Dynamics of circulating tumor DNA represented by the activating and resistant mutations in epidermal growth factor receptor tyrosine kinase inhibitor treatment

• Published in: Cancer science 2016-03, Vol.107 (3), p.353-358
• Main Authors: Uchida, Junji, Imamura, Fumio, Kukita, Yoji, Oba, Shigeyuki, Kumagai, Toru, Nishino, Kazumi, Inoue, Takako, Kimura, Madoka, Kato, Kikuya
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biomarkers, Tumor - blood; Biomarkers, Tumor - genetics; Biopsy; Carcinoembryonic antigen; circulating tumor DNA; Clonal deletion; Cytotoxic agents; Cytotoxicity; Deoxyribonucleic acid; Disease; DNA; DNA Mutational Analysis; DNA sequencing; DNA, Neoplasm - blood; DNA, Neoplasm - genetics; Drug Resistance, Neoplasm; Enzyme inhibitors; Epidermal growth factor; epidermal growth factor receptor tyrosine kinase inhibitor; Epidermal growth factor receptors; ErbB Receptors - genetics; Female; Gene deletion; Genetic testing; Genotyping; Humans; Kinases; Laboratories; Lung cancer; Lung Neoplasms - blood; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Male; massively parallel DNA sequencer; Middle Aged; Mutation; Mutation, Missense; Nucleotide sequence; Original; Patients; Plasma; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase receptors; Studies; Tumors
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.12860

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. Circulating tumor DNA (ctDNA) is an emerging field of cancer research. For lung cancer, noninvasive genotyping of EGFR is the foremost application. We examined the dynamics of ctDNA represented by activating and resistant mutations using deep sequencing with a massively parallel DNA sequencer.