HER3 protein expression as a risk factor for post-operative recurrence in patients with early-stage adenocarcinoma and adenosquamous carcinoma of the cervix

Abstract

Patients with cervical adenocarcinoma (AC) and adenosquamous carcinoma (ASC) have a poorer prognosis than those with squamous cell carcinoma (SCC). Erb-b2 receptor tyrosine kinase 3 (HER3) is a member of the epidermal growth factor receptor family and its expression is associated with unfavorable prognosis in several cancer types, including SCC of the cervix. As there is limited information on the prognostic value of HER3 for AC and ASC of the cervix, the present study aimed to evaluate the expression of HER3 and its impact on post-operative recurrence in patients with AC and ASC of the cervix. This retrospective study included 39 patients with early-stage AC and ASC who underwent primary surgery between January 1997 and December 2017. Immunohistochemical staining for HER3 was performed on formalin-fixed paraffin-embedded surgical specimens. The possible influence of HER3 expression on disease-free survival (DFS) was studied by using multivariate Cox regression with adjustment for established risk factors of post-operative recurrence. High expression of HER3 (HER3-high) was detected in 85.1% of cases of AC (23/27) and in 58.3% of cases of ASC (7/12). The median follow-up duration was 63.1 months and Kaplan-Meier analysis indicated that the 5-year DFS rates of patients with AC and ASC of the cervix were 56.7% in patients with HER3-high and 77.8% in patients with HER3-low (log rank, P=0.20). On multivariate analysis, HER3-high [hazard ratio (HR)=6.32, 95% CI: 1.10-36.26, P=0.039), pelvic lymph node metastasis (HR=7.61, 95% CI: 2.07-28.00, P=0.002) and vascular invasion (HR=4.28, 95% CI: 1.12-16.31, P=0.033) were indicated to be independent predictors of DFS. To date, the present study is the most comprehensive analysis to evaluate the expression of HER3 in patients with early-stage AC and ASC of the cervix. The results suggested that HER3 overexpression may be an independent risk factor for post-operative recurrence. However, these results and the prognostic value of HER3 should be confirmed in a larger sample.

Keywords: HER3 protein expression; biomarker; cervical cancer; prognostic factor.

Figure 1.

Representative histology images. (A) H&E staining. (B-D) Immunohistochemical staining for HER3; (B) endocervical adenocarcinoma, usual type, pT1bN0, with HER3 score of 1+; (C) endocervical adenocarcinoma, usual type, pT2bN1, HER3 score of 2+; (D) endocervical adenocarcinoma, usual type, pT2bN1, HER3 score of 3+ (original magnification of all the histological images, ×200). HER3 was predominantly expressed in the cytoplasm and on the membranes of tumor cells. HER3, Erb-b2 receptor tyrosine kinase 3; H&E, hematoxylin and eosin.

Figure 2.

Kaplan-Meier curves for disease-free survival and overall survival depending on the status of HER3 expression. Kaplan-Meier curves for (A) disease-free survival and (B) overall survival of patients with metastatic disease with high HER3 expression (dashed line) and low HER3 expression (solid line). HER3, Erb-b2 receptor tyrosine kinase 3.