Progression in circulating tumor DNA detection for minimal residual disease in patients with colorectal cancer liver metastasis

doi:10.16139/j.1007-9610.2025.04.10

Abstract

Abstract:

As a non-invasive biomarker, circulating tumor DNA (ctDNA) can sensitively identify minimal residual disease (MRD), offering a novel approach for prognosis prediction and efficacy evaluation in patients with colorectal cancer liver metastasis (CRLM), thereby aiding in the formulation of personalized treatment strategies. This article summarized the progress in the application of ctDNA detection for MRD in CRLM and provided insights into its future directions.

Key words: Colorectal cancer liver metastasis(CRLM), Circulating tumor DNA(ctDNA), Minimal residual disease(MRD), Prognostic prediction, Efficacy evaluation

CLC Number:

LI Yaqi, MO Shaobo, PENG Junjie. Progression in circulating tumor DNA detection for minimal residual disease in patients with colorectal cancer liver metastasis[J]. Journal of Surgery Concepts & Practice, 2025, 30(04): 351-357.

Figures/Tables 1

References 49

[1]	SIEGEL R L, GIAQUINTO A N, JEMAL A. Cancer statistics,2024[J]. CA Cancer J Clin, 2024, 74(1):12-49.
[2]	HAN B, ZHENG R, ZENG H, et al. Cancer incidence and mortality in China, 2022[J]. J Natl Cancer Cent, 2024, 4(1):47-53.
[3]	ABDALLA E K, VAUTHEY J N, ELLIS L M, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases[J]. Ann Surg, 2004, 239(6):818-825. doi: 10.1097/01.sla.0000128305.90650.71 pmid: 15166961
[4]	DEVAUD N, KANJI Z S, DHANI N, et al. Liver resection after chemotherapy and tumour downsizing in patients with initially unresectable colorectal cancer liver metastases[J]. HPB (Oxford), 2014, 16(5):475-480.
[5]	LEAL J N, BRESSAN A K, VACHHARAJANI N, et al. Time-to-surgery and survival outcomes in resectable colorectal liver metastases: a multi-institutional evaluation[J]. J Am Coll Surg, 2016, 222(5):766-779.
[6]	MARGONIS G A, SERGENTANIS T N, NTANASIS-STATHOPOULOS I, et al. Impact of surgical margin width on recurrence and overall survival following R0 hepatic resection of colorectal metastases: a systematic review and meta-analysis[J]. Ann Surg, 2018, 267(6):1047-1055. doi: 10.1097/SLA.0000000000002552 pmid: 29189379
[7]	MAHURON K M, FONG Y. Applications of liquid bio-psy for surgical patients with cancer: a review[J]. JAMA Surg, 2024, 159(1):96-103.
[8]	LOFT M, TO Y H, GIBBS P, et al. Clinical application of circulating tumour DNA in colorectal cancer[J]. Lancet Gastroenterol Hepatol, 2023, 8(9):837-852.
[9]	MALLA M, LOREE J M, KASI P M, et al. Using circula-ting tumor DNA in colorectal cancer: current and evolving practices[J]. J Clin Oncol, 2022, 40(24):2846-2857.
[10]	SATO R, SEMBA T, SAYA H, et al. Concise review: stem cells and epithelial-mesenchymal transition in cancer: biological implications and therapeutic targets[J]. Stem Cells, 2016, 34(8):1997-2007. doi: 10.1002/stem.2406 pmid: 27251010
[11]	RING A, NGUYEN-STRÄULI B D, WICKI A, et al. Bio-logy, vulnerabilities and clinical applications of circulating tumour cells[J]. Nat Rev Cancer, 2023, 23(2):95-111.
[12]	MASHOURI L, YOUSEFI H, AREF A R, et al. Exosomes: composition, biogenesis, and mechanisms in cancer metastasis and drug resistance[J]. Mol Cancer, 2019, 18(1):75. doi: 10.1186/s12943-019-0991-5 pmid: 30940145
[13]	ZHANG L, YU D. Exosomes in cancer development, metastasis, and immunity[J]. Biochim Biophys Acta Rev Cancer, 2019, 1871(2):455-468.
[14]	WU J, HU S, ZHANG L, et al. Tumor circulome in the liquid biopsies for cancer diagnosis and prognosis[J]. Theranostics, 2020, 10(10):4544-4556. doi: 10.7150/thno.40532 pmid: 32292514
[15]	HENRIKSEN T V, DRUE S O, FRYDENDAHL A, et al. Error characterization and statistical modeling improves circulating tumor DNA detection by droplet digital PCR[J]. Clin Chem, 2022, 68(5):657-667. doi: 10.1093/clinchem/hvab274 pmid: 35030248
