早期乳腺癌輔助化療進(jìn)展中國醫(yī)學(xué)科學(xué)院腫瘤醫(yī)院徐兵河課件

早期乳腺癌輔助化療進(jìn)展BreastCancerIncidenceTrendsOverTimeCancerIncidenceTrendsinChina2005–2015

IncidenceRatesProjectionbyCancerTypePer100,000CAGR2.98%CAGR4.5%CAGR0.65%CAGR–2.35%CAGR0.99%CAGR2.60%

Source:EstimatesofCancerIncidenceinChinafor2000andProjectionsfor2005,YangL,etal.近15年來乳腺癌

發(fā)病率上升

死亡率下降

死亡率下降的原因早期診斷綜合治療Thebenefitsofchemotherapy

datafromclinicaltrailsEarlyBreastCancerTrialists'CollaborativeGroup(EBCTCG).194randomisedtrialsofadjuvantchemotherapy(CMF,CAF,CEF)orhormonaltherapy(TAM)thatbeganby1995.Lancet2005Placebo42.4%20.435.00102030405060Breast

cancer

mortality

(%)15-yeargain10.0%(SE1.6)Log-rank2p<0.00001Polychemotherapy32.4%Time(years)05151015.727.115-yearprobabilitiesofbreastcancer

mortality

inwomenaged

<50years,

with/withoutpolychemotherapyEBCTCG.Lancet2005;365:1687-1717Youngerwomen,35%node-positive;olderwomen,70%node-positive010203040506015-yeargain4.1%(SE1.2)Log-rank2p<0.00001Placebo57.6%Polychemotherapy53.4%48.805151035.444.129.415-yearprobabilitiesofrecurrenceinwomenaged50-69years,with/withoutpolychemotherapyTime(years)EBCTCG.Lancet2005;365:1687-1717Recurrence

(%)Youngerwomen,35%node-positive;olderwomen,70%node-positivePlacebo50.4%21.338.3010203040506015-yeargain3.0%(SE1.3)Log-rank2p<0.00001Polychemotherapy47.4%18.705151035.415-yearprobabilitiesofbreastcancermortalityinwomenaged50-69years,

with/withoutpolychemotherapyTime(years)Youngerwomen,35%node-positive;olderwomen,70%node-positiveEBCTCG.Lancet2005;365:1687-1717Breast

cancer

mortality

(%)010203040506015-yeargain9.2%(SE1.2)Log-rank2p<0.00001Placebo34.8%About5years'tamoxifen25.6%25.705151011.98.317.815-yearprobabilitiesofbreastcancermortalityinwomenwithER+(orER-unknown)disease,

with/without~5years'tamoxifenTime(years)

10,386women:20%ER-unknown,30%node-positiveEBCTCG.Lancet2005;365:1687-1717Breast

cancer

mortality

(%)010203040506001354Time(years)25-yeargain11.9%(SE1.0)Log-rank2p<0.00001Nil25.8%About5years'tamoxifenalone13.9%5-yearrecurrenceinwomenwithER+(or

ER-unknown)diseasewith

nochemotherapy,with/without~5years'

tamoxifenEBCTCG.Lancet2005;365:1687-1717Recurrence

(%)

7056women:19%node-positive01020304050600135425-yeargain10.6%(SE1.5)Log-rank2p<0.00001Chemotherapyalone28.1%Chemotherapy+about5years'tamoxifen17.5%5-yearrecurrenceinwomenwithER+(or

ER-unknown)disease

withchemotherapy,

with/without~5years'

tamoxifenTime(years)EBCTCG.Lancet2005;365:1687-1717Recurrence

(%)

3330women:53%node-positiveChemotherapyversusendocrinetherapyinthetreatmentofbreastcancerInpatientswithER+disease,tamoxifenimproves15-yearrecurrenceby11.8%andsurvivalby9.2%GainsmadewithtamoxifentreatmentappeartobeirrespectiveofadjuvantchemotherapyEBCTCG.Lancet2005;365:1687-1717乳腺癌輔助化療進(jìn)展1960’s1970’s1980’s1990’s20002002～手術(shù)CMF1蒽環(huán)類藥物AC2,CAF3,FEC4Dose5,6CEF1207,15FEC1008EC9Meta-analysis12紫杉類藥物10,11,13DI14

