Predictive and prognostic value of ZEB1 protein expression in breast cancer patients with neoadjuvant chemotherapy

Ziping Wu, Lei Zhang, Shuguang Xu, Yanping Lin, Wenjin Yin, Jinglu Lu, Rui Sha, Xiaonan Sheng, Liheng Zhou, Jinsong Lu, Ziping Wu, Lei Zhang, Shuguang Xu, Yanping Lin, Wenjin Yin, Jinglu Lu, Rui Sha, Xiaonan Sheng, Liheng Zhou, Jinsong Lu

Abstract

Background: Zinc finger E-box binding homeobox 1 (ZEB1) is a molecule involved in the progression of epithelial-to-mesenchymal transition (EMT) in various kinds of cancers. Here, we aimed to determine whether the expression of the ZEB1 protein is related to the response of patients to neoadjuvant therapy as well as their survival outcome.

Methods: Immunohistochemistry (IHC) was performed on paraffin-embedded tumor samples from core needle biopsy before neoadjuvant therapy (NAT). Univariate and multivariate logistic regression analyses were used to analyze the associations between the protein expression of ZEB1 and the pathological complete response (pCR) outcome. Kaplan-Meier plots and log-rank tests were used to compare disease-free survival (DFS) between groups. A Cox proportional hazards model was used to calculate the adjusted hazard ratio (HR) with a 95% confidential interval (95% CI).

Results: A total of 75 patients were included in the IHC test. High ZEB1 protein expression was associated with a low pCR rate in both univariate (OR = 0.260, 95% CI 0.082-0.829, p = 0.023) and multivariate (OR = 0.074, 95% CI 0.011-0.475, p = 0.006) logistic regression analyses. High ZEB1 protein expression was also associated with a short DFS according to both the log-rank test (p = 0.023) and Cox proportional hazard model (HR = 9.025, 95% CI 1.024-79.519, p = 0.048). In hormone receptor positive (HorR-positive) patients, high ZEB1 protein expression was also associated with a lower pCR (OR = 0.054, 95% CI 0.007-0.422, p = 0.005) and a poorer DFS (HR = 10.516, 95% CI 1.171-94.435, p = 0.036) compared with low ZEB1 protein expression. In HER2-overexpressing patients, ZEB1 protein expression was also associated with poor survival (p = 0.042).

Conclusions: Our results showed that high ZEB1 protein expression was a negative predictive marker of pCR and DFS in neoadjuvant therapy in breast cancer patients and in HorR-positive and HER2-overexpressing subgroups.Trial registration NCT, NCT02199418. Registered 24 July 2014-Retrospectively registered, https://ichgcp.net/clinical-trials-registry/NCT02199418?term=NCT02199418&rank=1. NCT, Keywords: Breast cancer; Neoadjuvant chemotherapy; Predictive; Prognostic; ZEB1.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Different ZEB1 immunochemistry staining. a Weak ZEB1 expression with a staining score of 1 (≤ 6); b weak ZEB1 expression with a staining score of 6 (≤ 6); c strong ZEB1 expression with a staining score of 8 (> 6); d strong ZEB1 expression with a staining score of 12 (> 6)
Fig. 2
Fig. 2
Pathological complete response rates of different ZEB1 expression. a Pathological complete response rate of different ZEB1 expression in all patients; b Pathological complete response rate of different ZEB1 expression in hormone receptor positive patients; c Pathological complete response rate of different ZEB1 expression in HER2 positive patients
Fig. 3
Fig. 3
Kaplan–Meier plot of different ZEB1 expression groups. a Kaplan–Meier plot of different ZEB1 expression groups in all patients; b Kaplan–Meier plot of different ZEB1 expression groups in HorR-positive patients; c Kaplan–Meier plot of different ZEB1 expression groups in HER2 positive patients
Fig. 4
Fig. 4
Kaplan–Meier plot of different ZEB1 mRNA expression groups (KMPlotter). a Kaplan–Meier plot of different ZEB1 expression groups in all patients; b Kaplan–Meier plot of different ZEB1 expression groups in HorR-positive patients; c Kaplan–Meier plot of different ZEB1 expression groups in HER2 positive patients; d Kaplan–Meier plot of different ZEB1 expression groups in TNBC patients

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