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Global Translational Medicine ctDNA in management of patients with NSCLC

70 days . CAPP-Seq targeting 128 frequent genes in lung had statistically similar overall survival rate as ctDNA-
[15]
cancer was applied to detect ctDNA in NSCLC patients in negative group after initial therapy, which may change the
the study conducted in North America. The ctDNA levels therapy schedule in MRD-positive patients. Moreover, the
in 20 patients showed no reduction after surgery in at least growth rate was found stable after the surgery for a long
one post-operative timepoint and the patients experienced time; with only two timepoint of ctDNA examination, the
relapse without exception . The cohorts in Europe and ctDNA growth velocity can be determined, which can be
[56]
North America all exhibited close relationship between MRD used to predict relapse . This research supports ctDNA as
[59]
and relapse risk. Similar result was first reported in a study a biomarker of prognosis, but unfortunately no study has
of East Asian cohort and the study further illustrated the been performed to evaluate its application in lung cancer.
significant difference of recurrence-free survival in patients
who were either ctDNA-positive or ctDNA-negative at 3 days 4. Treatment selection and response
after resection surgery, thereby setting a precise timepoint of evaluation
MRD detection to predict long-term relapse. About 85.7% Patients with locally advanced lung cancer are barely subject
(6 / 7) of MRD-positive patients experienced recurrence and to resection surgery, but they receive adjuvant therapy to
MRD was 165 days earlier than clinical recurrence verified alleviate tumor burden. Certain people who are eligible
[11]
by post-operative CT . for targeted therapies or immunotherapies survive longer
[60]
ctDNA concentration in plasma is quite low after according to NCCN guidelines . Adjuvant therapy can
routine therapy. VAF of ctDNA after the surgery is <0.1% effectively improve the prognosis after the whole process of
in plasma, which is lower than the detection threshold of therapy, but each therapy is a double-edged sword. Misuse
most detection methods . Multi-omics are undoubtedly or overdose will bring about severe side effects and induce
[15]
considered an improvement to the detection sensitivity. drug resistance. A growing line of evidence points out
Chen et al. constructed an MRD prediction model based on that post-operative ctDNA acts as a reliable biomarker for
the combination of mutation score and regional methylation treatment selection and prognostic evaluation .
[61]
ratio. Sixty-seven genetic variants were selected after filtration In part of the data from DYNAMIC and TRACERx,
of clonal hematopoiesis with allele frequencies ranging from it is suggested that the curative effect of adjuvant therapy
0.03% to 6.00% and then a mutation score was constructed is associated with ctDNA level [11,15] . The therapeutic effect
by a weighted sum of the allele fractions. Three hundred and prediction ability of ctDNA has shown in patients receiving
fifteen DMRs were identified and fed into penalized Cox targeted therapy and immunotherapy. ENSURE study
regression analysis to obtain a 12 DMR-featured methylation- revealed that epidermal growth factor receptor (EGFR)
based prognostic score (MPS). Mutation score and MPS mutation-positive NSCLC patients taking erlotinib had
were used together to construct a bi-omics prognosis score to longer progression-free survival compared with patients
distinguish the high recurrence group who had worse overall receiving chemotherapy, and this result contributed to
[57]
survival . Another model called MRDetect used WGS FDA’s recognition of EGFR mutation as the first mutation
and tumor-informed methods to detect ctDNA at a lower employed in liquid biopsy test to guide the selection of EGFR
threshold. MRDetect-SNV and MRDetect-CNV, which TKI . Consequently, the benefit of osimertinib was found
[62]
focus on different characters of ctDNA mutation, reached in patients with EGFR Thr790Met-positive NSCLC, who
the detection limit of tumor fraction at 10 and 5 × 10 , reported 70% of objective response with toxicity effects of
-3
-5
respectively. Integrating these two MRDetect methods based <5% . The therapeutic effect prediction ability of MRD was
[63]
on various features of ctDNA, the model achieved high further demonstrated in patients receiving immunotherapy.
clinical specificity of 96%, while maintaining high sensitivity Immune checkpoint inhibition (ICI), such as PD-(L)1
[58]
of 67% in lung adenocarcinoma detection . blockade, showed high clinical response rate accompanied
More characters of MRD are being conceived for more by equivalent high level of toxic reaction in the treatment of
accurate and detailed depiction of relapse. Apart from the advanced NSCLC. However, only a minority of the patients
existence of MRD, ctDNA growth rate is another strong obtained long-term benefit from ICI. To identify the patients
prognostic factor and can describe biological behavior of who obtained long-term benefit before or at the beginning
residue tumor cells. In post-operative patients with Stage of the therapy, pre-treatment peripheral T cell level and early
III colorectal cancer, the increasing ctDNA growth rate was on-treatment reaction of ctDNA were investigated and found
bimodal, categorized into fast-growth pattern and slow- to be associated with checkpoint blockade response, which
growth pattern, in which ctDNA concentration increased served as ideal biomarkers. DIREct-On model combined
by 143% and 25% per month. Further survival analysis with pre-treatment ctDNA, immune profiling, and early
showed striking result that slow-growth pattern group on-treatment ctDNA information can robustly predict the

Volume 1 Issue 1 (2022) 8 https://doi.org/10.36922/gtm.v1i1.96