DTCvsDEC(乳腺癌THP对比EPI张文海)

RESEARCH ARTICLENeoadjuvant chemotherapy of breast cancerwith pirarubicin versus epirubicin in combination with cyclophosphamide and docetaxelXi Gu&Shi Jia&Wei Wei&Wen-Hai ZhangReceived:22December2014/Accepted:3February2015#International Society of Oncology and BioMarkers(ISOBM)2015Abstract Breast cancers(BC)are treated with surgery,radio-therapy,and chemotherapy.Neoadjuvant chemotherapy (NACT)is an emerging treatment option in many cancers and is given before primary therapy to shrink tumor size. The efficacy of NACT in varied settings of BC,such as inop-erable tumors,borderline resectable tumors,and breast-conserving surgery,has been debated extensively in literature, and the results remain unclear and depended on a wide variety of factors such as cancer type,disease extent,and the specific combination of chemotherapy drugs.This study was per-formed to examine the efficacy,toxicity,and tolerability of pirarubicin(THP)and epirubicin(EPI)in combination with docetaxel and cyclophosphamide in a NACTsetting for BC.A total of48patients with stage II or III breast cancers were randomly divided into two groups:THP group and EPI group. The patients in THP group received2–4cycles of neoadjuvant chemotherapy with DTC regimen(docetaxel,THP,cyclo-phosphamide),while patients in the EPI group received2–4 cycles of DEC regimen(docetaxel,EPI,cyclophosphamide) before surgery.The incidence of adverse reactions and the efficacy of the treatment regimen were compared between the two groups.Prognostic evaluation indexes were estimated by Kaplan-Meier survival analysis,including the5-year dis-ease-free survival(DFS)and overall survival(OS).The over-all response rate in THP group was83.3%,and the EPI group showed a response rate of79.2%,with no statistically signif-icant difference in response rate between the two groups.The incidence of cardiac toxicity,myelosuppression,nausea,and vomiting in the THP group was significantly lower than the EPI group(all P<0.05).The incidence of hepatic toxicity,alopecia,and diarrhea in the THP group was also lower than the EPI group,but these differences were not statistically sig-nificant.The5-year DFS and OS in THP versus EPI groups were80versus76%(DFS)and86versus81%(OS),respec-tively.Our study found that NACTwith DTC regimen and DEC regimen were both very effective in treatment of BC. However,THP-based combination therapy was associated with significantly lower incidence of cardiac toxicity, myelosuppression,nausea,and vomiting.Keywords Pirarubicin.Epirubicin.Breast cancer. Neoadjuvant chemotherapy.Efficacy.Toxicity.Tolerability IntroductionBreast cancer(BC)is the most common type of noncutaneous malignancy and is the second leading cause of cancer-related death in women globally[1,2].BC is not restricted to the females,and BC in males account for1%of total BC inci-dence[3].More than one million women are diagnosed with BC annually,and approximately41%of the newly diagnosed cases are between the ages of40–50years.Women over the age of65are more likely to suffer from BC.Approximately,0, 000women died from BC in2013in USA alone,and22,000 of these women were over the age of65[4].The morbidity and mortality rates of BC are considerably different across various countries,with the highest rates found in Europe and North America,and lowest rates in Asia[5].A variety of risk factors are associated with the susceptibility to BC,including age at first birth,age at menarche,sex,age at menopause, parity,and genetic mutations[6,7].Environmental factors such as changes in reproductive patterns,physical inactivity, and obesity also play a major role in BC incidence[8,9].With an aim of improving patient prognosis and survival inBC, X.Gu:S.Jia:W.Wei:W.