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1、三阴性乳腺癌的治疗现状 湖北省肿瘤医院乳腺科 吴 新 红2024/9/111三阴性乳腺癌的治疗现状 湖北省肿瘤医院乳腺科 吴 新 红 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），E
2、R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2024/9/112 2011年St Gallen共识乳腺癌亚型 2022一、三阴性乳腺癌（一、三阴性乳腺癌（TNBCTNBC） : : 概念概念 Triple Triple negative negative andandbasal-likebasal-likeBasalBasal but not triple but not triple negativenegative15-40% are 15-40% are ER+, PR+ or ER+, PR+ or HER2+HER2+Triple
3、negativeTriple negative but not basalbut not basalClinical Clinical assayassay(IHC)(IHC)GeneGenearraysarraysER- / PgR- / HER2- 2024/9/113一、三阴性乳腺癌（TNBC） : 概念 TripleBRCA1、Basal-Like 、TNBC乳腺癌的关系Leslie K. et al. Adv. Anat. Pathol. 2007; 14: 419-430Basal-likeTriple NegativeBRCA1 2024/9/114BRCA1、Basal-Lik
4、e 、TNBC乳腺癌的关系Le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 index (BMI)High waist to hip ratio Lack of exerciseFulford et al, Histopathology 2006; Livasy et al, Mod Pathol, 2006, Fulford et al, Histopath
5、ology 2006; Livasy et al, Mod Pathol, 2006, Bauer KR Cancer 2007 Carey JAMA 2006Bauer KR Cancer 2007 Carey JAMA 20062024/9/115二、TNBC的风险因素(排除 BRCA 状态)Younger三、TNBC预后因素Large tumor sizeLarge tumor sizePresence of nodal metastasisPresence of nodal metastasisPresence of distant metastasisPresence of dist
6、ant metastasisPresence of central necrosisPresence of central necrosisAbsence of androgen receptorAbsence of androgen receptorBasal phenotype Basal phenotype EGFREGFRAge 40 ? (Liedtke et al. ASCO 2010)Age 40 ? (Liedtke et al. ASCO 2010)2024/9/116三、TNBC预后因素Large tumor size2022占所有乳腺癌病理类型的 10.0%20.8%；具
7、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2024/9/117占所有乳腺癌病理类型的 10.0%20.8%；四、TNBC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 2024/9/118组织学分级多为级,五、TNBC分子病理特征 2022/9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
8、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 2024/9/119临床表现为侵袭性病程；六、TNBC临床特征 2022/TNBC: 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
9、, Pritchard K, Hana W, Narod S. et al. Clinical Cancer ResClinical Cancer Res 2007 2007“Triple “Triple Negative”Negative”Other Breast Other Breast CancerCancer2024/9/1110TNBC: Shorter Median Time fromTNBC与Non-TNBC的生存比较2024/9/1111TNBC与Non-TNBC的生存比较2022/9/2311TNBC: Recurrence and TNBC: Recurrence and
10、SurvivalSurvivalIncreased likelihood of distant recurrenceVisceral metastases to brain, lung, and distant nodal sites commonMetastases to bone and liver less commonRelapse most likely during the first 3 y after therapyMajority of deaths within first 5 yBy 10 years, OS differences between TNBC & non-
11、TNBC are minimalKim et al. SABCS 2009. Abstract 4065.Kim et al. SABCS 2009. Abstract 4065.2024/9/1112TNBC: Recurrence and SurvivalI七、七、TNBCTNBC的治疗策略的治疗策略TNBC paradox: chemosensitive, but relapse more aggressive with worse OSCannot treat with standard targeted therapies (hormonal therapy or anti-HER2
12、 agents)Question of bevacizumab openLimited data available from prospective trials in this populationBest available data mostly retrospective subpopulation analyses No specific recommendations within recognized treatment guidelinesManage same as other BCs with same grade & stage2024/9/1113七、TNBC的治疗策
13、略TNBC paradox: chemo(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2024/9/1114(1) 三阴性乳腺癌对标准化疗的疗效2022/9/2314(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2024/9/1115(2) 转移性TNBC较快发生化疗耐药2022/9/2315（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
14、=0.02)2024/9/1116（3）TNBC对新辅助化疗有较高的pCR率Compared 早期早期TNBCTNBC化疗化疗CRCR者预后好者预后好2024/9/1117早期TNBC化疗CR者预后好2022/9/2317TNBCTNBC对对新辅助化疗有较高的pCR率1118 pts received T-FACNote Paradox: Despite increase in pCR rate, TNBC had worse outcome (OS)TNBCNon-TNBCP ValuePts, no (%)265 (23)863 (77)pCR, %22110.034PFS (3-y),
15、%63760.0001OS (3-y), %74890.0001Liedtke et al. J Clin Oncol. 2008;26:1275-1281.Liedtke et al. J Clin Oncol. 2008;26:1275-1281.2024/9/1118TNBC对新辅助化疗有较高的pCR率1118 pts rec (4) Adjuvant (4) Adjuvant Anthracycline + Taxane for Anthracycline + Taxane for TNBCTNBCHugh et al. J Clin Oncol. 2009;27:1168-Hugh
16、et al. J Clin Oncol. 2009;27:1168-1176.1176.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: 2958-29652024/9/1119 (4) Adjuvant Anthracycline + (5) seque
17、ntial 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 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序贯多西他赛化疗有较好的反应。序贯多西他赛化疗有较好的反应。2024/9/1120 (5) sequential chemother高危乳腺癌术后辅助化疗的期临床试验 (2007年AS
18、CO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的亚组分析或回顾性分析, 尚需前瞻性研究的证实。 2024/9/1121高危乳腺癌术后辅助化疗的期临床试验 (2007年ASCO报(6) Platinum Agents for TNBC(6) Platinum Agents for T
19、NBCTrialPhase / 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)Retro (n=125)Sikov (2009)Platinum + DpCR=34%, OS 5yr=55%, OS greater with cis vs
