Abstract
BackgroundTumor budding (TB) is emerging as a prognostic factor in multiple cancers. Likewise, the stemness of cancer cells also plays a vital role in cancer progression. However, nearly no research has focused on the interaction of TB and tumor stemness in cancer.MethodsTissue microarrays including 229 cases of invasive breast cancer (BC) were established and subjected to pan-cytokeratin immunohistochemical staining to evaluate molecular expression. Univariate and multivariate analyses were applied to identify prognostic factors of BC, and the Chi-square test was used for comparison of categorical variables.ResultsHigh-grade TB was significantly associated with T stage, lymph node metastasis, tumor node metastasis (TNM) stage, epithelial-mesenchymal transition, and poor disease-free survival (DFS) of BC patients. We also found that the prognostic value of TB varied widely among different subtypes and subgroups. Cox regression analysis then showed that TB grade was an independent prognostic factor. Moreover, cancer stem cell (CSC) markers CD44 and ALDH1A1 were significantly higher in high-grade TB tumors. Consequently, patients were classified into high CSC score subgroup and low CSC score subgroups. Further research found that CSC scores correlated with clinicopathological features and DFS of BC patients. Based on TB grade and CSC scores, we classified BC patients into TBlow-CSCslow (type I), TBlow-CSCshigh (type II), TBhigh-CSCslow (type III), and TBhigh-CSCshigh (type IV) subgroups. Survival analysis showed that patients in the type I subgroup had the best DFS, whereas those in the type IV subgroup had the worst DFS. Finally, a TB-CSC-based nomogram for use in BC was established. The nomogram was well calibrated to predict the probability of 5-year DFS, and the C-index was 0.837. Finally, the area under the curve value for the nomogram (0.892) was higher than that of the TNM staging system (0.713).ConclusionThe combination of TB grade with CSC score improves the prognostic evaluation of BC patients. A novel nomogram containing TB grade and CSC score provides doctors with a candidate tool to guide the individualized treatment of cancer patients.
Highlights
Breast cancer (BC), which has the highest incidence of any female cancer worldwide, is one of the significant risk factors affecting women’s health [1]
We found that CD44 and ALDH1A1 were more likely upregulated in high-grade Tumor budding (TB) tissues (Figures 3D, E)
The current study revealed that high-grade TB was correlated with the TNM stage, lymph node metastasis (LNM), epithelial-mesenchymal transition (EMT), and cancer stem cells (CSCs) score of BC patients
Summary
Breast cancer (BC), which has the highest incidence of any female cancer worldwide, is one of the significant risk factors affecting women’s health [1]. Standardized and reproducible biomarkers, which could be applied to predict tumor progression, are a cornerstone of individualized cancer therapy. Tumor budding (TB), first introduced in colorectal cancer and typically defined as the formation of single malignant cells or cell clusters of fewer than five malignant cells at the invasive tumor front [3], is an emerging prognostic biomarker in solid cancers [4, 5]. The 2019 World Health Organization (WHO) classification of colorectal cancer introduce TB as a second major grading criterion [6]. Owing to the lack of standardized scoring systems and large-scale studies, whether TB represents an additional prognostic factor in BC requires further research. Tumor budding (TB) is emerging as a prognostic factor in multiple cancers. Nearly no research has focused on the interaction of TB and tumor stemness in cancer
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