Expression of VEGF and HIF-1α in locally advanced cervical cancer: potential biomarkers for predicting preoperative radiochemotherapy sensitivity and prognosis

Abstract

Locally advanced cervical cancer (LACC) is an early-stage cervical cancer characterized by a local tumor diameter of ≥4 cm. Patients with LACC have a relatively poor prognosis. Although preoperative radiochemotherapy (PRCT) might offer a valuable opportunity for subsequent radical surgery, surgeons should also consider the nonresponsive rate, the adverse effects of PRCT, and the surgical complications before designing a treatment plan. Therefore, biomarkers for predicting PRCT sensitivity and prognosis in patients with LACC are of high importance. We investigated the prognostic significance of vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1α (HIF-1α) in patients with LACC. A total of 43 patients with LACC who underwent PRCT (one course each of intravenous chemotherapy and after-loading intracavitary brachytherapy followed by a radical hysterectomy) during the period 2009-2014 were included in this study. VEGF and HIF-1α expression levels were evaluated by immunohistochemistry in LACC lesions before and after PRCT. In addition, we analyzed the association of these proteins with the clinical response and pathological findings of pelvic lymph node metastasis (PLNM) after the subsequent surgery. The total clinical response rate was 81.39% after PRCT, including five complete responses and 30 partial responses. VEGF and HIF-1α expression before PRCT was significantly higher than after PRCT (VEGF: 85.71% vs 66.67%; HIF-1α: 83.33% vs 59.52%, P<0.05). In addition, the same trend was found in patients with PLNM compared to those without PLNM (VEGF: 100% vs 77.78%; HIF-1α: 100% vs 74.07%, P<0.05). The areas under the receiver operating characteristic curves were 0.896 and 0.835 when using pre-PRCT VEGF and HIF-1α expression levels, respectively, to diagnose PLNM in patients with LACC. Serial detection of VEGF and HIF-1α demonstrated a sensitivity of 66.67% and specificity of 88.89%. These findings suggest that VEGF and HIF-1α expressions are potential biomarkers for PRCT and have great clinical significance for the prediction of PRCT response and prognosis in patients with LACC.

Keywords: HIF-1α; LACC; PRCT; VEGF; hypoxia inducible factor-1α; locally advanced cervical cancer; preoperative chemoradiotherapy; prognosis; vascular endothelial growth factor.

Figure 1

Immunohistochemical staining of VEGF in LACC lesion. Notes: Original magnification ×400. (A) Negative, (B) weak expression, (C) moderate expression, (D) strong expression. Abbreviations: LACC, locally advanced cervical cancer; VEGF, vascular endothelial growth factor.

Figure 2

Immunohistochemical staining of HIF-1α in LACC lesion. Notes: Original magnification ×400. (A) Negative, (B) weak expression, (C) moderate expression, (D) strong expression. Abbreviations: HIF-1α, hypoxia inducible factor-1α; LACC, locally advanced cervical cancer.

Figure 3

ROC curves for VEGF and HIF-1α expression for predicting PLNM in patients with LACC before PRCT. Abbreviations: HIF-1α, hypoxia inducible factor-1α; LACC, locally advanced cervical cancer; PLNM, pelvic lymph node metastasis; PRCT, preoperative chemoradiotherapy; ROC, receiver-operating characteristic; VEGF, vascular endothelial growth factor.