乳腺癌治疗研究进展.ppt

1、1,2010年乳腺癌治疗研究进展,2,乳腺癌的治疗方法,手 术,放 疗,乳腺癌,化疗,分子靶向治疗,内分泌治疗,3,乳腺癌化疗进展,术后辅助化疗转移性乳腺癌的化疗,4,FinXX 5年分析：中高危早期乳腺癌中随机、开放的III 期研究结果,Joensuu H, Kellokompu-Lehtinen P-L, Huovinen R, Jukkola-Vuorinen A, Tanner M, Kokko R, Ahlgren J, Auvinen P, Bono P, Lindman H On Behalf of the FinXX Study Investigators,5,FinXX 研究

2、: 设计,LN(+)LN(-)and T2cm and PR(-),6,中位随访5年,7,中位随访5年,8,中位随访5年,9,10,11,USON 01062：AC序贯T（多西他赛）卡培他滨辅助治疗高危早期乳腺癌的随机开放III期临床研究,OShaughnessy J, Paul D, Stokoe C, Pippen J, Blum JL, Krekow L, Holmes FA, Vukelja S, Lindquist D, Sedlacek S, Rivera R, Brooks R, McIntyre K, Pluenneke R, Schwartz J, Jones S, Brow

3、nstein C, Gilberg F,12,USON 01062：研究设计,13,14,15,16,乳腺癌化疗进展,术后辅助化疗转移性乳腺癌的化疗,17,eribulin 对既往治疗过的MBC 的II期临床研究,1Vahdat, et al. J Clin Oncol 2009; 2Vahdat, et al. ASCO 2008 (Abst 1084),18,Study Design,19,Results,N= 762 patientsAt least two prior metastatic chemo regimens Eribulin Physician choiceOS 13.1

4、m 10.6 m HR 0.81 p=0.04PFS 3.7 m 2.2.m HR0.87 p=0.14RR 12.2% 4.7%ToxicityMain toxicity associated with this agent FN 3.0% Grade Neuropathy 8.2%,20,乳腺癌的治疗方法,手 术,放 疗,分子靶向治疗,乳腺癌,化疗,内分泌治疗,21,乳腺癌内分泌治疗进展,术后辅助内分泌治疗转移性乳腺癌的内分泌治疗,22,在绝经后受体阳性乳腺癌中辅助 Exemestane 和 Anastrozole 的III期随机临床研究,P. E. GossJ. N. Ingle, J.

5、W. Chapman, M. J. Ellis, G.W. Sledge, G.T. Budd,M. Rabaglio, K. Gelmon, L. Shepherd, K.I. Pritchard.,NCICCTG MA.27,23,NCICCTG MA.27研究设计,primary objective :EFS Secondary objectives:OS、DDFS、CBC、safety,24,Percentage,# At Risk,AnastrozoleExemestane,Anastrozole,Exemestane,0,604020,MA.27 主要研究终点 (EFS)10080

6、,时间 (年)# At Risk(Anastrozole)# At Risk(Exemestane),037873789,136743655,234873461,331823190,421902230,5723734,65652,中位随访4.1 年分层HR: 1.02 (0.87-1.18) p = 0.85,25,Exemestane 比 Anastrozole,分层,事件 (%) 事件 (%),HR (95% CI),P-value,EFSOSDDFSDSS,350 (9.2)208 (5.5)157 (4.1)89 (2.4),343 (9.1)224 (5.9)164 (4.3)98

7、(2.6),1.02 (0.87, 1.18)0.93 (0.77, 1.13)0.95 (0.76, 1.18)0.93 (0.70, 1.24),0.850.640.460.62,MA.27 研究结果,26,MA.27: 不良反应- 各级别 (70% 1/2级),Exemestane n (%) Anastrozole n (%)P- value 潮热关节炎/关节痛 肌肉痛阴道出血ALTAST胆红素痤疮雄性化心梗中风/一过性脑缺血/TIA房颤高甘油三酯a高胆固醇骨质疏松任何临床骨折脆性骨折,2051 (55)253 (7)649 (17)40 (1)53 (1)47 (1)59 ( 2)1

