Transforming growth factor-β, insulin-like growth factor I/insulin-like growth factor I receptor and vascular endothelial growth factor-A: prognostic and predictive markers in triple-negative and non-triple-negative breast cancer

Abstract

In the current study, the prognostic and predictive values of serum transforming growth factor-β1 (TGF-β1), insulin-like growth factor I (IGF-I)/IGF-I receptor (IGF-IR) and vascular endothelial growth factor-A (VEGF-A) were evaluated in triple-negative and non-triple-negative breast cancer (TNBC and non-TNBC). The aim was to identify a group of serological biomarkers and to identify possible candidates for targeted therapy in patients with TNBC and non-TNBC. Protein levels of TGF-β1, IGF-I/IGF-IR and VEGF-A in the serum were measured in 43 TNBC, 53 non‑TNBC and 20 normal control participants using quantitative ELISA assays. Results were correlated against standard prognostic factors, response to treatment and survival. TNBC was identified to be associated with poor prognosis and serum levels of VEGF-A and IGF/IGF-IR were significantly higher in the TNBC group compared with the non-TNBC group. IGF-IR and VEGF-A overexpression was observed to be correlated with TGF-β1 expression and all of the markers investigated were associated with metastasis and disease progression. In the multivariate analysis, VEGF-A, IGF-I and IGF-IR were observed to be independent predictors for overall survival, whereas TGF-β1 and lymph node status were identified as independent predictors for disease-free survival. The overall response rate was significantly lower in patients with TNBC and those with high levels of TGF-β1, IGF-I/IGF-IR and VEGF-A. In view of the present results, it was concluded that TGF-β1, IGF-I/IGF-IR and VEGF-A overexpression is associated with the presence of aggressive tumors, which exhibit an increased probability of metastasis, a poor response to treatment and reduced survival rate. This indicates that VEGF-A, IGF-IR and IGF-I have the potential to be used as surrogate biomarkers and are promising candidates for targeted therapy, particularly in patients with TNBC.

Figure 1

Mean rank of the markers in the TNBC, non-TNBC and control groups. TGF-β1, transforming growth factor-β1; IGF-I, insulin-like growth factor I; IGF-IR, IGF-I receptor; VEGF-A, vascular endothelial growth factor-A; TNBC, triple-negative breast cancer.

Figure 2

ROC curve analysis for markers in triple-negative compared with non-triple-negative and normal control to calculate the optimal cut-off value. ROC, receiver operating characteristic; VEGF-A, vascular endothelial growth factor-A; IGF-I, insulin-like growth factor I; IGF-IR, IGF-I receptor; TGF-β1, transforming growth factor-β1.

Figure 3

Percentage of positive cases of each studied marker in different investigated groups. TNBC, triple-negative breast cancer; VEGF, vascular endothelial growth factor; IGF-I, insulin-like growth factor I; IGF-IR, IGF-I receptor; TGF-β1, transforming growth factor-β1.

Figure 4

Kaplan-Meier analysis. (A) Overall survival and (B) disease-free survival of the triple- and non-triple-negative patients with breast cancer. TNBC, triple-negative breast cancer.

Figure 5

Overall survival analysis for (A) VEGF-A, (B) IGF-I, (C) IGF-IR and (D) TGF-β1 expression. VEGF-A, vascular endothelial growth factor-A; IGF-I, insulin-like growth factor I; IGF-IR, IGF-I receptor; TGF-β1, transforming growth factor-β1.

Figure 6

Disease-free survival analysis for (A) VEGF-A, (B) IGF-I, (C) IGF-IR and (D) TGF-β1 expression. VEGF-A, vascular endothelial growth factor-A; IGF-I, insulin-like growth factor I; IGF-IR, IGF-I receptor; TGF-β1, transforming growth factor-β1.