复发或转移性乳腺癌的治疗策略培训课件

复发或转移性乳腺癌的治疗策略优选复发或转移性乳腺癌的治疗策略复发或转移性乳腺癌的現状大部分转移性乳腺癌是早期乳腺癌治疗后复发的病例<10%初诊时即为转移性乳腺癌常见的转移部位是骨、肝、肺和中枢神经系统50-75%患者仅有单一脏器受累全乳切除术后局部复发通常发生于胸壁及表面的皮肤这些患者中25%-30%出现远处转移复发或转移性乳腺癌的治疗目标控制肿瘤相关症状提高生活质量，改善无进展生存期延长总生存

晚期转移性乳腺癌的治疗选择

细胞毒药物蒽环类紫杉类卡培他滨长春瑞滨吉西他滨

激素类药物三苯氧胺芳香化酶抑制剂FulvestrantLHRH拮抗剂靶向治疗

EGFR抑制:Trastuzumab,Pertuzumab?T-DM1?

信号传导抑制剂:Lapatinib

Gefetinib?Erlotinib?

血管生成抑制剂:Bevacizumab双磷酸盐类支持与姑息治疗复发或转移性乳腺癌治疗指南(NCCN2011-2)内分泌治疗化疗靶向治疗靶向治疗复发或转移性乳腺癌治疗策略复发或转移性乳腺癌ER和或PR阳性内分泌治疗ER和或PR阴性化疗内分泌治疗失败HER2阳性化疗+曲妥珠单抗HER2阴性化疗化疗+拉帕替尼Logrankp=0.NonvisceraldiseaseAvastin+paclitaxel

E21002005AI失败者可选孕激素（如甲地孕酮）或氟维司群与紫杉醇相比，健择®联合紫杉醇可显著延长OSEMBRACE:Randomized,Open-LabelPhaseIIITrial(PrimaryEndpointOS)复发或转移性乳腺癌化疗适应症辅助治疗仅用内分泌治疗而未用化疗的患者可以选择CMF,CAF,AC方案。6mg 卵巢切除术

AnnOncol 或卵巢照射 或卵巢照射

1994;5:337–42.HER2阳性转移性乳腺癌的治疗<10%初诊时即为转移性乳腺癌Jahanzebetal.Brufskyetal2005存在广泛转移,特别是内脏转移（肝,肺）Lapatinib+卡培他滨治疗难治转移性乳腺癌

(EGF100151研究)HormonereceptorpositiveDocetaxel

Chan1999TwelvesC,etal.EMEAAvastinEuropeanPublicAssessmentReport,2007复发或转移性乳腺癌治疗细胞毒药物化疗内分泌治疗生物靶向治疗局部治疗姑息治疗复发或转移性乳腺癌化疗适应症DFS较短存在广泛转移,特别是内脏转移（肝,肺）疾病迅速进展内分泌治疗无效复发或转移性乳腺癌化疗

RR（CR)1960’s非蒽环类药单药化疗20～40％（0）1970’s非蒽环类药联合化疗50%（10％）70’末蒽环类药单药化疗30～50％(10％）1980’s含蒽环类药联合化疗50～70％（10～15％）1990’s紫杉类及其联合方案，60％～80％（15％）化疗＋靶向治疗

复发或转移性乳腺癌首选化疗药物蒽环类多柔比星表柔比星脂质体多柔比星紫杉类紫杉醇多西他赛白蛋白结合的紫杉醇健择®卡培他滨长春瑞滨

复发或转移性乳腺癌首选化疗方案CMF(CTX+MTX+5FU)CAF/FAC(CTX+ADM+5FU)CEF/FEC(CTX/EPI+5FU)AC(ADM+CTX)EC(EPI+CTX)AT(ADM+DTX，ADM+PTX)GT(GEM+PTX)XT(Xel+DTX)AvsTvsATTTFOS复发或转移性乳腺癌的化疗

