title: Monitoring EGFR T790M with plasma DNA from lung cancer patients in a prospective observational study.
abstract: Use of plasma DNA to detect mutations has spread widely as a form of liquid biopsy. EGFR T790M has been observed in half of lung cancer patients who have acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI). Effectiveness of monitoring T790M via plasma DNA during treatment with EGFR-TKI has not been established as an alternative to re-biopsy. This was a prospective multicenter observational study involving non-small cell lung cancer patients carrying EGFR L858R or exon 19 deletions, treated with EGFR-TKI. The primary objective was to determine whether T790M could be detected using plasma DNA in patients with progressive disease (PD). T790M was examined using the mutation-biased PCR and quenching probe (MBP-QP) method, a sensitive, fully-automated system developed in our laboratory. Eighty-nine non-small cell lung cancer patients were enrolled from seven hospitals in Japan. Sequential examinations revealed T790M in plasma DNA among 40% of patients who developed PD. Activating mutations, such as L858R and exon 19 deletions, were detected in 40% of patients using plasma DNA, and either T790M or activating mutations were observed in 62%. Dividing into four periods (before PD, at PD, at discontinuation of EGFR-TKI and subsequently), T790M was detected in 10, 19, 24 and 27% of patients, respectively. Smokers, males, patients having exon 19 deletions and patients who developed new lesions evidenced significantly frequent presence of T790M in plasma DNA. Monitoring T790M with plasma DNA using MBP-QP reflects the clinical course of lung cancer patients treated with EGFR-TKI. Detection of T790M with plasma DNA was correlated with EGFR mutation type, exon 19 deletions and tumor progression. Re-biopsy could be performed only in 14% of PD cases, suggesting difficulty in obtaining re-biopsy specimens in practice. Monitoring T790M with plasma DNA reflects the clinical course, and is potentially useful in designing strategies for subsequent treatment.
authors.affiliation: Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Saga University, Saga, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Sueoka-Aragane
authors.affiliation: Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Katakami
authors.affiliation: Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, Japan.
authors.forename: Miyako
authors.initials: M
authors.lastname: Satouchi
authors.affiliation: Department of Respiratory Medicine, National Hospital Organization Toneyama National Hospital, Toyonaka, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yokota
authors.affiliation: Department of Medical Oncology and Clinical Research, National Hospital Organization Yamaguchi-Ube Medical Center, Ube, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Aoe
authors.affiliation: Division of Respiratory Medicine, Saga-Ken Medical Centre Koseikan, Saga, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Iwanaga
authors.affiliation: Department of Respiratory Medicine, Kobe City Medical Center, General Hospital, Kobe, Japan.
authors.forename: Kojiro
authors.initials: K
authors.lastname: Otsuka
authors.affiliation: Department of Epidemiology and Health Care Research, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morita
authors.affiliation: Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Saga University, Saga, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
authors.affiliation: Department of Medical Oncology, Hyogo Cancer Center, Akashi, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Negoro
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000235:genetics* / Q000401:mortality; D004247:DNA / Q000097:blood / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000097:blood / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction / Q000379:methods; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D014408:Biomarkers, Tumor; D004247:DNA; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: DNA; erbB-1; lung neoplasms; molecular targeted therapy; mutation