陰性乳腺癌的治療進(jìn)展吳新紅

1、三陰性乳腺癌的治療現(xiàn)狀 陰性乳腺癌的治療進(jìn)展吳新紅 2011年St Gallen共識(shí)乳腺癌亞型 亞型 定義Luminal A型 ER和（或）PR陽性，HER2陰性，Ki67低表達(dá)（14%）Luminal B型 Luminal B（HER2陰性），ER和（或）PR陽性，HER2陰性，Ki67高表達(dá)（14%） Luminal B（HER2陽性），ER和（或）PR陽性，HER2過表達(dá)或增殖，Ki67任何水平HER-2過表達(dá)型 HER2陽性（非Luminal），ER和PR缺失，HER2過表達(dá)或增殖基底樣型 三陰性（導(dǎo)管），ER和PR缺失，HER2陰性陰性乳腺癌的治療進(jìn)展吳新紅一、三陰性乳腺癌（TNBC

2、） : 概念Triple negative andbasal-likeBasal but not triple negative15-40% are ER+, PR+ or HER2+Triple negative but not basalClinical assay(IHC)GenearraysER- / PgR- / HER2- 陰性乳腺癌的治療進(jìn)展吳新紅BRCA1、Basal-Like 、TNBC乳腺癌的關(guān)系Leslie K. et al. Adv. Anat. Pathol. 2007; 14: 419-430Basal-likeTriple NegativeBRCA1 陰性乳腺癌的

3、治療進(jìn)展吳新紅二、TNBC的風(fēng)險(xiǎn)因素(排除 BRCA 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 exerciseFulford et al, Histopathology 2006; Livasy et al, Mod Pathol, 2006, Bauer KR Cancer 2007 Carey JAMA

4、2006陰性乳腺癌的治療進(jìn)展吳新紅三、TNBC預(yù)后因素Large tumor sizePresence of nodal metastasisPresence of distant metastasisPresence of central necrosisAbsence of androgen receptorBasal phenotype EGFRAge 40 ? (Liedtke et al. ASCO 2010)陰性乳腺癌的治療進(jìn)展吳新紅占所有乳腺癌病理類型的 10.0%20.8%；具有特殊的生物學(xué)行為和臨床病理特征；預(yù)后較其他類型差；多發(fā)生于絕經(jīng)前年輕女性；尤其是非洲裔美國婦女：50

5、歲以下非洲裔美國婦女的發(fā)病率甚達(dá)39%；白種人則僅為16%。四、TNBC流行病學(xué)陰性乳腺癌的治療進(jìn)展吳新紅組織學(xué)分級(jí)多為級(jí),細(xì)胞增殖比例較高, c-kit、p53、EGFR表達(dá)多為陽性,基底細(xì)胞標(biāo)志物細(xì)胞角蛋白 (CK) 5/6、17也多為陽性。五、TNBC分子病理特征 陰性乳腺癌的治療進(jìn)展吳新紅臨床表現(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 陰性乳腺癌的治療進(jìn)展吳新紅TNBC: Shorter Median Time fromDistant Relapse to Death22 months9 monthsDe

6、nt R, Trudeau M, Pritchard K, Hana W, Narod S. et al. Clinical Cancer Res 2007“Triple Negative”O(jiān)ther Breast Cancer陰性乳腺癌的治療進(jìn)展吳新紅TNBC與Non-TNBC的生存比較陰性乳腺癌的治療進(jìn)展吳新紅TNBC: Recurrence and SurvivalIncreased likelihood of distant recurrenceVisceral metastases to brain, lung, and distant nodal sites commonMetas

7、tases 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 & non-TNBC are minimalKim et al. SABCS 2009. Abstract 4065.陰性乳腺癌的治療進(jìn)展吳新紅七、TNBC的治療策略TNBC paradox: chemosensitive, but relapse more aggre

8、ssive with worse OSCannot treat with standard targeted therapies (hormonal therapy or anti-HER2 agents)Question of bevacizumab openLimited data available from prospective trials in this populationBest available data mostly retrospective subpopulation analyses No specific recommendations within recog

9、nized treatment guidelinesManage same as other BCs with same grade & stage陰性乳腺癌的治療進(jìn)展吳新紅(1) 三陰性乳腺癌對(duì)標(biāo)準(zhǔn)化療的療效陰性乳腺癌的治療進(jìn)展吳新紅(2) 轉(zhuǎn)移性TNBC較快發(fā)生化療耐藥陰性乳腺癌的治療進(jìn)展吳新紅（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) Decreased OS (p=0.02)陰性乳腺癌的治療進(jìn)展吳新紅早期TNBC

10、化療CR者預(yù)后好陰性乳腺癌的治療進(jìn)展吳新紅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)TNBCNon-TNBCP ValuePts, no (%)265 (23)863 (77)pCR, %22110.034PFS (3-y), %63760.0001OS (3-y), %74890.0001Liedtke et al. J Clin Oncol. 2008;26:1275-1281.陰性乳腺癌的治療進(jìn)展吳新紅 (4

