1、1三阴性乳腺癌的治三阴性乳腺癌的治疗现状疗现状2 2011 2011年年St GallenSt Gallen共识乳腺癌亚型共识乳腺癌亚型 亚型 定义Luminal ALuminal A型型 ER和（或）PR阳性，HER2阴性，Ki67低表达（14%）Luminal BLuminal B型型 Luminal B（HER2阴性），ER和（或）PR阳性，HER2阴性，Ki67高表达（14%）Luminal B（HER2阳性），ER和（或）PR阳性，HER2过表达或增殖，Ki67任何水平HER-2HER-2过表达型过表达型 HER2阳性（非Luminal），ER和PR缺失，HER2过表达或增殖基底样型
2、基底样型 三阴性（导管），ER和PR缺失，HER2阴性2三阴性乳腺癌的治疗现状3一、三阴性乳腺癌（一、三阴性乳腺癌（TNBCTNBC）:概念概念Triple negative andbasal-likeBasal but not triple negative15-40%are ER+,PR+or HER2+Triple negative but not basalClinical assay(IHC)Genearrays ER-/PgR-/HER2-3三阴性乳腺癌的治疗现状4BRCA1BRCA1、Basal-Like Basal-Like、TNBC乳腺癌的关系Leslie K.et al.A
3、dv.Anat.Pathol.2007;14:419-430Basal-likeTriple NegativeBRCA1 4三阴性乳腺癌的治疗现状5二、二、TNBCTNBC的风险因素的风险因素(排除排除 BRCA BRCA 状态状态)Younger age at menarche Higher parity Younger age at full term pregnancy Shorter duration of breast feeding High body mass index(BMI)High waist to hip ratio Lack of exerciseFulford et
4、 al,Histopathology 2006;Livasy et al,Mod Pathol,2006,Bauer KR Cancer 2007 Carey JAMA 20065三阴性乳腺癌的治疗现状6三、三、TNBCTNBC预后因素预后因素 Large tumor sizeLarge tumor size Presence of nodal metastasisPresence of nodal metastasis Presence of distant metastasisPresence of distant metastasis Presence of central necros
5、isPresence of central necrosis Absence of androgen receptorAbsence of androgen receptor Basal phenotype Basal phenotype EGFREGFR Age 40?(Liedtke et al.ASCO 2010)Age 40?(Liedtke et al.ASCO 2010)6三阴性乳腺癌的治疗现状7 占所有乳腺癌病理类型的 10.0%20.8%；具有特殊的生物学行为和临床病理特征；预后较其他类型差；多发生于绝经前年轻女性；尤其是非洲裔美国妇女：50岁以下非洲裔美国妇女的发病率甚达39
6、%；白种人则仅为16%。四、四、TNBCTNBC流行病学流行病学7三阴性乳腺癌的治疗现状8 组织学分级多为级,细胞增殖比例较高,c-kit、p53、EGFR表达多为阳性,基底细胞标志物细胞角蛋白(CK)5/6、17也多为阳性。五、五、TNBCTNBC分子病理特征分子病理特征 8三阴性乳腺癌的治疗现状9 临床表现为侵袭性病程；远处转移风险较高,内脏转移几率较骨转移高,脑转移几率也较高。预后较差,死亡风险较高。六、六、TNBCTNBC临床特征临床特征 9三阴性乳腺癌的治疗现状10TNBC:Shorter Median Time fromTNBC:Shorter Median Time fromDi
7、stant Relapse to DeathDistant Relapse to Death22 months9 monthsDent R,Trudeau M,Pritchard K,Hana W,Narod S.et al.Clinical Cancer Res 2007“Triple Negative”Other Breast Cancer10三阴性乳腺癌的治疗现状11TNBCTNBC与与Non-TNBCNon-TNBC的生存比较的生存比较11三阴性乳腺癌的治疗现状12TNBC:Recurrence and SurvivalTNBC:Recurrence and Survival Incr
8、eased likelihood of distant recurrence Visceral metastases to brain,lung,and distant nodal sites common Metastases to bone and liver less common Relapse most likely during the first 3 y after therapy Majority of deaths within first 5 y By 10 years,OS differences between TNBC&non-TNBC are minimalKim
9、et al.SABCS 2009.Abstract 4065.12三阴性乳腺癌的治疗现状13七、七、TNBCTNBC的治疗策略的治疗策略 TNBC paradox:chemosensitive,but relapse more aggressive with worse OS Cannot treat with standard targeted therapies(hormonal therapy or anti-HER2 agents)Question of bevacizumab open Limited data available from prospective trials in
10、 this population Best available data mostly retrospective subpopulation analyses No specific recommendations within recognized treatment guidelines Manage same as other BCs with same grade&stage13三阴性乳腺癌的治疗现状14(1)(1)三阴性乳腺癌对标准化疗的疗效三阴性乳腺癌对标准化疗的疗效14三阴性乳腺癌的治疗现状15(2)(2)转移性转移性TNBCTNBC较快发生化疗耐药较快发生化疗耐药15三阴性乳
