Table 1.

ctDNA as a biomarker of MRD, therapeutic efficacy, and surveillance in CRC patients. Studies of plasma ctDNA in CRC and their main findings are shown. The number of patients included in each study is indicated (n). PFS, progression-free survival; OS, overall survival; CT, computed tomography.

Study	Tumor Type and Stage	Findings
Tie et al. [21]	Colon cancer Stage II (n = 230)	Patients ctDNA positive after curative intent surgery are at high risk of recurrence (HR, 28). Patients ctDNA positive at completion of adjuvant chemotherapy are at high risk of recurrence (HR,11; p ≤ 0.001).
Tie et al. [123]	Colon cancer Stage III (n= 96)	Patients ctDNA positive after surgery have poor outcomes despite adjuvant chemotherapy (3 years RFI 47% vs. 76% in those with ctDNA negative post-surgery) (HR, 3.8; p <0.001). When ctDNA is detectable despite adjuvant chemotherapy, the risk of recurrence is higher than when ctDNA is undetectable after treatment (HR, 6.8; p <0.001).
Tie et al. [125]	Rectal cancer Locally advanced (n = 159)	After surgery, 11 of 19 (58%) patients with ctDNA positive and 12 of 140 (8.6%) with ctDNA negative had recurrence (HR, 13; p < 0.001). Postoperative ctDNA detection was predictive of recurrence irrespective of adjuvant chemotherapy use (with chemo.: HR,10.0; p < 0.001; without chemo.: HR, 22.0; p < 0.001).
Tie et al. [126]	CRC Stage II–III	Meta-analysis; Studies from references: 21, 109, and 111 (n = 485).
Reinert et al. [91]	CRC Stage I–III (n = 130)	ctDNA positive patients at day 30 postoperatively were 7 times more likely to have recurrence compared to ctDNA negative patients (HR, 7.2; p < 0.001). ctDNA positive patients shortly after completion of chemotherapy had 17 times higher risk of recurrence compared with ctDNA negative ones (HR, 17.5; p < 0.001). During surveillance, ctDNA positive patients were more than 40 times more likely to have recurrence than ctDNA negative patients (HR, 43.5; p < 0.001).
Tarazona et al. [23]	Colon cancer Stage I–III (n = 150)	Detection of ctDNA after surgery and in plasma samples during follow up were associated with poorer disease-free survival (HR, 17.56; p= 0.0014 and HR, 11.33; p = 0.0001, respectively). ctDNA positive patients after adjuvant chemotherapy were at high risk of recurrence compared with ctDNA negative ones (HR, 10.02; p < 0.0001).
Scholer at al. [128]	CRC Stages I–IV (n = 45)	Patients with localized disease (Stages I-III) treated with curative intent and who were ctDNA positive within the first postoperative trimester had a high risk (100%) of relapse (HR, 37.7; p < 0.001); patients who were ctDNA negative were at a low risk of relapse (3-year RFS of 75%). Stage IV patients with liver metastasis treated with curative intent who were ctDNA positive within the first postoperative trimester were at high risk of relapse (HR, 4.9; p = 0.007).
Wang et al. [129]	CRC Stage I–III (n = 58)	Patients ctDNA positive postoperatively had 77% (10 of 13 patients) recurrence versus 0% (0 of 45 patients) with negative ctDNA. Patients who remained ctDNA negative through follow up had no relapse. Patients with ctDNA positive postoperatively could still be cured by chemotherapy.
Garlan et al. [132]	CRC Stage IV (n = 82)	Early change in ctDNA level (after cycle 1 or 2) was a marker of therapeutic efficacy in mCRC treated with first- or second line chemotherapy alone or in combination with targeted therapy.
Tie et al. [37]	CRC IV Chem. naive (n = 53)	Significant reduction in ctDNA (median 5.7-fold; p < 0.001) levels were observed before cycle 2 during first-line chemotherapy, which correlated with CT responses at 8–10 weeks. Major reductions (>10-fold) versus lesser reduction in ctDNA pre-cycle 2 chemotherapy were associated with a trend for increased PFS (median 14.7 versus 8.1 months).