Circulating tumor DNA (ctDNA) in adjuvant therapy of early stage colon cancer: current status and future perspectives

Figures & data

Table 1. Results of trials on ctDNA as a prognostic and predictive marker in early stage colorectal cancer.

Study	Reinert et al. [17]	Tie et al. [20]	Tie et al. [19]	Wang et al. [21]
Disease and stage	Colorectal cancer, st.^a I–III	Colon cancer, st. II	Colon cancer, st. III	Colorectal cancer, st. I-III
Setting	Pre- and postop.^b	Pre- and postop.	Pre- and postop.	Pre- and postop.
Analysis	Multiplex PCR and NGS (HiSeq 2500 system^®^1)	Safe-SeqS^®2	Safe-SeqS^®	Safe-SeqS^®
Number of patients	125	230	96	58
Outcome measure	Measurement of ctDNA, clinical recurrence and recurrence-free survival (RFS)	Measurement of ctDNA, RFS	Measurement of ctDNA and recurrence-free interval (RFI)	Measurement of ctDNA, comparison to CT^c and CEA levels, detection of recurrence

^1,2Illumina Inc, San Diego, CA, USA.

^ast = stage, ^bop = operative, ^cCT = computed tomography.

Figure 1. Recurrence-Free Interval (RFI) in stage III colon cancer patients according to post-operative ctDNA, Kaplan-Meier Estimates (published with permission, Tie et al. JAMA Oncol 2019).

Figure 2. Simplified description of design of the ongoing CIRCULATE-AIO adjuvant trial in localized colon cancer (n ≈ 4800).

Table 2. Ongoing European adjuvant trials in early stage colon cancer evaluating the use of ctDNA.

Name of study and country	CIRCULATE-PRODIGE 70, France	CIRCULATE Germany, Austria, Switzerland	IMPROVE-IT, Denmark	TRACC, United Kingdom	MEDOCC-CrEATE, The Netherlands	Pegasus, Italy, Spain
Disease and stage	Colorectal cancer, stage II	Colorectal cancer, stage II	Colon cancer, stage I-II	Colorectal cancer, high risk stage II or stage III	Colon cancer, low risk stage II	Colon cancer, high risk stage II or stage III
Analysis	ddPCR	Ultra-deep sequencing	NGS and ddPCR	ddPCR	PGDx elio platform®^1	LUNAR1®^2
Treatment	ctDNA-positive after surgery. Arm A: FOLFOX Arm B: Observation	Positive ctDNA: Cape or follow-up. Negative ctDNA: Follow-up	ctDNA-positive after surgery. Arm A: CapOx or FOLFOX Arm B: Intensified follow-up	ctDNA-positive before surgery. Arm A: SOC ACT. Arm B: Negative ctDNA: 3 months of Cape or no chemotherapy.	Arm A: Positive ctDNA: CapOx Negative ctDNA: Follow-up Arm B: Follow-up	Positive ctDNA: CapOx 3 months Negative ctDNA: Cape 6 months. Thereafter tailored treatment according to retesting of ctDNA.
Recruitment target	1980	4812	64	1000	1320	140
Phase	III	III	II	III	III	II
Status	Not yet recruiting	Recruiting	Recruiting	Recruiting	Recruiting	Recruiting

¹Personal Genome Diagnostics Inc, Baltimore, MD, USA.

²Guardant Health Inc, Redwood City, CA, USA.

Figure 3. Simplified description of design of the proposed CIRCULATE 3-EUROPE adjuvant trial in early stage colon cancer (n = 2046).

Table 3. Ongoing non-European adjuvant trials in early stage colon cancer evaluating the use of ctDNA.

Name of study and country	DYNAMIC II Australia, New Zealand	DYNAMIC III Australia, New Zealand	COBRA United States	CIRCULATE-Japan, VEGA Japan
Disease and stage	Colorectal cancer, stage II	Colorectal cancer, stage III	Colon cancer, stage IIA	Colon cancer, stage II high risk and stage III low risk, ctDNA negative
Analysis	Safe-SeqS^®^3	Safe-SeqS^®	LUNAR^®^4	Signatera^®^5
Treatment	Arm A: Positive ctDNA: ACT. Negative ctDNA: No chemotherapy. Arm B: Treatment at oncologist’s discretion: 3–6 months 5-FU or Cape +/− Oxaliplatin	Arm A: Treatment at oncologist’s discretion. Arm B: ctDNA-informed arm. De-escalation or escalation of chemotherapy based on clinician’s choice of regimen before randomization.	Arm A: Active surveillance Arm B: Positive ctDNA: FOLFOX. Negative ctDNA: Active surveillance	Arm A: No chemotherapy Arm B: CapOx 3 months
Recruitment target	450	1000	1408	1240
Phase	II	II	III	III
Status	Completed	Recruiting	Recruiting	Recruiting

³Illumina Inc, San Diego, CA, USA.

⁴Guardant Health Inc, Redwood City, CA, USA.

⁵Natera Inc, San Carlos, CA, USA.

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