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. 2023 Feb 10;12(4):1438. doi: 10.3390/jcm12041438

Table 3.

The prognostic significance of circulating tumor DNA (ctDNA) detection at different time periods for resectable NSCLC.

References
(Year)		 Sample Stage Detection Methods/Study Design Median Follow-Up Time (Month) Detection Time Clinical Relevance ctDNA Positivity Precedes Radiological Recurrence by a Median Lead Time (Month)
[131]
(2019)		 26 I–III NGS for a 9-gene panel/Pro 532 days for all patients and 629 days for patients who were free from progression

  • ♦ A: immediately before surgery

  • ♦ After tumor resection


B: 5 min; C: 30 min; D: 2 h

  • ♦ P1: 1 day post-surgery

  • ♦ P2: 3 days post-surgery

  • ♦ P3: 1 month post-surgery

  • ✓ Proportion of patients who were ctDNA− positive before surgery: 17.5% (36/205) and 20.3% (36/177)

  • ✓ Plasma ctDNA concentration showed a rapid decreasing trend after radical tumor resection. Median ctDNA half-life was 35.0 min

  • ✓ Patients with positive MRD detection had a significantly slower ctDNA half-life than those with negative MRD detection (103.2 min vs. 29.7 min; p = 0.001)

  • ✓ The RFS of patients with detectable and undetectable ctDNA concentrations at time P1 were 528 days and 543 days, respectively (p = 0.657) while at time P2, they were 278 days and 637 days, respectively (p = 0.002)

 NR
[132]
(2020)		 20 IIA–IIIA NGS for a 197-gene panel/Pro 12

  • ♦ 1–2 days before surgery

  • ♦ 3–12 days after surgery

  • ✓ Proportion of patients who were ctDNA− positive before surgery: 40% (8/20)

  • ✓ 8 patients (40%) were preoperatively positive for ctDNA

  • ✓ 4 patients (20%) were preoperatively positive for ctDNA.

  • ✓ Postoperative positivity for ctDNA also predicted shorter RFS (p = 0.015)

NR
[133]
(2020)		 38 IB–III NGS for a 425-gene panel/Pro 15.8

  • ♦ 1–7 days before surgery

  • ♦ Postoperatively (within 2 weeks)

  • ♦ After chemotherapy

  • ✓ Proportion of patients who were ctDNA− positive before treatment: 50% (19/38)

  • IB: 42.8%; II: 50%; III: 53.3%

  • ✓ ctDNA was detectable in the first postoperative prechemotherapy samples of 8/35 (22.9%) patients and was associated with inferior RFS (9.6 vs. 19.6; HR = 3.69; p = 0.033)

  • ✓ ctDNA was detected in the first post-chemotherapy samples of 8/36 (22.2%) patients and was also associated with inferior RFS (9.6 vs. NR; HR = 8.76; p < 0.001)

 NR
[134]
(2021)		 174 I–III ARMs for EGFR/Pro NA

  • ♦ 1 day before surgery

  • ✓ Proportion of patients with ctDNA EGFR mutations before surgery: 15.5% (27/174)

  • ✓ The overall 5-year survival rates for patients with ctDNA EGFR mutations and those without ctDNA EGFR mutations were 18.5% and 76.9%, respectively.

  • ✓ For patients with ctDNA EGFR mutations, the median OS and DFS were 29.00 ± 2.55 and 19.00 ± 2.50 months, respectively, which were both significantly worse than those of patients without ctDNA EGFR mutations (p < 0.001)

  • ✓ ctDNA EGFR mutations were an independent risk factor of OS (HR = 3.289; 95% CI = 1.816–5.956; p < 0.001) and DFS (HR = 4.860, 95% CI = 2.660–8.880, p < 0.001)

NR
[135]
(2021)		 116 I–IV NGS for a 139-gene panel/Pro NA

  • ♦ Before surgery

  • ♦ 1 month post-surgery

  • ♦ Post-ACT

  • ♦ Longitudinal detection

  • ✓ Proportion of patients who were ctDNA− positive before surgery: 69.3% (61/88)

I/II: 61.0% (25/41); III: 76.1% (35/46)
Proportion of patients who were ctDNA-positive after surgery: 21.2% (18/85); after the completion of ACT: 12.5% (8/64)

  • ✓ Both postsurgical (p < 0.001) and post-ACT (p < 0.05) ctDNA positivity were associated with worse recurrence-free survival rates

  • ✓ In stage II-III patients, those who were ctDNA-positive after surgery benefited from ACT (p < 0.05)

 2.93
[136]
(2021)		 77 I–IV cSMART for a 127-gene panel/Pro 46

  • ♦ 1–7 days before surgery

  • ♦ Longitudinal detection

  • ✓ Proportion of patients who were ctDNA-positive before surgery: 59.7% (46/77)

