1、三阴性乳腺癌的治疗现状 2011年St Gallen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基底样型 三阴性（导管），ER和PR缺失，HER2阴性2022-9-3
2、02一、三阴性乳腺癌（一、三阴性乳腺癌（TNBCTNBC）:概念概念 Triple Triple negative andnegative andbasal-likebasal-likeBasalBasal but not triple but not triple negativenegative15-40%are ER+,15-40%are ER+,PR+or HER2+PR+or HER2+Triple negativeTriple negative but not basalbut not basalClinical Clinical assayassay(IHC)(IHC)GeneG
3、enearraysarrays ER-/PgR-/HER2-2022-9-303BRCA1、Basal-Like、TNBC乳腺癌的关系Leslie K.et al.Adv.Anat.Pathol.2007;14:419-430Basal-likeTriple NegativeBRCA1 2022-9-304二、TNBC的风险因素(排除 BRCA 状态)Younger age at menarcheHigher parityYounger age at full term pregnancyShorter duration of breast feedingHigh body mass inde
4、x(BMI)High waist to hip ratio Lack of exerciseFulford et al,Histopathology 2006;Livasy et al,Mod Pathol,2006,Fulford et al,Histopathology 2006;Livasy et al,Mod Pathol,2006,Bauer KR Cancer 2007 Carey JAMA 2006Bauer KR Cancer 2007 Carey JAMA 20062022-9-305三、TNBC预后因素Large tumor sizeLarge tumor sizePres
5、ence of nodal metastasisPresence of nodal metastasisPresence of distant metastasisPresence of distant metastasisPresence of central necrosisPresence of central necrosisAbsence of androgen receptorAbsence of androgen receptorBasal phenotype Basal phenotype EGFREGFRAge 40?(Liedtke et al.ASCO 2010)Age
6、40?(Liedtke et al.ASCO 2010)2022-9-306 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2022-9-307 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 2022-9-308 临床表现为侵袭性病程；远处转移风险较高,内脏
7、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 2022-9-309TNBC:Shorter Median Time fromTNBC:Shorter Median Time fromDistant Relapse to DeathDistant Relapse to Death22 months22 months9 months9 monthsDent R,Trudeau M,Pritchard K,Hana W,Narod S.et al.Dent R,Trudeau M,Pritchard K,Hana W,Narod S.et a
8、l.Clinical Cancer ResClinical Cancer Res 2007 2007“Triple Negative”“Triple Negative”Other Breast Other Breast CancerCancer2022-9-3010TNBC与Non-TNBC的生存比较2022-9-3011TNBC:Recurrence and SurvivalTNBC:Recurrence and Survival Increased likelihood of distant recurrence Visceral metastases to brain,lung,and
9、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 et al.SABCS 2009.Abstract 4065.Kim et al.SABCS 2009.Abstract 4065.2022-9-3012
10、七、七、TNBCTNBC的治疗策的治疗策略略 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 this population Best available data mostly re
11、trospective subpopulation analyses No specific recommendations within recognized treatment guidelines Manage same as other BCs with same grade&stage2022-9-3013(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2022-9-3014(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2022-9-3015（3）TNBC对新辅助化疗有较高的pCR率 Compared with ER+luminal di
12、sease,TNBC and HER2+/ER-BC pts had:Decreased DFS(p=0.04)Decreased OS(p=0.02)2022-9-3016早期早期TNBCTNBC化疗化疗CRCR者预后好者预后好2022-9-3017TNBCTNBC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,%22110.034PF
13、S(3-y),%63760.0001OS(3-y),%74890.0001Liedtke et al.J Clin Oncol.2008;26:1275-1281.Liedtke et al.J Clin Oncol.2008;26:1275-1281.2022-9-3018 (4)Adjuvant (4)Adjuvant Anthracycline+Taxane for TNBC Anthracycline+Taxane for TNBCHugh et al.J Clin Oncol.2009;27:1168-1176.Hugh et al.J Clin Oncol.2009;27:1168
14、-1176.DFS(BCIRG 001):TAC vs FAC DFS(BCIRG 001):TAC vs FAC(n=192)(n=192)OS:ACOS:ACT vs ATT vs ATT(N=378)T(N=378)Loesch et al.J Clin Oncol.2010;28:2958-2965Loesch et al.J Clin Oncol.2010;28:2958-29652022-9-3019 (5)sequential chemotherapy for TNBC PACS 01试验（期随机临床试验）针对淋巴结阳性乳腺癌患者FEC FEC 6 6 VS FEC FEC 3
15、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序序贯多西他赛化疗有较好的反应。贯多西他赛化疗有较好的反应。2022-9-3020 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
16、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。2022-9-3021(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%Sil
17、ver(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=62.2%Carbo=ca
18、rboplatin;Cis=cisplatin;D=docetaxel;E=epirubicin;F=5-FU;H=trastuzumab;P=paclitaxel;retro=retrospective.Carbo=carboplatin;Cis=cisplatin;D=docetaxel;E=epirubicin;F=5-FU;H=trastuzumab;P=paclitaxel;retro=retrospective.2022-9-3022(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
19、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。2022-9-3023(8)Molecular targeted therapies for TNBCCell Cell CycleCycleTranscriptional ControlTranscriptional ControlMAP Kinase PathwayMAP Kinase PathwayAkt PathwayAkt PathwayE
20、GFR EGFR tyrosine tyrosine kinasekinasec-KIT c-KIT tyrosine tyrosine kinasekinaseDNA Repair DNA Repair pathway-pathway-platinum agents,platinum agents,PARP inhibitorsPARP inhibitorsAngiogenesisAngiogenesisMicrotubule Microtubule stabilizationstabilizationMAPK,Notch inhibitorsdasatinib,sunitinibcetux
21、imabixabepiloneTrabedectin,brostacillinbevacizumab2022-9-3024Bevacizumab 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.