Sequene生物治療

1Bonadonna19762B-15,B-231990,20003SECSG19944Coombes1996

5Bonadonna19956Wood19947MA-0519988FASG2001

9Belgium200110CALGB200011B-28200012EBCTCG1998,200013TACvsFAC14CALGB974115MA.0510years!評估紫杉類乳腺癌輔助化療的

隨機(jī)臨床試驗(yàn)CALGB9344ACvsACPNSABPB-28ACvsACP*ECTOACMFvsAPCMFBCIRG001TACvsFACNSABPB-27ACvsACTPACS01FECvsFECTECOG2197ATvsACECOG1199AC→P3vsP1vsD3vsD1……..T=多西他賽P=泰素*在化療時同時給予三苯氧胺FiveYearfollow-upofINTC9741:Dose-densechemotherapyissafeandeffectiveHudisC,CitronM,BerryD,CirrincioneC,GradisharW,DavidsonN,MartinoS,LivingstonR,IngleJ,PerezE,AbramsJ,SchilskyR,EllisM,CarpenterJ,MussH,NortonL,&WinerEOnbehalfofCALGB/ECOG/SWOG/NCCTGinvestigatorsHER2+BreastCancer

andAdjuvantTherapyHer-2Her-2是一種原癌基因，該基因與乳腺癌細(xì)胞增殖有關(guān)。約25～30%的乳腺癌Her-2過度表達(dá)。Her-2的過度表達(dá)的乳腺癌患者生存期短，預(yù)后差。成為乳腺癌治療的理想靶點(diǎn)。

HER2狀態(tài):預(yù)示腫瘤對治療的反應(yīng)

內(nèi)分泌治療HER2陽性患者相對耐藥

CMF方案 HER2陽性患者相對耐藥

蒽環(huán)類 對蒽環(huán)類相對敏感紫杉類藥物

相對敏感赫賽汀?

(曲妥珠單抗):

人源化抗HER2單克隆抗體高度親和性(Kd=0.1nM)和特異性95%人源化,5%鼠抗，顯著降低免疫原性(HAMA)全球第一種治療實(shí)體瘤的單克隆抗體，為HER2癌基因陽性的腫瘤患者帶來了新的希望！Trastuzumab是包含了完整的muMAB4D5抗原決定簇的人類IgG1κ的人體球蛋白赫賽汀?輔助治療循證醫(yī)學(xué)證據(jù)新英格蘭雜志2005年10月北美研究結(jié)果發(fā)表新英格蘭雜志2005年10月HERA研究結(jié)果發(fā)表新英格蘭雜志2006年2月FinHER結(jié)果發(fā)表1703159114341127742383140169815351330984639334127100806040200Patients(%)Monthsfromrandomisation12361year

trastuzumabObservation0186No.

atrisk赫賽汀輔助治療HERA研究無進(jìn)展生存時間(ITT)2430EventsHR95%CIpvalue0.640.54,0.76<0.00013-year

DFS80.674.32183216.3%HERA研究DFS風(fēng)險(xiǎn)(ITT)

觀察組和赫賽汀一年治療組Monthssincerandomisation1703162714981190794407146100806040200Patients(%)MonthsfromrandomisationObservationNo.

atrisk1698160814531097711366139赫賽汀輔助治療HERA研究總生存時間(ITT)1year

trastuzumabEventsHR95%CIpvalue0.660.47,0.910.01153-year

OS92.489.71236018624305990MedianFU2yrs2.7%赫賽汀輔助治療北美臨床N9831/B31

無進(jìn)展生存時間隨機(jī)分組后年RomondetalNEnglJMed2005;353:1673-168487%85%67%75%HR=0.48;p<0.000110090807060500123452-yearmedianfollow-upAC

PACPHnEventsAC PH 1672 133AC P 1679 261Patients

(%)18%RomondetalNEnglJMed2005;353:1673-168401234020406080100120Rateper1000Women/Yr隨機(jī)分組后年ACTHACTN9831/B31遠(yuǎn)處轉(zhuǎn)移風(fēng)險(xiǎn)赫賽汀輔助治療北美臨床N9831/B31

總生存時間ACTH94%91%87%92%ACT

N DeathsACT 1679 92ACTH 1672 62HR=0.67,2P=0.015YearsFromRandomizationPatients(%)Years10090807001234593%86%84%80%80%91%86%77%73%n107410751073Events7798147ACDHDCarboHACD6050HR=0.49HR=0.61BCIRG006研究DFSSlamonetal2005SABCS(abstract#1)

