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1、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22011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Tripl
2、e negative and basal-likeBasal but not triple negative15-40% are ER+, PR+ or HER2+Triple negative but not basalClinical assay (IHC)Gene arrays ER- / PgR- / HER2- 4BRCA1、Basal-Like 、TNBC乳腺癌的关系Leslie K. et al. Adv. Anat. Pathol. 2007; 14: 419-430Basal-likeTriple NegativeBRCA1 5二、TNBC的风险因素(排除 BRCA 状态)
3、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 exerciseFulford et al, Histopathology 2006; Livasy et al, Mod Pathol, 2006, Bauer KR Cancer 2007 Carey JAMA 20066三、TNBC预后因素 Large tum
4、or 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、TN
5、BC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 10TNBC: Shorter Median Time from Distant Relapse to Death22 months9 monthsDent R, Trudeau M, Pritchard K, Hana W, Narod S. et al. C
6、linical Cancer Res 2007“Triple Negative”Other Breast Cancer11TNBC与Non-TNBC的生存比较12TNBC: 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
7、 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 TNBCHugh 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
8、20(5) sequential chemotherapy for TNBCPACS 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) 4B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
9、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 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%Silver (2
10、010)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=
11、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
12、 获益最多。24(8) Molecular targeted therapies for TNBCCell CycleTranscriptional ControlMAP Kinase PathwayAkt PathwayEGFR tyrosine kinasec-KIT tyrosine kinaseDNA Repair pathway- platinum agents, PARP inhibitorsAngiogenesisMicrotubule stabilizationMAPK, Notch inhibitorsdasatinib, sunitinib cetuximabixabepi
13、loneTrabedectin, brostacillinbevacizumab25Bevacizumab for TNBCTrial / ArmMedian PFS (mo) in TNBC Subset E2100Paclitaxel (n=110)5.3Paclitaxel + bev (n=122)10.6AVADODocetaxel + placebo (n=52)5.4Docetaxel + bev 15 mg/kg (n=58)8.2RIBBON-1Taxane/anthracycline + placebo (n=46)6.2Taxane/anthracycline + bev
14、 (n=96)6.5Capecitabine + placebo (n=50)4.2Capecitabine + bev (n=87)6.1ATHENATaxane-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 no
15、n-bev treated groups (HR=0.96; 95% CI: 0.79 -1.16) OShaughnessy et al. ASCO 201026EGFR 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 + CarboplatinIrinotecan + Carboplatin + CetuximabORR,%6183049Clinical benefit, %1027NRNRPFS, mo24.75.1Efficacy 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 1
