乳腺癌治療研究進展

1、1,2010年乳腺癌治療研究進展,,2,乳腺癌的治療方法,手 術,放 療,,乳腺癌,化療,,,,,,分子靶向治療,,內分泌治療,3,乳腺癌化療進展,,術后輔助化療轉移性乳腺癌的化療,4,FinXX 5年分析：中高危早期乳腺癌中隨機、開放的III 期研究結果,,Joensuu H, Kellokompu-Lehtinen P-L, Huovinen R, Jukkola-Vuorinen A, Tanner M, Kokko R,

2、Ahlgren J, Auvinen P, Bono P, Lindman H On Behalf of the FinXX Study Investigators,5,FinXX 研究: 設計,,LN(+)LN(-)and T＞2cm and PR(-),6,,,,,中位隨訪5年,7,,,,中位隨訪5年,8,,,中位隨訪5年,9,,,,10,,,11,US

3、ON 01062：AC序貫T（多西他賽）±卡培他濱輔助治療高危早期乳腺癌的隨機開放III期臨床研究,O’Shaughnessy 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

4、J, Jones S, Brownstein C, Gilberg F,,,12,USON 01062：研究設計,,13,,,14,,,15,,,16,乳腺癌化療進展,,術后輔助化療轉移性乳腺癌的化療,17,eribulin 對既往治療過的MBC 的II期臨床研究,1Vahdat, et al. J Clin Oncol 2009; 2Vahdat, et al. ASCO 2008 (Abst 1084),,,,18,Study

5、Design,,19,Results,N= 762 patientsAt least two prior metastatic chemo regimens Eribulin Physician choiceOS 13.1 m 10.6 m HR 0.81 p=0.04PFS 3.7 m 2.2.m HR0.87 p=0.14RR 12.2%

6、 4.7%ToxicityMain toxicity associated with this agent – FN 3.0% – Grade ¾ Neuropathy 8.2%,,,,20,乳腺癌的治療方法,手 術,放 療,分子靶向治療,乳腺癌,化療,,,,,,內分泌治療,,21,乳腺癌內分泌治療進展,,術后輔助內分泌治療轉移性乳腺癌的內分泌治療,22,在

7、絕經后受體陽性乳腺癌中輔助 Exemestane 和 Anastrozole 的III期隨機臨床研究,P. E. GossJ. N. Ingle, J.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

8、設計,,,,,primary objective :EFS Secondary objectives:OS、DDFS、CBC、safety,24,Percentage,# At Risk,AnastrozoleExemestane,Anastrozole,Exemestane,0,604020,MA.27 – 主要研究終點 (EFS)10080,時間 (年)# At Risk(A

9、nastrozole)# At Risk(Exemestane),037873789,136743655,234873461,331823190,421902230,5723734,65652,中位隨訪4.1 年分層HR: 1.02 (0.87-1.18) p = 0.85,,25,,Exemestane 比 Anastrozole,分層,事件 (%) 事

10、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 (2.6),1.02 (0.87, 1.18)0.93 (0.77, 1.13)0.95 (0.76, 1.18)0.93

11、 (0.70, 1.24),0.850.640.460.62,MA.27 ——研究結果,,26,,,,,MA.27: 不良反應- 各級別 (70% 1/2級),Exemestane n (%) Anastrozole n (%)P- value 潮熱關節(jié)炎/關節(jié)痛 肌肉痛陰道出血ALTAST膽紅素痤瘡雄性化心梗中風/一

12、過性腦缺血/TIA房顫高甘油三酯a高膽固醇骨質疏松任何臨床骨折脆性骨折,2051 (55)253 (7)649 (17)40 (1)53 (1)47 (1)59 ( 2)12 (0)36 (1)38 (1)32 (1)

13、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)3

14、2 (1)38 (1)46 (1)124 (3) 665 (18)1304 (35)354 ( 9)136 (4),3761 (100),3759 (100),0.240.320.190.040.0010.001<0.00010.04<0.00010.5

15、50.470.020.002 0.01 0.0010.910.98,,,,,較好,,27,乳腺癌內分泌治療進展,,術后輔助內分泌治療轉移性乳腺癌的內分泌治療,28,氟維司瓊對比阿那曲唑一線治療轉移性乳腺癌： FIRST 研究,Robertson JF, Lindemann JP, Llombart-Cussac A, Rolsk