蒽环类和紫杉类目前最有效的乳腺癌化疗方案之一适用于未用过蒽环类和紫杉类的复发转移患者，如CMF辅助治疗失败乳腺癌患者复发转移患者中应用机会不多蒽环类成为辅助治疗基本药物后，复发或转移性乳腺癌的一线治疗？XDvsD:SurvivalO’ShaughnessyJ,etal.JClinOncol,2002;20:2812-2823.TTP

OSXT(n=255) 42%

T

(n=256) 30%ORRp=0.0060612182430364248 1.00.80.60.40.20.0OverallSurvivalTime(months)G,GEM;T,PTX;lbainetal.JClinOncol2008;26(24):X-X.与紫杉醇相比，健择®联合紫杉醇可显著延长OS18219518.6(16.6,20.7)15.8(14.4,17.4)TGTN

Events

Median(95%CI)266263HR=0.82(95%CI:0.67,1.00)Logrankp=0.0489ProbabilityHR=0.70(95%CI:0.59,0.85)Logrankp=0.0002Events227237Median(95%CI)6.1(5.3,6.7)4.0(3.5,4.4)06121824303642 481.00.80.60.40.20.0MonthsTGTProbabilityAlbainetal.JClinOncol2008;26(24):X-X.与紫杉醇相比，健择®联合紫杉醇可显著延长TTP

与紫杉醇相比，健择®联合紫杉醇可显著提高ORRGTArm

(N=266)TArm

(N=263)CR(%)7.94.6PR(%)33.521.7Totalresponses(%)41.426.295%CI

(35.4,47.3)(20.9,31.6)p-value0.0002Albainetal.JClinOncol2008;26(24):X-X..健择®联合多西紫杉醇vs.卡培他滨联合多西紫杉醇:

PFS相近ProgressionFreeSurvival(months)

N

Events

Median(95%CI)53 151 8.05(6.60,8.71)152 142 7.98(6.93,8.77)Logrankp=0.121HR=1.20(95%CI:0.96,1.50)GD

CD0 10203040 50Probability1.00.80.60.40.20.0D,DTX;G,GEM;C,CapeChanSetal.Presentedat:SanAntonioBreastCancerConference,December13-16,2007;SanAntonio,Texas.20*InvestigatorassessedGDArm

(N=153)CDArm(N=152)p-valueORR*,%32320.931CR,%53PR,%2729MedDR,mos7.759.070.047MedTTF,mos4.244.070.059MedOS,mos19.2921.450.983健择®联合多西紫杉醇vs.卡培他滨联合多西紫杉醇:

ORR,TTF,OSChanSetal.Presentedat:SanAntonioBreastCancerConference,December13-16,2007;SanAntonio,Texas.健择®联合多西紫杉醇→卡培他滨vs.

卡培他滨联合多西紫杉醇→健择®GD→C较CD→G方案二线治疗阶段及总的TTP更长注：健择®在中国批准的适应症为联合紫杉醇治疗复发或转移性乳腺癌targetedtherapyGDPaclitaxel

Seidman2004ProbabilityJonesetal.OS:notsignificant,*P<0.GT(GEM+PTX)1990’s紫杉类及其联合方案，60％～80％（15％）复发或转移性乳腺癌治疗Slamonetal.0 2 4 6 8 10 12 14P值(log-rank,1-side)O’ShaughnessyJ,etal.Avastin+paclitaxel

E21002005*Assessedinpatientswithmeasurablediseaseatbaseline:n=1105forchemotherapy单药序贯化疗？联合化疗？CAF/FAC(CTX+ADM+5FU)CobleighetalAbstract1005.Albainetal.(n=159) (n=159) (n=159) (n=159)

31 38 29月 32月Martyetal.2005紫杉醇+健择紫杉醇

+赫赛汀多西紫杉醇+健择

紫杉类各种治疗方案治疗转移性乳腺癌的RR多西紫杉醇+赫赛汀单药多西紫杉醇多西紫杉醇＋希罗达Slamonetal.2001Melemedetal.2007E21002007紫杉醇