11、腺癌的治疗现状16（3）TNBC对新辅助化疗有较高的pCR率 Compared with ER+luminal disease,TNBC and HER2+/ER-BC pts had:Decreased DFS(p=0.04)Decreased OS(p=0.02)16三阴性乳腺癌的治疗现状17早期早期TNBCTNBC化疗化疗CRCR者预后好者预后好17三阴性乳腺癌的治疗现状18TNBCTNBC对对新辅助化疗有较高的pCR率 1118 pts received T-FAC Note Paradox:Despite increase in pCR rate,TNBC had worse out
12、come(OS)TNBCNon-TNBCP ValuePts,no(%)265(23)863(77)pCR,%22110.034PFS(3-y),%63760.0001OS(3-y),%74890.0001Liedtke et al.J Clin Oncol.2008;26:1275-1281.18三阴性乳腺癌的治疗现状19 (4)Adjuvant (4)Adjuvant Anthracycline+Taxane for TNBC Anthracycline+Taxane for TNBCHugh et al.J Clin Oncol.2009;27:1168-1176.DFS(BCIRG 0
13、01):TAC vs FAC(n=192)OS:ACT vs ATT(N=378)Loesch et al.J Clin Oncol.2010;28:2958-296519三阴性乳腺癌的治疗现状2021 高危乳腺癌术后辅助化疗的期临床试验(2007年ASCO报告)A A组：组：ACAC 4 序贯 P P(175 mg/m2,Q3W)4B B组：组：APAP 4序贯 P P(80 mg/m2,QW)12 结论:对于三阴性乳腺癌,APAP序贯P P组五年OS优势更加明显(87%对79%,P=0.037)。紫杉类药物对TNBC有一定的疗效,序贯方式也可能是其获得较好疗效的方式之一。研究结果均来自试验
14、的亚组分析或回顾性分析,尚需前瞻性研究的证实。21三阴性乳腺癌的治疗现状22(6)Platinum Agents for TNBC(6)Platinum Agents for TNBCTrialPhase/No.of TNBC ptsSettingRegimenOutcome in TNBCII(n=12)Neoadjuvant Carbo-P vs carbo-P-HpCR=67%II(n=30)Neoadjuvant TNBC E-Cis-FPpCR=40%;ORR=86%Silver(2010)II(n=28)Neoadjuvant TNBCCispCR=22%Leone(2009)Re
15、tro(n=125)Sikov(2009)Platinum+DpCR=34%,OS 5yr=55%,OS greater with cis vs carboKern(2010)II(n=10)Torrisi(2008)Carbo+DpCR=40%Uhm(2009)II(n=36)MetastaticCarbo-P or Cis-PORR 37.5%Wang(2010)II(n=65)MetastaticGem-carboPFS=6.2 months,ORR=62.2%Carbo=carboplatin;Cis=cisplatin;D=docetaxel;E=epirubicin;F=5-FU;
16、H=trastuzumab;P=paclitaxel;retro=retrospective.22三阴性乳腺癌的治疗现状23(7)High dose chemotherapy(HDC)for TNBC WSG AM 01试验 9个以上淋巴结阳性的乳腺癌患者分为两组 A组：密集EC 2 序贯 HDC 2(EPI 90 mg/m2,CTX 3 g/m2,塞替派400 mg/m2)B组：密集EC 4 序贯 密集CMF 3 结果表明结果表明,年轻的三阴性乳腺癌患者从年轻的三阴性乳腺癌患者从HDCHDC中中获益最多。获益最多。23三阴性乳腺癌的治疗现状24(8)Molecular targeted th
17、erapies for TNBC(8)Molecular targeted therapies for TNBCCell CycleTranscriptional ControlMAP Kinase PathwayAkt PathwayEGFR tyrosine kinasec-KIT tyrosine kinaseDNA Repair pathway-platinum agents,PARP inhibitorsAngiogenesisMicrotubule stabilizationMAPK,Notch inhibitorsdasatinib,sunitinibcetuximabixabe
18、piloneTrabedectin,brostacillinbevacizumab24三阴性乳腺癌的治疗现状25Bevacizumab for TNBCBevacizumab for TNBCTrial/ArmMedian PFS(mo)in TNBC Subset E2100 Paclitaxel(n=110)5.3 Paclitaxel+bev(n=122)10.6AVADO Docetaxel+placebo(n=52)5.4 Docetaxel+bev 15 mg/kg(n=58)8.2RIBBON-1 Taxane/anthracycline+placebo(n=46)6.2 Tax
19、ane/anthracycline+bev(n=96)6.5 Capecitabine+placebo(n=50)4.2 Capecitabine+bev(n=87)6.1ATHENA Taxane-based regimen+bev(n=577)7.2*Median PFS vs non-TNBC subgroup.Thomssen,et al.SABCS 2009.Abstract 6093.OShaughnessy J,et al.SABCS 2009.Abstract 207.OS in TNBC population showed no difference between bev
20、and non-bev treated groups(HR=0.96;95%CI:0.79-1.16)OShaughnessy et al.ASCO 201025三阴性乳腺癌的治疗现状26EGFR Inhibition for TNBCEGFR Inhibition for TNBC TNBC strongly associated with EGFR expression EGFR inhibitors combined with platinum Current data conflictingTBCRC 001(n=102)OShaughnessy et al(n=78)Cetuxima
