紫杉醇通路基因单核苷酸多态性与转移性食道鳞癌治疗疗效及毒性的相关性分析

The incidence of esophageal squamous cell carcinoma (ESCC) in China ranked the first worldwide. Most patients were initially found in advanced stages already. The five year survival was less than 20% and the median survival time was less than 10 months. It seriously threat people’s health and life. Chemotherapy with paclitaxel was the most optimal choice for late stage ESCC; however, individuals responded differently to paclitaxel. Moreover, the toxicity of paclitaxel was not neglectable, and sometimes severe and irreversible. Currently, there were no valid biomarkers to predict the treatment response and toxicity of paclitaxel. Single nucleotide polymorphisms (SNPs) were a form of genetic varieties and played an important role in pharmacokinetics such as drug uptake, transportation, and metabolism and clearance; and pharmacodynamics. We would conduct a prospective cohort study, which would recruit 600 patients of ESCC, and collect blood samples; and then we genotyped several SNPs from the taxel pathway using iPLEX Gold SNP sequencing method. By survival analysis and Logistic regression, we would further explore the association between genetic variations and treatment response and toxicity of paclitaxel, which might help determine clinical practice and achieve precision medicine.

我国食道鳞癌的发病率居世界第一，一经发现多为中晚期，五年生存率不足20%，中位生存期不足10个月，严重威胁人民的生命与健康。含紫杉醇的化疗方案为中晚期食道鳞癌的一线选择，但个体对紫杉醇的反应各异；同时紫杉醇也会带来不同程度的不良反应，有的甚至是严重不可逆的。迄今为止，临床上缺乏预测紫杉醇疗效与毒性的分子标志物，无法做到个体化精准医疗。单核苷酸多态性（SNP）作为基因变异的形式之一，在药物的摄取、转运、代谢、清除等药代动力学及药效动力学上均有重要的影响。该课题采用前瞻性队列研究设计，拟在项目计划时间内招募共600名食道鳞癌患者，收集血液标本，采用iPLEX Gold SNP的方法，检测多个紫杉醇通路的SNP位点，应用生存分析及Logistic回归等统计学方法，探索紫杉醇通路SNP与食道鳞癌治疗疗效及毒性的关系，指导临床个体化用药及不良反应的预防，协助临床的诊治。

我国食道癌的发病与死亡占全球半数以上，病理以鳞癌为主，在恶性肿瘤中发病率排第三位，死亡率排第四位，五年生存率不足20%，预后差。国际上对于食道鳞癌相关的精准医疗的研究远远落后于其它癌种，临床上诊治缺乏依据与规范。目前在我国，含紫杉醇的化疗方案为中晚期食道鳞癌的一线选择，但个体疗效不一，且具备较强毒性。迄今临床上缺乏预测紫杉醇疗效与毒性的分子标志物。..本研究系统整理分析我科食道癌患者的诊断、治疗及随访等情况，首次构建临床预后模型，将肿瘤位于25cm及以下，腹腔腹膜后淋巴结转移，血行转移，白蛋白<39g/L作为食道鳞癌预后不良的风险因素，以风险因素总得分对患者行预后分层，可以有效预测预后，指导临床治疗决策。此外，本研究还发现，在体力状态好的患者中，二线及以上的积极治疗，可有效延长生存，并且推荐采用系统治疗与放疗及介入等局部治疗相结合的综合治疗策略，可以进一步改善预后。..研究发现，应用紫杉醇类药物治疗前，测定基因CYP1B1 rs1056836及ABCB1 rs1045642多态性，可指导用药，必要时减量，避免重度不良反应，尤其是末梢神经毒性。ABCC2 rs3740066基因多态性可提示患者预后，以对患者进行分层管理，根据预后制定不同的治疗方案，实现精准医疗。