16、i J, Felti D, Dewar J, Emerson L, Dean A, Ellis MJ,,29,,,30,,,,31,,,32,依維莫司聯(lián)合三苯氧胺對比三苯氧胺用于 HR+, HER2- 既往AI治療的轉移性乳腺癌 II 期隨機臨床試驗,BachelotT, BourgierC, CropetC, GuastallaJ-P, FerreroJ-M, Leger-FalandryC, SoulieP, EymardJ-C,

17、 DebledM, SpaethD, LegouffeE, DelozierT, El KouriC, ChidiacJ,TAMRAD:,,33,33,PI3K/AKt/mTOR信號傳導通路,mTOR （mammalian target of rapamycin）細胞內絲氨酸/蘇氨酸激酶，PI3K/Akt傳導途經中的一員mTOR是細胞內中樞調控器，可感知如下細胞因子的變化生長因子信號1,2 營養(yǎng)和能量信號1-3mTOR 活化可促

18、進細胞生長和增殖3血管生成4通過加強的營養(yǎng)物質攝取和利用，可加快腫瘤細胞代謝3,5,,,,,,,,,,血管生成,,mTOR,,AMPK,TSC1,TSC2,LKB1,細胞生長 &增殖,細胞代謝,,RHEB,,,IGF-1R,EGFR/HER2,,Nutrients,Harris and Lawrence. Sci STKE. 2003;(212):re15. Huang et al. Cancer Biol Ther.

19、 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,,,,,,,,,,,抑制血管生成,,mTOR,,AMPK,TSC1,TSC2,LKB1,細胞生長 &增殖

20、,細胞代謝,,RHEB,,,IGF-1R,EGFR/HER2,,Nutrients,多功能抑制劑細胞生長和增殖細胞代謝血管生成每日給藥，持續(xù)抑制mTOR目前在多種適應癥中進行II 期和 III 期試驗，如乳腺癌,胃癌,肝癌，淋巴瘤, 神經內分泌腫瘤, 腎癌,依維莫司 Everolimus(RAD001):口服mTOR 抑制劑,,,,,35,PI3K/AKt/mTOR信號傳導通路與內分泌治療耐藥,,ER通路與PI3K（磷酸肌醇

21、-3-激酶）/AKt/mTOR信號傳導通路之間的相互作用是內分泌治療耐藥的機制之一臨床前研究模型中，同時阻斷這兩條通路，就可以增強抗腫瘤活性,Yue.W.J Steroid Biochem Mol Biol 2007;106;102.-110,,36,,,TAMRAD 研究——試驗設計,隨機 II期臨床試驗先前使用過AI的轉移性乳腺癌患者 A: 三苯氧胺20

22、mg/day (TAM) B:三苯氧胺20 mg/day + RAD001 10 mg/day (TAM + RAD)分層: 原發(fā)或繼發(fā)的內分泌耐藥 –原發(fā): 輔助 AI復發(fā); 在MBC開始AI治療后6個月內復發(fā) –繼發(fā): 開始AI治療≥6 月后復發(fā)或 AI初始有效繼而進展 無換藥計劃

23、 BachelotT, et al. Cancer Res.2010;70(24 Suppl): Abstract S1-6.,R,,,,主要終點：CBR 次要終點：TTP、OS、ORR、安全性,37,主要研究終點: CBR,CBR = 臨床獲益率; RAD = RAD001; TAM = 三苯氧胺

24、 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,至疾病進展時間-TTP,,39,OS (2010年10月),,40,不同內分泌耐藥的TTP,原發(fā)內分泌耐藥 (n = 54)–TAM: 3.9 月–TAM + RAD: 5.4 月–HR

25、 = 0.74 (0.42-1.3)繼發(fā)內分泌耐藥 (n = 56)–TAM: 5.0 月–TAM + RAD: 17.4 月–HR = 0.38 (0.21-0.71)HR = 危險比; RAD = RAD001; TAM = 三苯氧胺BachelotT, et al. Cancer Res.2010;70(24 Suppl): Abstract S1-6.,,41,,,不良反應,發(fā)生率, n (%)

