Correlation between 8-OHdG and disease-free survival in patients with esophageal squamous cell carcinoma following neoadjuvant chemotherapy

Abstract

Abstract Background: Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy. Neoadjuvant chemotherapy (NAC) followed by surgery is the standard treatment strategy for the patients with stage II or III ESCC, but many develop resistance to treatment. Recent studies have suggested a correlation between therapeutic resistance and enhancement of the nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway in cancer cells but its details, including the antioxidant pathways which regulate the oxidative stress response after NAC, are unknown. Therefore, in this study, we investigated the status of heme oxygenase-1 (HO-1), a target of the Nrf2 pathway, and 8-hydroxy-2-deoxyguanosine (8-OHdG), an oxidative stress marker, in patients with ESCC who underwent NAC, and explored treatment strategies with relation to the findings and clinical outcomes and its correlation to clinical or histologic responsiveness. Methods: HO-1 and 8-OHdG were immunolocalized in 99 patients with ESCC who received NAC with cisplatin and 5-fluorouracil (CF) prior to esophagectomy. Among them, 53 had lymph node metastasis at the time of surgery. Results: Kaplan­­–Meier curves revealed that overall survival (OS) and disease-free survival (DFS) were both significantly prolonged in patients with ESCC and low HO-1 primary tumor H-score compared to those with high scores. DFS was significantly prolonged in the group with low 8-OHdG levels compared to that with high scores. Multivariate analysis demonstrated that high 8-OHdG levels adversely affected DFS in an independent fashion. In addition, Univariate analysis showed significantly prolonged OS and DFS in ESCC patients with higher histological effects of NAC, but multivariate analysis revealed that only regional lymph node metastasis (pN) was significantly correlated with OS and DFS. Conclusions: HO-1 and 8-OHdG levels in the primary tumor were significantly correlated with NAC response in patients with ESCC. In addition, a relatively high 8-OHdG level in tumors after NAC could predict poor DFS. Trial registration: Accession No. 2022-1-779. The trial was retrospectively registered.