<H.Zhang(*)Department of Breast Surgery,Shengjing Hospital,China MedicalUniversity,Sanhao Road No.36,Heping District,Shenyang110022,People’s Republic of Chinae-mail:zhangwenhai401@Tumor Biol.DOI10.1007/s13277-015-3221-9newer techniques have been introduced,including full-field digital mammography(FFDM),digital breast tomosynthesis, and computer-aided tomography[10,11].The management of BC also depends on various factors,such as tumor stage, menopausal status,histological features,and patient age [12].BC patients are typically treated with surgery(primary therapy),followed by radiotherapy,or chemotherapy(adju-vant therapy),and this protocol significantly decreases recur-rence and death.More recently,chemotherapy before primary therapy(neoadjuvant therapy),followed by the primary ther-apy,has gained popularity,and several previous studies have reported the efficacy of neoadjuvant chemotherapies in BC [13–15].Neoadjuvant chemotherapy(NACT)is a systemic chemo-therapy before partial operation or radiotherapy of malignant tumors[16,17].NACT is a standard treatment for patients with inflammatory and locally advanced BC because it can improve surgery outcomes by shrinking tumors first[18]. NACT may increase the chance for breast conservation to allow real-time evaluation of treatment efficacy in vivo for further therapeutic intervention in BC patients[19,20]. Existing NACT protocols often include docetaxel, anthracycline,cyclophosphamide,and trastuzumab,which are effective in treatment of BC[21].Notably,anthracyclines, such as pirarubicin(THP)and epirubicin(EPI),are standard combinations in NACT regimen in BC[22].THP and EPI treatment correlates with significantly elevated disease-free and overall survival in BC[23].THP has improved antitumor activity and lower acute cardiotoxicity,with a response rate of 23.2%in advanced BC[24].EPI is one of the most frequently used chemotherapy agents in BC treatment because of its few-er side effects,e.g.,lower cardiac toxicity than doxorubicin or mitoxantrone[22].The efficacy of combination therapy is generally better than single-agent chemotherapy in many as-pects,including higher overall survival in BC patients[25].To date,multiple studies have investigated the clinical response and efficacy of THP and EPI combination regimens as adju-vant therapy in BC patients[22,24,26].Few studies focused on THP or EPI in combination with docetaxel and cyclophos-phamide in NACT setting for breast cancer treatment.In view of this,the present study examined the efficacy,toxicity,and tolerability of THP or EPI in combination with docetaxel and cyclophosphamide in the treatment of BC.Materials and methodsEthics statementThis study was performed with the approval of the Institutional Review Board of the Shengjing Hospital of China Medical University.All procedures were conducted according to the Declaration of Helsinki.Each eligible patient signed the informed consent prior to the study.Patient populationA total of48female patients,aged between32and54years (mean age:46.2years old),were recruited at the Breast Surgery Department in the Shengjing Hospital of China Medical University between January2010and December 2012.All patients included in this study met the following eligibility criteria:(1)patients were histological diagnosed as primary invasive breast cancer stage II–III via core needle biopsy before any treatment;(2)the absence of systemic dis-ease measured by chest computed tomography scan,blood chemistry,abdominal ultrasound,and bone and computed to-mography scans;(3)no previous treatment of chemotherapy or radiotherapy;(4)no history of other malignancies;(5)ad-equate hematologic function(hemoglobin>10g/dL,neutro-phil count>2.0×109/L and platelets>150×109/L);(6)ade-quate hepatic and renal function(serum total bilirubin,AST, and ALT levels of less than twice the normal upper limit,and a serum creatinine level less than1.5mg/dL);(7)normal ECG and adequate cardiac function with the left ventricular ejection fraction(LVEF)≥60%.Exclusion criteria were as follows:(1) older than65years old;(2)the maximum diameter of primary breast carcinoma less than2cm with axillary lymph node metastasis;or the maximum diameter of primary breast carci-noma over than5cm;(3)preoperative detection of chest wall and pectoral violations by chest ultrasonography;(4)obvious contraindication of chemotherapy;(5)previous history of breast operation,adjuvant chemotherapy,and radiotherapy. Clinical stage of the patients was based on the TNM staging classification of American Joint Committee on Cancer[27]. TreatmentForty-eight patients were randomized into two treatment groups with equal number of patients,THP group,and EPI group,and were given THP and EPI treatment,respectively. Baseline patient