8、2 (0)36 (1)38 (1)32 (1)72 (2)80 (2) 577 (15)1171 (31)358 (10)136 ( 4),2101 (56)231 ( 6)606 (16)61 (2)23 (1)19 (1)24 (1)3 (0)11 (0)32 (1)38 (1)46 (1)124 (3) 665 (18)1304 (35)354 ( 9)136 (4),3761 (100),3759 (100),0.240.320.190.040.0010.0010.00010.040.00010.550.470.020.002 0.01 0.0010.910.98,较好,27,乳腺癌内

9、分泌治疗进展,术后辅助内分泌治疗转移性乳腺癌的内分泌治疗,28,氟维司琼对比阿那曲唑一线治疗转移性乳腺癌： FIRST 研究,Robertson JF, Lindemann JP, Llombart-Cussac A, Rolski J, Felti D, Dewar J, Emerson L, Dean A, Ellis MJ,29,30,31,32,依维莫司联合三苯氧胺对比三苯氧胺用于 HR+, HER2- 既往AI治疗的转移性乳腺癌 II 期随机临床试验,BachelotT, BourgierC, CropetC, GuastallaJ-P, FerreroJ-M, Leger-Fala

10、ndryC, SoulieP, EymardJ-C, DebledM, SpaethD, LegouffeE, DelozierT, El KouriC, ChidiacJ,TAMRAD:,33,33,PI3K/AKt/mTOR信号传导通路,mTOR （mammalian target of rapamycin）细胞内丝氨酸/苏氨酸激酶，PI3K/Akt传导途经中的一员mTOR是细胞内中枢调控器，可感知如下细胞因子的变化生长因子信号1,2 营养和能量信号1-3mTOR 活化可促进细胞生长和增殖3血管生成4通过加强的营养物质摄取和利用，可加快肿瘤细胞代谢3,5,血管生成,mTOR,AMPK,TS

11、C1,TSC2,LKB1,细胞生长 &增殖,细胞代谢,RHEB,IGF-1R,EGFR/HER2,Nutrients,Harris and Lawrence. Sci STKE. 2003;(212):re15. Huang et al. Cancer Biol Ther. 2003;2:222-232. Wullschleger et al. Cell. 2006;124:471-484. Humar et al. FASEB J. 2002;16:771-780. Edinger and Thompson. Mol Biol Cell. 2002;13:2276-2288.,34,抑制血管

12、生成,mTOR,AMPK,TSC1,TSC2,LKB1,细胞生长 &增殖,细胞代谢,RHEB,IGF-1R,EGFR/HER2,Nutrients,多功能抑制剂细胞生长和增殖细胞代谢血管生成每日给药，持续抑制mTOR目前在多种适应症中进行II 期和 III 期试验，如乳腺癌,胃癌,肝癌，淋巴瘤, 神经内分泌肿瘤, 肾癌,依维莫司 Everolimus(RAD001):口服mTOR 抑制剂,35,PI3K/AKt/mTOR信号传导通路与内分泌治疗耐药,ER通路与PI3K（磷酸肌醇-3-激酶）/AKt/mTOR信号传导通路之间的相互作用是内分泌治疗耐药的机制之一临床前研究模型中，同时阻断这两条通路

13、，就可以增强抗肿瘤活性,Yue.W.J Steroid Biochem Mol Biol 2007;106;102.-110,36,TAMRAD 研究试验设计,随机 II期临床试验先前使用过AI的转移性乳腺癌患者 A: 三苯氧胺20 mg/day (TAM) B:三苯氧胺20 mg/day + RAD001 10 mg/day (TAM + RAD)分层: 原发或继发的内分泌耐药 原发: 辅助 AI复发; 在MBC开始AI治疗后6个月内复发 继发: 开始AI治疗6 月后复发或 AI初始有效继而进展 无换药计划 BachelotT, et al. Cancer Res.2010;70(24 Su

