The Study On The Risk Factors Of Acute Drug-induced Liver Injury Induced By TECPostoperative Adjuvant Chemotherapy Regimen In Breast Cancer

[Objective]To explore the environmental risk factors of acute drug-induced liver injury induced by postoperative adjuvant chemotherapy with TEC(docetaxel 75mg/m~2d1+epirubicin 50mg/m~2d1+cyclophosphamide 500mg/m~2d1,q3w)regimen for breast cancer,and to study the relationship between the related genetic polymorphisms involved in the pathways of drug metabolic,transport,the immune response-mediated and anti-oxidative stress and acute drug-induced liver induced by TEC postoperative adjuvant chemotherapy regimen.And susceptible single nucleotide polymorphisms were screened to provide a reference for clinical effective prevention and treatment of liver damage caused by TEC regimen.[Methods]1.A case-control study was conducted for this study.Early breast cancer patients medical record received TEC regimen adjuvant chemotherapy in the Department of Breast Surgery,Union Hospital of Fujian Medical University from September 2013 to January 2017,were gathered and the patient's exposure information was collected by case inquiry and telephone follow-up method.The RUCAM scoring system was used to assess the correlated quantitative score of drug-induced liver injury for the liver damage case reports.Univariate and multivariate Logistic regression analysis were used to analyze the risk environmental factors of liver injury caused byTEC regimen in the treament of breast cancerand to screen thestatistically significant environmental influencing factors.2.According to the pathways of TEC regimen drug metabolic,transport,immune response-mediated and anti-oxidative stress,genes related to drug-induced liver injury including transporter genes SLCO1B3,ABCB1,ABCC1,ABCC2,ABCG2,I phase metabolic enzyme genes CYP2B6,CYP1B1,CYP3A5,II phase metabolism enzyme genes GSTP1,NAT2,antioxidant enzyme gene SOD2 and human leukocyte antigen genes HLA-DRB1,HLA-DQB1,HLA-DRA and their candidate SNPs were screened bybioinformatics.The genotyping of candidate SNPs was carried out by time of flight mass spectrometry.The?~2 test was used to analyze the Hardy-Weinberg genetic balance test,the distribution differences of genotypes and alleles of SNPs in case group and control group.Unconditional logistic regression analysis was used to analyze the correlation of genotype SNPs and breast cancer postoperative adjuvant chemotherapy with TEC regimen,and to screen the susceptibility SNP locus of liver injury caused byTEC regimen.[Results]1.A total of 112 patients who met RUCAM causality assessment were included in the case group of drug-induced liver injury by TEC regimen and 284 in the control group.Univariate unconditional logistic regression analysis showed that the age and menopause were protective factors for drug-induced liver injury induced by TEC adjuvant chemotherapy for breast cancer,the ORs(95%CI)were 0.244(0.113~0.527)and 0.476(0.283~0.799)respectively.The results of multivariate conditional Logistic regression analysis showed that the OR(95%CI)of fatty liver as a risk factor for drug-induced liver injury induced by TEC regimen was 2.078(1.217~3.551),the OR(95%CI)of age as a protective factor for drug-induced liver injury was 0.246(0.100~0.608).The correlation of BMI,drinking history,fertility,high blood pressure,diabetes,liver cyst,chronic cholecystitis,gallbladder polypoid lesion,cholelith disease,hepatitis B virus carriers,high cholesterol,high LDL hematic disease,high blood triglycerides and drug-induced liver injury induced by TEC adjuvant chemotherapy regimen was not statistically significant.2.Susceptibility of SNPs to drug-induced liver injury induced by TEC chemotherapy regimen for breast cancer:the results showed that carrying genotype of SOD2 rs4880AG,ABCG2rs2331142TT increased risk of drug-induced liver injury,the ORs(95%CI)were 2.004(1.162~3.456)and 2.377(1.116~5.063)respectively.The risk for genetype AG carriers of GSTP1 rs1695 was 0.537folds(95%CI:0.313~0.920)when comparied with genetype AA.However,the correlation of CYP1B1 rs1056836,CYP2B6 rs3745274,CYP3A5 rs776746,NAT2 rs1041983,rs1799930,rs1799931,SLCO1B3 rs117703648,rs3764006,rs4149117,rs7311358,ABCB1 rs1045642,rs3747802,ABCC1 rs212091,rs2230671,rs246221,rs246240,rs3743527,rs4148350,rs4148380,rs2273697,HLA-DQB1 rs9274407,rs3129859,rs9270986 and drug-induced liver injury induced by TEC adjuvant chemotherapy regimen was notstatistically significant.[Conclusion]1.The main environmental risk factor for drug-induced liver injury caused by TEC postoperative adjuvant chemotherapy regimen in thetreament of breast cancer was fatty liver.The main protective factors were age?55 years,postmenopausal.No association was found between drinking,fertility,high blood pressure,diabetes,liver cyst,chronic cholecystitis,gallbladder polypoid lesion,cholelith disease,hepatitis B virus carriers,high cholesterol,high LDL hematic disease,high blood triglycerides and drug-induced liver injury induced by TEC regimen.2.The risk of drug-induced liver injury due to TEC chemotherapy regimen wasincreasedfor breast cancer patients carring SOD2 rs4880AG and ABCG2 rs2331142 TT,while it dropped when carring GSTP1rs1695AG.No association was found between single nucleotide polymorphism of SLCO1B3,ABCB1,ABCC1,ABCC2,ABCG2,CYP2B6,CYP1B1,CYP3A5,NAT2,HLA-DRB1,HLA-DQB1,HLA-DRA and drug-induced liver injury induced by TEC regimen.