and tumor characteristics,including age, medical history,tumor stage and grade,nodal stage,estrogen receptor(ER),and progesterone receptor(PR)status,were not significantly different between the two groups.In the THP group(n=24),patients received pirarubicin(50mg/m2),do-cetaxel(75mg/m2),and cyclophosphamide(500mg/m2).In the EPI group(n=24),patients received epirubicin(75mg/ m2),docetaxel(75mg/m2),and cyclophosphamide(500mg/ m2).Both THP and EPI groups received4cycles by intrave-nous infusion every21days.Dexamethasone(8mg)was given as routine premedication by intravenous push twice per day for3days prior to docetaxel administration. Prophylactic with granulocyte colony-stimulating factor(G-CSF)was required in case of febrile neutropenia(neutrophilTumor Biol.count<2.5×106/L).Patients were seen every two cycles dur-ing the treatment for physical examination,ultrasound,and assessment of status before surgery.Patients with complete remission or partial response after two cycles of chemotherapy received surgery.Patients were counseled to withdrawn from this study,change chemotherapy regimen,or undergo salvage surgery,if progressive disease was confirmed after two cycles or the disease was stable after four cycles of treatment. Response and toxicity evaluationClinical and pathological response to neoadjuvant chemother-apy was assessed according to the Response Evaluation Criteria in Solid Tumors(RECIST version1.1)[28].The re-sponse was assessed in48BC patients at the end of NACT for both THP and EPT.A clinical complete remission(CR)was judged when there was no evidence of residual tumor in the breast and axillary lymph nodes.A30%or greater reduction in tumor diameter was graded as a partial response(PR).An increase in tumor diameter of more than20%or appearance of new disease was considered as progressive disease(PD). Tumors that did not meet the criteria for objective PR or PD were considered as stable disease(SD).The absence of inva-sive tumor in the final histological breast and axillary lymph nodes specimens was defined as pathological CR(pCR).The patients with complete and partial pathological response(CR +PR)were considered as responders,while patients with stat-ic and progressive disease(SD and PD)were considered as nonresponders.The overall response rate(RR)of the THP and EPT combination therapies was defined as the total responders among the total patients in each group.Toxicity was assessed according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version4.0(NCI-CTCAE)[29]. Follow-upKaplan-Meier estimates for prognosis of the study subjects were calculated based on the data obtained from the day of first hospitalization until death of the patient.Following the completion of the treatment regimen,patients were asked to return to the outpatient clinic for follow-ups.All patients were followed-up for survival every3months for2years,and thereafter,every6months until the death of the patient.Breast cancer risk was monitored each year of follow-up, using bilateral breast B ultrasound,breast X-ray,or MRI ex-amination,liver B ultrasound,and chest CT examination. Prognostic evaluation indexes included5-year disease-free survival(DFS)and overall survival(OS).Statistical analysisData were expressed as mean±SD.Statistical analysis was performed using the SPSS software(version18.0). Comparison of toxicity was calculated by usingχ2test and Fisher’s exact test.Nonparametric Spearman's rank test was used to measure correlations.A P value of<0.05was adopted for significance.ResultsEfficacyClinical response to therapy was measured in all patients who finished the scheduled THP or EPI chemotherapy reg-imen for four cycles.In THP group,the RR was83.3% (20/24),with4.2%(1/24)showing complete response (CR),and79.2%(19/24)showing partial response(PR) (Table1).In EPI group,the RR was79.2%,including CR and PR at8.3%(2/24)and70.8%(17/24),respectively. The results clearly showed that patients in THP group and EPI group displayed very similar clinical responses,and there was no statistically significant difference in the re-sponse rate between the two groups(all P>0.05)(Table1). Further,no statistically significant difference,in relation to pCR rate,was observed between the THP group and EPI