title: Dynamics of circulating tumor DNA represented by the activating and resistant mutations in epidermal growth factor receptor tyrosine kinase inhibitor treatment.
abstract: Circulating tumor DNA (ctDNA) is an emerging field of cancer research. For lung cancer, non-invasive genotyping of EGFR is the foremost application. The activating mutations represent the ctDNA from all cancer cells, and the T790M-resistant mutation represents that from resistant cells. We examined the ctDNA dynamics of EGFR mutations by using deep sequencing with a massively parallel DNA sequencer. We obtained 190 plasma samples from 57 patients at various times during the treatment course and classified them according to treatment status. The mutation detection rate of exon 19 deletion/L858R in plasma was high at the initiation of treatment with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI; P = 0.001), suppressed during EGFR-TKI treatment before disease progression, and elevated after the onset of disease progression (P = 0.023). The mutation detection rate of T790M was low until the onset of disease progression and elevated thereafter (P = 0.01). Samples across the development of disease progression were obtained from 10 patients and showed a correlation between increased ctDNA level and disease progression. Decreased ctDNA level in response to the initiation of EGFR-TKI was observed in 4 of 6 eligible patients. In two patients, the ctDNA dynamics suggested the presence of cancer cell populations only with the T790M mutation. In another patient, the T790M ctDNA represented cell subpopulations that respond to cytotoxic agents differently from the major population. Considering the high incidence, ctDNA could be a clinical parameter to complement information from image analyses.
authors.affiliation: Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Uchida
authors.affiliation: Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Imamura
authors.affiliation: Department of Molecular and Medical Genetics of Research Institute, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Kukita
authors.affiliation: Graduate School of Informatics, Kyoto University, Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kyoto, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Oba
authors.affiliation: Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kumagai
authors.affiliation: Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nishino
authors.affiliation: Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Kimura
authors.affiliation: Department of Molecular and Medical Genetics of Research Institute, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Kikuya
authors.initials: K
authors.lastname: Kato
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000097:blood* / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Carcinoembryonic antigen; circulating tumor DNA; epidermal growth factor receptor tyrosine kinase inhibitor; lung cancer; massively parallel DNA sequencer