卡培他滨为基础一线方案治疗Her2阴性转移性乳腺癌的单中心回顾性研究及TYMP基因多态性分析

Effects of thymidine phosphorylase genetic variation on the prognosis of Her2 negative metastatic breast cancer patients treated with capecitabine based first line chemotherapy

目的:本研究旨在探讨卡培他滨为基础一线方案治疗Her2阴性转移性乳腺癌的单中心回顾性研究及TYMP基因多态性分析。方法:本研究为回顾性分析,入组患者为2010年1月到2017年12月期间在首都医科大学附属北京天坛医院乳腺科和肿瘤科确诊为Her2阴性的且接受卡培他滨为基础一线治疗的转移性乳腺癌患者共215例。收集患者的外周血液进行基因分型,并进行mRNA表达测定和相关性分析,电话随访获取患者预后数据。用Kaplan-Meier生存分析方法分析不同基因型和预后的关联,用Cox模型对其他变量进行校正。结果:纳入分析的TYMP的遗传变异位点经过NCBI数据库查阅在中国人群中突变频率大于10%,在预后分析上发现1412C>T位点的关联性。1412C>T位点在本研究中的突变频率为:CC基因型137例(63.72%),CT基因型70例(32.56%),TT基因型8例(3.72%),最小等位基因频率为0.20,符合HW平衡(P=0.798)。以显性遗传的方式把CT和TT基因型合并,对两组基因型患者进行预后分析发现:CT/TT和CC基因型患者的客观缓解率(ORR)分别为56.41%和40.15%(P=0.021),疾病控制率分别为85.90%和72.99%(P=0.029),中位无进展生存期(mPFS)分别为11.5和7.6个月(P=0.001)。另外,两组基因型患者的中位总生存期(mOS)分别为26.6和24.7个月(P=0.022)。针对PFS构建多变量的Cox模型校正后,CT/TT基因型仍然是PFS的独立影响因素(OR=0.56,P=0.011)。87例癌组织标本的mRNA表达分析结果表明CT/TT基因型患者相对于CC型患者,癌组织中TYMP的mRNA表达明显较高(P<0.001)。结论:TYMP基因1412C>T位点是卡培他滨作为基础化疗药物在一线治疗Her2阴性转移性乳腺癌患者疗效的预测因子。

AIM:To investigate the effect of thymidine phosphorylase genetic variation the(TYMP)prognosis of Her2 negative metastatic breast cancer patients treated with capecitabine based first line chemotherapy.METHODS:For retrospective analysis,215 patients with metastatic breast cancer who were diagnosed as Her2 negative and received capecitabine-based first-line treatment in the Department of Mammary and Oncology,Beijing Tiantan Hospital Affiliated to Capital Medical University between January 2010 and December 2017 were enrolled in the study.The patients'peripheral blood was collected for TYMP gene mutation site typing,and the patients'biological specimens were retained for gene expression determination.The prognostic data were obtained by telephone follow-up.Kaplan-Meier survival analysis was used to analyze the association between different genotypes and prognosis,and Cox model was used to correct other variables.RESULTS:The genetic variation included in this study wAS collected in the NCBI database with the minor allele frequency>10%in Chinese population.Of the variations analyzed,only 1412C>T was of clinical significance.The prevalence of 1412C>T in analysis population were as follows:CC 137 cases(63.72%),CT 70 cases(32.56%),TT 8 cases(3.72%),minor allele frequency of 1412C>T is 0.20,the distribution of genetic variation were in accordance with Hardy-Weinberg Equilibrium(P=0.798).The efficacy analysis of patients with CT/TT and CC genotypes found that Objective remission rates(ORR)were 56.41%and 40.15%(P=0.021).And median progression-free survival(mPFS)was 11.5 and 7.6 months,respectively(P=0.001).Furthermore,the median overall survival(mOS)of the two genotypes was 26.6 and 24.7 months,respectively(P=0.022).After the analysis in Cox proportional hazards model for PFS,CT/TT was an independent factor for PFS(OR=0.56,P=0.011).Additionally,of the 87 postoperative tissue specimens,the results showed that the mRNA expression of TYMP in cancer tissues of the patients with CT/TT and CC genotype were significant difference(P<0.001).CONCLUSION:The clinical outcomes of Her 2 negative metastatic breast cancer patients receiving capecitabine based first line chemotherapy may be influenced by TYMP 1412C>T genetic variation through mediating the mRNA expression of TYMP.