group(both4.2%),which was postoperatively confirmed (all P>0.05)(Table1).SafetyAll48patients in THP or EPI groups were assessed for toxicity.Adverse events are summarized in Table2.With respect to hematologic toxicity,10patients in THP group and17patients in EPI group developed grade I~II neu-tropenia,which was a statistically significant differenceTable1Clinical response rates of patients with breast cancer after neoadjuvant chemotherapyGroups CR PR SD PD pCR RR(CR+RR)THP1(4.2%)19(79.2%)3(12.5%)1(4.2%)1(4.2%)20(83.3%) EPI2(8.3%)17(70.8%)5(70.8%)0(0%)1(4.2%)19(79.2%)THP pirarubicin,EPI epirubicin,CR complete remission,PR partial response,PD progressive disease,SD stable disease,pCR pathological CR,RR overall response rateTumor Biol.between the two groups(P=0.042).In addition,grade III~IV neutropenia in THP group and EPI group were observed at4%(1/24)and29%(7/24),respectively (P=0.048)(Table2).Although nausea and vomiting (WHO grades III or IV)was more frequent with EPI ther-apy compared with THP therapy(75versus37.5%;P= 0.009),grade I~II nausea and vomiting occurred more frequently in THP group compared to EPI group,at 62.5%(15/24)and25%(6/24),respectively(P=0.009) (Table2).None of the patients experienced grade III~IV cardiac toxicity in both groups,however,grade I~II car-diac toxicity occurred at4%(1/24)in THP group and 29%(7/24)in the EPI group(P=0.048)(Table2).In addition,none of the patients in both groups developed grade III~IV diarrhea and hepatic toxicity,with no signif-icant differences in grade I~II diarrhea and hepatic toxicity between the two groups.The incidence of alope-cia was also similar in both groups(P>0.05).Impact of THP and EPI chemotherapy on DFS and OSAll patients in both groups were followed-up until the death of the patient.The median follow-up of patients in THP group was8.6months,and the median time to progression(TTP) and median survival time(MST)were8.3months and 12.9months,respectively.Further,EPI group patients were followed-up with a median follow-up of9.5months,and me-dian TTP and MST were9.5months and12.3months,respec-tively.As shown in Fig.1a-b,the5-year DFS in THP and EPI groups were80%and76%,respectively.The5-year OS was 86%and81%in THP and EPI groups,respectively,and the OS was not significantly different between the two groups(all P>0.05).DiscussionNACT has been widely used in the clinical treatment of BC, especially for locally advanced breast cancer(LDBC)and inflammatory breast cancer(IBC)[30,31].NACT is also suit-able for operable BC patients with larger sized tumors,axillary lymph node metastasis,or other recurrence and metastases [32].NACT allows real-time assessment of early in vivo re-sponse to chemotherapy and provides the flexibility to choose the subsequent primary therapy in BC patients to improve therapy success[33].In recent years,a variety of combination therapies have been introduced into clinics for BC treatment and have proven to be effective[34–36].Previous clinical studies showed that anthracyclines,combined with paclitaxel chemotherapy drugs,displayed higher overall response rates compared with single-agent chemotherapy in BC treatment [37,38].Accordingly,docetaxel,combined with cyclophos-phamide or anthracycline,is a first-line treatment in NACT. However,these combination therapies may also carry severe side effects[39,40].Table2Adverse events and hematologic toxicity in breast cancer patients after treated with pirarubicin(THP)-based neoadjuvant chemotherapy and epirubicin(EPI)-based neoadjuvant chemotherapyTHP pirarubicin,EPI epirubicin Toxicity THP EPI PNeutropeniaI~II10170.042 III~IV170.048 Nausea/vomitingI~II1560.009 III~IV9180.009 DiarrheaI~II410.348 III~IV00AlopeciaI~II12 1.000 III~IV2322 1.000 Hepatic toxicityI~II250.416 III~IV00Cardiac toxicityI~II170.048 III~IV00Fig.1Impact of pirarubicin andepirubicin chemotherapy on the5-year disease-free survival andoverall survival.a Thecomparison of the5-year disease-free survival rate between groups.b The comparison of the5-yearoverall survival rate betweengroupsTumor Biol.The primary objective of this current study was to assess the efficacy and safety of THP-based combination therapy and the EPI-based combination therapy in the treatment of BC patients.In our study,we found that