Evolving landscape of biomarkers in colorectal cancer: From interleukin-8 to integrated multi-marker strategies

Table 1 Key clinical trials and studies evaluating circulating biomarkers in colorectal cancer

Biomarker	Study/trial	Population	Key findings	Level of evidence	Ref.
ctDNA (MRD detection)	DYNAMIC-III	Stage III colon cancer (n = 1002)	ctDNA-guided de-escalation reduced oxaliplatin exposure (88.6% → 34.8%) without compromising 3-year RFS in low-risk patients; non-inferiority not formally met	Phase II/III randomized	[45,46]
	TRACC Part B	Stage I-III CRC (n = 214 evaluable)	Tissue-free MRD detection; 2-year RFS 91.1% (ctDNA-) vs 50.4% (ctDNA+); HR 6.5; lead time 73 months	Prospective cohort	[44]
	Faulkner meta-analysis	37 studies (n = 3002)	Postoperative ctDNA positivity strongly associated with poorer PFS (HR 6.92; 95%CI 4.49-10.64)	Meta-analysis	[42]
	Barault et al[47]	mCRC (n = 182)	Five-gene methylation panel (EYA4, GRIA4, ITGA4, MAP3K14-AS1, MSC) detected in 85.7%; dynamics correlated with response and PFS	Prospective cohort	[47]
Methylation markers	Wang et al[48] MethylDT	Multicenter (n = 1194)	NTMT1/MAP3K14-AS1 methylation: Sensitivity 91.2% for CRC, 87.4% for stage I-II; specificity 92.4%	Multicenter validation	[48]
Protein markers	Duan et al[49]	Discovery (n = 72) + validation (n = 191)	SETD7 identified by proteomics; sensitivity 92.2%, specificity 81.1%, AUC 0.947; correlated with stage and MSI	Case-control + functional	[49]
IL-8 (prognostic)	Meta-analysis	Multiple studies	High IL-8 levels significantly correlated with shorter OS and PFS; effect stronger for circulating than tissue IL-8	Meta-analysis	[15]
	Meta-analysis	Multiple studies	Pooled diagnostic accuracy: AUC 0.92, sensitivity 70%, specificity 91%	Meta-analysis	[20]
	Björkman et al[31]	328 CRC patients	IL-8 was the only significant univariate prognostic factor after FDR correction (HR = 4.88); machine learning identified IL-8 and IL-2Ra for multivariate model	Prospective cohort	[31]
	Park et al[55]	400 CRC patients	IL-8 and LMR were independent prognostic factors for PFS and OS; composite classification enhanced prognostic value	Prospective cohort	[55]
IL-8 (Predictive)	Suenaga et al[58]	mCRC on bevacizumab/regorafenib (n = 125)	High IL-8 associated with liver metastasis and shorter OS (HR = 4.31)	Pooled analysis	[58]
	Sanmamed et al[59]	Melanoma/NSCLC on anti-PD-1	Changes in serum IL-8 reflected and predicted response to immunotherapy	Prospective cohort	[59]
IL-8 (Genetic)	Lurje et al[57]	Stage III colon cancer (n = 125)	IL-8 T-251A polymorphism predicted tumor recurrence; combined with VEGF C+936T identified highest risk group	Retrospective cohort	[57]
CEA	Beom et al[27]	Discovery (n = 2021) + validation (n = 171)	High-normal CEA (2.1-5.0 ng/mL) independently prognostic; optimal cutoff 2.1 ng/mL; influenced by smoking and tumor location	Retrospective + prospective validation	[27]
MMR	ATOMIC	Stage III dMMR colon cancer (n = 700)	mFOLFOX + atezolizumab improved DFS vs mFOLFOX alone	Phase III RCT	[26]
	NICHE-2	Locally advanced dMMR colon cancer (n = 112)	Neoadjuvant nivolumab + ipilimumab → pCR > 65%, excellent 3-year DFS	Phase II	[25]
KRAS + laterality	Kamphues et al[28]	International retrospective, n = 1093 resected non-metastatic CRC	KRAS mutation prognostic only in left-sided tumors; not in right-sided or rectal	Retrospective cohort	[28]
	Tran et al[32]	NCDB analysis, n = 5292 stage I-III colon cancer	Interaction between KRAS and laterality: In mutant KRAS, left-sided worse OS; in wild-type, left-sided better OS	Retrospective cohort	[32]
HER2	HERACLES	KRAS wild-type, HER2-positive mCRC (n = 27)	Trastuzumab + lapatinib active in HER2-positive mCRC	Phase II	[33]
NTRK	Drilon et al[37]	NTRK fusion-positive cancers (n = 55, including CRC)	Larotrectinib demonstrated high response rates across tumor types	Phase I/II	[37]

ctDNA: Circulating tumor DNA; MRD: Minimal residual disease; CRC: Colorectal cancer; mCRC: Metastatic colorectal cancer; RFS: Recurrence-free survival; HR: Hazard ratio; CI: Confidence interval; PFS: Progression-free survival; OS: Overall survival; AUC: Area under the curve; MSI: Microsatellite instability; FDR: False discovery rate; IL-2Ra: Interleukin-2 receptor alpha; LMR: Lymphocyte-to-monocyte ratio; CEA: Carcinoembryonic antigen; MMR: Mismatch repair; dMMR: Deficient mismatch repair; pCR: Pathological complete response; DFS: Disease-free survival; RCT: Randomized controlled trial; NCDB: National Cancer Database; HER2: Human epidermal growth factor receptor 2; NTRK: Neurotrophic tyrosine receptor kinase; IL-8: Interleukin-8; VEGF: Vascular endothelial growth factor; NSCLC: Non-small cell lung cancer; PD-1: Programmed cell death protein 1; SETD7: SET domain containing 7; KO: Knockout; mFOLFOX: Folinic acid, fluorouracil, and oxaliplatin; NTMT1: Pro-Lys N-methyltransferase 1; MAP3K14-AS1: MAP3K14 antisense RNA 1.