Dynamics of circulating tumor DNA represented by the activating and resistant mutations in the EGFR-TKI treatment

Abstract

Circulating tumor DNA (ctDNA) is an emerging field of cancer research. For lung cancer, noninvasive genotyping of epidermal growth factor receptor (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 timings during the treatment course and classified them according to treatment status. The mutation detection rate of exon 19 deletion/L858R in plasma was high in the initiation of EGFR tyrosine kinase inhibitor (EGFR-TKI; p = 0.001), suppressed during the 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 exhibited 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 2 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 of image analysis.

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