26、 TAM (n = 57) TAM + RAD (n = 54)等級 Any 3/4 Any 3/4常見不良事件 (AE)疲勞 30 (52.6) 6 (10.5) 40 (74.1) 3

27、 (5.6)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)食欲減退 10 (17.5) 2 (3.5)

28、 24 (44.4) 5 (9.3)腹瀉 5 (8.8) 0 21 (38.9) 1 (1.9)惡心 19 (33.3) 0 18 (33.3) 2 (3.7)嘔吐 7

29、 (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 (

30、5.6)疼痛 48 (84.2) 11 (19.3) 42 (77.8) 5 (9.3)因不良事件減輕劑量 0 15 (28.0)因不良事件出組 4 (7.0) 3 (5.6)B

31、achelotT, et al. Cancer Res.2010;70(24 Suppl): Abstract S1-6.,,,,,,42,乳腺癌進展后激素受體和HER2狀態(tài)變化,Lindstrom L, KarlssonE, WilkingU, Bergh J*,,43,,,,,The Karolinska HR and HER2—研究方法,receptorThe Karolinska cohort (1997-2007)105

32、1局部或全身復發(fā)乳腺癌患者Reported to Stockholm-Gotland Breast Cancer Registry,? 459 例患者原發(fā)和復發(fā)灶的ER?437例患者原發(fā)和復發(fā)灶的PR?118例患者原發(fā)和復發(fā)灶的HER2,多部位復發(fā)患者ER信息?101例患者多個復發(fā)部ER,? 74例患者2個復發(fā)部位ER?13例患者3個復發(fā)部位ER?10例患者4個復發(fā)部位ER?2例患者5個復發(fā)部位ER?2例患者6個復發(fā)部位

33、ER,BC = 乳腺癌; ER = 雌激素受體Lindstrom L, et al. Cancer Res.2010;70(24 Suppl): Abstract S3-5.,,,,,44,原發(fā)和復發(fā)腫瘤中ER, PR 和 HER2 狀態(tài),,45,受體的改變對生存的影響,,46,乳腺癌的治療方法,手 術,放 療,分子靶向治療,乳腺癌,化療,,,,,,內分泌治療,,47,,,,,,,,,,,,,,,,,,,,,,,,,Cell Gr

34、owth, Proliferation, Survival, Metastasis, Angiogenesis,,乳腺癌的靶向治療藥物,,RAD001Phase III,EGFR,HER2,4E-BP1,elF-4E,Protein Synthesis,,,,,,,,,,,,VEGFR,SunitinibPhase II,BevacizumabPhase III,VEGF,,,48,乳腺癌分子靶向治療進展,轉移性乳腺癌新輔助治療

35、,,49,1. Miller, et al. NEJM 2007 2. Miles, et al. ASCO 2008; 3. Robert, et al. ASCO 2009,貝伐珠單抗聯(lián)合化療一線治療LR/MBC臨床研究,LR = locally recurrentmBC = metastatic breast cancer; q2w = every 2 weeksq3w = every 3 weeks; PFS = pro

36、gression-free survival,,*Stratified and censored for non-protocol therapy before disease progression?These combinations are not included within the current SmPC§p value is exploratory; HR = hazard ratio; IRF = ind

37、ependent review facility,貝伐珠單抗聯(lián)合化療顯著提高PFS,1.00.80.60.40.20,PFS estimate,0612182430,Time (months),,,,9.2,8.0,AVADO3,4,HR=0.67* (0.54–0.83)p=0.0002§,1.00.80.60.40.20,PFS estimate,061218243036,Tim

38、e (months),,,,8.1,10.0,Placebo + docetaxel (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 (mon

39、ths),HR=0.64* (0.52–0.80)p<0.0001,HR=0.69* (0.56–0.84)p=0.0002,Placebo + capecitabine (n=206)Bevacizumab + capecitabine (n=409),,,,,,8.6,5.7,RIBBON-1?: taxane/anthracycline cohort2,HR=0.48* (0.39–0.61)p<0.0001

