Biomarker-Guided Adjuvant Therapy in Stage II/III Colon Cancer: A Systematic Review of Current Evidence and Clinical Implications.

Abstract

Background: The management of resectable stage II/III colon cancer (CC) has long relied on clinicopathological features and fluoropyrimidine-based adjuvant chemotherapy. However, this approach fails to capture the profound biological heterogeneity of the disease, often leading to overtreatment or undertreatment. A new generation of biomarkers now allows a shift toward precision oncology, refining prognosis and predicting therapeutic response. This systematic review critically appraises the evidence for biomarker-guided adjuvant therapy.

Methods: A systematic literature search of PubMed/MEDLINE and Cochrane Library was conducted up to December 2025. Eligible studies included phase II/III randomized controlled trials, prospective cohorts, and large retrospective analyses with independent validation. Due to significant heterogeneity in interventions, settings, and biomarker assays, a narrative synthesis was performed following PRISMA guidelines.

Results: Of 1,245 screened records, 52 studies were included. Universal MMR testing is mandatory: deficient MMR (dMMR)/microsatellite instability-high (MSI-H) tumors represent approximately 15% of stage II/III cases. For stage III CC, the phase III ATOMIC trial demonstrated that adding atezolizumab to mFOLFOX significantly improved 3-year disease-free survival (DFS) versus chemotherapy alone (86.4% vs. 76.6%; HR 0.50; 95% CI 0.34-0.72). Additionally, neoadjuvant immunotherapy (NICHE-2) achieved pathological complete response rates of 68% and 3-year DFS of 100%. In microsatellite-stable (MSS) tumors, integrated analysis of KRAS/BRAF mutations and tumor laterality refines prognosis. Pooled analyses of stage III patients showed that KRAS codon 12 mutations are independently associated with shorter time to recurrence and overall survival, specifically in left-sided tumors. Perioperative CEA retains prognostic value, and its incorporation into risk stratification models improves performance. ctDNA enables dynamic minimal residual disease detection; the DYNAMIC-III trial reduced oxaliplatin use by approximately 60% with comparable 3-year recurrence-free survival (85.3% vs. 88.1%). Large observational studies have confirmed the strong prognostic value of postoperative ctDNA, with hazard ratios for recurrence >5. Toxicity biomarkers (DPYD, UGT1A1) should be assessed before treatment.

Conclusions: The adjuvant treatment of stage II/III colon cancer is evolving from a one-size-fits-all approach to biomarker-driven precision oncology. A stepwise, resource-aware framework is proposed: universal MMR testing as the gateway, then CEA, mutational profiling, and selective ctDNA. Prospective validation of integrated models is urgently needed, especially in under-represented populations (elderly, organ impairment, ethnic minorities).