Department of Radiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China.
Department of Endoscopy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China.
JAMA Netw Open. 2023 Feb 1;6(2):e2253832. doi: 10.1001/jamanetworkopen.2022.53832.
Hepatitis B surface antigen (HBsAg) reportedly increases the risk of distant metastasis among patients with nasopharyngeal carcinoma (NPC). However, the associated potential interaction and changes in hazard ratios (HRs) between HBsAg and different plasma Epstein-Barr (EBV) DNA levels are unknown. Moreover, the potential HBsAg-positive-associated NPC metastatic mechanism remains unclear.
To investigate the prognostic value and biological associations of HBsAg and plasma EBV DNA levels on distant metastasis in patients with NPC.
DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study performed at Sun Yat-sen University Cancer Center between January 2010 and January 2013. A total of 792 patients with nonmetastatic NPC were enrolled. The median (range) follow-up time was 62.1 (1.4-83.4) months. Of these patients, 17.8% presented with HBsAg positivity. Cytological experiments were performed to evaluate the role of HBsAg in the invasion and migration of EBV-positive NPC cells. Data analysis was performed from July 2020 to April 2021.
The primary end point was distant metastasis-free survival. Association rules were used to identify new rules related to distant metastasis. Interaction plots, univariate and multivariate Cox regression analyses, stratification analysis, and quantification using HRs were conducted. Additionally, cell migration and invasion assays, as well as Western blotting, were performed in the cytological validation.
Among the 792 patients, 576 (72.7%) were male, with a median (IQR) age of 45 (38-53) years. The HBsAg-positive group exhibited a significant interaction and increased risk of distant metastasis when plasma EBV DNA cutoff levels were 1.5 × 1000 copies/mL or greater. The HR was 9.16 (95% CI, 2.46-34.14) when the plasma EBV DNA load reached 6 × 1000 copies/mL, which was higher than that in patients with stage IV disease (HR, 2.01; 95% CI, 1.13-3.56; P = .02). In cytological experiments, HBsAg promoted epithelial-mesenchymal transition by upregulating vimentin and fibronectin in EBV-positive NPC cells in vitro, thereby promoting invasion and migration of EBV-positive NPC cells.
In this cohort study, the observed synergistic association between HBsAg and plasma EBV DNA load represented a novel potential mechanism underlying the increased risk of distant metastasis in patients with NPC. Hence, attention should be paid to patients with NPC with HBsAg positivity, especially when the plasma EBV DNA level is 6 × 1000 copies/mL or greater. Consideration of this synergistic association will contribute to more accurate individualized management.
据报道，乙型肝炎表面抗原（HBsAg）会增加鼻咽癌（NPC）患者发生远处转移的风险。然而，HBsAg 与不同的血浆 Epstein-Barr（EBV）DNA 水平之间潜在的相互作用和危险比（HRs）变化尚不清楚。此外，HBsAg 阳性相关 NPC 转移的潜在机制仍不清楚。
探讨 HBsAg 和 EBV 阳性 NPC 患者血浆 EBV DNA 水平对远处转移的预后价值和生物学相关性。
设计、地点和参与者：中山大学肿瘤防治中心 2010 年 1 月至 2013 年 1 月进行的回顾性队列研究。共纳入 792 例无远处转移 NPC 患者。中位（范围）随访时间为 62.1（1.4-83.4）个月。其中 17.8%的患者 HBsAg 阳性。细胞实验评估了 HBsAg 在 EBV 阳性 NPC 细胞侵袭和迁移中的作用。数据分析于 2020 年 7 月至 2021 年 4 月进行。
主要终点为无远处转移生存。使用关联规则识别与远处转移相关的新规则。进行交互图、单变量和多变量 Cox 回归分析、分层分析和使用 HR 进行量化。此外，在细胞学验证中进行了细胞迁移和侵袭实验以及 Western blot 分析。
在 792 例患者中，576 例（72.7%）为男性，中位（IQR）年龄为 45（38-53）岁。当血浆 EBV DNA 截距水平为 1.5×1000 拷贝/ml 或更高时，HBsAg 阳性组显示出显著的相互作用和远处转移的风险增加。当 EBV DNA 负荷达到 6×1000 拷贝/ml 时，HR 为 9.16（95%CI，2.46-34.14），高于 IV 期疾病患者（HR，2.01；95%CI，1.13-3.56；P=0.02）。在细胞学实验中，HBsAg 通过上调 EBV 阳性 NPC 细胞中的波形蛋白和纤维连接蛋白，促进上皮-间充质转化，从而促进 EBV 阳性 NPC 细胞的侵袭和迁移。
在这项队列研究中，观察到 HBsAg 与血浆 EBV DNA 负荷之间的协同关联，代表了 NPC 患者远处转移风险增加的一个新的潜在机制。因此，应注意 HBsAg 阳性的 NPC 患者，尤其是当血浆 EBV DNA 水平达到 6×1000 拷贝/ml 或更高时。考虑到这种协同关联将有助于更准确的个体化管理。
