PROGNOSTIC VALUE OF TUMOR BUDDING AND ASSOCIATED MOLECULAR ALTERATIONS IN COLORECTAL CANCER: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract

Background: Tumor budding has emerged as an important histopathological marker of tumor aggressiveness in colorectal cancer (CRC), while molecular alterations such as KRAS, BRAF, TP53 mutations, and microsatellite instability (MSI) are established determinants of tumor behavior and prognosis. However, the relationship between tumor budding, molecular alterations, and survival outcomes remains incompletely understood. This systematic review and meta-analysis aimed to evaluate the prognostic significance of tumor budding and its association with key molecular alterations in colorectal cancer.

Methods: A systematic literature search was conducted across PubMed, Embase, Scopus, Web of Science, and Cochrane Library databases from January 2000 to December 2025 following PRISMA 2020 guidelines. Studies assessing tumor budding in histologically confirmed colorectal adenocarcinoma and reporting survival outcomes and/or molecular alterations were included. Hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were pooled using random-effects models. Study quality was assessed using the Newcastle-Ottawa Scale.

Results: Twenty-eight studies comprising 12,846 patients were included in the meta-analysis. High-grade tumor budding was significantly associated with poorer overall survival (HR=2.18, 95% CI: 1.82-2.61; I²=48%), disease-free survival (HR=2.41, 95% CI: 1.95-2.97; I²=52%), and cancer-specific survival (HR=2.07, 95% CI: 1.68-2.56; I²=45%). Tumor budding demonstrated significant associations with lymphovascular invasion (OR=3.12, 95% CI: 2.45-3.97), perineural invasion (OR=2.76, 95% CI: 2.01-3.79), lymph node metastasis (OR=2.86, 95% CI: 2.21-3.69), distant metastasis (OR=2.44, 95% CI: 1.88-3.18), and advanced TNM stage (OR=2.59, 95% CI: 2.04-3.29). Molecular analyses revealed significant associations between high-grade tumor budding and KRAS mutations (OR=1.74, 95% CI: 1.35-2.23), BRAF mutations (OR=1.89, 95% CI: 1.28-2.79), and TP53 mutations (OR=1.67, 95% CI: 1.21-2.29). Conversely, MSI-high tumors demonstrated a significantly lower prevalence of high-grade tumor budding (OR=0.58, 95% CI: 0.43-0.78). No significant association was observed with NRAS mutations (OR=1.29, 95% CI: 0.94-1.77).

Conclusion: High-grade tumor budding is a robust predictor of adverse prognosis in colorectal cancer and is strongly associated with aggressive clinicopathological characteristics and unfavorable molecular alterations. Integration of tumor budding assessment with molecular profiling may improve prognostic stratification, support personalized therapeutic decision-making, and enhance risk-adapted management strategies in colorectal cancer patients.