1、1三阴性乳腺癌的治疗现状三阴性乳腺癌的治疗现状 湖北省肿瘤医院乳腺科 吴 新 红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
2、缺失，HER2过表达或增殖基底样型基底样型 三阴性（导管），ER和PR缺失，HER2阴性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-/HER2-4BRCA1BRCA1、Basal-Like Basal-Like、TNBC乳腺癌的关系Leslie K.et al.Adv.Ana
3、t.Pathol.2007;14:419-430Basal-likeTriple NegativeBRCA1 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 al,Histopathology
4、 2006;Livasy et al,Mod Pathol,2006,Bauer KR Cancer 2007 Carey JAMA 20066三、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 necrosisPresence of central necrosis
5、 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)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%；白种人则仅为16%。四、四、TNBCTNBC流行病学流行病学8 组织学分级多为级
6、,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 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 10TNBC:Shorter Median Time fromTNBC:Shorter Median Time fromDistant Relapse to DeathDistant Relapse to Death22 months9 monthsDent R,Trudeau
7、M,Pritchard K,Hana W,Narod S.et al.Clinical Cancer Res 2007“Triple Negative”Other Breast Cancer11TNBCTNBC与与Non-TNBCNon-TNBC的生存比较的生存比较12TNBC:Recurrence and SurvivalTNBC:Recurrence and Survival Increased likelihood of distant recurrence Visceral metastases to brain,lung,and distant nodal sites common
8、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 et al.SABCS 2009.Abstract 4065.13七、七、TNBCTNBC的治疗策略的治疗策略 TNBC paradox:chemosensitive,but relapse more agg
9、ressive 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 this population Best available data mostly retrospective subpopulation analyses No specific recommendations within r
10、ecognized treatment guidelines Manage same as other BCs with same grade&stagePlatinum agents14(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)17早期早期T
11、NBCTNBC化疗化疗CRCR者预后好者预后好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 outcome(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;26:1275-1281.19 (4)(4)AdjuvantAd
12、juvant AnthracyclineAnthracycline+TaxaneTaxane for TNBC for TNBCHugh et al.J Clin Oncol.2009;27:1168-1176.DFS(BCIRG 001):TAC vs FAC(n=192)OS:ACT vs ATT(N=378)Loesch et al.J Clin Oncol.2010;28:2958-296520 (5)sequential chemotherapy (5)sequential chemotherapy for TNBCfor TNBC PACS 01试验（期随机临床试验）针对淋巴结阳性
13、乳腺癌患者 FEC FEC 6 6 VS FEC FEC 3 3 序贯序贯 D D 3 3，序贯治疗组中,基底样乳腺癌患者基底样乳腺癌患者的无病生存(DFS)率(P=0.05)和总生存(OS)率(P=0.005)较好。因此因此,虽然基底样乳腺癌的预后较差虽然基底样乳腺癌的预后较差,但对但对FECFEC序贯序贯多西他赛化疗有较好的反应。多西他赛化疗有较好的反应。21 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,APA
14、P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的亚组分析或回顾性分析,尚需前瞻性研究的证实。22(6)(6)Platinum Agents for TNBCPlatinum 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=4
15、0%;ORR=86%Silver(2010)II(n=28)Neoadjuvant TNBCCispCR=22%Leone(2009)Retro(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=
16、62.2%Carbo=carboplatin;Cis=cisplatin;D=docetaxel;E=epirubicin;F=5-FU;H=trastuzumab;P=paclitaxel;retro=retrospective.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H
17、DCHDC中中获益最多。获益最多。24(8)Molecular targeted therapies 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
18、inhibitorsdasatinib,sunitinibcetuximabixabepiloneTrabedectin,brostacillinbevacizumab25BevacizumabBevacizumab for TNBC 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/anth
19、racycline+placebo(n=46)6.2 Taxane/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 sho
20、wed no difference between bev and non-bev treated groups(HR=0.96;95%CI:0.79-1.16)OShaughnessy et al.ASCO 201026EGFR 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
21、 al(n=78)CetuximabCarboplatin+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
22、 et al.ASCO 2008;abstr 1009;OShaughnessy et al.SABCS 2007;abstr 308.27Other 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%(
23、Burstein 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
24、;14.28PARP1 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 samples ex
25、ceeding 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 TNBC29 The rat
26、e 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).30(9(9）Radiotherapy for TNBCRadiotherapy for TNBC Haffty等对442（100TNBC)例保乳手术乳腺癌进行了分析,比较局部复
27、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31（1010）TNBC:Ongoing Clinical TrialsTNBC:Ongoing Clinical Trials Numerous prospective trials ongoing to evaluate various therapeutic options specifically in TNBC
28、population 57 open trials currently listed on clinicaltrials.gov Most include TNBC populations only Studies include targeted agents,vaccines Across stages of disease32 （11 11）TNBC:ConclusionsTNBC:Conclusions TNBC is a distinct subtype of BC and is associated with treatment challenges due to its aggr
29、essive 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 Introduction of novel agents(PARPi)is showing promiseiniparib Results from ongoing phase III trials will help determine the best treatment strategy33Treat ment choices in TNBC Treat ment choices in TNBC TODAYTOMORROWChemotherapyChemotherapyChemotherapyTailored chemotherapyMolecular targeted therapies34
