Prognostic effect of hENT1, dCK and HuR expression by morphological type in periampullary adenocarcinoma, including pancreatic cancer

<i>Background</i>: Putative biomarkers of gemcitabine response have been extensively studied in pancreatic cancer, but less so in other types of periampullary adenocarcinoma. The most studied biomarker is human equilibrative nucleoside transporter 1 (hENT1), and the activating enzyme deoxycytidine kinase (dCK) has also been linked to treatment response. The RNA-binding protein human antigen R (HuR) has been demonstrated to confer increased dCK levels in vitro and to predict gemcitabine response in vivo. Here, we investigated the prognostic impact of hENT1, dCK and HuR in pancreatobiliary (PB) and intestinal (I) type periampullary cancers, respectively. <i>Material and methods</i>: Immunohistochemical expression of hENT1, dCK and HuR was evaluated in tissue microarrays with all primary tumours and 103 paired lymph node metastases from a consecutive retrospective cohort of 175 patients with resected periampullary adenocarcinomas. <i>Results</i>: In patients with PB-type tumours, neither hENT1 nor dCK expression was prognostic. A high HuR cytoplasmic/nuclear ratio was associated with a significantly reduced five-year overall survival (OS) in patients receiving adjuvant gemcitabine (HR 2.07, 95% CI 1.03–4.17) but not in untreated patients (p_interaction = 0.028). In patients with I-type tumours receiving adjuvant chemotherapy, high dCK expression was significantly associated with a prolonged recurrence-free survival (RFS) (HR 0.09, 95% CI 0.01–0.73, p_interaction = 0.023). Furthermore, HuR expression was associated with a prolonged OS and RFS in unadjusted but not in adjusted analysis and hENT1 expression was an independent predictor of a prolonged RFS (HR 0.24, 95% CI 0.10–0.59), regardless of adjuvant treatment. <i>Conclusion</i>: hENT1 expression is a favourable prognostic factor in I-type, but not in PB-type tumours. High dCK expression is a favourable prognostic factor in patients with I-type tumours receiving adjuvant treatment and a high cytoplasmic/nuclear HuR ratio is a negative prognostic factor in gemcitabine-treated PB-type tumours. Morphological subtype should always be considered in biomarker studies on periampullary cancer.

**背景**：吉西他滨（gemcitabine）应答的潜在生物标志物已在胰腺癌中被广泛研究，但在其他类型壶腹周围腺癌（periampullary adenocarcinoma）中的研究相对较少。研究最为广泛的生物标志物是人平衡型核苷转运蛋白1（human equilibrative nucleoside transporter 1，hENT1），而活化酶脱氧胞苷激酶（deoxycytidine kinase，dCK）也与治疗应答相关。研究已证实，RNA结合蛋白人抗原R（RNA-binding protein human antigen R，HuR）可在体外提高dCK水平，并在体内预测吉西他滨的治疗应答。本研究分别探讨了hENT1、dCK及HuR在胰胆型（pancreatobiliary，PB）和肠型（intestinal，I）壶腹周围癌中的预后价值。
**材料与方法**：针对175例接受根治性切除的壶腹周围腺癌连续回顾性队列，利用组织微阵列对所有原发肿瘤及103例配对淋巴结转移灶的hENT1、dCK及HuR免疫组化表达水平进行评估。
**结果**：对于胰胆型肿瘤患者，hENT1与dCK表达均无预后价值。在接受辅助吉西他滨治疗的患者中，较高的HuR胞质/胞核比值与5年总生存期（overall survival，OS）显著缩短相关（风险比（hazard ratio，HR）2.07，95%置信区间（confidence interval，CI）1.03~4.17），但在未接受治疗的患者中无此关联（交互作用P值=0.028）。在接受辅助化疗的肠型肿瘤患者中，较高的dCK表达与无复发生存期（recurrence-free survival，RFS）显著延长相关（HR 0.09，95%CI 0.01~0.73，交互作用P值=0.023）。此外，在未校正分析中，HuR表达与OS及RFS延长相关，但在校正分析中无此意义；而无论辅助治疗情况如何，hENT1表达均为RFS延长的独立预测因子（HR 0.24，95%CI 0.10~0.59）。
**结论**：hENT1表达是肠型壶腹周围癌的有利预后因子，但对胰胆型肿瘤无此作用。较高的dCK表达是接受辅助治疗的肠型肿瘤患者的有利预后因子，而较高的HuR胞质/胞核比值是接受吉西他滨治疗的胰胆型肿瘤患者的不良预后因子。在壶腹周围癌的生物标志物研究中，应始终考虑肿瘤的形态学亚型。