| Objective: The Neoadjuvant chemotherapy(NAC) as the standardtreatment protocols for locally advanced breast cancer,(LABC) has beenextensively accepted currently. The long-term survival of breast cancerpatients who acquire pCR after NAC can be significantly improved.Inreducing tumor stage, improve the rate of breast-conserving, eliminating thesystemic micrometastases and evaluating the chemosensitivity as asusceptibility testing,NAC has outstanding advantages. However, a largenumber of clinical practice has proved the difference of chemotherapysensitivity between patients accepted neoadjuvant chemotherapy.Forinsensitive patients,they may delay the timing of local therapy, and be brougtcertain side effects of chemotherapy.With the development of molecular biology, many molecular markers ofbreast cancer have been or are being used in clinical treatment,prognosis andprediction of the efficacy of chemotherapy. Routine clinical examinationincludes ER, PR, P53, C-erbB-2,Ki-67and other biological factors at present.Angiogenesis is a capital process in tumor growth and metastasis of breastcancer and other tumors, which cannot be separated from the generation mediaof blood vessels(vascular endothelial growth factor, VEGF). The incidence ofbreast cancer involves in a variety of factors, including oncogene activationand inactivation of suppressor genes. DBC2(deleted in breast cancer, DBC2)is a candidate suppressor gene for tumor,which closely relates to sporadic,non-familial breast cancers and involves in a variety of signal transductionpathways.The main purpose of this experiment is exporing the relationshipbetween the expression status of biological factors and the response toneoadjuvant chemotherapy in breast cancer patients before neoadjuvant chemotherapy, and predicting the role of neoadjuvant chemotherapy of breastcancer before chemotherapy and then looking for biological indicators whichcoulde predict the efficacy of chemotherapy and provide a reference forguiding clinical treatment.Methods: Cases with primary breast cancer of stage IIb-IIIc from2010.5to2011.12in Breast Center of4th hospital of Hebei MedicalUniversity are45. All of the cases were women aged27-69years old and themean age was52years old.Before chemotherapy, all cases were confirmed asbreast cancer by the core needle biopsy,also the expression of ER, PR, Ki-67,P53, C-erbB-2,VEGF and DBC2was examined by the method ofimmunohistochemistry. All the patients were confirmed no distant metastasisby ultrasound, X-ray, chest and upper abdominal CT,whole body bone scanand other tests. Undergoing2-4cycles of anthracyclines program (specificprograms include EC or AC program: cyclophosphamide500mg/m~2, d1;epirubicin100mg/m~2or pirarubicin60mg/m~2, d1, every3weeks for acycle.) or taxinol and anthracyclines programs (specific programs include: TEor TEC program: epirubicin75mg/m~2, d1, paclitaxel175mg/m2ordocetaxel75mg/m~2, d2, TEC program plus cyclophosphamide500mg/m2,d1; every three weeksa cycle. TA or TAC program: pirarubicin50mg/m~2, d1,paclitaxel175mg/m2or docetaxel75mg/m~2and d2, TAC program pluscyclophosphamide500mg/m2, d1; every three weeks of a cycle)chemotherapy, we assess the efficacy of neoadjuvant chemotherapy, detect theexpression of the same biological factors by the same immunohistochemicalmethod after operation,and analyse the relationship between efficacy ofchemotherapy and biological factors by statistics,in order to find predictorsof neoadjuvant chemotherapy.Results:1The general clinical features of patients,and the clinical, pathologicalefficacyThe45patients were all female, age27-69years, median age52years.Premenopausal patients were17cases, postmenopausal patients were28 cases.According to tumor size, Phase T1were3cases, Phase T2were15cases,Phase T3were11cases, Phase T4were16cases. According to the TNM stage,Phase II were5cases Phase III were40cases. The anthracycline group were16cases, the axinol plus anthracycline group were29cases.The45patients were evaluable for clinical efficacy and pathologicalefficacy. According to WHO tumor remission criterion, clinical total effectiverate (cCR+cPR) was67.3%(30/45). the cCR were3cases (3/45,6.7%), thecPR were27cases (27/45,60.0%), the cSD were11cases (11/45,24.4%), thecPD were4cases (4/45,8.9%). The pCRwere13cases (13/45,28.9%), thecases of MP graded4-5were21cases (21/45,46.7%).2Comparison of NAC clinical efficacy between Anthracycline group andtaxinol plus anthracycline group2.1Comparison of clinical efficacyIn Anthracycline group, the