14、ppl): Abstract S1-6.,R,主要终点：CBR 次要终点：TTP、OS、ORR、安全性,37,主要研究终点: CBR,CBR = 临床获益率; RAD = RAD001; TAM = 三苯氧胺 BachelotT, et al. Cancer Res.2010;70(24 Suppl): Abstract S1-6.,(29.1-55.9),(46.9-74.1),P=.045(探索分析),N=57,N=54,38,至疾病进展时间-TTP,39,OS (2010年10月),40,不同内分泌耐药的TTP,原发内分泌耐药 (n = 54)TAM: 3.9 月TAM + RAD: 5

15、.4 月HR = 0.74 (0.42-1.3)继发内分泌耐药 (n = 56)TAM: 5.0 月TAM + RAD: 17.4 月HR = 0.38 (0.21-0.71)HR = 危险比; RAD = RAD001; TAM = 三苯氧胺BachelotT, et al. Cancer Res.2010;70(24 Suppl): Abstract S1-6.,41,不良反应,发生率, n (%) TAM (n = 57) TAM + RAD (n = 54)等级 Any 3/4 Any 3/4常见不良事件 (AE)疲劳 30 (52.6) 6 (10.5) 40 (74.1) 3 (5

16、.6)口腔炎 4 (7.0) 0 28 (51.9) 6 (11.1)皮疹 3 (5.3) 1 (1.8) 21 (38.9) 3 (5.6)食欲减退 10 (17.5) 2 (3.5) 24 (44.4) 5 (9.3)腹泻 5 (8.8) 0 21 (38.9) 1 (1.9)恶心 19 (33.3) 0 18 (33.3) 2 (3.7)呕吐 7 (12.3) 2 (3.5) 9 (16.7) 0肺炎 2 (3.5) 2 (3.5) 9 (16.7) 1 (1.9)血栓 4 (7.0) 4 (7.0) 7 (13.0) 3 (5.6)疼痛 48 (84.2) 11 (19.3) 42 (

17、77.8) 5 (9.3)因不良事件减轻剂量 0 15 (28.0)因不良事件出组 4 (7.0) 3 (5.6)BachelotT, et al. Cancer Res.2010;70(24 Suppl): Abstract S1-6.,42,乳腺癌进展后激素受体和HER2状态变化,Lindstrom L, KarlssonE, WilkingU, Bergh J*,43,The Karolinska HR and HER2研究方法,receptorThe Karolinska cohort (1997-2007)1051局部或全身复发乳腺癌患者Reported to Stockholm-G

18、otland Breast Cancer Registry, 459 例患者原发和复发灶的ER437例患者原发和复发灶的PR118例患者原发和复发灶的HER2,多部位复发患者ER信息101例患者多个复发部ER, 74例患者2个复发部位ER13例患者3个复发部位ER10例患者4个复发部位ER2例患者5个复发部位ER2例患者6个复发部位ER,BC = 乳腺癌; ER = 雌激素受体Lindstrom L, et al. Cancer Res.2010;70(24 Suppl): Abstract S3-5.,44,原发和复发肿瘤中ER, PR 和 HER2 状态,45,受体的改变对生存的影响,46

19、,乳腺癌的治疗方法,手 术,放 疗,分子靶向治疗,乳腺癌,化疗,内分泌治疗,47,Cell Growth, Proliferation, Survival, Metastasis, Angiogenesis,乳腺癌的靶向治疗药物,RAD001Phase III,EGFR,HER2,4E-BP1,elF-4E,Protein Synthesis,VEGFR,SunitinibPhase II,BevacizumabPhase III,VEGF,48,乳腺癌分子靶向治疗进展,转移性乳腺癌新辅助治疗,49,1. Miller, et al. NEJM 2007 2. Miles, et al. AS

