Tumour Budding Demonstrates Independent Prognostic Value for Disease-Free and Overall Survival in Patients with Stage III Colon Cancer

Tumour 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 post-hoc analysis of IDEA-France, intermediate (Bd2) and high (Bd3) tumour budding categories strongly associated with poor disease-free survival (DFS) and overall survival (OS) in stage III colon cancer. According to Prof. Magali Svrcek of Sorbonne University, AP-HP, Department of Pathology, Saint-Antoine Hospital, Paris and Prof. Julien Taieb of the Department of Oncology, European Georges Pompidou Hospital in Paris, France and colleagues, who published the findings of this post-hoc analysis on 16 March 2022 in the Annals of Oncology, tumour 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 tumours. Although clinically useful, it represents yet incomplete data set for patient-specific prognostic prediction. Therefore, further classification beyond pT and pN staging and other pathological features influencing outcomes in stage III colon cancer, remains of interest to refine risk classification and to guide adjuvant treatment.

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

In patients with pT1 colon cancer, intermediate (Bd2) and high (Bd3) tumour 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, high tumour budding category (Bd3) represents a poor prognostic factor that should be considered for guidance of adjuvant treatment decision. However, to date, the prognostic impact of tumour budding in patients with stage III colon cancer has been limited to small and retrospective cohorts.

In the present post-hoc analysis of IDEA-France phase III study, the researchers aimed to assess the prognostic role of tumour budding applying the ITBCC 2016 criteria in patients with stage III colon cancer. The predictive value of tumour budding for survival benefit according to duration of adjuvant treatment has been further investigated. The researchers also explored the association between tumour budding and Immunoscore® with idea that the combination of tumour 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. Tumour 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 tumour 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 = 0.002) and perineural invasions (p = 0.0009).

The 3-year DFS and the 5-year OS rates for tumour budding (Bd1 versus Bd2-3) was 79.4% versus 67.2% (p = 0.001) and 89.2% versus 80.8% (p = 0.001). This was confirmed after adjustment for relevant clinicopathological features for DFS (hazard ratio [HR] 1.41, 95% confidence interval [CI] 1.12 to 1.77; p = 0.003) and OS (HR 1.65, 95% CI 1.22 to 2.22; p = 0.001).

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

The authors concluded that both intermediate (Bd2) and high (Bd3) tumour budding categories are strongly associated with worse OS and DFS in patients with stage III colon cancer who were treated with oxaliplatin-based standard adjuvant chemotherapy in IDEA-France study. Tumour 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 the tumour 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.

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.


Basile D, Broudin C, Emile JF, et al. Tumor budding is an independent prognostic factor in stage III colon cancer patients: A post-hoc analysis of the IDEA-France phase III trial (PRODIGE-GERCOR). Annals of Oncology; Published online 16 March 2022. DOI: https://doi.org/10.1016/j.annonc.2022.03.002