Predictive Value Of Gamma-Glutamyltransferase And GGT1 Single Nucleotide Polymorphism For Efficacy And Adverse Reaction Of Neoadjuvant Chemotherapy In Breast Cancer

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.