| Objective:Chemotherapy can make the most breast cancer patientsbenefit,especially in patients with ER-negative or endocrine therapyresistance,therefore chemotherapy has become the treatment of breast canceressential. Neoadjuvant chemotherapy(NAC) has been widely used inclinic,and supplies opportunity to the first visit patients with inoperable.NACcan improve the percentage of breast conserved operation and can filter outthe senstive chemotherapy drugs.Postoperative chemotherapy can consolidatethe results of operations and elevate overall survival(OS) and disease freesurvival(DFS).But there is a part of breast cancer patients express with stabledisease and even show as progression disease after NAC.Relapse andmetastasis occur soon on patients who received postoperativechemotherapy.This suggests that some breast cancer patients is not senitive tochemotherapeutic drugs.Therefore,it is important to identify the patientswhether is sensitive to chemotherapeutic drugs before chemotherapy.It iscontributed to develop chemotherapy regimens,thereby enhancing theeffectiveness of chemotherapy and the potential long-term survival. NAC isan ideal model for studying the potential predictive factors of response toantitumoral agents and the molecular changes induced by anticancer treatment.In fact, molecular and pathologic markers can be analyzed in pre-andpost-treatment tissue samples and they can be correlated to the differentend-points.We selected P130/Cas,APE/ref-1,TIMP-1and TopoIIαfor studying,thereports of the relationship between the four markers and chemotherapeuticdrugs are also rare at home and abroad. P130/Cas is a key molecule inintergrin-mediated intracellular signal transdution process,it plays animportant role in cell proliferation, aggravation,differentiation aspects,and accelerating cell cycle and resistancing to apoptosis.As a multifunctionalprotein, APE/ref-1is one of the core members of the DNA-based excisionrepair pathway,it maintains the completeness and correctness of DNA byrepairing DNA damage caused by a variety of reasons. TIMP-1which is anatural inhibitor of MMPs which have been discovered in recent years hasbeen recognised as the multifunctional molecule in tumor development andgrowth process. TopoIIα plays an fundamental role in the process of DNAsynthesis,transcription,nuclear fission,as well as in the formation of correctchromosome structure, chromosome segregation and concentrated.Theexperiment has evaluated the value of the four markers as a predictor ofchemotherapy drugs by studying the relationship between their expressions atpre-and post-NAC and the effect of NAC.It provides a reference for theselection of breast cancer treatment.Methods:To measure the protein expression of P130/Cas,APE/ref-1,TIMP-1and TopoIIα by horseradish peroxidase(HRP) immunohistochemicalmethod in44breast cancer cases at pre-and post-NAC. In order to analyze therelationship of the protein expression of four markers and clinicopathologicalfactors and responses to chemotherapy.According to the solid tumors commoneffect evalutation standard of World Health Organization,44patients withbreast cancer after NAC were evaluated and divided into four groups:clinicalcompleted release(cCR), clinical partial release(cPR), clinical diseasestability(cSD),and clinical progressive disease(cPD),.Clinical effeciency wasdefined as cCR+cPR.When one marker of P130/Cas,TIMP-1and TopoIIα was studied,according to the protein expression of them,44patients weredivided into over expression group and low expression group. According tothe expression site,we divided APE/ref-1into4groups:negative group,nucleus expression group, cytoplasm expression group and nucleoplasmexpression group.Miller and Payne System(MP) was used as the pathologicalclassification of treatment,the partly pathological response was distinguishedinto1to4classes,and5class was defined as complete pathologicalresponse(pCR).SPSS13.0statistical software was applied to process all data,and the difference was statistically significant when p＜0.05.Results:1Clinical and pathological dataPatients were females with primary unilateral breast cancer,29to74years,median age is54years;17cases(38.64%) of the premenopausal andpostmenopausal27cases(61.36%).TNM stage IIB5cases(11.36%),11cases(25%)in stage IIIA,stage IIIB of13cases(29.55%),stage IIIC is15cases(34.09%);histological grade:Class I2case(s4.55%);class II11case(s25%),classIII6cases(13.64%),that can not be graded in25cases(56.81%)。