The Research Of The Relationship Between The Polymorphisms Of GSTM1, GSTT1and GSTP1with Cliniopathology Features, Chemotherapy Response And Toxicities In Breast Cancer

BackgroundBreast cancer is the most common cancer around the world, which bring a big threat tothe health to women. Anthracycline and Paclitaxel are the cornerstone of breast cancerchemotherapy. However, in clinical work, according to the body surface area, the standardprogram were given to patients who has same molecular typing, same stage and samehistological type, while, the outcome and side-effect were extreamly different. Thedrug-metabolizing enzyme related gene single nucleotide polymorphisms play an importantrole in response and toxicities with Anthracycline/Paclitaxel-based chemotherapy. Manyresearch suggested that glutathione s-transferase genes were polymorphsims, which changethe potential of drug-metabolizing enzyme, we hypothesis that it may cause the difference ofthe response and toxicity in breast cancer chemotherapy.ObjectiveTo examine the effects of genetic polymorphisms in GSTM1,GSTT1and GSTP1geneson cliniopathology features, treatment response and side-effects of breast cancer patientsreceiving Anthracycline/Paclitaxel-based chemotherapy, to assess their feasibility assensitivity and toxicity indicator of Anthracycline/Paclitaxel-based chemotherapy, and providea reference of the development of individualized and reasonable chemotherapy in clinicaltherapy.MethodsPatients who were included in the study were recruited between january2011to january 2013from The General Hospital of Ningxia Medical University, and the blood samples werecollected before treatment from252patients who were confirmed by pathology, recievingAnthracycline/Paclitaxel-based chemotherapy. The genome DNA were extract from bloodsamples, the Multiply-polymerase chain reaction(M-PCR) technique were used to examinethe genotype of GSTM1and GSTT1, the High Resolution Melting technique were used toexamine the genotype of GSTP1.Results1. The genetic polymorphisms of GSTM1, GSTT1and GSTP1genes in breast cancerpatientsIn252cases of breast cancer, GSTM1(+) genotype accounting for42.9%(108/252),GSTM1(-)genotype accounting for57.1%(144/252); GSTT1(+)genotype accounting for70.6%(178/252), GSTT1(-)genotype accounting for29.4%(74/252); GSTP1(rs1695)AAgenotype accounting for56.7%(143/252), GSTP1(rs1695)AG genotype accounting for40.5%(102/252), GSTP1(rs1695)GG genotype accounting for2.8%(7/252)。2. The The genetic polymorphismsof GSTM1, GSTT1and GSTP1genes in breast cancerand its clinical significance①There is statistic difference between GSTM1and GSTT1gene polymorphism withestrogen receptor(x2=32.302andx2=6.988, all P<0.05), and the proportion of GSTM1nullgenotyoe and GST1null genotype were higher in estrogen receptor positive group than inestrogen receptor negative group(69.94%vs33.71%,34.97%vs19.10%). no statisticdifference between GSTM1and GSTT1polymorphism with patients age, nations, menopausestates, ECOG score, and progesterone receptor, Cerb-B-2states, Ki-67indexes, tumor range,axillary lymph node metastasis, histological grading, pathological differentiation and TNMstage(P>0.05).②There was a statistic difference between GSTP1(rs1695) polymorphism with TNMstage, there were no statistic difference between GSTP1(rs1695) polymorphism with patients age, nations, menopause states, ECOG score, and progesterone receptor,strogen receptor,Cerb-B-2states, Ki-67indexes, tumor range, axillary lymph node metastasis, histologicalgrading, pathological differentiation(all P>0.05).③There was statistic difference between GSTT1gene polymorphism with moleculartype of breast cancers(x2=6.525，P=0.011), GSTT1(-)genotype accounting for88.57%(62/70)in non-tripple(Luminal A+Luminal B+Her-2overexpression) breast cancer higher than thosein tripple breast cancer11.43%(8/70)；no statistic difference were found between GSTM1andGSTP1(rs1695) gene polymorphism with molecular type(P>0.05).3、The relationships between the Polymorphisms of GSTM1, GSTT1and GSTP1onresponse with Anthracycline/Paclitaxel-based chemotherapy in breast cancer①128cases of stage IV received Paclitaxel-based chemotherapy, after2cycles ofchemotherapy,the efficacy were determined according to the RESIST criteria for all128cases of stage IV breast cancer patients:18case were complete remission,55cases werepartial remission,24cases were stable condition and31cases were disease progression. Theefficiency accounting for57.03%(73/128),and inefficiency accounting for42.97%(55/128).There was statistic difference between GSTP1(rs1695) gene polymorphismwith the Efficiency of128cases received Paclitaxel-based chemotherapy(x2=13.606,P=0.000), the Efficiency of AG/GG genotype was higher than the AA genotype(OR=4.139,95%CI:1.907~8.985),and the Efficiency of G allele carrier was higher than the A allelecarrier(x2=12.163, P=0.000)； no statistic difference were found the efficiency ofPaclitaxel-based chemotherapy with GSTM1and GSTT1gene polymorphism(P>0.05).