三陰性乳腺癌治療進(jìn)展--吳新紅

1、三陰性乳腺癌的治療現(xiàn)狀,湖北省腫瘤醫(yī)院乳腺科 吳 新 紅,2011年St Gallen共識(shí)乳腺癌亞型,亞型 定義Luminal A型 ER和（或）PR陽(yáng)性，HER2陰性，Ki67低表達(dá)（＜14%）Luminal B型 Luminal B（HER2陰性），ER和（或）PR陽(yáng)性，HER2陰性，Ki67高表達(dá)（≥14%） Luminal B（HER2陽(yáng)性），ER和（或）

2、PR陽(yáng)性，HER2過(guò)表達(dá)或增殖，Ki67任何水平HER-2過(guò)表達(dá)型 HER2陽(yáng)性（非Luminal），ER和PR缺失，HER2過(guò)表達(dá)或增殖基底樣型 三陰性（導(dǎo)管），ER和PR缺失，HER2陰性,一、三陰性乳腺癌（TNBC） : 概念,Triple negative andbasal-like,Basal but not triple negative15-40% are ER+, PR+ or HER2+,T

3、riple negative but not basal,Clinical assay(IHC),Genearrays,ER- / PgR- / HER2-,BRCA1、Basal-Like 、TNBC乳腺癌的關(guān)系,Leslie K. et al. Adv. Anat. Pathol. 2007; 14: 419-430,,,Basal-like,Triple Negative,,BRCA1,二、TNBC的風(fēng)險(xiǎn)因素(排除 BRC

4、A 狀態(tài)),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 exercise,Fulford et al, Histopathology 2006; L

5、ivasy et al, Mod Pathol, 2006, Bauer KR Cancer 2007 Carey JAMA 2006,三、TNBC預(yù)后因素,Large tumor sizePresence of nodal metastasisPresence of distant metastasisPresence of central necrosisAbsence of androgen receptorBasa

6、l phenotype EGFRAge < 40 ? (Liedtke et al. ASCO 2010),占所有乳腺癌病理類(lèi)型的 10.0%~20.8%；具有特殊的生物學(xué)行為和臨床病理特征；預(yù)后較其他類(lèi)型差；多發(fā)生于絕經(jīng)前年輕女性；尤其是非洲裔美國(guó)婦女：50歲以下非洲裔美國(guó)婦女的發(fā)病率甚達(dá)39%；白種人則僅為16%。,四、TNBC－流行病學(xué),組織學(xué)分級(jí)多為Ⅲ級(jí),細(xì)胞增殖比例較高, c-kit、p53、EGFR

7、表達(dá)多為陽(yáng)性,基底細(xì)胞標(biāo)志物細(xì)胞角蛋白 (CK) 5/6、17也多為陽(yáng)性。,五、TNBC－分子病理特征,臨床表現(xiàn)為侵襲性病程；　　遠(yuǎn)處轉(zhuǎn)移風(fēng)險(xiǎn)較高,內(nèi)臟轉(zhuǎn)移幾率較骨轉(zhuǎn)移高,腦轉(zhuǎn)移幾率也較高。預(yù)后較差,死亡風(fēng)險(xiǎn)較高。,六、TNBC－臨床特征,TNBC: Shorter Median Time fromDistant Relapse to Death,22 months,9 months,Dent R, Trudeau M,

8、Pritchard K, Hana W, Narod S. et al. Clinical Cancer Res 2007,“Triple Negative”,Other Breast Cancer,TNBC與Non-TNBC的生存比較,TNBC: Recurrence and Survival,Increased likelihood of distant recurrenceVisceral metastases to brai

9、n, 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 & n

10、on-TNBC are minimal,Kim et al. SABCS 2009. Abstract 4065.,,七、TNBC的治療策略,TNBC paradox: chemosensitive, but relapse more aggressive with worse OSCannot treat with standard targeted therapies (hormonal therapy or anti-HER2

11、agents)Question of bevacizumab openLimited data available from prospective trials in this populationBest available data mostly retrospective subpopulation analyses No specific recommendations within recognized treatm

12、ent guidelinesManage same as other BCs with same grade & stage,(1) 三陰性乳腺癌對(duì)標(biāo)準(zhǔn)化療的療效,(2) 轉(zhuǎn)移性TNBC較快發(fā)生化療耐藥,（3）TNBC對(duì)新輔助化療有較高的pCR率,Compared with ER+ luminal disease, TNBC and HER2+/ER- BC pts had: Decreased DFS (p=0.04)

13、Decreased OS (p=0.02),早期TNBC化療CR者預(yù)后好,TNBC對(duì)新輔助化療有較高的pCR率,1118 pts received T-FACNote Paradox: Despite increase in pCR rate, TNBC had worse outcome (OS),Liedtke et al. J Clin Oncol. 2008;26:1275-1281.,(4) Adjuvant Anthrac