40、,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

41、. JCO 2009. Reprinted with permission © 2009 American Society of Clinical Oncology; 2. Robert, et al. ASCO 20093. Miles, et al. SABCS 2009; 4. Avastin SmPC,,51,貝伐珠單抗聯(lián)合化療顯著提高 ORR,*p value is exploratory; ?in patie

42、nts with measurable disease at baseline§mg/kg q3w; ¶These combinations are not included within the current SmPCORR = overall response rate; Pl = placebo; P = paclitaxel D = docetaxel; T = taxaneBev = bevaciz

43、umab; 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%p<0.0001,22%,PBev +

44、 P (n=243?)(n=229?),RIBBON-1¶4,100806040200,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

45、=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 2009,貝伐珠單抗聯(lián)合化療: 未延長總生存,*15mg/kg q3w; ?Exploratory p values§

46、These 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

47、 LVEF = left ventricular ejection fraction; ATE = arterial thromboembolic eventsVTE = venous thromboembolic events; *These combinations are not included within the current SmPC,Grade ≥3 events,貝伐珠單抗一線治療MBC臨床研究不良反應,,其它抗

48、血管生成劑一線治療MBC臨床研究,1. Barrios, et al. SABCS 2009; 2. Mackey, et al. SABCS 2009 3. Martin, et al. ECCO/ESMO 2009; 4. Baselga, et al. SABCS 2009; 5. Gradishar, et al. SABCS 2009,?Patients must have progressed during or afte

49、r treatment with bevacizumab,*Trial performed in mixed first-/second-line population,,55,拉帕替尼,口服的雙重酪氨酸激酶抑制劑，對ErbB1（EFGR）和ErbB2受體都有特異性與胞漿中激酶的ATP結合部位發(fā)生可逆性結合，從而防止受體磷酸化和受體激活,N-{3-氯-4-[(3-氟苯基)氧基]苯基}-6-[5-({[2(甲磺?；?乙基]氨基}甲基)-

50、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,,,,,,,,,拉帕替尼阻斷ErbB家族的信號傳導途徑,,57,,,EGF104535：拉帕替尼+紫杉醇一線治療HER2陽性MBC的I

51、II期臨床研究,隨機分組,,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 + 安慰劑,MBC一線FISH+*,*中心實驗室進行FISH檢測,開放性延長期研究拉帕替尼單藥治療,終點臨床受益**OSPFS,中國 (302)泰國香港巴西秘魯,分層激素受體(陽性/陰性)和病灶部位(內臟/非內臟),,,主要研究終點：OS

52、次要研究終點：PFS 、ORR 、CBR、安全性,,58,療 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%

53、 50% OR 2.3 P＜0.001CBR 75% 56% OR 2.34 P＜0.001,,,,,,,59,不良反應,,,,The incidence of withdrawal from treatment due to AEs(13% vs 10%) was a simila

54、r.,,60,乳腺癌分子靶向治療進展,轉移性乳腺癌新輔助治療,,61,拉帕替尼對比曲妥珠單抗聯(lián)合蒽環(huán)+紫杉的新輔助化療：GEPARQUINTO (GBG44) 研究療效分析,UntchM, LoiblS, Bischoff J, EidtmannH, Kaufmann M, BlohmerJU, HilfrichJ, StrumbergD, FaschingP, KreienbergR, TeschH, HanuschC, Gerb

55、er B, RezaiM, JackischC, HuoberJ, KühnT, NekljudovaV, von MinckwitzG On Behalf of the German Breast Group,,62,,,63,,,64,,,65,,,66,Neo-ALTTO研究：拉帕替尼、曲妥珠單抗或兩者聯(lián)合+紫杉醇新輔助治療HER2陽性原發(fā)性乳腺癌的隨機開放的III期臨床研究,Ba

56、selga 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, Untch M, Gelber RD, Piccart-Gebhart M

57、 On Behalf of the Neo-ALTTO Study Team,,67,,,68,,,NSABP guidelines,breast AND lymph nodes,69,,,70,,,71,,,72,新輔助帕妥珠單抗聯(lián)合曲妥珠單抗：一項隨機II 期臨床研究療效及安全性分析 (NeoSphere),Gianni L, Pienkowski T, Im Y-H, Roman L, Tseng L-M, Liu M-C, L