②In128cases of stage IV received Paclitaxel-based chemotherapy,70cases in it alsoreceived Anthracycline-based chemotherapy. There was statistic difference betweenGSTP1(rs1695) gene polymorphism with the Efficiency of70cases receivedAnthracycline-Paclitaxel-based chemotherapy(x2=7.048, P=0.008), the Efficiency of AG/GGgenotype was higher than the AA genotype(OR=4.016,95%CI:1.404~11.483),and the Efficiency of G allele carrier was higher than the A allele carrier(x2=5.943, P=0.015)；nostatistic difference were found the efficiency of the combination of Anthracycline andPaclitaxel-based chemotherapy with GSTM1and GSTT1gene polymorphism.③Compared with GSTM1(+)/GSTM1(-)+GSTT1(+)/GSTT1(-)+GSTP1AG/GGcombination, GSTM1(+)+GSTT1(+)+GSTP1AA combination more likely to have badresponse(x2=14.709, P=0.000).4、The relationships between the Polymorphisms of GSTM1、GSTT1and GSTP1ontoxicity with Anthracycline/Paclitaxel-based chemotherapy in breast cancerAfter2cycles of chemotherapy,the Hematologic toxicity were determined according tothe chemotherapy drugs acute and subacute toxicity of indexing standards for all252casesbreast cancer patients.①There were no statistic difference between GSTM1, GSTT1and GSTP1(rs1695) genepolymorphism with the Hematologic toxicity of124cases received Anthracycline-basedchemotherapy(all P>0.05).②There were statistic difference between GSTP1(rs1695) gene polymorphism with theHematologic toxicity of58cases received Paclitaxel-based chemotherapy, the Neutropenia ofAG/GG genotype was severer than the AA genotype(OR=6.111,95%CI:1.526~24.469,P<0.05), and the Efficiency of G allele carrier was higher than the A allele carrier(x2=7.584,P<0.01)；no statistic difference were found the Hematologic toxicity of Paclitaxel-basedchemotherapy with GSTM1and GSTT1gene polymorphism(all P>0.05).③There were statistic difference between GSTP1(rs1695) gene polymorphism with theHematologic toxicity of70cases received Anthracycline-Paclitaxel-based chemotherapy, theNeutropenia of AG/GG genotype was severer than the AAgenotype(OR=9.257,95%CI:2.903-29.522,P<0.01),and the Efficiency of G allele carrier washigher than the A allele carrier(P<0.01)；no statistic difference were found the Hematologictoxicity of Anthracycline-Paclitaxel-based chemotherapy with GSTM1and GSTT1gene polymorphism(all P>0.05).④The GSTM1(+)+GSTT1(+)+GSTP1AA combination more likely to have severerNeutropenia than GSTM1(+)/GSTM1(-)+GSTT1(+)/GSTT1(-)+GSTP1AG/GG combination(x2=13.139, P=0.000).⑤There were statistic difference between GSTM1gene polymorphism of thehepatotoxicity with Anthracycline-Paclitaxel-based chemotherapy, No statistic difference wasfound between GSTT1and GSTP1(rs1695) gene polymorphisms on hepatotoxicity of breastcancer patients receiving Anthracycline-base chemotherapy, Paclitaxel-based chemotherapyand Anthracycline-Paclitaxel-based chemotherapy.Conclusion1. There were GSTM1(±), GSTT1(±) and GSTP1(rs1695) AA/AG/GG genotype inbreast cancer patients.2There is statistic difference between GSTM1and GSTT1polymorphism with estrogenreceptor, it may take part in Estrogen receptor pathway of breast cancer. There is statisticdifference between GSTT1(-) genotype with molecular type of breast cancer, it maycontribute to the Highly heterogeneous of breast cancer.3.GSTP1(rs1695) gene polymprphysim can be genetic markers for forecasting thechemotherapy response of breast cancer patients received Anthracycline/Paclitaxel-basedchemotherapy, GSTP1(rs1695) AA genotype resistant to chemotherapy, but AG/GG genotypewere more likely to have a better response than the AA genotype, it`s need further study forwhether given exogenous complement GST-π enzyme inhibitors or higher dose ofchemotherapy agent can improve the outcome of AA allele carriers.4. GSTP1(rs1695) gene polymorphism can be a genetic markers for forecasting theAnthracycline/Paclitaxel-based chemotherapy related Neutropenia, AG/GG genotype weremore likely to suffer a severer Neutropenia toxicity than the AA genotype and it was obviousin combined chemotherapy. Prophylactic administration of G-CSF to whom carrried GSTP1 GG/AG genotype, it can prevent the occurrence of chemotherapy-related severe marrowsuppression and protect patients completed on schedule chemotherapy.5. There were statistic difference between GSTM1gene polymorphism of thehepatotoxicity with Anthracycline-Paclitaxel-based chemotherapy.