無病生存率總生存率HR(95%CI)P值HR(95%CI)P值N9831/B-310.48(0.41~0.57)<0.000010.65(0.51~0.84)0.0007HERA0.54(0.43~0.67)<0.00010.76(0.47~1.23)<0.26FinHER0.42(0.21~0.83)0.010.41(0.16~1.08)0.07BCIRG

AC-THTCH0.61(0.48~0.86)0.67(0.54~0.83)<0.00010.00030.59(0.42~0.85)0.66(0.47~0.93)0.0040.017曲妥珠單抗輔助治療Trastuzumab:AdjuvantBreastCancerAlltrialsdemonstratedanimportantbenefitindiseasefreesurvivalinthetrastuzumab-treatedgroupSometrialsalsodemonstratedastrikingbenefitinoverallsurvivalHoweversomeconcernsexistforcardiacsafety激素受體陽性、HER-2陽性乳腺癌的全身輔助治療組織學(xué)類型：導(dǎo)管癌小葉癌混合型癌化生性癌pT1、pT2或pT3；和pN0或pN1mi（腋窩淋巴結(jié)轉(zhuǎn)移灶≤2mm）腫瘤≤0.5cm或微浸潤或腫瘤0.6~1.0cm，且高分化pN0不進(jìn)行輔助治療pN1mi考慮輔助內(nèi)分泌治療腫瘤0.6~1.0cm，且中/低分化或伴預(yù)后不良因素輔助內(nèi)分泌治療±輔助化療（1類）腫瘤>1cm輔助內(nèi)分泌治療+輔助化療+曲妥珠單抗（1類）淋巴結(jié)陽性（指1個或多個同側(cè)腋窩淋巴結(jié)有1個或多個轉(zhuǎn)移灶>2mm）輔助內(nèi)分泌治療+輔助化療+曲妥珠單抗（1類）BINV-5輔助化療不含曲妥珠單抗的化療方案（均為1類）FAC/CAF（氟尿嘧啶/多柔比星/環(huán)磷酰胺）或FEC/CEF（環(huán)磷酰胺/表柔比星/氟尿嘧啶）AC（多柔比星/環(huán)磷酰胺）±序貫紫杉醇EC（表柔比星/環(huán)磷酰胺）TAC（多西他賽/多柔比星/環(huán)磷酰胺）聯(lián)合非格司亭支持A→CMF（多柔比星序貫環(huán)磷酰胺/甲氨喋呤/氟尿嘧啶）E→CMF（表柔比星序貫環(huán)磷酰胺/甲氨喋呤/氟尿嘧啶）CMF（環(huán)磷酰胺/甲氨喋呤/氟尿嘧啶）AC×4（多柔比星/環(huán)磷酰胺）＋序貫紫杉醇×4，每2周1次，聯(lián)合非格司亭支持A→T→C（多柔比星序貫紫杉醇再序貫環(huán)磷酰胺）每2周1次，聯(lián)合非格司亭支持FEC→T（氟尿嘧啶/表柔比星/環(huán)磷酰胺序貫多西他賽）TC（多西他賽和環(huán)磷酰胺）含曲妥珠單抗的化療方案（均為1類）首選的輔助方案：AC→T＋同步曲妥珠單抗（多柔比星/環(huán)磷酰胺序貫紫杉醇＋曲妥珠單抗)其他輔助方案：多西他賽＋曲妥珠單抗→FECTCH（多西他賽、卡鉑、曲妥珠單抗）化療后序貫曲妥珠單抗AC→多西他賽＋曲妥珠單抗新輔助化療：T＋曲妥珠單抗→CEF+曲妥珠單抗（紫杉醇＋曲妥珠單抗序貫環(huán)磷酰胺/表柔比星/氟尿嘧啶＋曲妥珠單抗）BINV-JAdverseeventprofilesof

chemotherapyvstamoxifenTamoxifenChemotherapy

(CMF/FAC/FEC)HotflushesVaginaldrynessVaginaldischargeThromboemboliceventsEndometrialcancerNauseaVomitingFatigueHairlossPainCNSproblemsImmunesystemproblemsEBCTCG.Lancet2005;365:1687-1717CMF=cyclophosphamide,methotrexateandfluorouracilFAC=fluorouracil,doxorubicinandcyclophosphamideFEC=fluorouracil,epirubicinandcyclophosphamideTheriseofAIsinthetreatmentof

breastcancerTheadjuvanttreatmentofHR+earlybreastcancerhasbeenrevolutionisedinthelast5yearsAIshavechallenged5years’tamoxifenuseastheoptimumadjuvanttreatmentforpostmenopausalwomeninthissettingAIshavebeeninvestigatedinnewlydiagnosedpatientspatientswhohavestartedadjuvanttamoxifenpatientswhohavecompleted5years’tamoxifentreatmentAI=aromataseinhibitor;

