早期乳腺癌辅助化疗进展中国医学科学院肿瘤医院徐兵河课件

早期乳腺癌辅助化疗进展BreastCancerIncidenceTrendsOverTimeCancerIncidenceTrendsinChina2005–2015

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

Source:EstimatesofCancerIncidenceinChinafor2000andProjectionsfor2005,YangL,etal.近15年来乳腺癌

发病率上升

死亡率下降

死亡率下降的原因早期诊断综合治疗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乳腺癌辅助化疗进展1960’s1970’s1980’s1990’s20002002～手术CMF1蒽环类药物AC2,CAF3,FEC4Dose5,6CEF1207,15FEC1008EC9Meta-analysis12紫杉类药物10,11,13DI14

Sequene生物治疗

1Bonadonna19762B-15,B-231990,20003SECSG19944Coombes1996

5Bonadonna19956Wood19947MA-0519988FASG2001

9Belgium200110CALGB200011B-28200012EBCTCG1998,200013TACvsFAC14CALGB974115MA.0510years!评估紫杉类乳腺癌辅助化疗的

随机临床试验CALGB9344ACvsACPNSABPB-28ACvsACP*ECTOACMFvsAPCMFBCIRG001TACvsFACNSABPB-27ACvsACTPACS01FECvsFECTECOG2197ATvsACECOG1199AC→P3vsP1vsD3vsD1……..T=多西他赛P=泰素*在化疗时同时给予三苯氧胺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是一种原癌基因，该基因与乳腺癌细胞增殖有关。约25～30%的乳腺癌Her-2过度表达。Her-2的过度表达的乳腺癌患者生存期短，预后差。成为乳腺癌治疗的理想靶点。

HER2状态:预示肿瘤对治疗的反应

内分泌治疗HER2阳性患者相对耐药

CMF方案 HER2阳性患者相对耐药

蒽环类 对蒽环类相对敏感紫杉类药物

相对敏感赫赛汀®

(曲妥珠单抗):

人源化抗HER2单克隆抗体高度亲和性(Kd=0.1nM)和特异性95%人源化,5%鼠抗，显著降低免疫原性(HAMA)全球第一种治疗实体瘤的单克隆抗体，为HER2癌基因阳性的肿瘤患者带来了新的希望！Trastuzumab是包含了完整的muMAB4D5抗原决定簇的人类IgG1κ的人体球蛋白赫赛汀®辅助治疗循证医学证据新英格兰杂志2005年10月北美研究结果发表新英格兰杂志2005年10月HERA研究结果发表新英格兰杂志2006年2月FinHER结果发表1703159114341127742383140169815351330984639334127100806040200Patients(%)Monthsfromrandomisation12361year

trastuzumabObservation0186No.

atrisk赫赛汀辅助治疗HERA研究无进展生存时间(ITT)2430EventsHR95%CIpvalue0.640.54,0.76<0.00013-year

DFS80.674.32183216.3%HERA研究DFS风险(ITT)

观察组和赫赛汀一年治疗组Monthssincerandomisation1703162714981190794407146100806040200Patients(%)MonthsfromrandomisationObservationNo.

atrisk1698160814531097711366139赫赛汀辅助治疗HERA研究总生存时间(ITT)1year

trastuzumabEventsHR95%CIpvalue0.660.47,0.910.01153-year

OS92.489.71236018624305990MedianFU2yrs2.7%赫赛汀辅助治疗北美临床N9831/B31

无进展生存时间随机分组后年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随机分组后年ACTHACTN9831/B31远处转移风险赫赛汀辅助治疗北美临床N9831/B31

总生存时间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)