58、luch-Hernandez A, Semiglazov V, Szado T, Ross G,,73,帕妥珠單抗（Pertuzumab ）: 第一個HER2二聚體形成的抑制劑,Hubbard 2005,曲妥珠單抗,帕妥珠單抗,,74,HER2:HER3 二聚體形成產生對曲妥珠單抗的逃避,+,+,+,+,+,+,+,+,+,+,+,,Signalling activity,+,+,+,+,,,Homodimers,Heterodim

59、ers,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 et al. Nature 2007,,帕妥珠單抗和曲妥珠單抗與HER2的不同區(qū)域結合產生協(xié)同作用,,HER2 receptor,Trastuzum

60、ab,Pertuzumab,Subdomain IV of HER2,Dimerisation domain of HER2,,,Juntila et al. Cancer Cell 2009,激活抗體依賴的細胞毒作用增強ErbB2的內化抑制細胞胞外結構域脫落抑制血管發(fā)生,激活抗體依賴的細胞毒作用防止受體二聚體形成是ErbB介導的信號傳導途徑的強效抑制劑,,76,臨床前研究:帕妥珠單抗和曲妥珠單抗具有協(xié)同作用,Pe

61、rtuzumab treatment after progression following trastuzumab treatment,Mean tumour volume (mm3) ? SEM,6/10 animals cured,6005004003002001000,01020304050607080,Treatment period (days),Pertuzumab + trastuzumab

62、initial combination,Vehicle control,Pertuzumab (30/15 mg/kg/w ip),Trastuzumab (30/15 mg/kg/w ip),Pertuzumab (30/15 mg/kg/w ip)+ trastuzumab (30/15 mg/kg/w ip),0102030405060708090,Treatment period (days),Vehicl

63、e 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,0,200,400,600,800,1000,1200,1400,

64、Scheuer et al. Cancer Res 2009. Reproduced and adapted with permission from the American Association for Cancer Research,,77,,,78,,79,,,80,,,81,小結(1),化療FinXX研究：T/CEF輔助治療方案中加入卡培他濱未顯著改善RFS或OS，亞組分析顯示TX/CEX 改善了乳腺癌特異性的生存率及三陰

65、性乳腺癌的RFSUSON 01062研究：AC → T輔助治療方案加入卡培他濱，顯著改善OSEMBRACE(E7389)研究：eribulin 對既往多重治療過的MBC可以改善生存,,82,小結（2）,內分泌治療MA-27研究：絕經后HR(+)乳腺癌的輔助內分泌治療，依西美坦與阿那曲唑療效相似，不良反應有所不同TAMRAD研究：對先前AI治療的MBC，依維莫司聯(lián)合他莫西芬治療CBR、TTP、OS均優(yōu)于他莫昔芬，繼發(fā)內分泌耐

66、藥的患者臨床獲益更高氟維司瓊500 mg一線治療ER+的MBC,TTP較阿那曲唑顯著獲益乳腺癌進展后激素受體和HER2狀態(tài)變化：在該研究中, 復發(fā)轉移后，1/3乳腺癌患者HR狀態(tài)改變，1/10患者HER2 狀態(tài)改變，ER陽性患者腫瘤進展后轉為陰性的死亡風險較穩(wěn)定者增加,,83,小結（3）,分子靶向治療貝伐珠單抗聯(lián)合化療一線治療LR/MBC的三項臨床研究：顯著提高PFS、ORR,未改善OS,增加高血壓、蛋白尿、胃腸穿孔、出血、血

67、栓風險EGF104535：拉帕替尼聯(lián)合紫杉醇一線治療HER2陽性MBC較紫杉醇顯著改善OS、PFS、ORR、CBR，增加了腹瀉、肝功能異常、粒細胞減少的發(fā)生率,,84,小結（4）,在HER2陽性乳腺癌的新輔助治療中 GEPARQUINTO (GBG44)研究：EC-Doc+T組pCR率顯著高于EC-Doc+L ，EC-Doc + L的耐受性低于EC-Doc + T Neo-ALTTO研究:在化療的基礎上，聯(lián)合靶向治療（