HR+=hormonereceptor-positive芳香化酶抑制劑用于乳腺癌術(shù)后輔助治療MA17試驗(yàn)：三苯氧胺5年＋來曲唑5年vs三苯氧胺5年IES031試驗(yàn)：三苯氧胺＋依西美5年vs三苯氧胺5年ATAC試驗(yàn)：阿那曲唑5年vs三苯氧胺5年Big-198試驗(yàn)：三苯氧胺5年

vs來曲唑5年vs三苯氧胺2年來曲唑3年vs來曲唑2年三苯氧胺3年輔助內(nèi)分泌治療輔助內(nèi)分泌治療絕經(jīng)后芳香化酶抑制劑5年（1類）他莫昔芬2~3年芳香化酶抑制劑直至5年（1類）或更久(2B類）他莫昔芬4.5~6年芳香化酶抑制劑5年（1類）患者有芳香化酶抑制劑禁忌證或不能接受芳香化酶抑制劑，或不能耐受芳香化酶抑制劑，可以服用他莫昔芬5年（1類）BINV-1輔助內(nèi)分泌治療輔助內(nèi)分泌治療絕經(jīng)前他莫昔芬2~3年（1類）±卵巢抑制/切除（2B類）絕經(jīng)后絕經(jīng)前BINV-I輔助內(nèi)分泌治療絕經(jīng)后他莫昔芬直至5年（1類）芳香化酶抑制劑直至5年（1類）或更久（2B類）芳香化酶抑制劑5年（1類）絕經(jīng)前絕經(jīng)后芳香化酶抑制劑5年（1類）絕經(jīng)前不進(jìn)行進(jìn)一步內(nèi)分泌治療BINV-I他莫昔芬直至5年（1類）ConclusionsEndocrinetherapyisaneffectiveandwell-toleratedlong-termtreatmentstrategyinreducingtheriskofrecurrenceafterprimarysurgeryThird-generationAIsarebecomingthenew‘goldstandard’inendocrinetherapyNovelTreatmentsTheerbBfamilyTargetingHer2andEGFRinbreastcancerAnti-angiogenesisTargetingVEGFsignalingpathwayswithmonoclonalantibodiesandTKIsOtherimportantpathwaysPotentialbenefitsthroughinhibitionofPARP,SRCandotherpathwaysTailoredtherapy個體化治療（TailoredTherapy)化療化療化療ThreeBreastCancerStudiesUsed

ToSelect21GenePanelPROLIFERATIONKi-67STK15SurvivinCyclinB1MYBL2ESTROGENERPRBcl2SCUBE2INVASIONStromolysin3CathepsinL2HER2GRB7HER2BAG1GSTM1REFERENCEBeta-actinGAPDHRPLPOGUSTFRCCD6816Cancerand5ReferenceGenes

BestRT-PCRperformanceandmostrobustpredictionsPaikS,etal:NEJM2004RecurrenceScore(RS)Algorithm>31Highrisk>18and<31Intermediaterisk<18LowriskRecurrenceScore(RS)CategoryScale:0to100PaikS,etal:SABCS200321-基因RT-PCR檢測的應(yīng)用限于ER+、淋巴結(jié)陰性腫瘤僅對接受初次化療和他莫昔芬治療的患者有效絕大多數(shù)HER-2陽性的患者RS較高因而主要應(yīng)用于ER+、HER-2陰性、淋巴結(jié)陰性腫瘤。激素受體陽性、HER-2陰性乳腺癌的全身輔助治療組織學(xué)類型：導(dǎo)管癌小葉癌混合型癌化生性癌pT1，pT2，或pT3；和pN0或pN1mi（腋窩淋巴結(jié)轉(zhuǎn)移灶≤2mm）