Invasive ductal carcinoma in43cases(97.73%),squamous cell carcinoma in1case(2.27%).The patients were divided into2groups according to thechemotherapy:anthracycline group has13cases(29.55%), anthracycline+paclitaxel group has31cases(70.45%).17cases(38.64%)completed2cyclesNAC and27cases(61.36%) comleted4cycles NAC.2Clinical effect of chemotherapyWe carried out evaluation to clinical effect of chemotherapy after2or4cycles NAC in44breast cancer patients.The cases of cCR,cPR,cSD and cPDwere14(31.82%),15(34.09%),10(22.73%),5(11.36%).The clinicaltotal effective rate(cCR+cPR) was65.91%.After operation,we estimated thepathological efficacy,according to MP grading standards,class1to4were8cases(18.18%),4cases(9.09%),11cases(25.00%)and8cases(18.18%),class5(pCR) was13cases(29.55%).3The relationship between the protein expression of four markers pre-NACand clinicopathological factors3.1P130/CasThe level of P130/Cas protein was independent of age,menopausalstatus,the size of tumor,chemotherapy,PR and Ki-67expression(p＞0.05).There are22cases with ER positive,P130/Cas protein over expressioncases is15and low expression cases is7.The opposite expression in ERnegative group. There was significant difference between ER positive groupand negative group(p=0.016).19patients with HER2low expression,which P130/Cas protein over expression in4cases and low expression in15cases;25cases in HER2over expression group,which P130/Cas protein over expressionin18cases and low expression in7cases. There was obvious difference of thetwo groups after statistical analysis(p=0.001).Low protein expression ofP130/Cas in12cases and over protein expression of P130/Cas in5cases,the17cases with no metastasis lymph node.In27cases with metastasis lymphnode,over and low protein expression of P130/Cas groups were10cases and17cases respectively.It had correlation between metastasis lymph node andthe protein expression of P130/Cas(p=0.030).However,according to thenumber of metastasis lymph node,44patients were divided into3groups,17cases with zero,7cases with1to3and19cases with≥4metastasislymph node.There was no difference in3groups(p=0.076).3.2APE/ref-1The protein expression of APE/ref-1was unrelated with age,menopausalstatus,the size of tumor,chemotherapy, the number of metastasis lymphnode,ER,PR,HER2and Ki-67expression.(p＞0.05)3.3TIMP-1The factors of age,menopausal status,the size of tumor,chemotherapy, thenumber of metastasis lymph node,ER,PR,HER2and Ki-67expression had noeffect on The protein expression of TIMP-1.(p＞0.05)3.4TopoIIαThe factors of age,menopausal status,the size of tumor,chemotherapy, thenumber of metastasis lymph node,ER,PR,HER2and Ki-67expression had noeffect on The protein expression of TopoIIα.(p＞0.05)There are22cases withER positive, TopoIIα protein over expression cases is21and low expressioncases is1.In ER negative group, TopoIIα protein over expression cases is14and low expression cases is8. There was significant difference between ERpositive group and negative group(p=0.021).19patients with HER2lowexpression,which TopoIIα protein over expression in12cases and lowexpression in7cases;25cases in HER2over expression group,which TopoIIαprotein over expression in23cases and low expression in2cases. There was obvious difference of the two groups after statistical analysis(p=0.027).4The protein expression of P130/Cas,APE/ref-1,TIMP-1and TopoIIα inpre-and post-NACThere were9cases with low protein expression and35cases with overprotein expression of TopoIIα before NAC;after NAC,low expression grouphad18cases and over expression group had26cases.The change of TopoIIαpeotein expression had statistical fifference(χ2=16.510,P=0.001).Despite theprotein expression of P130/Cas,APE/ref-1and TIMP-1changed,there is noobviously statistcally significant(p＞0.05).5The relationship between the protein expression of four markers beforeNAC and responses to chemotherapyIn22cases with low protein expression of P130/Cas beforeNAC,chemotherapy is effective in19cases(86.36%) and ineffective in3cases(13.64%).In over protein expression of P130/Cas groups(n=22cases),there were effectively in10cases(45.45%) and ineffectively in12cases(27.27%). There was obvious difference in two groups after statisticalanalysis (χ2=8.193；p=0.010).According to the expression site,we dividedAPE/ref-1into4groups.In8cases of negative group,chemotherapy iseffective in3cases(37.5%) and ineffective in5cases(62.5%).The12cases ofnucleus expression group,chemotherapy is effective in5cases(41.67%) andineffective in7cases(58.33%). In10cases of cytoplasm expressiongroup,chemotherapy is effective in8cases(80.00%) and ineffective in2cases(20.00%). In14cases of nucleoplasm expression