20、CO 2008; 3. Robert, et al. ASCO 2009,贝伐珠单抗联合化疗一线治疗LR/MBC临床研究,LR = locally recurrentmBC = metastatic breast cancer; q2w = every 2 weeksq3w = every 3 weeks; PFS = progression-free survival,*Stratified and censored for non-protocol therapy before disease progressionThese combinations are not included w

21、ithin the current SmPCp value is exploratory; HR = hazard ratio; IRF = independent review facility,贝伐珠单抗联合化疗显著提高PFS,1.00.80.60.40.20,PFS estimate,0612182430,Time (months),9.2,8.0,AVADO3,4,HR=0.67* (0.540.83)p=0.0002,1.00.80.60.40.20,PFS estimate,061218243036,Time (months),8.1,10.0,Placebo + docetaxe

22、l (n=241)Bevacizumab 15mg/kg q3w + docetaxel (n=247),Placebo + docetaxel (n=207)Bevacizumab + taxane/ anthracycline (n=415),1.00.80.60.40.20,0612182430,Time (months),HR=0.64* (0.520.80)p0.0001,HR=0.69* (0.560.84)p=0.0002,Placebo + capecitabine (n=206)Bevacizumab + capecitabine (n=409),8.6,5.7,RIBBON

23、-1: taxane/anthracycline cohort2,HR=0.48* (0.390.61)p0.0001,PFS estimate,1.00.80.60.40.20,PFS estimate,061218243036,Time (months),Paclitaxel (n=354)Bevacizumab + paclitaxel (n=368),5.8,11.3,E2100 (IRF assessment)1,RIBBON-1: capecitabine cohort2,1. Gray R, et al. JCO 2009. Reprinted with permission 2

24、009 American Society of Clinical Oncology; 2. Robert, et al. ASCO 20093. Miles, et al. SABCS 2009; 4. Avastin SmPC,51,贝伐珠单抗联合化疗显著提高 ORR,*p value is exploratory; in patients with measurable disease at baselinemg/kg q3w; These combinations are not included within the current SmPCORR = overall response

25、 rate; Pl = placebo; P = paclitaxel D = docetaxel; T = taxaneBev = bevacizumab; Cap = capecitabine anthr = anthracycline-based therapy,E2100 (IRF)1,2,AVADO3,1. Klencke, et al. ASCO 2008; 2. Avastin SmPC3. Miles, et al. SABCS 20094. Robert, et al. ASCO 2009,ORR (%),50%p0.0001,22%,PBev + P (n=243)(n=2

26、29),RIBBON-14,100806040200,ORR (%),64%p=0.0003*,46%,PI + DBev 15 + D (n=207)(n=206),100806040200,ORR (%),35%p=0.0097,24%,PI +Bev +PI +Bev +capcapT/anthrT/anthr(n=161) (n=325) (n=177) (n=345),100806040200,38%,51%p=0.0054,52,1. Cameron. EJC Suppl 20082. Miles, et al. SABCS 2009; 3. Robert, et al. ASCO

27、 2009,贝伐珠单抗联合化疗: 未延长总生存,*15mg/kg q3w; Exploratory p valuesThese combinations are not included within the current SmPC,Patients, %,NR,Miles. EJC Suppl 2008Miles, et al. SABCS 2009Robert, et al. ASCO 2009,NR = data for ATEs not reported for RIBBON-1 studyGI = gastrointestinal LVEF = left ventricular e

28、jection fraction; ATE = arterial thromboembolic eventsVTE = venous thromboembolic events; *These combinations are not included within the current SmPC,Grade 3 events,贝伐珠单抗一线治疗MBC临床研究不良反应,其它抗血管生成剂一线治疗MBC临床研究,1. Barrios, et al. SABCS 2009; 2. Mackey, et al. SABCS 2009 3. Martin, et al. ECCO/ESMO 2009;

