Detection of Mutations in EGFR in Circulating Lung-Cancer Cells

Maheswaran, Shyamala; Sequist, Lecia V.; Nagrath, Sunitha; Ulkus, Lindsey; Brannigan, Brian; Collura, Chey V.; Inserra, Elizabeth; Diederichs, Sven; Iafrate, A. John; Bell, Daphne W.; Digumarthy, Subba; Muzikansky, Alona; Irimia, Daniel; Settleman, Jeffrey; Tompkins, Ronald G.; Lynch, Thomas J.; Toner, Mehmet; Haber, Daniel A.

doi:10.1056/nejmoa0800668

Cited by 1,617Cancer Genomics and DiagnosticsLung Cancer Treatments and MutationsLung Cancer Diagnosis and Treatment

Detection of Mutations in EGFR in Circulating Lung-Cancer Cells

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Maheswaran, Shyamala, Sequist, Lecia V., Nagrath, Sunitha, Ulkus, Lindsey, Brannigan, Brian, Collura, Chey V., Inserra, Elizabeth, Diederichs, Sven +10 more·2008·New England Journal of Medicine

DOI 10.1056/nejmoa0800668PMC PMC3551471

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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.

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Using highly sensitive detection methods, low-level pretreatment T790M mutations can be detected in up to 65% of cases and are constantly associated with shorter PFS.
“Using highly sensitive detection methods, low-level pretreatment T790M mutations can be detected in a significant fraction of patients (up to 65% of cases) and are constantly associated with shorter PFS [93,94,95].”
From Heterogeneous Responses to Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) in Patients with Uncommon EGFR Mutations: New Insights and Future Perspectives in this Complex Clinical Scenario (2019) · cites this paper as [94]
T790M pre-exists in a small fraction of cells, and those cells are selected for during the course of treatment.
“This suggests, but does not prove, that it pre-exists in a small fraction of cells, and that those cells are selected for during the course of treatment (Maheswaran et al., 2008; Rosell et al., 2011).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Maheswaran et al., 2008
Highly sensitive methods can detect the T790M mutation in approximately 35% of pre-treatment biopsies.
“Recent studies suggest that highly sensitive methods can detect the T790M mutation in ~35% of pre-treatment biopsies.”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Maheswaran et al., 2008

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Authors: Maheswaran, S., Sequist, L. V., Nagrath, S., Ulkus, L., Brannigan, B., Collura, C. V., Inserra, E., Diederichs, S., Iafrate, A. J., Bell, D. W., Digumarthy, S., Muzikansky, A., Irimia, D., Settleman, J., Tompkins, R. G., Lynch, T. J., Toner, M., & Haber, D. A.
Affiliations: Harvard University (US)
Howard Hughes Medical Institute (US)
ORCID: Maheswaran, Shyamala
Sequist, Lecia V.
Nagrath, Sunitha
Diederichs, Sven
Iafrate, A. John
Bell, Daphne W.
Digumarthy, Subba
Muzikansky, Alona
Irimia, Daniel
Settleman, Jeffrey
Tompkins, Ronald G.
Lynch, Thomas J.
Toner, Mehmet
Haber, Daniel A.
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 2008-07-24
Volume: 359
Issue: 4
Pages: 366-377
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejmoa0800668
PMC: PMC3551471
OpenAlex: W2139799027
Cited by: 1,617
References: 33
Citations by year: 2026: 9 · 2025: 22 · 2024: 26 · 2023: 32 · 2022: 50 · 2021: 47 · 2020: 56 · 2019: 82 · 2018: 84 · 2017: 128 · 2016: 139 · 2015: 120 · 2014: 127 · 2013: 158 · 2012: 138
FWCI: 45.32
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: New England Journal of Medicine (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Howard Hughes Medical Institute
National Cancer Institute (R01CA129933)
National Institute of Biomedical Imaging and Bioengineering (P41EB002503)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
Keywords: circulating tumor cells, EGFR mutation, non-small cell lung cancer, T790M mutation, tyrosine kinase inhibitors, drug resistance, liquid biopsy, microfluidic cell capture, allele-specific PCR, progression-free survival
MeSH terms: Adult, Aged, Carcinoma, Non-Small-Cell Lung, DNA Mutational Analysis, DNA, Neoplasm, Female, Genetic Markers, Genotype, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Neoplastic Cells, Circulating, Proportional Hazards Models, Drug Monitoring, Disease Progression, Genes, erbB-1, Nucleic Acid Amplification Techniques, Microfluidic Analytical Techniques, Protein Kinase Inhibitors, Kaplan-Meier Estimate

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