三阴性乳腺癌的治疗现状培训课件

Click to edit Master text styles,Second level,Third level,Fourth Level,Fifth Level,Click to edit Master title style,34,*,三阴性乳腺癌的治疗现状,*,1,Click to edit Master text styles,Second level,Third level,Fourth Level,Fifth Level,Click to edit Master title style,*,三阴性乳腺癌的治疗现状,*,三阴性乳腺癌的治疗现状,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 A,型,ER,和（或）,PR,阳性，,HER2,阴性，,Ki67,低表达（,14%,）,Luminal B,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-2,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,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,2011年St Gallen共识乳腺癌亚型 2三阴性,一、三阴性乳腺癌（,TNBC,）,:,概念,Triple negative andbasal-like,Basal,but not triple negative,15-40% are ER+, PR+ or HER2+,Triple negative,but not basal,Clinical assay(IHC),Gene,arrays,ER- / PgR- / HER2-,3,三阴性乳腺癌的治疗现状,一、三阴性乳腺癌（TNBC） : 概念Triple nega,BRCA1,、,Basal-Like,、,TNBC,乳腺癌的关系,Leslie K. et al. Adv. Anat. Pathol. 2007; 14: 419-430,Basal-like,Triple Negative,BRCA1,4,三阴性乳腺癌的治疗现状,BRCA1、Basal-Like 、TNBC乳腺癌的关系Le,二、,TNBC,的风险因素,(,排除,BRCA,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 exercise,Fulford et al, Histopathology 2006; Livasy et al, Mod Pathol, 2006,Bauer KR Cancer 2007 Carey JAMA 2006,5,三阴性乳腺癌的治疗现状,二、TNBC的风险因素(排除 BRCA 状态)Younger,三、,TNBC,预后因素,Large tumor size,Presence of nodal metastasis,Presence of distant metastasis,Presence of central necrosis,Absence of androgen receptor,Basal phenotype,EGFR,Age 40 ? (Liedtke et al. ASCO 2010),6,三阴性乳腺癌的治疗现状,三、TNBC预后因素Large tumor size6三阴性,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、,TNBC,流行病学,7,三阴性乳腺癌的治疗现状,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、,TNBC,分子病理特征,8,三阴性乳腺癌的治疗现状,组织学分级多为级,五、TNBC分子病理特征 8三阴性乳腺,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、,TNBC,临床特征,9,三阴性乳腺癌的治疗现状,临床表现为侵袭性病程；六、TNBC临床特征 9三阴性乳,TNBC: Shorter Median Time fromDistant Relapse to Death,22 months,9 months,Dent R, Trudeau M, Pritchard K, Hana W, Narod S. et al.,Clinical Cancer Res,2007,“Triple Negative”,Other Breast Cancer,10,三阴性乳腺癌的治疗现状,TNBC: Shorter Median Time from,TNBC,与,Non-TNBC,的生存比较,11,三阴性乳腺癌的治疗现状,TNBC与Non-TNBC的生存比较11三阴性乳腺癌的治疗现,TNBC: Recurrence and Survival,Increased 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 minimal,Kim et al. SABCS 2009. Abstract 4065,.,12,三阴性乳腺癌的治疗现状,TNBC: Recurrence and SurvivalI,七、,TNBC,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 this population,Best available data mostly retrospective subpopulation analyses,No specific recommendations within recognized treatment guidelines,Manage same as other BCs with same grade & stage,13,三阴性乳腺癌的治疗现状,七、TNBC的治疗策略TNBC paradox: chemo,(1),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,(1) 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,(2),转移性,TNBC,较快发生化疗耐药,15,三阴性乳腺癌的治疗现状,(2) 转移性TNBC较快发生化疗耐药15三阴性乳腺癌的治疗,（,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,（3）TNBC对新辅助化疗有较高的pCR率Compared,早期,TNBC,化疗,CR,者预后好,17,三阴性乳腺癌的治疗现状,早期TNBC化疗CR者预后好17三阴性乳腺癌的治疗现状,TNBC,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),TNBC,Non-TNBC,P Value,Pts, no (%),265 (23),863 (77),pCR, %,22,11,0.034,PFS (3-y), %,63,76,0.0001,OS (3-y), %,74,89,0.0001,Liedtke et al. J Clin Oncol. 2008;26:1275-1281.,18,三阴性乳腺癌的治疗现状,TNBC对新辅助化疗有较高的pCR率1118 pts rec,(4) Adjuvant,Anthracycline + Taxane for TNBC,Hugh et al. J Clin Oncol. 2009;27:1168-1176.,DFS (BCIRG 001): TAC vs FAC (n=192),OS: AC,T vs ATT (N=378),Loesch et al. J Clin Oncol.2010; 28: 2958-2965,19,三阴性乳腺癌的治疗现状,(4) Adjuvant Anthracycline +,三阴性乳腺癌的治疗现状培训课件,高危乳腺癌术后辅助化疗的,期临床试验,(2007,年,ASCO,报告,),A,组：,AC, 4,序贯,P,(175 mg/m2,Q3W),4,B,组：,AP, 4,序贯,P,(80 mg/ m2,QW),12,结论,:,对于三阴性乳腺癌,AP,序贯,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。,21,三阴性乳腺癌的治疗现状,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,Trial,Phase / No. of TNBC pts,Setting,Regimen,Outcome in TNBC,II (n=12),Neoadjuvant,Carbo-P vs carbo-P-H,pCR=67%,II (n=30),Neoadjuvant TNBC,E-Cis-F,P,pCR=40%; ORR=86%,Silver (2010),II (n=28),Neoadjuvant TNBC,Cis,pCR=22%,Leone (2009),Retro (n=125),Sikov (2009),Platinum + D,pCR=34%, OS 5yr=55%, OS greater with cis vs carbo,Kern (2010),II (n=10),Torrisi (2008),Carbo + D,pCR=40%,Uhm (2009),II (n=36),Metastatic,Carbo-P or Cis-P,ORR 37.5%,Wang (2010),II (n=65),Metastatic,Gem-carbo,PFS=6.2 months, ORR=62.2%,Carbo=carboplatin; Cis=cisplatin; D=docetaxel; E=epirubicin; F=5-FU; H=trastuzumab; P=paclitaxel; retro=retrospective.,22,三阴性乳腺癌的治疗现状,(6) Platinum Agents for TNBCTr,(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,年轻的三阴性乳腺癌患者从,HDC,中获益最多。