total effective rate was (CR+PR):37.5%(6/16), while in axinol plus anthracycline group was82.8%(24/29).Comparedwith two groups, there was statistical difference in clinical efficiency. Intaxinol plus anthracycline group,the total effective rate was significantlyhigher than that of anthracycline group(χ~2=9.500,p=0.002). Detailed analysisof the anthracycline group:in the6cases of AC group, the total efficiency was16.7%(1/6), while the EC group (10cases), the total efficiency was50.0%(5/10), the efficiency was no significant difference in the two groups(χ~2=1.780, p=0.307). Taxinol plus anthracycline group: in the9cases of TA/TAC group, the total efficiency was88.9%(8/9), while the TE/TEC group(20cases), the total efficiency was80.0%(16/20), the efficiency was nosignificant difference in the two groups (χ~2=0.340,p=1.000).2.2Comparison of pCRIn the16cases of Anthracycline group,2cases achieved pCR(2/16,12.5%), while in the taxinol plus anthracycline group (29cases),11cases achieved pCR (11/29,37.93%), In taxinol plus anthracycline group,pCR rate was higher than that of anthracycline group, but the pCR rate was nosignificant difference in the two groups (χ~2=3.250, p=0.072). In the6cases of AC group, there were non-pCR cases, the EC group (10cases), the pCR ratewas20%(2/10), the pCR rates was no significant difference(χ~2=1.370,p=0.500). In Taxinol plus anthracycline group: the pCR rate was33.3%(3/9)in the9cases of TA/TAC group, while the pCR rate was40.0%(8/20),in the20cases of TAE/TEC group, the pCR rate was no significant difference(χ~2=0.120,p=1.000).2.3Chemotherapy response in Miller and Payne (MP) classification systemIn the16cases of Anthracycline group, the cases of grade4-5chemotherapy response were3(3/6,18.8%),while in the taxinol plusanthracycline group (29cases), the cases of grade4-5chemotherapyresponse were18(18/29,62.1%). Compared with two groups, the grade4-5chemotherapy response were significantly different (χ~2=7.770,p=0.005). Inaddition to,in Anthracycline group:in the6cases of AC group,no cases weregrade4-5chemotherapy response.While in the EC group (10cases), thepercents of grade4-5chemotherapy response were30.0%(3/10), there was nosignificant difference between two groups(χ~2=0.680,p=0.408). In the9casesof TA/TAC group, the percents of grade4-5chemotherapy response were55.6%(5/9), while the percents of grade4-5chemotherapy response were70.0%(14/20) in the20cases of TE/TEC group,there was no statisticaldifference,(χ~2=0.570,p=0.675).3The general influence factors of clinical efficacyAnalysing according to patients'age, menopausal status, clinical stage,chemotherapy cycle, we found that clinical efficacy had no significantcorrelation with age, menopausal status, clinical stage,but a positivecorrelation with chemotherapy cycle(r=0.450, p=0.002).4The relationship between molecular subtypes with neoadjuvantchemotherapy4.1The molecular subtypes and clinical efficacyIn the17cases of luminal subtype,the total clinical effective rate was64.7%(11/17), in the17cases of CerbB-2+subtype, the total clinicaleffective rate was72.2%(13/18), in the10cases of triple negative subtype, the total clinical effective rate was60.0%(6/10), there was no significantdifference between the clinical total effective rate of three subtypes (χ~2=0.481,p=0.786).4.2The molecular subtypes and pCRIn luminal subtype group,1patients achieved pCR (1/17,5.9%), inCerbB-2+subtype group,7patients achieved pCR (7/18,38.9%), while intriple negative subtypes group,6patients achieved pCR (6/10,60.0%).ThepCR rates of three subtypes were statistically different (χ~2=7.426,p=0.024).Pairwise comparisons between the three type:(1) the pCR rate ofCerbB-2+subtype was higher than that of luminal subtype, the pCR rate wassignificantly different (χ~2=5.402, p=0.020).(2) the pCR rate of triple negativesubtype was higher than that of the luminal sub type with a significantdifference (χ~2=7.090, p=0.008).(3) Compared CerbB-2+subtype and triplenegative subtype, the pCR rates was no significant difference (χ~2=0.324, p=0.569).4.3The molecular subtyps and pathological response of the MPclassification systemIn luminal subtype group, the cases of grade4-5were4(4/7,23.5%),inCerbB-2+subtype group, the cases of grade4-5were11(11/18,61.1%), intriple negative subtype group, the cases of grade4-5were7(7/10,70.0%). Thecases of grade4-5were significantly different between three subtypes (χ~2=9.449, p=0.009). Pairwise comparisons between the three subtype:(1) InCerbB-2+subgroup, the cases of grade4-5were higher than that of luminalsubtype with significant difference (χ~2=6.882, p=0.009).