RESUMEN
BACKGROUND: Tumor budding (TB) is an adverse prognostic factor in colorectal cancer (CRC). International consensus on a standardized assessment method has led to its wider reporting. However, uncertainty regarding its clinical value persists. This study aimed to (1) confirm the prognostic significance of TB, particularly in stage II CRC; (2) to determine optimum thresholds for TB risk grouping; and (3) to determine whether TB influences responsiveness to chemotherapy. METHODS: TB was assessed in CRC sections from 1575 QUASAR trial patients randomized between adjuvant chemotherapy and observation. Optimal risk group cutoffs were determined by maximum likelihood methods, with their influence on recurrence and mortality investigated in stratified log-rank analyses on exploratory (n = 504), hypothesis-testing (n = 478), and final (n = 593) data sets. RESULTS: The optimal threshold for high-grade TB (HGTB) was ≥ 10 buds per 1.23 mm2. High-grade TB tumors had significantly worse outcomes than those with lower TB: 10-year recurrence 36% versus 22% (risk ratio, 2.00 [95% CI, 1.62-2.45]; 2P < .0001) and 10-year mortality 50% vs. 37% (risk ratio, 1.53 [95% CI, 1.34-1.76]; 2P < .0001). The prognostic significance remained equally strong after allowance for other pathological risk factors, including stage, grade, lymphovascular invasion, and mismatch repair status. There was a nonsignificant trend toward increasing chemotherapy efficacy with increasing bud counts. CONCLUSIONS: TB is a strong independent predictor of recurrence. Chemotherapy efficacy is comparable in patients with higher and lower TB; hence, absolute reductions in recurrence and death with chemotherapy should be about twice as large in patients with ≥ 10 than < 10 TB counts.