the overall response rate in THP group was83.3%,and the overall response rate in EPI group was79.2%,with no significant differences between the two therapies.The results revealed that both THP-based com-bination therapy and EPI-based combination therapy were equally effective therapies for BC treatment,and both treat-ments relieved the symptom and improve the prognosis of BC in this patient cohort.THP is a derivate of doxorubicin(also known as Adriamycin,ADM),and THP shows higher antitu-mor activity in vivo and a significantly lower acute cardiac toxicity compared to ADM[41,42].On the other hand,EPI is an isomer of ADM,and its efficacy is similar to ADM in treating BC,but has lower cardiac toxicity compared to ADM[43,44].CPF regimen(THP,cyclophosphamide and 5-fluorouracil combination)and CEF regimen(EPI,cyclo-phosphamide and5-fluorouracil combination)improved the prognosis in BC patients,and both are effective in adjuvant chemotherapy of BC[22].Ying Li et al.showed that the5-year survival rate of BC patients treated with FPC regimen (fluorouracil–pirarubicin-cyclophosphamide)was88.7%, and for BC patients treated with FEC regimen(fluorouracil–epirubicin–cyclophosphamide),the5-year survival rate was 85.7%.These result showed that THP and EPI are useful chemotherapy drugs for BC patients in various combinations [24].Our results are consistent with previous studies and show that the overall response rates were excellent for both THP-based combination therapy and EPI-based combination thera-py in treatment of BC and both chemotherapy regimens im-proved the outcomes in BC patients.In this study,we found that the incidence of cardiac toxic-ity,myelosuppression,and nausea and vomiting in THP group were significantly lower than the EPI group.The incidence of nausea and vomiting in grades III or IV was more frequent in the EPI group compared to THP therapy,while the incidence of grade I~II nausea and vomiting occurred more frequently in the THP group compared to the EPI group.The observed grade I~II nausea and vomiting caused by the combination therapies were alleviated after completion of adjuvant therapy. Therefore,the results suggest that the toxicity of THP-based combination therapy is milder compared with EPI-based com-bination therapy.It is known that limiting or eliminating tox-icity and side effects of chemotherapy drugs is crucial in can-cer therapy[45–47],and a good tolerance to combination therapy is associated with better prognosis of BC patients [22,34,35].BC patients treated with FPC and FEC regimens often suffer gastrointestinal toxicity and leucopenia,negative-ly influencing the prognosis of BC patients[24].Zang MF et al.,demonstrated that the incidence of gastrointestinal reac-tions in nausea and vomiting was significantly lower in the TAC group(pirarubicin in combination with docetaxel and cyclophosphamide)compared to TEC group(epirubicin in combination with docetaxel and cyclophosphamide)[48]. Thus,our results provide important information of drug com-binations for NACT in BC,with the purpose of improving patient survival.In summary,our results support the view that BC patients treated with the THP-based combination therapy or EPI-based combination therapy were associated with excellent overall response rates.Patients treated with THP-based combination therapy exhibited lower toxicity;therefore,the use of THP in chemotherapy drug combination is favorable based on our study results.Acknowledgments This study was supported by the Science and Tech-nology Research Project of Liaoning Province(No.2012225016).We would like to acknowledge the reviewers for their helpful comments on this paper.Conflicts of interest NoneReferences1.Jemal A,Siegel R,Xu J,Ward E.Cancer statistics,2010.CA CancerJ Clin.2010;60:277–300.2.Assi HA,Khoury KE,Dbouk H,Khalil LE,Mouhieddine TH,et al.Epidemiology and prognosis of breast cancer in young women.J Thorac Dis.2013;5:S2–8.3.Germano S,O’Driscoll L.Breast cancer:understanding sensitivityand resistance to chemotherapy and targeted therapies to aid in personalised medicine.Curr Cancer Drug Targets.2009;9(3):398–418.4.Anders CK,Carey LA.Biology,metastatic patterns,and treatment ofpatients with triple-negative breast cancer.Clin Breast