29、 4. Baselga, et al. SABCS 2009; 5. Gradishar, et al. SABCS 2009,Patients must have progressed during or after treatment with bevacizumab,*Trial performed in mixed first-/second-line population,55,拉帕替尼,口服的双重酪氨酸激酶抑制剂，对ErbB1（EFGR）和ErbB2受体都有特异性与胞浆中激酶的ATP结合部位发生可逆性结合，从而防止受体磷酸化和受体激活,N-3-氯-4-(3-氟苯基)氧基苯基-6-5

30、-(2(甲磺酰基)乙基氨基甲基)-2-呋喃基-4-喹唑啉胺,拉帕替尼,56,ErbB3,ErbB4,PI3K/AKTRas/MEK/MAPK(STAT),TF,CoA,CoR,增殖游走分化凋亡,TK,X,TK,TK,ErbB2,ErbB2,ErbB1/EGFR,拉帕替尼,拉帕替尼阻断ErbB家族的信号传导途径,57,EGF104535：拉帕替尼+紫杉醇一线治疗HER2阳性MBC的III期临床研究,随机分组,N = 444,紫杉醇 80 mg/m2 IV 每周1次 + 拉帕替尼 1500 mg po QD,紫杉醇80 mg/m2 IV 每周1次 + 安慰剂,MBC一线FISH+*,*中心实验室进

31、行FISH检测,开放性延长期研究拉帕替尼单药治疗,终点临床受益*OSPFS,中国 (302)泰国香港巴西秘鲁,分层激素受体(阳性/阴性)和病灶部位(内脏/非内脏),主要研究终点：OS次要研究终点：PFS 、ORR 、CBR、安全性,58,疗 效,L+P (n=222) P(n=222)OS 27.8m 20.5m HR 0.64 p=0.0005PFS 9.7 m 6.5m HR0.52 p=0.0001ORR 69% 50% OR 2.3 P0.001CBR 75% 56% OR 2.34 P0.001,59,不良反应,The incidence of withdrawal from tre

32、atment due to AEs(13% vs 10%) was a similar.,60,乳腺癌分子靶向治疗进展,转移性乳腺癌新辅助治疗,61,拉帕替尼对比曲妥珠单抗联合蒽环+紫杉的新辅助化疗：GEPARQUINTO (GBG44) 研究疗效分析,UntchM, LoiblS, Bischoff J, EidtmannH, Kaufmann M, BlohmerJU, HilfrichJ, StrumbergD, FaschingP, KreienbergR, TeschH, HanuschC, Gerber B, RezaiM, JackischC, HuoberJ, KhnT, Ne

33、kljudovaV, von MinckwitzG On Behalf of the German Breast Group,62,63,64,65,66,Neo-ALTTO研究：拉帕替尼、曲妥珠单抗或两者联合+紫杉醇新辅助治疗HER2阳性原发性乳腺癌的随机开放的III期临床研究,Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, Aura C, de Azambuja E, Gomez H, Dinh P, Fauria K, Van Dooren V, Paoletti P, Goldhirsch A, Chang T-W, Lang I, Un

34、tch M, Gelber RD, Piccart-Gebhart M On Behalf of the Neo-ALTTO Study Team,67,68,NSABP guidelines,breast AND lymph nodes,69,70,71,72,新辅助帕妥珠单抗联合曲妥珠单抗：一项随机II 期临床研究疗效及安全性分析 (NeoSphere),Gianni L, Pienkowski T, Im Y-H, Roman L, Tseng L-M, Liu M-C, Lluch-Hernandez A, Semiglazov V, Szado T, Ross G,73,帕妥珠单抗（

35、Pertuzumab ）: 第一个HER2二聚体形成的抑制剂,Hubbard 2005,曲妥珠单抗,帕妥珠单抗,74,HER2:HER3 二聚体形成产生对曲妥珠单抗的逃避,+,+,+,+,+,+,+,+,+,+,+,Signalling activity,+,+,+,+,Homodimers,Heterodimers,HER1:HER1,HER2:HER2,HER3:HER3,HER4:HER4,HER1:HER2,HER1:HER3,HER1:HER4,HER2:HER3,HER2:HER4,HER3:HER4,Tzahar et al. Mol Cell Biol 1996;Sergina