+贝伐Jonesetal.2005Melemedetal.2007E21002007Slamonetal.2001Jonesetal.2005Martyetal.2005O’Shaughnessyetal.2002O’Shaughnessyetal.2002Chanetal.2005Chanetal.2005*********仅包括有可测量病灶的患者SlamonDJ,etal.NEnglJMed2001;344:783–92;O’ShaughnessyJ,etal.JClinOncol2002;20:2812–23;JonesSE,etal.JClinOncol2005;23:5542–51;MartyM,

etal.JClinOncol2005;23:4265–74;ChanS,etal.JClinOncol2005;23

(June1suppl.):24s(Abstract581);MelemedAS,etal.PresentedatASCOBreastCancer2007;AvastinSummaryofProductCharacteristics客观缓解率(%)单药紫杉醇 0 10 20 30 40 50 60 70

各种方案治疗转移性乳腺癌的PFSDocetaxel

Chan1999Doxorubicin

Chan1999Paclitaxel

Seidman2004Vinorelbine

Muhoz2006Doxorubicin+paclitaxel

Jassem2001Capecitabine+docetaxel

O’Shaughnessy2002Gemcitabine+paclitaxel

Albain2004Fluorouracil+epirubicin

Zielinski2005Gemcitabine+vinorelbine

Muñoz2006Epirubicin+taxane

Pacilio2006Avastin+paclitaxel

E21002005Paclitaxel

E210020050 2 4 6 8 10 12 14MonthsMonotherapyCombination

chemotherapychemotherapy

+targetedtherapyMedianPFS/TTP9monthsEMEAAvastinEuropeanPublicAssessmentReport,2007Patientswithheavilypretreatedlocallyrecurrentormetastaticbreastcancer(N=762)EribulinMesylate1.4mg/m22-5minIVonDays1,8

q3w(n=508)TreatmentofPhysician’sChoice(TPC)Anymonotherapyapprovedforcancertreatment(chemotherapeutic,hormonal,orbiological),*orsupportivecareonly†(n=254)Randomized2:1;stratifiedby

geographicregion,previouscapecitabinetreatment,HER2/neustatusTwelvesC,etal.ASCO2010.AbstractCRA1004.EMBRACE:Randomized,Open-LabelPhaseIIITrial(PrimaryEndpointOS)

*FDAapprovedforthetreatmentofcancer.†Palliativetreatmentorradiotherapyaccordingtolocalpractice.96%ofpatientsinTPCarmreceivedchemotherapyTwelvesC,etal.ASCO2010.AbstractCRA1004.EMBRACE:OverallandProgression-FreeSurvival(ITT)OutcomeEribulin(n=508)Physician’sChoice(n=254)MedianOS(independentreview),mos13.1210.65HR(95%CI)0.81(0.66-0.99)

Pvalue.0411-yrsurvival,%53.943.7MedianPFS(independentreview),mos3.72.2HR(95%CI)0.87(0.71-1.05)Pvalue.14MedianPFS(investigatorreview),mos3.62.2HR(95%CI)0.76(0.64-0.90)Pvalue.002晚期转移性乳腺癌选用一线化疗方案辅助治疗仅用内分泌治疗而未用化疗的患者可以选择CMF,CAF,AC方案。辅助治疗未用过蒽环类和/或紫杉类化疗的患者或虽用过但临床判定未耐药或治疗失败者,首选AT方案。蒽环类辅助治疗失败者，首选健择®联合紫杉醇方案和卡培他滨联合多西紫杉醇方案。紫杉类辅助治疗失败的患者，目前尚无标准治疗方案，可以考虑的药物有Cape、NVB、健择®和铂类，采取单药或联合化疗。单药序贯化疗？联合化疗？单药序贯化疗或联合化疗联合化疗客观缓解率较高，至疾病进展时间较长，但是毒性较大，目前没有强有力的证据证实生存获益。一般状况好，疾病进展较快或有内脏转移的患者，可能从更强的联合化疗中受益。一般状况较差，无症状的转移的患者，可能更从单药序贯治疗中获益。晚期转移性乳腺癌治疗细胞毒药物化疗内分泌治疗生物靶向治疗局部治疗姑息治疗Bursteinetal.健择®联合多西紫杉醇vs.复发或转移性乳腺癌化疗适应症VogeletalUSOncology