[16]	O'LEARY B, HREBIEN S, BEANEY M, et al. Comparison of BEAMing and droplet digital PCR for circulating tumor DNA analysis[J]. Clin Chem, 2019, 65(11):1405-1413. doi: 10.1373/clinchem.2019.305805 pmid: 31551314
[17]	NIKANJAM M, KATO S, KURZROCK R. Liquid biopsy: current technology and clinical applications[J]. J Hematol Oncol, 2022, 15(1):131.
[18]	NAJAFI S, MAJIDPOOR J, MORTEZAEE K. Liquid bio-psy in colorectal cancer[J]. Clin Chim Acta, 2024,553:117674.
[19]	TORRESAN S, DE SCORDILLI M, BORTOLOT M, et al. Liquid biopsy in colorectal cancer: onward and upward[J]. Crit Rev Oncol Hematol, 2024,194:104242.
[20]	LUO H, WEI W, YE Z, et al. Liquid biopsy of methylation biomarkers in cell-free DNA[J]. Trends Mol Med, 2021, 27(5):482-500. doi: 10.1016/j.molmed.2020.12.011 pmid: 33500194
[21]	NASSAR F J, MSHEIK Z S, NASR R R, et al. Methy-lated circulating tumor DNA as a biomarker for colorectal cancer diagnosis,prognosis, and prediction[J]. Clin Epigenetics, 2021, 13(1):111.
[22]	JIN S, ZHU D, SHAO F, et al. Efficient detection and post-surgical monitoring of colon cancer with a multi-marker DNA methylation liquid biopsy[J]. Proc Natl Acad Sci U S A, 2021, 118(5):e2017421118.
[23]	LUO H, ZHAO Q, WEI W, et al. Circulating tumor DNA methylation profiles enable early diagnosis, prognosis prediction, and screening for colorectal cancer[J]. Sci Transl Med, 2020, 12(524):eaax7533.
[24]	MO S, DAI W, WANG H, et al. Early detection and prognosis prediction for colorectal cancer by circulating tumour DNA methylation haplotypes: a multicentre cohort study[J]. E Clin Med, 2022,55:101717.
[25]	MO S, YE L, WANG D, et al. Early detection of molecular residual disease and risk stratification for stage Ⅰ to Ⅲ colorectal cancer via circulating tumor DNA methylation[J]. JAMA Oncol, 2023, 9(6):770-778.
[26]	DAWOOD Z S, ALAIMO L, LIMA H A, et al. Circulating tumor DNA, imaging, and carcinoembryonic antigen: comparison of surveillance strategies among patients who underwent resection of colorectal cancer-a systematic review and meta-analysis[J]. Ann Surg Oncol, 2023, 30(1):259-274. doi: 10.1245/s10434-022-12641-7 pmid: 36219278
[27]	KOTANI D, OKI E, NAKAMURA Y, et al. Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer[J]. Nat Med, 2023, 29(1):127-134. doi: 10.1038/s41591-022-02115-4 pmid: 36646802
[28]	REINERT T, HENRIKSEN T V, CHRISTENSEN E, et al. Analysis of plasma cell-free DNA by ultradeep sequencing in patients with stages Ⅰ to Ⅲ colorectal cancer[J]. JAMA Oncol, 2019, 5(8):1124-1131.
[29]	TIE J, WANG Y, TOMASETTI C, et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage Ⅱ colon cancer[J]. Sci Transl Med, 2016, 8(346):346ra392.
[30]	CHEN G, PENG J, XIAO Q, et al. Postoperative circulating tumor DNA as markers of recurrence risk in stages Ⅱ to Ⅲ colorectal cancer[J]. J Hematol Oncol, 2021, 14(1):80.
[31]	LI Y, MO S, ZHANG L, et al. Postoperative circulating tumor DNA combined with consensus molecular subtypes can better predict outcomes in stage Ⅲ colon cancers: a prospective cohort study[J]. Eur J Cancer, 2022,169:198-209.
[32]	TIE J, COHEN J D, WANG Y, et al. Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: a prospective biomarker study[J]. Gut, 2019, 68(4):663-671. doi: 10.1136/gutjnl-2017-315852 pmid: 29420226
[33]	TIE J, COHEN J D, WANG Y, et al. Circulating tumor DNA analyses as markers of recurrence risk and benefit of adjuvant therapy for stage Ⅲ colon cancer[J]. JAMA Oncol, 2019, 5(12):1710-1717.
[34]	NAKAMURA Y, WATANABE J, AKAZAWA N, et al. ctDNA-based molecular residual disease and survival in resectable colorectal cancer[J]. Nat Med, 2024, 30(11):3272-3283. doi: 10.1038/s41591-024-03254-6 pmid: 39284954
[35]	TIE J, COHEN J D, LAHOUEL K, et al. Circulating tumor DNA analysis guiding adjuvant therapy in stage Ⅱ colon cancer[J]. N Engl J Med, 2022, 386(24):2261-2272.
[36]	TIE J, WANG Y, COHEN J, et al. Circulating tumor DNA dynamics and recurrence risk in patients undergoing curative intent resection of colorectal cancer liver metastases: a prospective cohort study[J]. PLoS Med, 2021, 18(5):e1003620.
