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Abstract
Monitoring of disease/therapeutic conditions is an important application of circulating tumor DNA (ctDNA). We devised numerical indices, based on ctDNA dynamics, for therapeutic response and disease progression. 52 lung cancer patients subjected to the EGFR-TKI treatment were prospectively collected, and ctDNA levels represented by the activating and T790M mutations were measured using deep sequencing. Typically, ctDNA levels decreased sharply upon initiation of EGFR-TKI, however this did not occur in progressive disease (PD) cases. All 3 PD cases at initiation of EGFR-TKI were separated from other 27 cases in a two-dimensional space generated by the ratio of the ctDNA levels before and after therapy initiation (mutation allele ratio in therapy, MART) and the average ctDNA level. For responses to various agents after disease progression, PD/stable disease cases were separated from partial response cases using MART (accuracy, 94.7%; 95% CI, 73.5–100). For disease progression, the initiation of ctDNA elevation (initial positive point) was compared with the onset of objective disease progression. In 11 out of 28 eligible patients, both occurred within ±100 day range, suggesting a detection of the same change in disease condition. Our numerical indices have potential applicability in clinical practice, pending confirmation with designed prospective studies.
Highlights
Disease progression therapeutic responses and disease progression is important from a clinical viewpoint
The performance of these indices was evaluated using the current standards, namely the Response Evaluation Criteria In Solid Tumors (RECIST)[16]. We demonstrate that these indices, the therapeutic response index, appear to be useful for studying Circulating tumor DNA (ctDNA) dynamics and should be further investigated with designed prospective studies
The initial PCR amplification of EGFR exon fragments was successful in all the samples, and mutation data were obtained from all the samples
Summary
Our previous study with a retrospective data set revealed that ctDNA levels of activating and T790M mutations were suppressed during the EGFR-TKI treatment until the onset of objective disease progression, but increased thereafter[17]. In patients 12–15, named “type II” patients, the IP point preceded the PD point in time by more than 100 days (IP from PD, Table 2), and there were two data points in the interval (Fig. 2d–f, Supplementary Figure S3h) In these patients, ctDNA dynamics diverged from medical imaging and elevated ahead of objective disease progression. These events were classified according to objective response, except for radiation therapy, and plotted in the two-dimensional space generated by MART and the average of PM scores (Fig. 1b). Unlike anti-cancer agents, radiation therapy did not change ctDNA dynamics, and segregated in the upper right part of the two-dimensional space
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