(IHC3+population)O’Shaughnessyetal.部分抗雌激素药物-选择性雌激素受体调节剂ProbabilityAbstractCRA1004.Bursteinetal.Hormonereceptorpositive卡培他滨联合多西紫杉醇→健择®Tsavdaridisetal.USOncology

(IHC3+population)紫杉类辅助治疗失败的患者，目前尚无标准治疗方案，可以考虑的药物有Cape、NVB、健择®和铂类，采取单药或联合化疗。Cobleighetal000125.复发或转移性乳腺癌化疗适应症6mg 戈舍瑞林3.内分泌治疗内分泌治疗药物部分抗雌激素药物-选择性雌激素受体调节剂他莫昔芬芳香化酶抑制剂非甾体类：阿那曲唑，来曲唑甾体类：依西美坦雌激素受体抑制剂氟维司群LHRH类似物戈舍瑞林孕激素甲地孕酮哈里森肿瘤学手册.人民军医出版社2010年9月第一版.Anti-AromataseAgentsvsTamoxifenin1stLine

TherapyofAdvancedBreastCancer:SummaryExemestane

25mg

vsTAMAnastrozole

1mgvsTAMLetrozole2.5mgvsTAMNo.ofpatientsCR+PR,%

61vs5944vs14325vs32621.1vs17453vs45430vs20*Clin.Benefit,% 55vs39* 59.1vs45.6* 49vs38*MedianTTP,mo

8.9vs5.2

8.5vs7.0

9.4vs6.0*

OS:notsignificant,*P<0.05ReportedatSABCS2001IndirectComparison:AIsvsTamoxifenasFirst-lineTreatmentofABCRefNORR%P1TAMvsLET90721vs320.0022TAMvsANA102127vs29NS3TAMvsEXE38229vs44NI1.Mouridsenetal.JClinOncology2003;21:2101–92.Bonneterreetal.Cancer2001;92:2247–583.Paridaensetal.ProcASCO2004;23:6(Abstract575)32戈舍瑞林3.6mg用于绝经前/围绝经期

晚期乳腺癌：Ⅲ

期临床试验参考文献客观缓解率(%)中位生存期

TaylorCW,etal

戈舍瑞林3.6mg 卵巢切除术 戈舍瑞林3.6mg 卵巢切除术JClinOncol (n=29*) (n=30*) (n=69) (n=67)

1998;16:994–9. 31 27 37月 33月

BoccardoF,etal

戈舍瑞林3.6mg 卵巢切除术 戈舍瑞林3.6mg 卵巢切除术

AnnOncol

或卵巢照射 或卵巢照射

1994;5:337–42. (n=22*) (n=15*) (n=24) (n=18) 27(+19) 47(+25) 36月 38月JonatW,etal

戈舍瑞林3.6mg 戈舍瑞林3.6mg 戈舍瑞林3.6mg 戈舍瑞林3.6mg+

EurJCancerPartA +三苯氧胺 三苯氧胺

1995;31A:137–42.

(n=159) (n=159) (n=159) (n=159)

31 38 29月 32月*

可评价病例复发或转移性乳腺癌内分泌治疗药物选择不重复使用辅助治疗或一线治疗用过的药物既往未用过抗雌激素治疗者，仍可使用TAMTAM辅助治疗失败者，首选AI(绝经前者卵巢去势±AI)AI失败者可选孕激素（如甲地孕酮）或氟维司群2nd-/3rd-line

HerceptinVinorelbine

Muhoz2006VogeletalBrufskyetal20056* 49vs38*VisceraldiseaseTotalresponses(%)96%ofpatientsinTPCarmreceivedchemotherapyP值(log-rank,1-side)大部分转移性乳腺癌是早期乳腺癌治疗后复发的病例TwelvesC,etal.AI失败者可选孕激素（如甲地孕酮）或氟维司群(first-line)ACorPalone324.TaylorCW,etal 戈舍瑞林3.提高生活质量，改善无进展生存期Avastin+paclitaxel

E21002005Logrankp=0.Combination

chemotherapy):24s(Abstract581);MelemedAS,etal.HER2阳性转移性乳腺癌的治疗晚期转移性乳腺癌治疗细胞毒药物化疗内分泌治疗生物靶向治疗局部治疗姑息治疗

