【作者】 孙璐；

【导师】 陆劲松；

【作者基本信息】 上海交通大学 ， 外科学（普外）， 2018， 博士

【摘要】 第一部分治疗前血清GGT水平预测乳腺癌新辅助化疗疗效和副反应目的:探索治疗前血清GGT水平与局部晚期乳腺癌患者新辅助化疗疗效、远期生存及副反应的关系,评价治疗前血清GGT水平对新辅助化疗敏感性和副反应的预测价值。方法:针对接受紫杉醇联合顺铂方案前瞻性新辅助临床试验的乳腺癌患者,根据治疗前血清GGT水平分为低水平组(<28.5 U/L)和高水平组(≥28.5U/L),采用Pearson卡方检验对比两组间pCR率的差异,单因素及多因素Logistic回归模型分析GGT水平与pCR的相关性。通过ROC曲线下面积评价多因素模型的预测价值,并通过H-L拟合优度检验进行一致性检验。采用Kaplan-Meier法拟合生存曲线,通过Log-rank检验和多因素Cox比例风险回归模型进行生存分析。采用卡方检验和多因素Logistic回归模型计算治疗前血清GGT水平与副反应的相关性。结果:本研究共纳入129例乳腺癌新辅助化疗患者,在总体患者当中,治疗前血清GGT水平与pCR显著相关(tpCR:OR=0.15,95%CI 0.03-0.80,p=0.026;bpCR:OR=0.23,95%CI 0.06-0.96,p=0.043;npCR:OR=0.13,95%CI 0.03-0.54,p=0.005),GGT 低水平患者更容易获得pCR,同时无复发生存(HR=4.34,95%CI 1.11-16.93,p=0.035)和无病生存(HR=4.13,95%CI 1.09-15.62,p=0.037)更好。在 HR 阳性和HER-2阳性的患者中,也观察到相似结果。治疗前血清GGT的水平与血液系统不良反应和肝脏损伤显著相关,GGT低水平的患者3-4级血液系统不良反应发生率更高(OR=0.28,95%CI 0.10-0.80,p=0.017),尤其是中性粒细胞减少的发生率更高(OR=0.34,95%CI 0.12-0.97,p=0.044),同时肝功能异常的发生率更低(OR=4.40,95%CI1.44-13.42,p=0.009)。结论:治疗前血清GGT水平是紫杉醇联合顺铂方案新辅助化疗疗效、预后及副反应的潜在标志物。治疗前血清GGT高水平预示着较低的pCR率,较差的DFS和RFS以及较低的血液系统3-4不良反应发生率。第二部分GGT1单核苷酸多态性预测新辅助化疗疗效和副反应目的:探索GGT1 SNP与乳腺癌紫杉醇联合顺铂新辅助化疗疗效及副反应的关系,以及GGT1 SNP与血清GGT水平的相关性。方法:选取 3 个 GGT1 SNP(rs5751901,rs8135987,rs2017869),以143例接受紫杉醇联合顺铂新辅助化疗的乳腺癌患者为研究对象,接受治疗前采集的全血或组织标本为样本,对SNP进行基因分型。分别在共显性、显性、隐性和超显性模型下,通过Pearson卡方检验和多因素Logistic回归模型分析GGT1基因型与新辅助化疗疗效(pCR)及毒副反应的关系。通过多因素Logistic回归模型分析GGT1基因型与血清GGT水平的关系。结果:在疗效上,rs8135987(T>C)的TC基因型在显性(p=0.039)、超显性(OR=0.30,95%CI 0.10-0.88,p=0.029)和共显性(OR=0.30,95%CI0.09-0.90,p=0.033)模型中均与新辅助化疗 bpCR(ypT0ypN0/+)相关,TC基因型较其他基因型更不容易获得bpCR。在毒副反应上,rs8135987的超显性模型与2级以上周围神经病变的发生相关(OR=0.39,95%CI0.15-0.96,p=0.042),隐性模型与 2 级以上白细胞降低相关(OR=0.16,95%CI0.05-0.68,p=0.014)以及 AST 升高相关(OR=5.40,95%CI 1.24-23.4,p=0.024)。rs2017869 和 rs5751901 的隐性模型均与2级以上白细胞降低和中性粒细胞减少相关,其罕见等位基因纯合子白细胞和中性粒细胞减少的发生率低(p均<0.05)。在与血清GGT水平的关系上,rs8135987的TC基因型,rs5751901的CC基因型和rs201786的CC基因型均与血清GGT高水平相关。结论:GGT1 SNPs是乳腺癌紫杉醇联合顺铂新辅助化疗的疗效及副反应潜在的预测因子。GGT1 SNPs可能通过影响血清GGT水平进而影响乳腺癌患者新辅助化疗的敏感性。更多还原