14、ycline + 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 AT?T (N=378),Loesch et al. J Clin Oncol.2010; 28: 2958-2965,(5) sequential chemotherapy for TNBC,PACS

15、 01試驗(yàn)（Ⅲ期隨機(jī)臨床試驗(yàn)）　　針對(duì)淋巴結(jié)陽(yáng)性乳腺癌患者FEC × 6 VS FEC × 3 序貫 D × 3，序貫治療組中,基底樣乳腺癌患者的無(wú)病生存(DFS)率(P=0.05)和總生存(OS)率(P=0.005)較好。 因此,雖然基底樣乳腺癌的預(yù)后較差,但對(duì)FEC序貫多西他賽化療有較好的反應(yīng)。,高危乳腺癌術(shù)后輔助化療的Ⅲ期臨床試驗(yàn) (2007年ASCO報(bào)告)A組：AC &

16、#215; 4 序貫 P (175 mg/m2,Q3W) × 4B組：AP × 4序貫 P (80 mg/ m2,QW) ×12 結(jié)論: 對(duì)于三陰性乳腺癌, AP序貫P組五年OS優(yōu)勢(shì)更加明顯(87%對(duì)79%, P=0.037)。 紫杉類(lèi)藥物對(duì)TNBC有一定的療效,序貫方式也可能是其獲得較好療效的方式之一。研究結(jié)果均來(lái)自試驗(yàn)的亞組分析或回顧性分析, 尚需前瞻性研究的證實(shí)。,(6) Plati

17、num 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試驗(yàn) 9個(gè)以上淋巴結(jié)陽(yáng)性的乳腺癌患者分為兩組 A組：密

18、集EC× 2 序貫 HDC × 2 ( EPI 90 mg/m2,CTX 3 g/m2,塞替派400 mg/m2)B組：密集EC × 4 序貫 密集CMF × 3結(jié)果表明,年輕的三陰性乳腺癌患者從HDC中獲益最多。,(8) Molecular targeted therapies for TNBC,,,,Cell Cycle,,,,,,,,Transcriptional Control,,

19、,,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, sunitini

20、b,cetuximab,ixabepilone,Trabedectin, brostacillin,bevacizumab,Bevacizumab for TNBC,*Median PFS vs non-TNBC subgroup.,Thomssen, et al. SABCS 2009. Abstract 6093. O’Shaughnessy J, et al. SABCS 2009. Abstract 207.,OS in TNB

21、C population showed no difference between bev and non-bev treated groups (HR=0.96; 95% CI: 0.79-1.16)O’Shaughnessy et al. ASCO 2010,EGFR Inhibition for TNBC,TNBC strongly associated with EGFR expressionEGFR inhibitors

22、combined with platinum Current data conflicting,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. ASC

23、O 2008; abstr 1009; O’Shaughnessy 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 percentage of samples exceeding the 95% UCL

24、of normal tissue distribution,Infiltrating ductal carcinoma (IDC) is a highly invasive tumor, accounting for 70-80% of all breast malignanciesIDC shows statistically significant PARP1 upregulation in comparison with no

25、rmal breast tissues: p = 2x10-27 PARP1 is upregulated 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 progres

26、sion, 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等對(duì)442（100TNBC)例保乳手術(shù)乳腺癌進(jìn)行了分析,比較局部復(fù)發(fā)和遠(yuǎn)處轉(zhuǎn)移TNBC的OS(67%對(duì)75%,P=0.096)、無(wú)遠(yuǎn)處轉(zhuǎn)移生存率(61%對(duì)75%,P=0.002)、特異性生存率(67%對(duì)78%,P=

27、0.03)和無(wú)淋巴結(jié)轉(zhuǎn)移生存率(93%對(duì)99%,P=0.021)局部控制率方面沒(méi)有差異(均為83%),證明了其對(duì)放射線的敏感性,（10）TNBC: Ongoing Clinical Trials,Numerous prospective trials ongoing to evaluate various therapeutic options specifically in TNBC population57 open trial

28、s currently listed on clinicaltrials.govMost include TNBC populations onlyStudies include targeted agents, vaccinesAcross stages of disease,（11）TNBC: Conclusions,TNBC is a distinct subtype of BC and is associated with

29、 treatment challenges due to its aggressive natureTNBC has no specific target…yetAntracycline and taxane work (but not very well…)Molecular pathways that control tumor development could determine treatment Platinum-b

30、ased chemotherapy is emerging as backbone of new treatments Introduction of novel agents (PARPi) is showing promise—iniparibResults from ongoing phase III trials will help determine the best treatment strategy,Treat me