[37]	WANG D S, YANG H, LIU X Y, et al. Dynamic monitoring of circulating tumor DNA to predict prognosis and efficacy of adjuvant chemotherapy after resection of colorectal liver metastases[J]. Theranostics, 2021, 11(14):7018-7028.
[38]	LI Y, XU J, HU X, et al. Personalized circulating tumor DNA monitoring improves recurrence surveillance and management after curative resection of colorectal liver metastases: a prospective cohort study[J]. Int J Surg, 2024, 110(5):2776-2787. doi: 10.1097/JS9.0000000000001236 pmid: 38445460
[39]	COHEN S A, LIU M C, ALESHIN A. Practical recommendations for using ctDNA in clinical decision making[J]. Nature, 2023, 619(7969):259-268.
[40]	BOLHUIS K, VAN 'T ERVE I, MIJNALS C, et al. Postoperative circulating tumour DNA is associated with pathologic response and recurrence-free survival after resection of colorectal cancer liver metastases[J]. EBioMedicine, 2021,70:103498.
[41]	ØGAARD N, REINERT T, HENRIKSEN T V, et al. Tumour-agnostic circulating tumour DNA analysis for improved recurrence surveillance after resection of colorectal liver metastases: a prospective cohort study[J]. Eur J Cancer, 2022,163:163-176.
[42]	REINERT T, PETERSEN L M S, HENRIKSEN T V, et al. Circulating tumor DNA for prognosis assessment and postoperative management after curative-intent resection of colorectal liver metastases[J]. Int J Cancer, 2022, 150(9):1537-1548. doi: 10.1002/ijc.33924 pmid: 34994972
[43]	KATAOKA K, MORI K, NAKAMURA Y, et al. Survival benefit of adjuvant chemotherapy based on molecular residual disease detection in resected colorectal liver metastases: subgroup analysis from CIRCULATE-Japan GALAXY[J]. Ann Oncol, 2024, 35(11):1015-1025. doi: 10.1016/j.annonc.2024.08.2240 pmid: 39293512
[44]	BANDO H, KAGAWA Y, KATO T, et al. A multicentre, prospective study of plasma circulating tumour DNA test for detecting RAS mutation in patients with metastatic colorectal cancer[J]. Br J Cancer, 2019, 120(10):982-986.
[45]	KAGAWA Y, ELEZ E, GARCÍA-FONCILLAS J, et al. Combined analysis of concordance between liquid and tumor tissue biopsies for RAS mutations in colorectal cancer with a single metastasis site: the METABEAM study[J]. Clin Cancer Res, 2021, 27(9):2515-2522.
[46]	SAIURA A, YAMAMOTO J, KOGA R, et al. Favorable outcome after repeat resection for colorectal liver metastases[J]. Ann Surg Oncol, 2014, 21(13):4293-4299. doi: 10.1245/s10434-014-3863-7 pmid: 24962942
[47]	SALAH S, ARDISSONE F, GONZALEZ M, et al. Pulmonary metastasectomy in colorectal cancer patients with previously resected liver metastasis: pooled analysis[J]. Ann Surg Oncol, 2015, 22(6):1844-1850. doi: 10.1245/s10434-014-4173-9 pmid: 25326396
[48]	OBA M, HASEGAWA K, SHINDOH J, et al. Survival benefit of repeat resection of successive recurrences after the initial hepatic resection for colorectal liver metastases[J]. Surgery, 2016, 159(2):632-640.
[49]	LIU W, LIU J M, WANG K, et al. Recurrent colorectal liver metastasis patients could benefit from repeat hepatic resection[J]. BMC Surg, 2021, 21(1):327.

Technical route	Tumor-informed assay	Tumor-agnostic assay
Panel type	Whole exome or whole genome sequencing + personalized panel /multiple PCR	Non-personalized, fixed panel
Tumor tissue	Required	Not required
Detection genes	16-40 genes	200-500 genes
Detection level	Genomic	Genomic and epigenomic
Initial detection cycle	4-6 weeks	7-10 days
Subsequent detection cycle	7-10 days	7-10 days
Limit of detection	0.02%-0.005%	0.1%-0.05%
Cancer type applicability	Not affected by tumor type, widely applicable to various cancers	Can simultaneously detect multiple cancer types or highly heterogeneous tumors
Main advantages	High sensitivity, high accuracy	Do not require tumor tissue, lower cost
Main disadvantages	Requires tumor tissue sample, longer customization time, higher cost	High false-positive rate