(2), In triple negativesubtype group, the cases of grade4-5were higher than that of than luminalsubtype,with a significant difference(χ~2=5.325, p=0.021).(3) ComparedCerbB-2+subtype and triple negative subtype, the grade4-5chemotherapyresponse was no significant difference (χ~2=0.221, p=0.638).5The preoperative relationship between expression status of biologicalfactors and neoadjuvant chemotherapy efficacy5.1The preoperative relationship between expression status of biological factors and clinic efficacy5.1.1The relationship between expression status of ER,PR and clinic efficacyIn the28cases of ER (-) group, the total clinic effective rate was67.9%(18/28); while in the17cases of ER (+) group, the total effective rate was64.7%(11/17). In ER (-) group, the clinical efficiency rate was slightly higherthan that of ER (+) group, but no significant difference (χ~2=0.047, p=0.828).In the34cases of PR (-) group, total clinical effective rate was64.7%(22/34); PR (+) group(11cases) was72.7%(8/11). In PR (-) group, theclinical efficiency slightly was lower than that of PR (+), but no significantdifference (χ~2=0.015, p=0.902).5.1.2The relationship between expression status of Ki-67,VEGF and clinicefficacyIn the the20cases of Ki-67high expression group, total clinical effectiverate was80.0%(16/20); while the group of Ki-67low expression(25cases)was56.0%(14/25). In the group of Ki-67high expression, the clinicalefficiency was higher than that of Ki-67low expression group, but nosignificant difference (χ~2=2.880,p=0.090).In the31cases of VEGF high expression group, total clinical effectiverate was77.4%(24/31); while the group of VEGF low expression(14cases)was42.9%(6/14). In the group of VEGF high expression, the clinicalefficiency was higher than that of VEGF low expression group, and there wasstatistical difference in clinical efficiency (χ2=5.184,p=0.023).5.1.3The relationship between expression status of P53,C-erbB-2,DBC2andclinic efficacyIn the14cases of P53high expression group, the clinical effective ratewas57.1%(8/14); while the group of P53low expression (31cases)was80.0%(22/31). The total effective rate was no significant difference (χ~2=0.829,p=0.362).In the17cases of C-erbB-2high expression group, the clinical effectiverate was52.9%(9/17); while the group of C-erbB-2low expression (28cases)was75.0%(21/28). The total effective rate was no significant difference (χ~2=2.316,p=0.128).In the39cases of DBC2(+) group, total clinical effective rate was69.2%(27/39); DBC2(-) group (6cases)was50.0%(3/6). In DBC2(+) group, theclinical efficiency was higher than that of DBC2(-), but no significantdifference (χ~2=0.216,p=0.642).5.2The preoperative relationship between expression status of biologicalfactors and pCR5.2.1The relationship between expression status of ER,PR and pCRIn ER (-) group of28cases,12cases achieved pCR (12/28,42.9%);while in ER (+) group(17cases),1cases achieved pCR (1/17,5.9%); In ER(-) group, the pCR rate was obviously higher than that of ER (+) group, thepCR rate was significantly different (χ~2=5.355,p=0.021).In PR (-) group of34cases,13cases achieved pCR(13/34,38.2%);while there was no pCR case inPR (+). In PR (-) group, the pCR rate wasobviously higher than that of PR (+) group, and the pCR rate was significantlydifferent between two groups(χ~2=5.915,p=0.019).5.2.2The relationship between expression status of Ki-67,VEGF and pCRIn the20cases of Ki-67high expression group,10cases achieved pCR(10/20,50.0%); while in the group of Ki-67low expression(25cases),3casesachieved pCR (3/25,12.0%);. In the group of Ki-67high expression, the pCRrate was obviously higher than that of Ki-67low expression group, the pCRrate was significantly different (χ~2=7.370,p=0.007).In the31cases of VEGF high expression group,13cases achieved pCR(13/31,41.9%); while in the group of VEGF low expression(14cases),therewas no pCR case. In the group of VEGF high expression, the pCR rate washigher than that of VEGFlow expression group, the pCR rate was significantlydifferent (χ~2=6.341,p=0.012).5.2.3The relationship between expression status of P53,C-erbB-2,DBC2andpCRIn the14cases of P53high expression group,6cases achievedpCR(6/14,42.9%); while in the group of P53low expression(31cases),7cases achieved pCR (7/31,22.6%).The pCR rate was no significant differencebetween two groups (χ~2=1.069,p=0.300).In the17cases of C-erbB-2high expression group,6cases achievedpCR(6/17,35.3%); while