Decreasing expression of HIF-1α, VEGF-A, and Ki67 with efficacy of neoadjuvant therapy in locally advanced cervical cancer

Abstract

Background: Neoadjuvant chemotherapy (NACT) before radical hysterectomy has been widely used for locally advanced cervical cancer (LACC); However, its efficacy is yet to be determined.

Methods: Effective and predictive biomarkers, which may aid in predicting the chemotherapy responses, were explored in this study. Initially, the expression of HIF-1α, VEGF-A, and Ki67 was detected in 42 paired (pre-NACT and post-NACT) LACC tissues, as well as 40 nonneoplastic cervical epithelial tissues by immunohistochemistry. Then, the correlation of the expression of HIF-1α, VEGF-A, Ki67 with the efficacy of NACT, as well as factors that affect the efficacy of NACT was analyzed.

Results: A clinical response occurred in 66.7% (28/42) of the patients, including 57.1% (16/28) with a complete response and 42.9% (12/28) with a partial response; While 33.33% (14/42) were non-responders, including 42.9% (6/14) with stable disease and 57.1% (8/14) with progressive disease. HIF-1α, VEGF-A, and Ki67 were overexpressed in LACC tissues compared to nonneoplastic tissues (P < .01, respectively); While the expression of HIF-1α, VEGF-A, and Ki67 was significantly decreased after NACT (P < .01, respectively). What's more, in the response group, HIF-1α, VEGF-A, and Ki67 expression were significantly decreased after chemotherapy in the post-chemotherapy cervical cancer tissues compared with the pre-chemotherapy cervical cancer tissues (all P < .05). Additionally, patients with lower histological grade and lower expression of HIF-1α, VEGF-A, and Ki67 were more responsive to NACT (P < .05, respectively); Moreover, the histological grade [P = .025, HR (95% CI): 0.133 (0.023-0.777)], HIF-1α [P = .019, HR (95% CI): 0.599 (0.390-0.918)], and Ki67 [P = .036, HR (95% CI): 0.946 (0898-0.996)] were independent risk factors affecting the efficacy of NACT in LACC.

Conclusion: Expression of HIF-1α, VEGF-A, and Ki67 were significantly decreased after NACT, and decreasing expression of HIF-1α, VEGF-A, and Ki67 were related to good response to NACT, suggesting HIF-1α, VEGF-A, and Ki67 may be implicated in evaluating the efficacy of NACT in LACC.

Figure 1.

Expression of HIF-1α, VEGF-A, and Ki67 was mainly in LACC tumor cells pre- and post-NACT and basal layer cells of normal cervix squamous epithelium by IHC (SP staining, × 200). HIF-1α protein, (A) was detected primarily in the cytoplasm and partially in the nuclei; VEGF-A protein, (B) was detected primarily in the cytoplasm; and Ki67, (C) was detected primarily in the nuclei. Scores for HIF-1α, (D) and VEGF-A, (E) staining and Ki67 index, (F) in basal layer cells of normal cervical tissues vs LACC pre- and post-NACT. Asterisks (* and **) indicate P < .05. HIF-1α = hypoxia-inducible factor 1α, IHC = immunohistochemical, LACC = locally advanced cervical cancer, NACT = neoadjuvant chemotherapy, VEGF-A = vascular endothelial growth factor.

Figure 2.

HIF-1α, VEGF-A, and Ki67 expression in pre- and post-chemotherapy LACC tissues between the response group and the nonresponse group. In the response group, HIF-1α (A), VEGF-A (B), and Ki67 (C) expression were significantly decreased in the post-chemotherapy cervical cancer tissues compared with the pre-chemotherapy cervical cancer tissues; While the same was not seen in the nonresponse group. HIF-1α = hypoxia-inducible factor 1α, LACC = locally advanced cervical cancer, VEGF-A = vascular endothelial growth factor.