-10-03 Impact factor: 44.544
Authors: W Jeffrey Allard; Jeri Matera; M Craig Miller; Madeline Repollet; Mark C Connelly; Chandra Rao; Arjan G J Tibbe; Jonathan W Uhr; Leon W M M Terstappen Journal: Clin Cancer Res Date: 2004-10-15 Impact factor: 12.531
Authors: Eunice L Kwak; Raffaella Sordella; Daphne W Bell; Nadia Godin-Heymann; Ross A Okimoto; Brian W Brannigan; Patricia L Harris; David R Driscoll; Panos Fidias; Thomas J Lynch; Sridhar K Rabindran; John P McGinnis; Allan Wissner; Sreenath V Sharma; Kurt J Isselbacher; Jeffrey Settleman; Daniel A Haber Journal: Proc Natl Acad Sci U S A Date: 2005-05-16 Impact factor: 11.205
Authors: James Bean; Cameron Brennan; Jin-Yuan Shih; Gregory Riely; Agnes Viale; Lu Wang; Dhananjay Chitale; Noriko Motoi; Janos Szoke; Stephen Broderick; Marissa Balak; Wen-Cheng Chang; Chong-Jen Yu; Adi Gazdar; Harvey Pass; Valerie Rusch; William Gerald; Shiu-Feng Huang; Pan-Chyr Yang; Vincent Miller; Marc Ladanyi; Chih-Hsin Yang; William Pao Journal: Proc Natl Acad Sci U S A Date: 2007-12-18 Impact factor: 11.205
Authors: Christopher Greenman; Philip Stephens; Raffaella Smith; Gillian L Dalgliesh; Christopher Hunter; Graham Bignell; Helen Davies; Jon Teague; Adam Butler; Claire Stevens; Sarah Edkins; Sarah O'Meara; Imre Vastrik; Esther E Schmidt; Tim Avis; Syd Barthorpe; Gurpreet Bhamra; Gemma Buck; Bhudipa Choudhury; Jody Clements; Jennifer Cole; Ed Dicks; Simon Forbes; Kris Gray; Kelly Halliday; Rachel Harrison; Katy Hills; Jon Hinton; Andy Jenkinson; David Jones; Andy Menzies; Tatiana Mironenko; Janet Perry; Keiran Raine; Dave Richardson; Rebecca Shepherd; Alexandra Small; Calli Tofts; Jennifer Varian; Tony Webb; Sofie West; Sara Widaa; Andy Yates; Daniel P Cahill; David N Louis; Peter Goldstraw; Andrew G Nicholson; Francis Brasseur; Leendert Looijenga; Barbara L Weber; Yoke-Eng Chiew; Anna DeFazio; Mel F Greaves; Anthony R Green; Peter Campbell; Ewan Birney; Douglas F Easton; Georgia Chenevix-Trench; Min-Han Tan; Sok Kean Khoo; Bin Tean Teh; Siu Tsan Yuen; Suet Yi Leung; Richard Wooster; P Andrew Futreal; Michael R Stratton Journal: Nature Date: 2007-03-08 Impact factor: 49.962
Authors: Mary Nora Dickson; Pavel Tsinberg; Zhongliang Tang; Farideh Z Bischoff; Timothy Wilson; Edward F Leonard Journal: Biomicrofluidics Date: 2011-08-22 Impact factor: 2.800
Authors: Minoru Kitago; Kazuo Koyanagi; Takeshi Nakamura; Yasufumi Goto; Mark Faries; Steven J O'Day; Donald L Morton; Soldano Ferrone; Dave S B Hoon Journal: Clin Chem Date: 2009-02-20 Impact factor: 8.327