,23,三阴性乳腺癌的治疗现状,(7) High dose chemotherapy(H,(8) Molecular targeted therapies for TNBC,Cell Cycle,Transcriptional Control,MAP Kinase Pathway,Akt Pathway,EGFR tyrosine kinase,c-KIT tyrosine kinase,DNA Repair pathway- platinum agents, PARP inhibitors,Angiogenesis,Microtubule stabilization,MAPK, Notch inhibitors,dasatinib, sunitinib,cetuximab,ixabepilone,Trabedectin, brostacillin,bevacizumab,24,三阴性乳腺癌的治疗现状,(8) Molecular targeted therapi,Bevacizumab for TNBC,Trial / Arm,Median PFS (mo) in TNBC Subset,E2100,Paclitaxel (n=110),5.3,Paclitaxel + bev (n=122),10.6,AVADO,Docetaxel + placebo (n=52),5.4,Docetaxel + bev 15 mg/kg (n=58),8.2,RIBBON-1,Taxane/anthracycline + placebo (n=46),6.2,Taxane/anthracycline + bev (n=96),6.5,Capecitabine + placebo (n=50),4.2,Capecitabine + bev (n=87),6.1,ATHENA,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 and non-bev treated groups (HR=0.96; 95% CI: 0.79-1.16),OShaughnessy et al. ASCO 2010,25,三阴性乳腺癌的治疗现状,Bevacizumab for TNBCTrial / Ar,EGFR Inhibition for TNBC,TNBC strongly associated with EGFR expression,EGFR inhibitors combined with platinum,Current data conflicting,TBCRC 001,(n=102),OShaughnessy et al,(n=78),Cetuximab,Carboplatin + Cetuximab,Irinotecan + Carboplatin,Irinotecan + Carboplatin + Cetuximab,ORR,%,6,18,30,49,Clinical benefit, %,10,27,NR,NR,PFS, mo,2,4.7,5.1,Efficacy data from phase II trials,NR=not reported; PFS=progression-free survival; RR=response rate; TBCRC=Translational Breast Cancer Research Consortium,Carey et al. ASCO 2008; abstr 1009;,OShaughnessy et al. SABCS 2007; abstr 308.,26,三阴性乳腺癌的治疗现状,EGFR Inhibition for TNBCTNBC s,Other Targets for TNBC,Target,Agent/Approach,Initial Outcomes,DNA repair pathways,PARP inhibitors (BSI-201, olaparib, AG014699, ABT-888), trabectedin,PFS=6.9m, OS=12.2m, ORR=22-41% (OShaughnessy, Tutt),VEGFR,Sunitinib,ORR=15% (Burstein 2008),Angiogenesis,Endo TAG-1, metronomic chemotherapy,Src kinase,Dasatinib,CBR=9.3% (Finn 2009),Checkpoint kinase 1,UCN-01,mTOR,RAD001, everolimus, temsirolimus,Androgen receptor,Bicalutamide,TRAIL,Lexatumumab,TGF-beta,GC1008, AP 12009, LY2157299,PDGFR, c-KIT,Imatinib,Adapted from Tan and Swain. Cancer Journal. 2008;14.,27,三阴性乳腺癌的治疗现状,Other Targets for TNBCTargetAg,PARP1 in Breast Cancer,PARP1 mRNA level,700,600,500,400,300,200,100,0,Normal,IDC,Mean,99.9%UCL,99%UCL,95%UCL,90%UCL,IDC Subtype,% PARP1 upregulation,Normal,2.9%,IDC,30.2%,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 exceeding the 95% UCL of normal tissue distribution,Infiltrating ductal carcinoma (IDC) is a highly invasive tumor, accounting for 70-80% of all breast malignancies,IDC shows statistically significant PARP1 upregulation in comparison with normal breast tissues: p = 2x10,-27,PARP1 is upregulated in TNBC,28,三阴性乳腺癌的治疗现状,PARP1 in Breast CancerPARP1 mR,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,The rate of clinical benefit f,(9）Radiotherapy 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,(9）Radiotherapy for TNBCHaffty,（,10,）,TNBC: Ongoing Clinical Trials,Numerous prospective trials ongoing to evaluate various 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 disease,31,三阴性乳腺癌的治疗现状,（10）TNBC: Ongoing Clinical Tri,（,11,）,TNBC: Conclusions,TNBC is a distinct subtype of BC 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,Introduction of novel agents (PARPi) is showing promiseiniparib,Results from ongoing phase III trials will help determine the best treatment strategy,32,三阴性乳腺癌的治疗现状,（11）TNBC: Concl,Treat ment choices in TNBC,TODAY,TOMORROW,Chemotherapy,Chemotherapy,Chemotherapy,Tailored chemotherapy,Molecular targeted therapies,33,三阴性乳腺癌的治疗现状,Treat ment choices in TNBC T,34,三阴性乳腺癌的治疗现状,34三阴性乳腺癌的治疗现状,