Cancer.2009;9Suppl2:S73–81.5.Tam C,Li Q,Friedenreich C,Martin LJ,Hislop G,Hanley AJ,et al.Lifetime physical activity in postmenopausal Caucasian and Chinese-Canadian women.Eur J Cancer Prev.2014;23(2):90–5.6.Nickels S,Truong T,Hein R,Stevens K,Buck K,et al.Evidence ofgene-environment interactions between common breast cancer sus-ceptibility loci and established environmental risk factors.PLoS Genet.2013;9:e1003284.7.Reeves GK,Pirie K,Green J,Bull D,Beral V,et parison ofthe effects of genetic and environmental risk factors on in situ and invasive ductal breast cancer.Int J Cancer.2012;131:930–7.8.Lee SA,Shu XO,Li H,Yang G,Cai H,et al.Adolescent and adultsoy food intake and breast cancer risk:results from the Shanghai Women’s Health Study.Am J Clin Nutr.2009;89:1920–6.hart IM,Reichl C,Metsios GS,Nevill AM,Carmichael AR.Physical activity and awareness in breast screening attendees in Black Country,UK.Health Promot Int.2014;doi:10.1093/heapro/ dau053.10.Waldherr C,Cerny P,Altermatt HJ,Berclaz G,Ciriolo M,et al.Valueof one-view breast tomosynthesis versus two-view mammography in diagnostic workup of women with clinical signs and symptoms and in women recalled from screening.AJR Am J Roentgenol.2013;200: 226–31.11.Azavedo E,Zackrisson S,Mejare I,Heibert Arnlind M.Is singlereading with computer-aided detection(CAD)as good as double reading in mammography screening?A systematic review.BMC Med Imaging.2012;12:22.Tumor Biol.12.Campiglio M,Sandri M,Sasso M,Bianchi F,Balsari A,Menard S,et al.Prognostic role of tumor size in T1HER2-positive breast can-cers treated with adjuvant trastuzumab.Ann Oncol.2014;25(5): 1073–4.13.Collins B,MacKenzie J,Tasca GA,Scherling C,Smith A.Cognitiveeffects of chemotherapy in breast cancer patients:a dose-response study.Psychooncology.2013;22:1517–27.14.Martin-Castillo B,Dorca J,Vazquez-Martin A,Oliveras-Ferraros C,Lopez-Bonet E,et al.Incorporating the antidiabetic drug metformin in HER2-positive breast cancer treated with neo-adjuvant chemother-apy and trastuzumab:an ongoing clinical-translational research ex-perience at the Catalan Institute of Oncology.Ann Oncol.2010;21: 187–9.15.Hurley J,Reis IM,Rodgers SE,Gomez-Fernandez C,Wright J,et al.The use of neoadjuvant platinum-based chemotherapy in locally ad-vanced breast cancer that is triple negative:retrospective analysis of 144patients.Breast Cancer Res Treat.2013;138:783–94.16.Byrski T,Gronwald J,Huzarski T,Grzybowska E,Budryk M,et al.Response to neo-adjuvant chemotherapy in women with BRCA1-positive breast cancers.Breast Cancer Res Treat.2008;108:289–96.17.Smith IC,Heys SD,Hutcheon AW,Miller ID,Payne S,et al.Neoadjuvant chemotherapy in breast cancer:significantly enhanced response with docetaxel.J Clin Oncol.2002;20:1456–66.18.Sanchez-Munoz A,Plata-Fernandez Y,Jaen A,Lomas M,FernandezM,et al.Proliferation determined by ki67marker and pCR in locally advanced breast cancer patients treated with neo-adjuvant chemother-apy.Breast J.2013;19:685–6.19.Guarneri V,Frassoldati A,Bottini A,Cagossi K,Bisagni G,et al.Preoperative chemotherapy plus trastuzumab,lapatinib,or both in human epidermal growth factor receptor2-positive operable breast cancer:results of the randomized phase II CHER-LOB study.J Clin Oncol.2012;30:1989–95.20.Yamaguchi T,Mukai H.Ki-67index guided selection of preoperativechemotherapy for HER2-positive breast cancer:a randomized phase II trial.Jpn J Clin Oncol.2012;42:1211–4.21.von Minckwitz G,Untch M,Nuesch E,Loibl S,Kaufmann M,et al.Impact of treatment characteristics on response of different breast cancer phenotypes:pooled analysis of the German neo-adjuvant che-motherapy trials.Breast Cancer Res Treat.2011;125:145–56.22.Li JJ,Di GH,Tang LC,Yu KD,Hu Z,et al.Adjuvant therapy ofbreast cancer with pirarubicin versus epirubicin in combination with cyclophosphamide and5-fluorouracil.Breast J.2011;17:657–60. 