20、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; H=trastuzumab; P=paclitaxel; Carbo=carboplatin; Cis=cispla
21、tin; D=docetaxel; E=epirubicin; F=5-FU; H=trastuzumab; P=paclitaxel; retro=retrospective.retro=retrospective.2024/9/1122(6) Platinum Agents for TNBCTr (7) High dose chemotherapy(HDC ) for TNBCWSG 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
22、 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。2024/9/1123 (7) High dose chemotherapy(H(8) Molecular targeted therapies for TNBCCell Cell CycleCycleTranscriptional Transcriptional ControlControlMAP Kinase PathwayMAP Kinase PathwayAkt PathwayAkt PathwayEGFR EGFR tyrosine tyrosine kinasekinase
23、c-KIT c-KIT tyrosine tyrosine kinasekinaseDNA Repair DNA Repair pathway- pathway- platinum platinum agents, PARP agents, PARP inhibitorsinhibitorsAngiogenesisAngiogenesisMicrotubule Microtubule stabilizatiostabilization nMAPK, Notch inhibitorsdasatinib, sunitinibcetuximabixabepiloneTrabedectin, bros
24、tacillinbevacizumab2024/9/1124(8) Molecular targeted therapiBevacizumab 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 +
25、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.*Median PFS vs non-TNBC subgroup.Thomssen, et al. SABCS 2009. Abstract 6093. Thomssen, et al. SABCS 2009. A
26、bstract 6093. OShaughnessy J, et al. SABCS 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-between bev and non-bev treated groups bev treated groups (HR=0.96; 95% CI: (HR=0.96
27、; 95% CI: 0.79-1.16)0.79-1.16)OShaughnessy et al. ASCO 2010OShaughnessy et al. ASCO 20102024/9/1125Bevacizumab for TNBCTrial / ArEGFR Inhibition for TNBCEGFR Inhibition for TNBCTNBC strongly associated with EGFR expressionEGFR inhibitors combined with platinum Current data conflictingTBCRC 001(n=102
28、)OShaughnessy et al(n=78)CetuximabCarboplatin + CetuximabIrinotecan + CarboplatinIrinotecan + 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 ra
29、te; TBCRC=Translational Breast Cancer Research Consortium Carey et al. ASCO 2008; abstr 1009; Carey et al. ASCO 2008; abstr 1009; OShaughnessy et al. SABCS 2007; abstr 308. OShaughnessy et al. SABCS 2007; abstr 308. 2024/9/1126EGFR Inhibition for TNBCTNBC sOther Targets for TNBCOther Targets for TNB
30、CTargetAgent/ApproachInitial OutcomesDNA repair pathwaysPARP inhibitors (BSI-201, olaparib, AG014699, ABT-888), trabectedinPFS=6.9m, OS=12.2m, ORR=22-41% (OShaughnessy, Tutt)VEGFRSunitinibORR=15% (Burstein 2008)AngiogenesisEndo TAG-1, metronomic chemotherapySrc kinaseDasatinibCBR=9.3% (Finn 2009)Che
31、ckpoint kinase 1UCN-01mTORRAD001, everolimus, temsirolimusAndrogen receptorBicalutamideTRAILLexatumumabTGF-betaGC1008, AP 12009, LY2157299PDGFR, c-KITImatinibAdapted from Tan and Swain. Cancer Journal. 2008;14.Adapted from Tan and Swain. Cancer Journal. 2008;14.2024/9/1127Other Targets for TNBCTarge
32、tAgPARP1 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 exce
33、eding the 95% UCL of normal tissue distributionInfiltrating ductal Infiltrating ductal carcinoma (IDC) is a carcinoma (IDC) is a highly invasive highly invasive tumor, accounting for tumor, accounting for 70-80% of all breast 70-80% of all breast malignanciesmalignanciesIDC shows IDC shows statistic
34、ally statistically significant PARP1 significant PARP1 upregulation in upregulation in comparison with comparison with normal breast normal breast tissues: p = 2x10tissues: p = 2x10-27-27 PARP1 is upregulated PARP1 is upregulated in TNBCin TNBC2024/9/1128PARP1 in Breast CancerPARP1 mRThe rate of cli
35、nical 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).2024/9/1129The rate of clinical benefit f(9）Radiotherapy for TNBCHaffty等对442（100TNBC
36、)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2024/9/1130(9）Radiotherapy for TNBCHaffty（1010）TNBC: Ongoing Clinical TNBC: Ongoing Clinical TrialsTrialsNumerous prospective trials ongoing to
37、 evaluate various therapeutic options specifically in TNBC population57 open trials currently listed on clinicaltrials.govMost include TNBC populations onlyStudies include targeted agents, vaccinesAcross stages of disease2024/9/1131（10）TNBC: Ongoing Clinical Tri （1111）TNBC: ConclusionsTNBC: Conclusi
38、onsTNBC is a distinct subtype of BC and is associated with treatment challenges due to its aggressive natureTNBC has no specific targetyetAntracycline and taxane work (but not very well)Molecular pathways that control tumor development could determine treatment Platinum-based chemotherapy is emergin
39、g as backbone of new treatments Introduction of novel agents (PARPi) is showing promiseiniparibResults from ongoing phase III trials will help determine the best treatment strategy2024/9/1132 （11）TNBC: ConclTreat ment choices in TNBC TODAYTOMORROWChemotherapyChemotherapyChemotherapyTailored chemotherapyMolecular targeted therapies2024/9/1133Treat ment choices in TNBC T2024/9/11342022/9/2334
