Tumor Budding May Provide Independent Prognostic Value for Disease-Free and Overall Survival in Patients With Stage III Colon Cancer

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Tumor budding is an emerging prognostic biomarker in colon cancer and currently influences decision-making in patients with pT1 and stage II colon cancer. In stage III colon cancer, its prognostic impact has been limited to small and retrospective cohorts. In a post hoc analysis of the IDEA-France phase III trial, intermediate (Bd2) and high (Bd3) tumor budding categories were strongly associated with poor disease-free survival and overall survival in stage III colon cancer. According to Basile et al, who published these findings in Annals of Oncology, tumor budding could provide additional and clinically relevant prognostic information beside risk groups and Immunoscore.

The authors wrote in the study background that the TNM staging system remains the gold standard for the classification of malignant tumors. Although clinically useful, it represents yet incomplete data set for patient-specific prognostic prediction. Therefore, further classification beyond pT and pN staging and other pathologic features influencing outcomes in stage III colon cancer remains of interest to refine risk classification and to guide adjuvant treatment.

What Is Tumor Budding?

Tumor budding is defined as a single cancer cell of up to four cancer cells at the tumor-invasive margin. Biologically, it could reflect an aggressive growth pattern. It plays a key role in the tumor microenvironment as surrogate of morphologic expression of epithelial-mesenchymal transition representing the dynamic process of cancer infiltration. In 2016, the International Tumor Budding Consensus Conference (ITBCC) recommended standardized tumor budding assessment and its reporting by pathologists in colorectal cancer.

In patients with pT1 colon cancer, intermediate (Bd2) and high (Bd3) tumor budding categories are associated with node involvement, and it is used to decide whether to perform complementary radical surgery following endoscopic resection. In stage II colon cancer, a high tumor budding category (Bd3) represents a poor prognostic factor that should be considered for guidance of adjuvant treatment decisions. However, to date, the prognostic impact of tumor budding in patients with stage III colon cancer has been limited to small and retrospective cohorts.

Post Hoc Analysis

In the present post hoc analysis of the IDEA-France phase III study, the researchers aimed to assess the prognostic role of tumor budding applying the ITBCC 2016 criteria in patients with stage III colon cancer. The predictive value of tumor budding for survival benefit according to duration of adjuvant treatment has been further investigated. The researchers also explored the association between tumor budding and Immunoscore, with idea that the combination of tumor budding and immune infiltrate could better refine the prognosis of patients with colon cancer.

This post-hoc study was conducted on tissue slides from 1,048 patients with stage III colon cancer. Tumor budding was scored by central review according ITBCC 2016 criteria and classified as Bd1 (0–4 buds/0.785 mm2), Bd2 (5–9 buds), and Bd3 (≥ 10 buds). Clinicopathologic features and Immunoscore were correlated with tumor budding.

Overall, Bd1, Bd2, and Bd3 were observed in 39%, 28%, and 33% of patients with colon cancer. Bd2 and Bd3 were associated with vascular (P = .002) and perineural invasions (P = .0009).

The 3-year disease-free survival and the 5-year overall survival rates for tumor budding (Bd1 vs Bd2–3) were 79.4% vs 67.2% (P = .001) and 89.2% vs 80.8% (P = .001). This was confirmed after adjustment for relevant clinicopathologic features for disease-free survival (hazard ratio [HR] = 1.41, 95% confidence interval [CI] = 1.12–1.77, P = .003) and overall survival (HR = 1.65, 95% CI = 1.22–2.22, P = .001).

When combined with pTN stage and Immunoscore subgroups, tumor budding significantly improved disease prognostication.

The authors concluded that both Bd2 and Bd3 tumor budding categories are strongly associated with worse overall and disease-free survival in patients with stage III colon cancer who were treated with oxaliplatin-based standard adjuvant chemotherapy in the IDEA-France study. Tumor budding seems to provide additional and clinically relevant prognostic information beside risk groups and Immunoscore. Its association with the duration of treatment remains to be better defined by prospective studies stratified according to Bd1 and Bd2–3.

Based on these results, the authors stated that tumor budding should be reported according to the ITBCC 2016 criteria as a microscopic biomarker in routine practice in every pathology report of patients with resected stage III colon cancer.

Disclosure: The authors acknowledged the GERCOR team, the PRODIGE investigators, the French National Cancer Institute (INCa), French Ministry of Health by Program Hospitalier de Recherche Clinique 2009, and Groupe Coopérateur Multidisciplinaire en Oncologie for funding the study. For full disclosures of the study, visit

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