11、) 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陰性乳腺癌的治療進(jìn)展吳新紅 (5) sequential chemotherapy for TNBC PACS 01試驗(yàn)（期隨機(jī)臨床試驗(yàn)）針對(duì)淋巴結(jié)陽性乳腺癌患者FEC 6 VS FEC 3 序貫 D 3，序貫治療組中,基

12、底樣乳腺癌患者的無病生存(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)。陰性乳腺癌的治療進(jìn)展吳新紅高危乳腺癌術(shù)后輔助化療的期臨床試驗(yàn) (2007年ASCO報(bào)告)A組：AC 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)果均來自試驗(yàn)的亞組分析或回顧性分析, 尚

13、需前瞻性研究的證實(shí)。 陰性乳腺癌的治療進(jìn)展吳新紅(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 (2010)II (n=28)Neoadjuvant TNBCCispCR=22%Leone (2009)Retro (n=125)Sikov (2009)Platinu

14、m + 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=62.2%Carbo=carboplatin; Cis=cisplatin; D=docetaxel; E=epirubicin; F=5-FU; H=trastuz

15、umab; P=paclitaxel; retro=retrospective.陰性乳腺癌的治療進(jìn)展吳新紅 (7) High dose chemotherapy(HDC ) for TNBCWSG AM 01試驗(yàn) 9個(gè)以上淋巴結(jié)陽性的乳腺癌患者分為兩組 A組：密集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。陰性乳腺癌的治療進(jìn)展吳新紅(8) Molecular targeted therapies for TNBCCell CycleTrans

16、criptional ControlMAP Kinase PathwayAkt PathwayEGFR tyrosine kinasec-KIT tyrosine kinaseDNA Repair pathway- platinum agents, PARP inhibitorsAngiogenesisMicrotubule stabilizationMAPK, Notch inhibitorsdasatinib, sunitinibcetuximabixabepiloneTrabedectin, brostacillinbevacizumab陰性乳腺癌的治療進(jìn)展吳新紅Bevacizumab

17、for TNBCTrial / ArmMedian PFS (mo) in TNBC Subset E2100 Paclitaxel (n=110)5.3 Paclitaxel + bev (n=122)10.6AVADO Docetaxel + placebo (n=52)5.4 Docetaxel + bev 15 mg/kg (n=58)8.2RIBBON-1 Taxane/anthracycline + placebo (n=46)6.2 Taxane/anthracycline + bev (n=96)6.5 Capecitabine + placebo (n=50)4.2 Cape

18、citabine + bev (n=87)6.1ATHENA 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.

19、16)OShaughnessy et al. ASCO 2010陰性乳腺癌的治療進(jìn)展吳新紅EGFR Inhibition for TNBCTNBC strongly associated with EGFR expressionEGFR inhibitors combined with platinum Current data conflictingTBCRC 001(n=102)OShaughnessy et al(n=78)CetuximabCarboplatin + CetuximabIrinotecan + CarboplatinIrinotecan + Carboplatin +

20、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 1009; OShaughnessy et al. SABCS 2007; abstr 308. 陰性乳腺癌

21、的治療進(jìn)展吳新紅Other Targets for TNBCTargetAgent/ApproachInitial OutcomesDNA repair pathwaysPARP inhibitors (BSI-201, olaparib, AG014699, ABT-888), trabectedinPFS=6.9m, OS=12.2m, ORR=22-41% (OShaughnessy, Tutt)VEGFRSunitinibORR=15% (Burstein 2008)AngiogenesisEndo TAG-1, metronomic chemotherapySrc kinaseDas

22、atinibCBR=9.3% (Finn 2009)Checkpoint kinase 1UCN-01mTORRAD001, everolimus, temsirolimusAndrogen receptorBicalutamideTRAILLexatumumabTGF-betaGC1008, AP 12009, LY2157299PDGFR, c-KITImatinibAdapted from Tan and Swain. Cancer Journal. 2008;14.陰性乳腺癌的治療進(jìn)展吳新紅PARP1 in Breast CancerPARP1 mRNA level 700600500

23、4003002001000NormalIDCMean99.9%UCL99%UCL95%UCL90%UCLIDC Subtype% PARP1 upregulationNormal2.9%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 distributionInfiltrating ductal carcin

24、oma (IDC) is a highly invasive tumor, accounting for 70-80% of all breast malignanciesIDC shows statistically significant PARP1 upregulation in comparison with normal breast tissues: p = 2x10-27 PARP1 is upregulated in TNBC陰性乳腺癌的治療進(jìn)展吳新紅The rate of clinical benefit from 34% to 56% (P=0.01) The rate o

25、f 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).陰性乳腺癌的治療進(jìn)展吳新紅(9）Radiotherapy for TNBCHaffty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=0.03)和無淋巴結(jié)轉(zhuǎn)移生存率(93%對(duì)99%,P=0.021)局部控制率方面沒有差異(均為83%),證明了其對(duì)放射線的敏感性陰性乳腺癌的治療進(jìn)展吳新紅（10）TNBC: Ongoing Clinical TrialsNumerous prospective trials ongoing to evaluate various therapeutic options specifically in