in the group of C-erbB-2low expression(28cases),7cases achieved pCR(7/28,25.0%). The pCR rate was no significantdifference (χ~2=0.160,p=0.690).In the39cases of DBC2(+) group,12cases achieved pCR (12/39,30.8%); while in DBC2(-) group(6cases),1cases achieved pCR (1/6,16.7%). In DBC2(+) group, the pCR rate was higher than that of DBC2(-),but no significant difference (χ~2=0.051,p=0.821).5.3The preoperative relationship between expression status of biologicalfactors and pathological response of the MP classification system5.3.1The relationship between expression status of ER,PR and pathologicalresponse of the MP classification systemIn ER (-) group of28cases, the cases of grade4-5chemotherapyresponse were17(17/28,60.7%); while in ER (+) group of17cases, the casesof grade4-5were4(4/17,23.5%). In ER (-) group,the cases of grade4-5werehigher than that of ER (+) group,and the statistical difference was significant(χ~2=5.877,p=0.015).In PR (-) group of34cases, the cases of grade4-5were19(19/34,55.9%); while in PR (+) group of11cases, the cases of grade4-5were2(2/11,18.2%). In PR (-) group, the cases of grade4-5were higher than thatof PR (+) group,and the statistical difference was significant (χ~2=4.746,p=0.024).5.3.2The relationship between expression status of Ki-67, VEGF andpathological response of the MP classification systemIn the20cases of Ki-67high expression group, the cases of grade4-5chemotherapy response were13(13/20,65.0%); while in the group of Ki-67low expression(25cases),the cases of grade4-5were8(8/25,32.0%).In thegroup of Ki-67high expression, the cases of grade4-5were higher than that ofKi-67low expression group,and the statistical difference was significant (χ~2=4.862,p=0.027).In the31cases of VEGF high expression group, the cases of grade4-5chemotherapy response were18(18/31,58.1%); while in the group of VEGFlow expression(14cases),the cases of grade4-5were3(3/14,21.4%). In thegroup of VEGF high expression, the cases of grade4-5were higher than thatof VEGF low expression group, and the statistical difference was significant(χ~2=5.201,p=0.023).5.3.3The relationship between expression status of P53,C-erbB-2,DBC2andpathological response of the MP classification systemIn the14cases of P53high expression group, the cases of grade4-5chemotherapy response were6(6/14,42.9%); while in the group of P53lowexpression(31cases), the cases of grade4-5were15(15/31,48.4%). Comparedtwo groups, the grade4-5chemotherapy response was no significantdifference (χ~2=0.118,p=0.731).In the17cases of C-erbB-2high expression group, the cases of grade4-5were8(8/17,47.1%); while in the group of C-erbB-2low expression(28cases), the cases of grade4-5were13(13/28,46.4%). the grade4-5chemotherapy response was no significant difference (χ~2=0.002,p=0.967).In the39cases of DBC2(+) group, the cases of grade4-5chemotherapyresponse were19(19/39,48.7%); while in DBC2(-) group(6cases), the casesof grade4-5were2(2/6,33.3%). Compared two groups, the grade4-5chemotherapy response was no significant difference(χ~2=0.070,p=0.792).Conclusion:1In taxinol plus anthracyclines group, the total clinical effective rate andgrade4/5pathological response in MP system were higher than that ofanthracycline group, statistical difference was significant.2In taxinol plus anthracycline group, pCR rate was higher than that ofanthracycline group, but no significant difference.3Compared EC group and AC group, TE/TEC group and TA/TACgroup,the total clinical efficiency, pCR rate and grade4/5pathologicalresponse in MP system were not statistically different. 4The clinical effective rate had no significant correlation with age,menopausal status, clinical stage,but a positive correlation with chemotherapycycl.5The CerbB-2+subtype and three negative subtype were more sensitivityto neoadjuvant chemotherapy than the luminal subtype.6In ER (-), PR (-), Ki-67high expression and VEGF high expressiongroup, the pCR rate and grade4/5pathological response in MP system wereseparately higher than that of ER (-), PR (-), Ki-67low expression and VEGFlow expression group,and the statistical difference was significant. Promptingus,ER (-) and PR (-), Ki-67high expression and VEGF high expression weremore sensitive to NAC and they could be used as predictors of NAC.7There were not significant relationship between expression status of P53,C-erbB-2,DBC2and chemotherapy efficacy, this study does not yet supportthat P53, C-erbB-2,DBC2were breast cancer predictor of NAC. |
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