StudyRegimenNo.RRMTTPMST(%)P(M)P(M)PSlamonACorP+Tvs.46950vs.<0.00017.4vs.<0.000125.1vs.0.046(first-line)ACorPalone324.020.3MartyD+Tvs.18661vs.0.00211.7vs.0.000131.2vs.0.033(first-line)Dalone346.122.7CobleighT222159.1(MRT)13(pretreated)VagelT11426;FISH+353.824.4(first-line)

ASCO2006June2-6

HER2阳性转移性乳腺癌的治疗Trastuzumab一线治疗HER2阳性乳腺癌Carbo,carboplatinMonthsH+PP

onlyH+DD

onlyHP

CarboP

CarboH0648g

(IHC3+population)M77001USOncology

(IHC3+population)Martyetal2005;Robertetal2006;Smithetal2001Trastuzumab治疗HER2阳性转移性乳腺癌方案Trastuzumab

联合紫杉醇（每周）Trastuzumab一线单药联合长春瑞宾ORR:75%ORR:35%ORR:83%联合卡培他滨联合多西紫杉醇ORR:73%ORR:53-62%Seidmanetal95PtnsG.Fountzilasetal.34PtnsTsavdaridisetal.28PtnsBurrisetal.16PtnsEstevaetal.30PtnsFranciscoJ.etal.30PtnsBursteinetal.40PtnsJahanzebetal.29PtnsBangemannetal.13PtnsCharlesLetal.114Ptns

Brufskyetal2005Trastuzumab

:equallyeffectiveinhormonereceptor-negativeand-positivediseaseHerceptin/chemotherapyChemotherapy1st-line

Herceptin2nd-/3rd-line

HerceptinSlamonetalVogeletalCobleighetalOverallresponserate(%)HormonereceptorpositiveHormonereceptornegativeEvidenceofbenefitfromTrastuzumabinmultiplelinesBartschetal2006Overallresponserate(%)HER2-positivediseaseisnotrefractory

tomultiplelinesofHerceptinTrastuzumab+anastrozole

(TAnDEM试验)：PFS

103483117141311941100A+H10436229542100000AProbability1.00.80.60.40.2051015202530354045505560Months95%CI3.7,7.02.0,4.6pvalue0.0016MedianPFS4.8months2.4monthsEvents87990.0No.atriskPFS,timefromrandomisationtodateofprogressivediseaseordeath

An,anastrozole;CI,confidenceinterval;HR,hazardratioKaufmanetal2006Trastuzumab+anastrozole

(TAnDEM试验)：ORRPatients

(%)A+H(n=74)A(n=73)p=0.018PR,partialresponse;SD,stabledisease(>6months);PD,progressivedisease0102030405060PRSDPD6.8%20.3%38.4%37.8%40.5%49.3%Kaufmanetal2006

Trastuzumab+ChemotherapyCurrenttherapeuticcascadeinHER2+MBCHER2+/ER+MBCGoodperformancestatusVisceraldiseaseRapidlyprogressingPoorperformancestatusNonvisceraldiseaseSlowprogression

Trastuzumabmonotherapy

Trastuzumab+AromataseInhibitorPriorA.I.?YESNOLapatinib+卡培他滨治疗难治转移性乳腺癌

(EGF100151研究)Lap+卡培他滨N=160卡培他滨N=161病人数160161进展或死亡60(38%)78(48%)中位PFS(月)8.44.4HazardRatio(95%CI)0.49(0.34-0.71)P值(log-rank,1-side)<0.001蒽环、紫彬、

Trastuzumab治疗失败患者ORR(95%CI)28.8%(21.9-36.4)16.1%(10.8-22.8)p值(Fisher,sexact,2-sided)0.017Paridaensetal.AI失败者可选孕激素（如甲地孕酮）或氟维司群Presentedat:SanAntonioBreastCancerConference,December13-16,2007;SanAntonio,Texas.JClinOncol2005;23:5542–51;MartyM,

etal.Trastuzumab一线治疗HE