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. 2022 Jun 23;14(13):3078. doi: 10.3390/cancers14133078

Table 2.

Selected studies supporting the value of circulating tumor DNA (ctDNA) for minimal residual disease assessment and surveillance in patients with resected CRC.

Study Patient Population n ctDNA Assay ctDNA Testing Time Points Major Findings Comments
Tie et al.,
2016 [55]		 Stage II CC 230 Safe-SeqS 4–10 weeks post-op and every 3 months for 2 years Cohort not receiving ACT
If ctDNA-+ve post-op: HR for cancer recurrence—18 (95% CI, 7.9 to 40).
Cohort receiving ACT
If ctDNA-+ve post-ACT: HR for recurrence—11 (95% CI, 1.8 to 68).		 ctDNA detection preceded radiologic recurrence by a median of 5.5 months.
Reinert et al.,
2019 [29]		 Stages I to III CRC 130 Signatera Preop, post-op day 30, and every 3 months for up to 3 years. HR for cancer recurrence with positive ctDNA:
  • ₋

    Post-op day 30: 7.2 (95% CI, 2.7–19.0)

  • ₋

    Shortly after completion of ACT: 17.5 (95% CI, 5.4–56.5).

  • ₋

    Serial monitoring post-ACT: 43.5 (95% CI, 9.8–193.5).

 Serial ctDNA analyses revealed disease recurrence up to 16.5 months ahead of radiologic imaging (mean, 8.7 months; range, 0.8–16.5 months).
Tie et al.,
2019 [32]		 Stage III CC 96 Safe-SeqS 4–10 weeks post-op and within 6 weeks of ACT completion HR for cancer recurrence with positive ctDNA:
  • ₋

    Post-op: 7.5 on multivariable analysis (95% CI, 3.5–16.1).

  • ₋

    Shortly after ACT: 6.8 (95% CI, 11.0–157.0).

 RFS at 3 years in patients who are ctDNA-positive vs. -negative: post-op 47% vs. 76%, post-ACT 30% vs. 77%.
Tarazona et al., 2019 [30] Stages I to III CC 150 Tumor-informed ddPCR Preop, 6–8 weeks post-op and every 4 months up to 5 years. HR for recurrence with positive ctDNA:
  • ₋

    Post-op (multivariable adjustment): 11.6 (95% CI, 3.6–36.8).

  • ₋

    Post-ACT: 10.02 (95% CI, 9.2–307.3).

 ctDNA detection during surveillance preceded radiological recurrence by a median of 11.5 months.
Henriksen et al., 2022 [27] Stage III CRC 168 Signatera 2–4 weeks post-op and every 3 months thereafter Detection of ctDNA was a strong recurrence predictor post-o (HR = 7.0; 95% CI, 3.7–13.5) and immediately after ACT (HR = 50.76; 95% CI, 15.4–167). ctDNA detected recurrence with a median lead-time of 9.8 months compared with radiologic studies.
Parikh et al.,
2021 [28]		 Stages I–IV CRC 103 Tumor-uninformed
assay (REVEAL)		 Post-op, post-ACT, and longitudinally in some patients HR for recurrence when +ve for ctDNA post definitive therapy and with >1 year of follow-up: 11.28. Integrating epigenomic signatures increased sensitivity by 25–36% versus genomic alterations alone.
Tie et al.,
2019 [33]		 Locally advanced rectal carcinoma 159 Safe-SeqS Pretreatment, post CRT, and 4–10 weeks after surgery. Significantly worse RFS if ctDNA was detectable after CRT (HR, 6.6; p < 0.001) or after surgery (HR, 13.0; p < 0.001). The estimated 3-year RFS was 33% for the post-op ctDNA-positive patients and 87% for the post-op ctDNA-negative patients.
McDuff et al.,
2021 [59]		 Locally advanced rectal carcinoma 29 ddPCR Baseline, preop, and post-op At a median follow-up of 20 months, patients with detectable post-op ctDNA experienced poorer RFS (HR, 11.56; p = 0.007). All patients (4 of 4) with detectable post-op ctDNA recurred, whereas only 2 of 15 patients with undetectable ctDNA recurred (negative predictive value = 87%).
Tie et al.,
2021 [60]		 CRC with liver metastasis 54 Safe-SeqS Preop and post-op samples, serial samples during pre- or post-op chemotherapy, and follow-up Detectable post-op ctDNA predicted a significantly lower RFS (HR, 6.3; 95% CI, 2.58 to 15.2; p < 0.001) and OS (HR, 4.2; 95% CI, 1.5 to 11.8; p < 0.001) End-of-treatment (surgery +/− ACT) ctDNA detection was associated with a 5-year RFS of 0% compared to 75.6% for patients with an undetectable end-of-treatment ctDNA (HR, 14.9; 95% CI, 4.94 to 44.7; p < 0.001).
Loupakis et al.,
2021 [61]		 CRC undergoing liver resection 112 Signatera Post-op, at the time of radiologic relapse or last follow-up. ctDNA-positive status was also associated with an inferior overall survival: HR: 16.0; 95% CI, 3.9 to 68.0; p < 0.001. ctDNA was detectable in the post-op sample in 54.4% (61 of 112) of patients, of which 96.7% (59 of 61) progressed at the time of data cutoff (HR: 5.8; 95% CI, 3.5 to 9.7; p < 0.001).
Kotaka et al., 2022
(Galaxy study) [62]		 Stages I–IV CRC patients 1365 Signatera Before surgery, 1-month post-op and every 3 months thereafter for 2 years Six-month DFS rate was significantly higher in patients whose ctDNA was converted with ACT compared to patients who remained positive after ACT with an HR of 52.3 (95% CI: 7.2–380.5; p < 0.001), after a median follow-up of 6.6 months. Cumulative incidence of ctDNA clearance was significantly higher with ACT vs. non-ACT (67% vs. 7% by 24 weeks; cumulative HR = 17.1; 95% CI: 6.7–43.4, p < 0.001).
Tie et al., 2022
(DYNAMIC) [63]		 Stage II CC 455 SafeSeqS 4 and 7 weeks post-surgery Adjuvant therapy guided by ctDNA resulted in chemotherapy administration in lower proportion of patients without any detriment to 2-year RFS. DYNAMIC is the first reported prospective randomized study supporting the ctDNA-guided adjuvant therapy approach in stage II colon cancer.

Abbreviations: CC, colon cancer; n, number of patients; Preop, preoperative; Post-op, postoperative; Post-ACT, after adjuvant chemotherapy; ctDNA, circulating tumor DNA; Safe-SeqS, safe sequencing system; HR, hazard ratio; CI, confidence interval; MRD, minimal residual disease; CRC, colorectal cancer; RFS, relapse-free survival; ddPCR, digital droplet polymerase chain reaction; NGS, next-generation sequencing; CRT, chemoradiotherapy; DFS, disease-free survival.