22、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.Median PFS vs non-TNBC subgroup.Thomssen,et al.SABCS 2009.Abstract 6093.Thomssen,et al.SABCS 2009.Abstract 6093.OShaughnessy J,et al.SA
23、BCS 2009.Abstract 207.OShaughnessy J,et al.SABCS 2009.Abstract 207.OS in TNBC population OS in TNBC population showed no difference showed no difference between bev and non-bev between bev and non-bev treated groups(HR=0.96;treated groups(HR=0.96;95%CI:0.79-1.16)95%CI:0.79-1.16)OShaughnessy et al.AS
24、CO 2010OShaughnessy et al.ASCO 20102022-9-3025EGFR 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)CetuximabCarboplatin+CetuximabIrinotecan+CarboplatinIrin
25、otecan+Carboplatin+CetuximabORR,%6183049Clinical benefit,%1027NRNRPFS,mo24.75.1Efficacy data from phase II trialsEfficacy 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;abstr 1009;Car
26、ey et al.ASCO 2008;abstr 1009;OShaughnessy et al.SABCS 2007;abstr 308.OShaughnessy et al.SABCS 2007;abstr 308.2022-9-3026Other Targets for TNBCOther Targets for TNBCTargetAgent/ApproachInitial OutcomesDNA repair pathwaysPARP inhibitors(BSI-201,olaparib,AG014699,ABT-888),trabectedinPFS=6.9m,OS=12.2m,
27、ORR=22-41%(OShaughnessy,Tutt)VEGFRSunitinibORR=15%(Burstein 2008)AngiogenesisEndo TAG-1,metronomic chemotherapySrc kinaseDasatinibCBR=9.3%(Finn 2009)Checkpoint kinase 1UCN-01mTORRAD001,everolimus,temsirolimusAndrogen receptorBicalutamideTRAILLexatumumabTGF-betaGC1008,AP 12009,LY2157299PDGFR,c-KITIma
28、tinibAdapted from Tan and Swain.Cancer Journal.2008;14.Adapted from Tan and Swain.Cancer Journal.2008;14.2022-9-3027PARP1 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.
29、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 exceeding the 95%UCL of normal tissue distributionInfiltrating ductal Infiltrating ductal carcinoma(IDC)is a carcinoma(IDC)is a highly invasive tumor,highly invasive tumor,accounting for 70-80
30、%of accounting for 70-80%of all breast malignanciesall breast malignanciesIDC shows statistically IDC shows statistically significant PARP1 significant PARP1 upregulation in comparison upregulation in comparison with normal breast tissues:with normal breast tissues:p=2x10p=2x10-27-27 PARP1 is upregu
31、lated in PARP1 is upregulated in TNBCTNBC2022-9-3028 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).2022-9-3029(9）Radiotherapy fo
32、r TNBC Haffty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2022-9-3030（1010）TNBC:Ongoing Clinical TrialsTNBC:Ongoing Clinical Trials Numerous prospective trials ongoing to eva
33、luate various therapeutic options specifically in TNBC population 57 open trials currently listed on clinicaltrials.govMost include TNBC populations onlyStudies include targeted agents,vaccinesAcross stages of disease2022-9-3031 （1111）TNBC:ConclusionsTNBC:Conclusions TNBC is a distinct subtype of BC
34、 and is associated with treatment challenges due to its aggressive nature TNBC has no specific targetyetAntracycline 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 Int
35、roduction of novel agents(PARPi)is showing promiseiniparibResults from ongoing phase III trials will help determine the best treatment strategy2022-9-3032Treat ment choices in TNBC TODAYTOMORROWChemotherapyChemotherapyChemotherapyTailored chemotherapyMolecular targeted therapies2022-9-30332022-9-3034