无病生存率总生存率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曲妥珠单抗辅助治疗Trastuzumab:AdjuvantBreastCancerAlltrialsdemonstratedanimportantbenefitindiseasefreesurvivalinthetrastuzumab-treatedgroupSometrialsalsodemonstratedastrikingbenefitinoverallsurvivalHoweversomeconcernsexistforcardiacsafety激素受体阳性、HER-2阳性乳腺癌的全身辅助治疗组织学类型：导管癌小叶癌混合型癌化生性癌pT1、pT2或pT3；和pN0或pN1mi（腋窝淋巴结转移灶≤2mm）肿瘤≤0.5cm或微浸润或肿瘤0.6~1.0cm，且高分化pN0不进行辅助治疗pN1mi考虑辅助内分泌治疗肿瘤0.6~1.0cm，且中/低分化或伴预后不良因素辅助内分泌治疗±辅助化疗（1类）肿瘤>1cm辅助内分泌治疗+辅助化疗+曲妥珠单抗（1类）淋巴结阳性（指1个或多个同侧腋窝淋巴结有1个或多个转移灶>2mm）辅助内分泌治疗+辅助化疗+曲妥珠单抗（1类）BINV-5辅助化疗不含曲妥珠单抗的化疗方案（均为1类）FAC/CAF（氟尿嘧啶/多柔比星/环磷酰胺）或FEC/CEF（环磷酰胺/表柔比星/氟尿嘧啶）AC（多柔比星/环磷酰胺）±序贯紫杉醇EC（表柔比星/环磷酰胺）TAC（多西他赛/多柔比星/环磷酰胺）联合非格司亭支持A→CMF（多柔比星序贯环磷酰胺/甲氨喋呤/氟尿嘧啶）E→CMF（表柔比星序贯环磷酰胺/甲氨喋呤/氟尿嘧啶）CMF（环磷酰胺/甲氨喋呤/氟尿嘧啶）AC×4（多柔比星/环磷酰胺）＋序贯紫杉醇×4，每2周1次，联合非格司亭支持A→T→C（多柔比星序贯紫杉醇再序贯环磷酰胺）每2周1次，联合非格司亭支持FEC→T（氟尿嘧啶/表柔比星/环磷酰胺序贯多西他赛）TC（多西他赛和环磷酰胺）含曲妥珠单抗的化疗方案（均为1类）首选的辅助方案：AC→T＋同步曲妥珠单抗（多柔比星/环磷酰胺序贯紫杉醇＋曲妥珠单抗)其他辅助方案：多西他赛＋曲妥珠单抗→FECTCH（多西他赛、卡铂、曲妥珠单抗）化疗后序贯曲妥珠单抗AC→多西他赛＋曲妥珠单抗新辅助化疗：T＋曲妥珠单抗→CEF+曲妥珠单抗（紫杉醇＋曲妥珠单抗序贯环磷酰胺/表柔比星/氟尿嘧啶＋曲妥珠单抗）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芳香化酶抑制剂用于乳腺癌术后辅助治疗MA17试验：三苯氧胺5年＋来曲唑5年vs三苯氧胺5年IES031试验：三苯氧胺＋依西美5年vs三苯氧胺5年ATAC试验：阿那曲唑5年vs三苯氧胺5年Big-198试验：三苯氧胺5年

vs来曲唑5年vs三苯氧胺2年来曲唑3年vs来曲唑2年三苯氧胺3年辅助内分泌治疗辅助内分泌治疗绝经后芳香化酶抑制剂5年（1类）他莫昔芬2~3年芳香化酶抑制剂直至5年（1类）或更久(2B类）他莫昔芬4.5~6年芳香化酶抑制剂5年（1类）患者有芳香化酶抑制剂禁忌证或不能接受芳香化酶抑制剂，或不能耐受芳香化酶抑制剂，可以服用他莫昔芬5年（1类）BINV-1辅助内分泌治疗辅助内分泌治疗绝经前他莫昔芬2~3年（1类）±卵巢抑制/切除（2B类）绝经后绝经前BINV-I辅助内分泌治疗绝经后他莫昔芬直至5年（1类）芳香化酶抑制剂直至5年（1类）或更久（2B类）芳香化酶抑制剂5年（1类）绝经前绝经后芳香化酶抑制剂5年（1类）绝经前不进行进一步内分泌治疗BINV-I他莫昔芬直至5年（1类）ConclusionsEndocrinetherapyisaneffectiveandwell-toleratedlong-termtreatmentstrategyinreducingtheriskofrecurrenceafterprimarysurgeryThird-generationAIsarebecomingthenew‘goldstandard’inendocrinetherapyNovelTreatmentsTheerbBfamilyTargetingHer2andEGFRinbreastcancerAnti-angiogenesisTargetingVEGFsignalingpathwayswithmonoclonalantibodiesandTKIsOtherimportantpathwaysPotentialbenefitsthroughinhibitionofPARP,SRCandotherpathwaysTailoredtherapy个体化治疗（TailoredTherapy)化疗化疗化疗ThreeBreastCancerStudiesUsed

ToSelect21GenePanelPROLIFERATIONKi-67STK15SurvivinCyclinB1MYBL2ESTROGENERPRBcl2SCUBE2INVASIONStromolysin3CathepsinL2HER2GRB7HER2BAG1GSTM1REFERENCEBeta-actinGAPDHRPLPOGUSTFRCCD6816Cancerand5ReferenceGenes

BestRT-PCRperformanceandmostrobustpredictionsPaikS,etal:NEJM2004RecurrenceScore(RS)Algorithm>31Highrisk>18and<31Intermediaterisk<18LowriskRecurrenceScore(RS)CategoryScale:0to100PaikS,etal:SABCS200321-基因RT-PCR检测的应用限于ER+、淋巴结阴性肿瘤仅对接受初次化疗和他莫昔芬治疗的患者有效绝大多数HER-2阳性的患者RS较高因而主要应用于ER+、HER-2阴性、淋巴结阴性肿瘤。激素受体阳性、HER-2阴性乳腺癌的全身辅助治疗组织学类型：导管癌小叶癌混合型癌化生性癌pT1，pT2，或pT3；和pN0或pN1mi（腋窝淋巴结转移灶≤2mm）