Rethinking carcinoembryonic antigen and carbohydrate antigen 19-9 in gastric cancer surveillance: From statistical association to clinical utility

Table 1 Summary of key methodological concerns and recommended improvements

Methodological issue	Concern in Qi and Wu’s study[8]	Recommended approach
Selection bias	Only patients completing 6 cycles with good compliance were included	Intention-to-treat analysis; sensitivity analyses including non-completers
Temporal ambiguity	Biomarkers measured 1-3 months postoperatively; recurrence at 1 year	Landmark analysis; trajectory modeling; joint longitudinal-survival models
Confounding	Unadjusted comparisons; key covariates not measured or controlled	Multivariable Cox models; penalized regression; propensity score adjustment
Survival analysis	RFS reported as mean without censoring; no KM curves or Cox models	KM curves, log-rank tests, Cox regression; hazard ratios with CIs
Multiple testing	Multiple comparisons without correction; no primary endpoint	Prespecified primary endpoint; Bonferroni/FDR correction
Predictive performance	No AUC, calibration, or incremental value assessment	ROC/AUC; calibration plots; decision curve analysis; TRIPOD adherence
Molecular context	No molecular subtyping; Lewis antigen status not assessed	Incorporate MSI, HER2, EBV status; assess Lewis antigen phenotype

RFS: Recurrence-free survival; KM: Kaplan-Meier; CI: Confidence interval; AUC: Area under the curve; ROC: Receiver operating characteristic; FDR: False discovery rate; MSI: Microsatellite instability; HER2: Human epidermal growth factor receptor 2; EBV: Epstein-Barr virus.

Table 2 Emerging biomarker technologies for postoperative gastric cancer surveillance

Biomarker	Advantages	Limitations	Clinical readiness
CEA/CA19-9	Inexpensive, widely available, easily serialized	Low sensitivity/specificity; affected by non-malignant conditions	Established in guidelines but not validated as a standalone prognostic tool
Circulating tumor DNA (ctDNA)	Tumor-specific; detects MRD; identifies actionable mutations	Cost, assay standardization; CHIP interference; limited early-stage sensitivity	Investigational; multiple ongoing trials in GC
Circulating tumor cells	Captures metastatic phenotype; whole-cell analysis	Technical isolation challenges; low counts in early disease	Experimental; limited GC validation
Extracellular vesicles	Rich molecular cargo; immunomodulatory insights	Isolation variability; lack of standardized protocols	Pre-clinical/early translational
Methylated cfDNA	Epigenetic signal: High sensitivity in some assays	Assay complexity; limited prospective data	Investigational; promising early results
Multi-analyte panels (ctDNA + protein + fragmentomics)	Combines complementary signals; highest accuracy potential	Complexity; cost; validation needed	Active clinical trials; not yet guideline-endorsed

CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; MRD: Minimal residual disease; CHIP: Clonal hematopoiesis of indeterminate potential; GC: Gastric cancer; cfDNA: Cell-free DNA.