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,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,一、三阴性乳腺癌（TNBC） : 概念,
2、Triple negative and basal-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-,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,BRCA1,二、TNBC的风险因素(
3、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 2006,三、TNBC预
4、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),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
5、则仅为16%。,四、TNBC流行病学,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,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,TNBC: Shorter Median Time from Distant Relapse to Death,22 months,9 months,Dent R, Trudeau M, Pritchard K, Hana W, Narod S. et
6、al. Clinical Cancer Res 2007,“Triple Negative”,Other Breast Cancer,TNBC与Non-TNBC的生存比较,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 fi
7、rst 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.,七、TNBC的治疗策略,TNBC paradox: chemosensitive, but relapse more aggressive with worse OS Cannot treat with standard targeted therapies (hormonal
8、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 & st
9、age,(1) 三阴性乳腺癌对标准化疗的疗效,(2) 转移性TNBC较快发生化疗耐药,（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),早期TNBC化疗CR者预后好,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
10、 (OS),Liedtke et al. J Clin Oncol. 2008;26:1275-1281.,(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: ACT vs ATT (N=378),Loesch et al. J Clin Oncol.2010; 28: 2958-2965,(5) sequential chemotherapy for TNBC,PACS 01试验（期随机
11、临床试验）针对淋巴结阳性乳腺癌患者 FEC 6 VS FEC 3 序贯 D 3， 序贯治疗组中,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,虽然基底样乳腺癌的预后较差,但对FEC序贯多西他赛化疗有较好的反应。,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
12、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。,(6) Platinum Agents for TNBC,Carbo=carboplatin; Cis=cisplatin; D=docetaxel; E=epirubicin; F=5-FU; H=trastuzumab; P=paclitaxel; retro=retrospective.,(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 m
13、g/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。,(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,Micro
14、tubule stabilization,MAPK, Notch inhibitors,dasatinib, sunitinib,cetuximab,ixabepilone,Trabedectin, brostacillin,bevacizumab,Bevacizumab for TNBC,*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 showe
15、d no difference between bev and non-bev treated groups (HR=0.96; 95% CI: 0.79-1.16) OShaughnessy et al. ASCO 2010,EGFR Inhibition for TNBC,TNBC strongly associated with EGFR expression EGFR inhibitors combined with platinum Current data conflicting,Efficacy data from phase II trials,NR=not reported;
16、 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.,Other Targets for TNBC,Adapted from Tan and Swain. Cancer Journal. 2008;14.,PARP1 in Breast Cancer,*defined by percen
17、tage 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 u
18、pregulated in TNBC,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).,(9）Radiotherapy for TNBC,Haffty等对442（100TNBC)例保乳
19、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,（10）TNBC: Ongoing Clinical Trials,Numerous prospective trials ongoing to evaluate various therapeutic options specifically in TNBC population 57
20、 open trials currently listed on clinicaltrials.gov Most include TNBC populations only Studies include targeted agents, vaccines Across stages of disease,（11）TNBC: Conclusions,TNBC is a distinct subtype of BC and is associated with treatment challenges due to its aggressive nature TNBC has no specif
21、ic 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,Treat ment choices in TNBC,TODAY,TOMORROW,Chemotherapy,Chemotherapy,Chemotherapy,Tailored chemotherapy,Molecular targeted therapies,