【Abstract】 Section OneObject:The present study aims to evaluate the association between pre-therapeutic serum GGT level and efficacy,long-term survival and side effects of neoadjuvant chemotherapy and investigate its role in predicting the sensitivity of neoadjuvant chemotherapy in patients with breast cancer.Method:One hundred and twenty-nine patients with LABC were recruited in this study,all patients were treated with a combination of weekly paclitaxel and cisplatin as neoadjuvant chemotherapy for four cycles prior to surgery.The association of pre-therapeutic serum GGT levels with clinical-pathological parameters was examined.The correlation between pre-therapeutic serum GGT levels and outcome of tpCR,bpCR and npCR was analyzed by univariate and multivariate logistic regression.Univariate and multivariate survival analyses of RFS,DFS and OS were performed.Pearson’s chi-square test and multivariate logistic regression model were used to analyze the correlation between pre-therapeutic serum GGT level and adverse reaction.Result:Overall,pre-therapeutic serum GGT level is significantly associated with pCR(tpCR:OR=0.15,95%CI 0.03-0.80,p=0.026;bpCR:OR=0.23,95%CI 0.06-0.96,p=0.043;npCR:OR=0.13,95%CI 0.03-0.54,p=0.005),patients with low GGT level are more likely to have pCR and have a better relapse-free survival(HR=4.34,95%CI 1.11-16.93,p=0.035)and disease-free survival(HR=4.13,95%Cl 1.09-15.62,p=0.037).Subgroup analysis of HER-2 positive subgroup and HR positive subgroup shows similar results.Pre-therapeutic serum GGT level is significantly associated with adverse reactions.Low level of GGT related with higher incidence of grade 3-4 hematologic toxicity(OR=0.28,95%Cl 0.10-0.80,p=0.017)as well as grade 3-4 neutropenia(p=0.044,95%Cl 0.12-0.97,OR=0.34).But the incidence of liver enzyme elevation is lower(OR=4.40,95%Cl 1.44-13.42,p=0.009)in low level GGT patients.Therefore,we speculate that GGT might be a predictor of the efficacy of neoadjuvant chemotherapy containing paclitaxel and cisplatin and the prognosis in patients with locally advanced breast cancer.Conclusion:Pre-therapeutic serum GGT is an independent and novel prognostic biomarker for predicting the efficiency,prognosis and adverse reactions of neoadjuvant chemotherapy in patients with LABC.Patients with low pre-therapeutic serum GGT level are more likely to have higher pCR rate,better relapse-free survival and disease-free survival,as well as lower hematologic toxicity.Section TwoObject:The aim of the study was to estimate the predictive value of GGT1 SNP in predicting the efficacy and adverse reactions of neoadjuvant chemotherapy in breast cancer,and to explore the correlation between GGT1 SNP and serum GGT levels.Method:We select three GGT1 SNPs(rs5751901,rs8135987,rs201786)and these SNPs were genotyped in 143 breast patients receiving the combination of paclitaxel and cisplatin neoadjuvant chemotherapy.The relationship between GGT1 genotypes and pathologic complete response and adverse reactions of neoadjuvant chemotherapy was analyzed by chi-square test and multivariate logistic regression model.The correlation between GGT1 genotypes and serum GGT levels was analyzed by a multivariate logistic regression model.Result:The TC genotype of rs8135987(T>C)was significantly correlated with bpCR when analyzed by dominant(p=0.039),over-dominant(OR=0.30,95%CI 0.10-0.88,p=0.029)and co-dominant(OR=0.30,95%CI 0.09-0.90,p=0.033)models.TC genotype was less likely to obtain bpCR(ypTO ypN0/+)than other genotypes.The over-dominant model of rs8135987 was associated with the occurrence of grade 2 or higher peripheral neuropathy(OR=0.39,95%CI 0.15-0.96,p=0.042),and the recessive model was associated with leukopenia(OR=0.16,95%CI 0.05-0.68,p=0.014)and elevated AST(OR=5.40,95%Cl 1.24-23.4,p=0.024).Both rs2017869 and rs5751901 were associated with leukopenia and neutropenia when analyzed by recessive model,with rare occurrences of grade 2 or higher leukopenia and neutropenia(p<0.05).The dominant model(OR=3.11,95%Cl 1.07-9.0,p=0.036)and over-dominant model(OR=2.76,95%CI 0.99-7.61,p=0.05)of rs8135987,recessive models of rs2017869(univariate p=0.022;multivariate p=0.046)and rs5751901(univariate p=0.028)were all associated with high level of serum GGT.Conclusion:GGT1 SNPs are potential predictors of the efficacy and adverse reactions of DP regimen neoadjuvant chemotherapy in breast cancer rs8135987 is correlated with bpCR(ypTO ypN0/+)of neoadjuvant chemotherapy.GGT1 SNPs may affect the sensitivity of neoadjuvant chemotherapy by affecting serum GGT level.更多还原