The relationship between cancer associated fibroblasts biomarkers and prognosis of breast cancer: a systematic review and meta-analysis

Abstract

Background: To elucidate the relationship between cancer-associated fibroblast (CAFs) biomarkers and the prognosis of breast cancer patients for individualized CAFs-targeting treatment.

Methodology: PubMed, Web of Science, Cochrane, and Embase databases were searched for CAFs-related studies of breast cancer patients from their inception to September, 2023. Meta-analysis was performed using R 4.2.2 software. Sensitivity analyses were performed to explore the sources of heterogeneity. Funnel plot and Egger's test were used to assess the publication bias.

Results: Twenty-seven studies including 6,830 patients were selected. Univariate analysis showed that high expression of platelet-derived growth factor receptor-β (PDGFR-β) (P = 0.0055), tissue inhibitor of metalloproteinase-2 (TIMP-2) (P < 0.0001), matrix metalloproteinase (MMP) 9 (P < 0.0001), MMP 11 (P < 0.0001) and MMP 13 (P = 0.0009) in CAFs were correlated with reduced recurrence-free survival (RFS)/disease-free survival (DFS)/metastasis-free survival (MFS)/event-free survival (EFS) respectively. Multivariate analysis showed that high expression of α-smooth muscle actin (α-SMA) (P = 0.0002), podoplanin (PDPN) (P = 0.0008), and PDGFR-β (P = 0.0470) in CAFs was associated with reduced RFS/DFS/MFS/EFS respectively. Furthermore, PDPN and PDGFR-β expression in CAFs of poorly differentiated breast cancer patients were higher than that of patients with relatively better differentiated breast cancer. In addition, there is a positive correlation between the expression of PDPN and human epidermal growth factor receptor-2 (HER-2).

Conclusions: The high expression of α-SMA, PDPN, PDGFR-β in CAFs leads to worse clinical outcomes in breast cancer, indicating their roles as prognostic biomarkers and potential therapeutic targets.

Keywords: Breast cancer; Cancer associated fibroblasts; Meta-analysis; Prognostic biomarkers.

Figure 1. Flow chart describing steps carried out in selecting articles.

Figure 2. Forest plots indicating the association between the expression of PDPN, PDGFR-β in CAFs and histopathological feature of breast cancers.

(A) PDPN expression and histological grade. (B) the correlation between PDPN and HER-2 expression. (C) PDGFR-β expression and histological grade. Strell et al. (2019); Paulsson et al. (2009); Pula et al. (2013a); Pula et al. (2013b); Schoppmann et al. (2012); Pula et al. (2011); Tanaka et al. (2021).