Prognostic role of vitamin D receptor in breast cancer: a systematic review and meta-analysis

Abstract

Background: A higher vitamin D intake improves the prognosis of early stage breast cancer (BC) patients. We hypothesized that vitamin D intake should refer to vitamin D receptor (VDR) expression. In order to prove this hypothesis, we first intend to evaluate the correlation between VDR expression and prognosis of BC patients using meta-analysis.

Methods: Literatures from PubMed, Embase, and the Cochrane Library (last update by May 20, 2020) were retrieved to find studies assessing the prognostic role of VDR in BC. The hazard ratios (HRs) for patients' survival were extracted for pooled analyses. Subgroup analysis, sensitivity analysis and meta-regression were performed to explore the sources of heterogeneity.

Results: Seven articles containing eight studies with 2503 patients were enrolled. The results from the pooled analyses showed that the VDR expression generally had no relationship with BC patients' overall survival (OS), disease-free survival (DFS), cancer-specific survival (CSS), and progression-free survival (PFS) (P > 0.05). Because only the number of studies exploring the relationship between VDR expression and OS is greater than five and there is heterogeneity, we explored the sources of heterogeneity of these studies. Subgroup analyses showed that the VDR expression in the nucleus had no relationship with OS, but high total VDR expression in the nucleus and cytoplasm was related to a better OS (pooled HR = 0.41; 95% CI = 0.18-0.95; P = 0.038). In addition, in subgroup of studies using cut-off values other than 'immunoreactive score (IRS)>5' and 'IRS > 25', high VDR expression was associated with a better OS (pooled HR = 0.47; 95% CI = 0.30-0.74; P = 0.001). Sensitivity analysis showed that the result pattern was not obviously affected by any single study. Meta-regression showed that the source of heterogeneity was not country (P = 0.657), pathological type (P = 0.614), molecular type (P = 0.423), staining location (P = 0.481), or cut-off value (P = 0.509).

Conclusions: The protein expression level of VDR in entire BC cells evaluated by immunohistochemistry is related to the OS of BC patients. It is expected that a more individualized vitamin D intake and a more accurate prognosis assessment can be recommended for BC patients based on the VDR expression. Of course, more preclinical and clinical studies are needed.

Keywords: Breast cancer; Meta-analysis; Prognosis; Vitamin D receptor.

Fig. 1

Flow diagram of the study selection process for the meta-analysis

Fig. 2

Forest plot of studies evaluating the hazard ratio of high VDR expression for the overall survival of breast cancer patients. VDR: vitamin D receptor; HR: hazard ratio; CI: confidence interval

Fig. 3

Forest plot of studies evaluating the hazard ratio of high VDR expression for the overall survival of breast cancer patients stratified by staining location. VDR: vitamin D receptor; HR: hazard ratio; CI: confidence interval

Fig. 4

Forest plot of studies evaluating the hazard ratio of high VDR expression for the overall survival of breast cancer patients stratified by cut-off value. VDR: vitamin D receptor; IRS: immunoreactive score; HR: hazard ratio; CI: confidence interval

Fig. 5

Sensitivity analysis of studies evaluating the relationship between VDR expression and patients’ overall survival in breast cancer. VDR: vitamin D receptor; CI: confidence interval

Fig. 6

Funnel plot of publication bias for studies evaluating the relationship between VDR expression and patients’ overall survival in breast cancer

Fig. 7

Forest plot of studies evaluating the hazard ratio of high VDR expression for the disease-specific survival of breast cancer patients. VDR: vitamin D receptor; HR: hazard ratio; CI: confidence interval