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Global Translational Medicine ctDNA in management of patients with NSCLC

diagnostic purposes. Many studies have demonstrated the NSCLC, ctDNA has a fast clearance, allowing for dynamic
wide utility of ctDNA in early detection, post-operative surveillance. Based on statistical analysis, the half-life of
minimal residual disease (MRD) detection, surveillance ctDNA after radical resection has been determined to be
of subclonal evolution, and prediction of therapeutic effect 35 min, so ctDNA can be detected in real-time and used to
(Figure 1). reflect tumor burden .
[11]
ctDNA is present relatively low in peripheral blood. This Histopathological examination is the gold standard
is because on average, at each cell’s death, only 0.014% total of NSCLC’s diagnosis, but ctDNA also shows unique
DNA of a tumor cell is shed into the bloodstream . The advantages over other detection methods. First, ctDNA
[6]
detection of ctDNA is further confounded by constituent contains the whole genome information of the tumor tissue.
of cfDNA that originates from normal cells, especially Tumor cells consistently release ctDNA into the circulation
fragmented DNA from germline of hematopoietic lineage and thus rendered as a surrogate of tumor tissue on the
with strong metabolism, such as lymphoid and myeloid cell grounds of the same genomic information they carry. In
lines. This phenomenon is termed clonal hematopoiesis late stage lung cancer, plasma ctDNA was found to possess
of indeterminate potential, which increases with age at least one targeted driver mutations, which is similar to
and is the most common interference factor in ctDNA tumor tissue at a concordance of 81.6% and 50.4% in early
detection . The concentration of cfDNA in peripheral stage NSCLC, probably due to low rate of ctDNA positivity
[7]
blood is estimated to be 1 – 100 ng/ml but only 0.1 – 1% in low tumor-burden individuals [12,13] . Second, ctDNA is
of which originates from tumor tissue. The density of capable of capturing intratumor heterogeneity. Due to
ctDNA is even lesser in low tumor-burden individuals, the fact that the cancer cells malignantly proliferate and
such as patients with early stage cancers or patients after release ctDNA into bloodstream, ctDNA is able to show the
the resection surgery [8,9] . The fragment length is another mutation landscape of tumor tissue, especially intratumor
characteristic that differentiate ctDNA from cfDNA of non- subclones, which generally is not captured by the traditional
cancerous origins. The size of cfDNA is around 166 bp, tissue histopathological examination . In a systematic
[14]
and it has been observed that ctDNA is 23 bp shorter than comparative sequencing analysis among Tracking Non-
normal cfDNA in plasma. cfDNA shows strong relation to Small-Cell Lung Cancer Evolution Through Therapy (Rx)
nucleosome and core histones and is conferred protection (TRACERx) cohort conducted by Abbosh et al., intratumor
from endonuclease, while ctDNA presented a more single nucleotide variants (SNVs) were identified in ctDNA
fragmented pattern. However, the underlying reason for in 59% patients with early stage NSCLC . Thirdly, ctDNA
[15]
these differences remains unknown . In patients with enables dynamic monitoring of post-operative residual
[10]
Table 1. Research progress on the application of ctDNA in the treatment process in NSCLC patients
Author/Ref. Year ctDNA assay Number of TNM stage of Early Prognostic Prediction of
patients involved patients detection evaluation therapeutic effect
Cohen et al. [41] 2018 Cancer-SEEK 1850 Pan cancer √
Newman et al. [42] 2014 CAPP-Seq 407 I~IV √
(139 mutated genes)
Chabon et al. [43] 2020 Lung-CLip (255 mutated genes) 160 I~III √ √
Abbosh et al. [15] 2017 WES-PCR (personalized based 100 I~III √ √
on 16 SNVs) First European
cohort
Chaudhuri et al. [56] 2017 CAPP-Seq (128 mutated genes) 40 IB~III √
First North
America cohort
Chen et al. [11] 2019 cSMART (9 genes) 36 I~III √
First East Asian
cohort
Qiu et al. [76] 2021 NGS-panel (139 genes) 91 I~IV √
Nabet et al. [64] 2020 DIRect-On (ctDNA on 94 Unresectable √
treatment and immunotherapy IIIB~IV
response)
Moding et al. [65] 2020 CAPP-Seq (97 mutated genes) 65 Unresectable √
IIB~IIIB

Volume 1 Issue 1 (2022) 3 https://doi.org/10.36922/gtm.v1i1.96