36、 et al. Nature 2007,帕妥珠单抗和曲妥珠单抗与HER2的不同区域结合产生协同作用,HER2 receptor,Trastuzumab,Pertuzumab,Subdomain IV of HER2,Dimerisation domain of HER2,Juntila et al. Cancer Cell 2009,激活抗体依赖的细胞毒作用增强ErbB2的内化抑制细胞胞外结构域脱落抑制血管发生,激活抗体依赖的细胞毒作用防止受体二聚体形成是ErbB介导的信号传导途径的强效抑制剂,76,临床前研究:帕妥珠单抗和曲妥珠单抗具有协同作用,Pertuzumab treatment af

37、ter progression following trastuzumab treatment,Mean tumour volume (mm3) SEM,6/10 animals cured,6005004003002001000,01020304050607080,Treatment period (days),Pertuzumab + trastuzumabinitial combination,Vehicle control,Pertuzumab (30/15 mg/kg/w ip),Trastuzumab (30/15 mg/kg/w ip),Pertuzumab (30/15 mg/

38、kg/w ip)+ trastuzumab (30/15 mg/kg/w ip),0102030405060708090,Treatment period (days),Vehicle control,Trastuzumab (30/15 mg/kg/w ip),Pertuzumab (30/15 mg/kg/w ip) + trastuzumab (30/15 mg/kg/w ip),Xenograft model KPL-4w, week; ip, intraperitoneally; SEM, standard error of mean,0,200,400,600,800,1000,1

39、200,1400,Scheuer et al. Cancer Res 2009. Reproduced and adapted with permission from the American Association for Cancer Research,77,78,79,80,81,小结(1),化疗FinXX研究：T/CEF辅助治疗方案中加入卡培他滨未显著改善RFS或OS，亚组分析显示TX/CEX 改善了乳腺癌特异性的生存率及三阴性乳腺癌的RFSUSON 01062研究：AC T辅助治疗方案加入卡培他滨，显著改善OSEMBRACE(E7389)研究：eribulin 对既往多重治疗过的M

40、BC可以改善生存,82,小结（2）,内分泌治疗MA-27研究：绝经后HR(+)乳腺癌的辅助内分泌治疗，依西美坦与阿那曲唑疗效相似，不良反应有所不同TAMRAD研究：对先前AI治疗的MBC，依维莫司联合他莫西芬治疗CBR、TTP、OS均优于他莫昔芬，继发内分泌耐药的患者临床获益更高氟维司琼500 mg一线治疗ER+的MBC,TTP较阿那曲唑显著获益乳腺癌进展后激素受体和HER2状态变化：在该研究中, 复发转移后，1/3乳腺癌患者HR状态改变，1/10患者HER2 状态改变，ER阳性患者肿瘤进展后转为阴性的死亡风险较稳定者增加,83,小结（3）,分子靶向治疗贝伐珠单抗联合化疗一线治疗LR/MBC的

41、三项临床研究：显著提高PFS、ORR,未改善OS,增加高血压、蛋白尿、胃肠穿孔、出血、血栓风险EGF104535：拉帕替尼联合紫杉醇一线治疗HER2阳性MBC较紫杉醇显著改善OS、PFS、ORR、CBR，增加了腹泻、肝功能异常、粒细胞减少的发生率,84,小结（4）,在HER2阳性乳腺癌的新辅助治疗中 GEPARQUINTO (GBG44)研究：EC-Doc+T组pCR率显著高于EC-Doc+L ，EC-Doc + L的耐受性低于EC-Doc + T Neo-ALTTO研究:在化疗的基础上，联合靶向治疗（L+T)pCR率优于单一靶向治疗 NeoSphere研究：曲妥珠单抗联合化疗中加入帕妥珠单抗提高了pCR ，单独靶向治疗（帕妥珠单抗联合曲妥珠单抗）疗效肯定且毒性明显减低,85,Thank you,