三阴性乳腺癌的治疗进展 ppt课件

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 2 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 3 一、三阴性乳腺癌（TNBC） : 概念 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- 4 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 5 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 6 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) 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、TNBC流行病学 8 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 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、TNBC临床特征 10 TNBC: Shorter Median Time from Distant 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 11 TNBC与Non-TNBC的生存比较 12 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 26:1275-1281. 19 (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 20 (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 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。 21 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。 22 (6) Platinum Agents for TNBC TrialPhase / No. of TNBC pts SettingRegimenOutcome in TNBC II (n=12)Neoadjuvant Carbo-P vs carbo -P-H pCR=67% II (n=30)Neoadjuvant TNBC E-Cis-FPpCR=40%; ORR=86% Silver (2010)II (n=28)Neoadjuvant TNBC CispCR=22% Leone (2009)Retro (n=125) Sikov (2009)Platinum + DpCR=34%, OS 5yr=55%, OS greater with cis vs carbo Kern (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; 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,年轻的三阴性乳腺癌患者从HDC中 获益最多。 24 (8) Molecular targeted therapies for TNBC Cell Cycle Transcriptional Control MAP Kinase PathwayAkt 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 25 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 26 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,%6183049 Clinical benefit, %1027NRNR PFS, mo24.75.1 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. 27 Other Targets for TNBC TargetAgent/ApproachInitial Outcomes DNA repair pathways PARP inhibitors (BSI-201, olaparib, AG014699, ABT-888), trabectedin PFS=6.9m, OS=12.2m, ORR=22-41% (OShaughnessy, Tutt) VEGFRSunitinib ORR=15% (Burstein 2008) Angiogenesis Endo TAG-1, metronomic chemotherapy Src kinaseDasatinibCBR=9.3% (Finn 2009) Checkpoint kinase 1UCN-01 mTORRAD001, everolimus, temsirolimus Androgen receptorBicalutamide TRAILLexatumumab TGF-betaGC1008, AP 12009, LY2157299 PDGFR, c-KITImatinib Adapted from Tan and Swain. Cancer Journal. 2008;14. 28 PARP1 in Breast Cancer PARP1 mRNA level 700 600 500 400 300 200 100 0 NormalIDC Mean 99.9%UCL 99%UCL 95%UCL 90%UCL IDC Subtype % PARP1 upregulation Normal2.9% 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 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 29 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). 30 (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 31 （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.