联合EBV DNA拷贝数和EGFR表达建立基于调强放射治疗局部晚期鼻咽癌的预后模型

Nasopharyngeal carcinoma (NPC) is a common malignancy in South China and closely related with Epstein-Barr virus (EBV). The prognosis of locally advanced NPC is relatively poor. Intensity-modulated radiotherapy (IMRT) is the mainstyle treatment modality. The outcome of NPC treated with the art state of IMRT has been largely improved, which resulted in decreased predictive power of clinical prognostic factors such as Tumor-Node-Metastasis staging system. Bio-marker predicting prognosis is being a new research hotspot gradually for NPC. To the best of our knowledge, the most important prognostic bio-markers including plasm EBV DNA copies and EGFR expression in tumor tissue have explored for locally advanced NPC treated with conventional radiotherapy. But the predictive value of both plasm EBV DNA copies and EGFR expression in tumor tissue have not been confirmed for those treated with IMRT. In our previous study, we have demonstrated that both pre- and post- treatment plasm EBV DNA copies can well predict the prognosis of EBV-related NK/T-cell lymphoma. To date, there is no report on predictive prognostic model based on plasm EBV DNA copies and EGFR expression in tumor tissue for locally advanced NPC treated with IMRT. So, the aim of this study is to investigate the prognostic bio-markers for locally advanced NPC treated with IMRT. And to clarify the relationship between plasm EBV DNA copies and clinical features and prognosis, EGFR expression pattern in tumor tissue and clinical features and prognosis, respectively. Finally, to establish a predictive prognostic model based on EBV DNA copies and EGFR expression for locally advanced NPC treated with IMRT. Based on series of basic and clinical datum, the present study is combined prospective clinical observation with bio-makers analysis. The predictive prognostic model originated from this research may be applied to the clinic and provide some evidences including guidance for prognosis evaluation, stratified research, individualized treatment and outcome improvement for NPC patients.

鼻咽癌是我国南方常见的EBV相关恶性肿瘤。局部晚期鼻咽癌预后较差。首选调强放射治疗。EBV DNA拷贝数和EGFR表达是基于常规放射治疗鼻咽癌最重要的生物预后标记物，但在基于调强放射治疗鼻咽癌的预后价值并未得以验证。在我们既往的研究中已经证实EBV DNA拷贝数可预测EBV相关NK/T细胞淋巴瘤的预后。目前，暂未见联合EBV DNA拷贝数和EGFR表达特征预测局部晚期鼻咽癌预后模型的研究。因此，本研究的主要目的是确立血浆EBV DNA 拷贝数以及EGFR 表达特征和鼻咽癌临床特征以及预后的关系，建立联合EBV DNA拷贝数和EGFR表达特征预测基于调强放射治疗局部晚期鼻咽癌的预后模型。本研究设计基于系列基础和临床研究，通过前瞻性临床研究与生物标记物分析，建立的联合EBV DNA拷贝数和EGFR表达特征的预后模型可在临床推广应用，为鼻咽癌患者进行分层研究、个体化治疗以及提高治疗结果提供依据。

鼻咽癌首选调强放射治疗。EBV DNA拷贝数和EGFR表达是基于常规放射治疗鼻咽癌最重要的生物预后标记物，但在基于调强放射治疗后的预后价值并未得以验证。.分析2014年4月-2016年1月间共入组基于调强放射治疗128例III/IVa/b期局部晚期鼻咽癌患者的资料。确立血浆EBV DNA 拷贝数以及EGFR 表达特征和鼻咽癌临床特征以及预后的关系，建立联合EBV DNA拷贝数和EGFR表达特征的预后模型。后续进行了鼻咽癌患者血浆中自身抗体的相关研究。.全组128例鼻咽癌患者的3年总生存率(overall survival, OS)和无进展生存率(progression-free survival, PFS)分别为89.5%和77.7%，临床特征中仅合并症与PFS有关（p=0.007）。鼻咽癌患者放疗前（＜8000比≥8000拷贝数/mL）、放疗结束时（0比>0拷贝数/mL）和放疗结束后1个月（0比>0拷贝数/mL）血浆EBV DNA拷贝数均和预后相关，3年OS分别为96.0%和83.7%(p=0.026)，91.2%和70.0%(p=0.006)和91.1%和62.5%(p=0.001)。放疗结束后1个月血浆EBV DNA拷贝数对预后的预测力度最大。EGFR染色范围阳性细胞比例为25%-75%的患者的OS可能优于其它患者 (95.0%比86.1%，p=0.203)。分子预后模型显示，低危组、中危组和高危组3年OS分别为96.3%、86.0%和74.9%(p=0.011)。放化综合治疗和单纯放疗、同步放化疗和单纯放疗以及同步放化疗和同步放化疗+（新）辅助化疗3年OS分别为90.5%和86.4%（p=0.517），94.5%和86.4%（p=0.197）和94.5%和82.3%（p=0.089）。.本研究的关键数据如下：①基于调强放射治疗局部晚期鼻咽癌的临床特征中仅合并症与PFS有关；②放疗前、放疗结束时和放疗结束后1个月血浆EBV DNA拷贝数均和预后相关，放疗结束后1个月血浆EBV DNA拷贝数对预后的预测力度可能最大；③鼻咽癌组织中EGFR染色范围阳性细胞比例为25%-75%可能是预后切点值；④分子预后模型可将局部晚期鼻咽癌患者的预后明显分开；⑤放化综合治疗较单纯放疗未明显提高OS。这些研究结果为鼻咽癌患者进行预后判断、个体化治疗以及提高治疗结果可提供一定的参考。