Prognostic significance of tumor budding in rectal cancer biopsies before neoadjuvant therapy

Tumor budding is an increasingly important prognostic feature for pathologists to recognize. The aim of this study was to correlate intra-tumoral budding in pre-treatment rectal cancer biopsies with pathological response to neoadjuvant chemoradiotherapy and with long-term outcome. Data from a prospectively maintained database were acquired from patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy. Pre-treatment rectal biopsies were retrospectively reviewed for evidence of intra-tumoral budding. Multivariate logistic regression was used to identify factors contributing to cancer-specific death, expressed as hazard ratios with 95% confidence intervals. Of the 185 patients with locally advanced rectal cancer, 89 patients met the eligibility criteria, of whom 18 (20%) exhibited budding in a pre-treatment tumor biopsy. Intra-tumoral budding predicted a poor pathological response to neoadjuvant chemoradiotherapy (higher ypT stage, P = 0.032; lymph node involvement, P = 0.018; lymphovascular invasion, P = 0.004; and residual poorly differentiated tumors, P = 0.005). No patient with intra-tumoral budding exhibited a tumor regression grade 1 or complete pathological response, providing a 100% specificity and positive predictive value for non-response to neoadjuvant chemoradiotherapy. Intra-tumoral budding was associated with a lower disease-free 5-year survival rate (33 vs 78%, P<0.001), cancer-specific 5-year survival rate (61 vs 87%, P = 0.021) and predicted cancer-specific death (hazard ratio 3.51, 95% confidence interval 1.03-11.93, P = 0.040). Intra-tumoral budding at diagnosis of rectal cancer identifies those who will poorly respond to neoadjuvant chemoradiotherapy and those with a poor prognosis.