I: 43.9% (18/41); II: 72.2% (13/18); III: 81.3% (13/16); IV:100% (2/2)

  • ✓Proportion of patients who were ctDNA-positive post-surgery: 42.25% (30/71)

I: 29.0% (11/38); II: 41.2% (7/17); III: 71.4% (10/14); IV: 100% (2/2)

  • ✓ Patients with higher stage (III/IV) cancers and preoperative ctDNA-positive status demonstrated significant risks for recurrence and death, (2.8–3.4-fold risk and 3.8–4.0-fold risk, respectively)

  • ✓ Preoperative ctDNA-positive patients were associated with lower RFS (HR = 3.812; p = 0.0005) and OS (HR = 5.004; p = 0.0009)

  • ✓ Postoperative ctDNA-positive patients were also associated with lower RFS (HR = 3.076; p= 0.0015) and OS (HR = 3.195; p = 0.0053)

  • ✓ Disease recurrence occurred in 63.3% (19/30) of postoperative ctDNA-positive patients

12.6
[137]
(2021)		 119 I–IIIA NGS for a 425-gene panel/Pro 30.7

  • ♦ 1 week before surgery

  • ♦ 1 month after surgery

  • ♦ Longitudinal detection

  • ✓ Preoperative ctDNA was detectable in 29/117 patients (24.8%) and was associated with inferior RFS (HR = 2.42; 95% CI = 1.11–5.27; p = 0.022) and inferior OS (HR = 5.54; 95% CI = 1.01–30.35; p = 0.026)

  • ✓ ctDNA was detected in 12/116of the first postsurgical samples (10.3%) and was associated with shorter RFS (HR = 3.04; 95% CI = 1.22–7.58; p = 0.012)

  • ✓ Longitudinal ctDNA-positive patients (37/119; 31.1%) had shorter RFS (HR, 3.46; 95% CI, 1.59–7.55; p < 0.001) and shorter OS (HR = 9.99; 95% CI = 1.17–85.78; p = 0.010) in comparison to longitudinal ctDNA-negative patients

 8.71
[138]
(2022)		 21 IA–IIIB NGS for an18-gene panel/Pro 26.2

  • ♦ Before surgery

  • ♦ During surgery

  • ♦ 1–2 weeks post-surgery

  • ♦ Longitudinal detection

  • ✓ Proportion of patients who were ctDNA-positive before surgery: 57% (12/21)

  • ✓ ctDNA detection rates and ctDNA concentrations were significantly higher in plasma obtained during surgery compared to preoperative specimens (57% vs. 19%; 12.47 ng/mL vs. 6.64 ng/mL)

  • ✓ Positive ctDNA detection in early postoperative plasma samples was associated with shorter RFS (p = 0.013) and OS (p = 0.004)

 10.31
[139]
(2022)		 330 I–III NGS for a 769-gene panel/Pro 35.6

  • ♦ 1 week before surgery

  • ♦ 3 days after surgery

  • ♦ 1 month after surgery

  • ✓ Preoperative ctDNA positivity was associated with lower RFS (HR = 4.2; p < 0.001)

  • ✓ The presence of MRD (ctDNA positivity at 3 days and/or 1 month post-surgery) was a strong predictor for disease relapse (HR = 11.1; p < 0.001)

  • ✓ MRD-positive patients who received adjuvant therapies had improved RFS compared to those who did not receive adjuvant therapy (HR = 0.3; p = 0.008), whereas MRD-negative patients who received adjuvant therapies had lower RFS compared to those who did not receive adjuvant therapy (HR = 3.1; p < 0.001)

NR
[140]
(2022)		 88 IA–IIIB RaDaRTMNGS 36

  • ♦ Before treatment

  • ♦ During treatment

  • ♦ After the end of treatment

  • ♦ Longitudinal detection

  • ♦ Treatment:

surgery (n = 61);
surgery + adjuvant chemotherapy/radiotherapy (n = 8);
chemoradiotherapy (n = 19)

  • ✓ Proportion of patients who were ctDNA− positive before treatment: 51% (40/78)

  • I: 24% (10/41); II: 77% (17/22); III: 87% (13/15)

  • ✓ ctDNA was detected after treatment in 18/28 (64.3%) of patients who demonstrated a clinical recurrence of their primary tumor

  • ✓ Detection within the landmark timepoint of 2 weeks 4 months after the end of treatment occurred in 17% of patients and was associated with shorter RFS (HR = 14.8, p < 0.00001) and OS (HR = 5.48, p < 0.0003)

  • ✓ ctDNA was detected 1–3 days after surgery in 25% of patients and was not associated with disease recurrence

  • ✓ Preoperative detection was associated with shorter OS (HR = 2.97; p = 0.01) and RFS (HR = 3.14, p = 0.003)

 7.08