23.Gennari A,Sormani MP,Pronzato P,Puntoni M,Colozza M,et al.HER2status and efficacy of adjuvant anthracyclines in early breast cancer:a pooled analysis of randomized trials.J Natl Cancer Inst.2008;100:14–20.24.Li Y,Tang JH,Huang XE,Li CG.Clinical comparison on the safetyand efficacy of fluorouracil/pirarubicin/cyclophosphamide(FPC) with fluorouracil/epirubicin/cyclophosphamide(FEC)as postopera-tive adjuvant chemotherapy in breast n Pac J Cancer Prev.2011;12:1795–8.25.Chlebowski RT.Re:International guidelines for management of met-astatic breast cancer:combination vs sequential single-agent chemo-therapy.J Natl Cancer Inst.2010;102:137.26.Li JF,Ouyang T,Wang TF,Lin BY.Neoadjuvant chemotherapy forprimary breast cancer.Chin J Oncol.2004;26:493–5.27.Singletary SE,Allred C,Ashley P,Bassett LW,Berry D,et al.Revision of the American joint committee on cancer staging system for breast cancer.J Clin Oncol.2002;20:3628–36.28.Eisenhauer EA,Therasse P,Bogaerts J,Schwartz LH,Sargent D,et al.New response evaluation criteria in solid tumours:revised RECIST guideline(version1.1).Eur J Cancer.2009;45:228–47. 29.Chen AP,Setser A,Anadkat MJ,Cotliar J,Olsen EA,et al.Gradingdermatologic adverse events of cancer treatments:the common ter-minology criteria for adverse events version4.0.J Am Acad Dermatol.2012;67:1025–39.30.Gianni L,Pienkowski T,Im YH,Roman L,Tseng LM,et al.Efficacyand safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced,inflammatory,or early HER2-positive breast cancer(NeoSphere):a randomised multicentre,open-label,phase2 ncet Oncol.2012;13:25–32.31.Gianni L,Eiermann W,Semiglazov V,Manikhas A,Lluch A,et al.Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone,in patients with HER2-positive locally advanced breast cancer(the NOAH trial):a randomised controlled superiority trial with a parallel HER2-negative ncet.2010;375:377–84.32.Rousseau C,Devillers A,Campone M,Campion L,Ferrer L,et al.FDG PET evaluation of early axillary lymph node response to neo-adjuvant chemotherapy in stage II and III breast cancer patients.Eur J Nucl Med Mol Imaging.2011;38:1029–36.33.Rastogi P,Anderson SJ,Bear HD,Geyer CE,Kahlenberg MS,et al.Preoperative chemotherapy:updates of national surgical adjuvant breast and bowel project protocols B-18and B-27.J Clin Oncol.2008;26:778–85.34.Baselga J,Cortes J,Kim SB,Im SA,Hegg R,et al.Pertuzumab plustrastuzumab plus docetaxel for metastatic breast cancer.N Engl J Med.2012;366:109–19.35.Swain SM,Ewer MS,Cortes J,Amadori D,Miles D,et al.Cardiactolerability of pertuzumab plus trastuzumab plus docetaxel in patients with HER2-positive metastatic breast cancer in CLEOPATRA:a ran-domized,double-blind,placebo-controlled phase III study.Oncologist.2013;18:257–64.36.Mehta RS,Barlow WE,Albain KS,Vandenberg TA,Dakhil SR,et al.Combination anastrozole and fulvestrant in metastatic breast cancer.N Engl J Med.2012;367:435–44.37.Dear RF,McGeechan K,Jenkins MC,Barratt A,Tattersall MH,et al.Combination versus sequential single agent chemotherapy for meta-static breast cancer.Cochrane Database Syst Rev.2013;12, CD008792.38.Carrick S,Parker S,Thornton CE,Ghersi D,Simes J,et al.Singleagent versus combination chemotherapy for metastatic breast cancer.Cochrane Database Syst Rev.2009.CD003372.39.Joensuu H,Kellokumpu-Lehtinen PL,Huovinen R,Jukkola-Vuorinen A,Tanner M,et al.Adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for breast can-cer:an open-label,randomised controlled ncet Oncol.2009;10:1145–51.40.Piccart-Gebhart MJ,Burzykowski T,Buyse M,Sledge G,Carmichael J,et al.Taxanes alone or in combination with anthracyclines as first-line therapy of patients with metastatic breast cancer.J Clin Oncol.2008;26:1980–6.41.Wang LZ,Ouyang T,Wang TF,Xie YT,Fan ZQ,et al.Efficacyanalysis of THP-containing regimens as neoadjuvant and adjuvant chemotherapy for primary breast cancer.Chin J Oncol.2012;34:143–6.42.van Dalen EC,Michiels EM,Caron HN,Kremer LC.Differentanthracycline derivates for reducing cardiotoxicity in cancer patients.Cochrane Database Syst Rev.2010.CD005006.43.Untch M,von Minckwitz G,Konecny GE,Conrad U,Fett W,et al.PREPARE trial:a randomized phase III trial comparing preoperative, dose-dense,dose-intensified chemotherapy with epirubicin,paclitax-el,and CMF versus a standard-dosed epirubicin-cyclophosphamide followed by paclitaxel with or without darbepoetin alfa in primary breast cancer-outcome on prognosi.Ann Oncol.2011;22:1999–2006.44.Joensuu H,Kellokumpu-Lehtinen PL,Huovinen R,Jukkola-Vuorinen A,Tanner M,et al.Adjuvant capecitabine,docetax-el,cyclophosphamide,and epirubicin for early breast cancer: final analysis of the randomized FinXX trial.J Clin Oncol.2012;30:11–8.Tumor Biol.。