group,chemotherapyis effective in13cases(92.86%) and ineffective in1cases(7.14%).There wasstatistical difference in four groups(χ2=11.274；p=0.008). The differenceexpression of APE/ref-1between nucleoplasm expression group andnegative group(χ2=7.865；p=0.011) and between nucleoplasm expressiongroup and nucleus expression group (χ2=7.949, P=0.009) were bothatatistically significant.Among the other groups,pairwise comparisons were noignificant differences(p＞0.05). In27cases with low protein expression ofTIMP-1before NAC,chemotherapy is effective in21cases(77.78%) and ineffective in6cases(22.22%).In over protein expression of TIMP-1groups(n=17cases),there were effectively in8cases(47.06%) andineffectively in9cases(52.94%). There was obvious difference in two groupsafter statistical analysis (χ2=4.381；p=0.036). In9cases with low proteinexpression of TopoIIα pre-NAC,chemotherapy is effective in3cases(33.33%)and ineffective in6cases(66.67%).In over protein expression of TopoIIαgroups(n=35cases),there were effectively in26cases(74.29%) andineffectively in9cases(25.71%). There was obvious difference in two groupsafter statistical analysis(χ2=5.344；p=0.021).6The relationship between the protein expression of four markers beforeNAC and pCR rateThere were9cases(40.91%) acquired pCR in P130/Cas low expressiongroup(n=22) and4cases (18.18%) acquired pCR in P130/Cas overexpression group(n=22).The pCR rate was no significant difference(χ2=2.730；p=0.099). In APE/ref-1four groups,there were1case(12.5%),2cases(18.18%),3cases(27.27%)and7cases(50%) acquired pCR respectivelyin negative group, nucleus expression group, cytoplasm expression group andnucleoplasm expression group.The pCR rate of nucleoplasm expression groupwas significantly higher than the other three groups,but differences betweenthe four groups was not statistically significant(χ2=4.640；p=0.230).There wasnot statistically significant among the four groups after pairing and comparing(p＞0.05). There were9cases(33.33%) acquired pCR in TIMP-1lowexpression group(n=27) and4cases(23.53%) acquired pCR in TIMP-1overexpression group(n=17).The pCR rate was no significant difference(χ2=0.649；p=0.420). There were3cases(33.33%) acquired pCR inTopoIIα low expression group(n=9) and10cases(28.57%) acquired pCR inTopoIIα over expression group(n=35).The pCR rate was no significantdifference(χ2=0.078；p=1.000).Conclusion:1The protein expression of P130/Cas was related to the expression levelof ER,HER2,and metastasis lymph node,when ER and PR were over expression, lymph node was positive, the protein expression of P130/Caswas excessively. Which suggested the protein expression level of P130/Cascould help to evaluate the prognosis of breast cancer.2TopoIIα protein expression was related to the level of ER and HER2,when ER and PR were over expression, the protein expression of TopoIIα wasexcessively.But it was unrelated to age,menopausal status and other factors.Itwas demonstrated that TopoIIα could be excepted as an indicator to predict theeffect of anthracyclines chemotherapy drugs,and might be a prognosticindicator of breast cancer.3The protein expression of APE/ref-1and TIMP-1were unrelated withage,menopausal status,the size of tumor,chemotherapy drugs, the number ofmetastasis lymph node,ER,PR,HER2and Ki-67expression.(p＞0.05).4Anthracyclines chemotherapeutic drugs could reduce the proteinexpression of TopoIIα in breast cancer tissue,therefore,low expression ofTopoIIα protein after NAC could not be considerd to anthracyclineschemotherapy drugs was invalid.The protein expression of P130/Cas,APE/ref-1and TIMP-1were not changed in pre-NAC and post-NAC,which isindicated that Anthracyclines and Taxane chemotherapeutic drugs could noteffected the protein expression of the three markers.5The low expression groups of P130/Cas and TIMP-1indicated that breastcancer patients were sensitive to anthracyclines and Taxane chemotherapeuticdrugs,over expression groups indicated breast cancer patients were resistanceto them. Compared with each other,APE/ref-1nucleoplasm expression groupwas the most sensitive to Anthracyclines and Taxane chemotherapeuticdrugs,and the sensitivity of negative group was the worst. The over expressionof TopoIIα protein indicated breast cancer patients were sensitive toAnthracyclines and Taxane.6The pCR rates in different groups of the four markers were notstatistically significant,therefore,the four mrkers could not be used to predictthe rate of pCR when the patients had used Anthracyclines and Taxanechemotherapeutic drugs. |
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