21、bCarboplatin+CetuximabIrinotecan+CarboplatinIrinotecan+Carboplatin+CetuximabORR,%6183049Clinical benefit,%1027NRNRPFS,mo24.75.1Efficacy data from phase II trialsNR=not reported;PFS=progression-free survival;RR=response rate;TBCRC=Translational Breast Cancer Research Consortium Carey et al.ASCO 2008;
22、abstr 1009;OShaughnessy et al.SABCS 2007;abstr 308.26三阴性乳腺癌的治疗现状27Other Targets for TNBCOther Targets for TNBCTargetAgent/ApproachInitial OutcomesDNA repair pathwaysPARP inhibitors(BSI-201,olaparib,AG014699,ABT-888),trabectedinPFS=6.9m,OS=12.2m,ORR=22-41%(OShaughnessy,Tutt)VEGFRSunitinibORR=15%(Burs
23、tein 2008)AngiogenesisEndo TAG-1,metronomic chemotherapySrc kinaseDasatinibCBR=9.3%(Finn 2009)Checkpoint kinase 1UCN-01mTORRAD001,everolimus,temsirolimusAndrogen receptorBicalutamideTRAILLexatumumabTGF-betaGC1008,AP 12009,LY2157299PDGFR,c-KITImatinibAdapted from Tan and Swain.Cancer Journal.2008;14.
24、27三阴性乳腺癌的治疗现状28PARP1 in Breast CancerPARP1 in Breast CancerPARP1 mRNA level 7006005004003002001000NormalIDCMean99.9%UCL99%UCL95%UCL90%UCLIDC Subtype%PARP1 upregulationNormal2.9%IDC30.2%ER+22.9%ER-55.6%PR+23.1%PR-45.0%HER2+29.2%HER2-70.0%ER+/PR+/HER2+20.0%ER-/PR-/HER2-80.0%*defined by percentage of s
25、amples exceeding the 95%UCL of normal tissue distributionInfiltrating ductal carcinoma(IDC)is a highly invasive tumor,accounting for 70-80%of all breast malignanciesIDC shows statistically significant PARP1 upregulation in comparison with normal breast tissues:p=2x10-27 PARP1 is upregulated in TNBC2
26、8三阴性乳腺癌的治疗现状29 The rate of clinical benefit from 34%to 56%(P=0.01)The rate of overall response from 32%to 52%(P=0.02).PFS：3.6 M to 5.9 M(hazard ratio for progression,0.59;P=0.01)OS：7.7 M to 12.3 M(hazard ratio for death,0.57;P=0.01).29三阴性乳腺癌的治疗现状30(9(9）Radiotherapy for TNBCRadiotherapy for TNBC Haff
27、ty等对442（100TNBC)例保乳手术乳腺癌进行了分析,比较局部复发和远处转移 TNBC的OS(67%对75%,P=0.096)、无远处转移生存率(61%对75%,P=0.002)、特异性生存率(67%对78%,P=0.03)和无淋巴结转移生存率(93%对99%,P=0.021)局部控制率方面没有差异(均为83%),证明了其对放射线的敏感性30三阴性乳腺癌的治疗现状31（1010）TNBC:Ongoing Clinical TrialsTNBC:Ongoing Clinical Trials Numerous prospective trials ongoing to evaluate v
28、arious therapeutic options specifically in TNBC population 57 open trials currently listed on clinicaltrials.gov Most include TNBC populations only Studies include targeted agents,vaccines Across stages of disease31三阴性乳腺癌的治疗现状32 （11 11）TNBC:ConclusionsTNBC:Conclusions TNBC is a distinct subtype of B
29、C and is associated with treatment challenges due to its aggressive nature TNBC has no specific targetyet Antracycline and taxane work(but not very well)Molecular pathways that control tumor development could determine treatment Platinum-based chemotherapy is emerging as backbone of new treatments I
30、ntroduction of novel agents(PARPi)is showing promiseiniparib Results from ongoing phase III trials will help determine the best treatment strategy32三阴性乳腺癌的治疗现状33Treat ment choices in TNBC Treat ment choices in TNBC TODAYTOMORROWChemotherapyChemotherapyChemotherapyTailored chemotherapyMolecular targeted therapies33三阴性乳腺癌的治疗现状3434三阴性乳腺癌的治疗现状
