1、 乳腺癌的分子靶向治疗乳腺癌的分子靶向治疗 恶性肿瘤的发生发展,侵袭转移和肿瘤血管生成，是多数肿瘤共同的生物学过程,其间涉及许多细胞和分子学机制. 对恶性肿瘤的细胞和分子生物学机制的研究，推动乳腺癌的基础和临床研究以及分子靶向药物研发. 分子靶向药物已经成为抗肿瘤药物的新兴门类，已经并进一步对肿瘤治疗产生日益重要的影响。恶性肿瘤发生的细胞和分子学机制 自我生长促进 对生长抑制信号敏感性下降 逃避凋亡和死亡 侵袭和转移 肿瘤血管生长分子靶向药物的研究 抗HER2的研究 抗肿瘤血管生成研究 PARP 抑制剂 抗骨转移的研究 M-TOR 三阴乳腺癌中抗EGFRHER2阳性乳腺癌Her2/neu是4个
2、表皮生长因子受体家族成员之一，与细胞的生长，分化生存重要相关。Her2蛋白的过渡表达或基因扩增的乳腺癌约占1/4,是肿瘤恶性程度高，预后差 的标志。Trastuzumab(Herceptin,赫赛汀)是人源化单克隆抗体，针对Her2受体细胞外功能簇。单药或者与化疗联合应用，治疗Her2阳性MBC改善疗效。1998年FDA批准治疗Her2阳性MBC，与紫杉类联合成为标准一线方案。辅助性治疗的 临床研究也已经完成，并在2006年获得FDA批准。NCCN 和 St.gallen 2007 HER2成为风险分级和治疗分组的指标。曲妥珠单抗治疗HER2阳性乳腺癌 MBC1st lineHO648gM77
3、001 US OncologyBCIRG 007CHATTAnDEMRHEA 2nd+ linesGBG-26BO17929EGF104900Numerous Phase II studies曲妥珠单抗治疗HER2阳性乳腺癌 EBCAdjuvant:HERANSABP B-31NCCTG N9831BCIRG 006PACS 04Neo Adjuvant:NOAHMDACCGeparQuattro曲妥珠单抗 in EBC Trial 无病生存期无病生存期 (ITT分析分析): 4-年中位随访时间年中位随访时间1008060402000612182430483642随机分组后月随机分组后月169
4、817031564161914401552136314851297141412401352712854118012809921020No. at risk事件数事件数4583694-年年DFS72.278.6风险系风险系数数0.7695% 可信可信区间区间0.66, 0.87p 值值0.00011-年赫赛汀组年赫赛汀组观察组观察组6.4%患者患者(%)新辅助治疗显著提高病理完全缓解率(pCR) MDACC:PCR: H + (P FEC) vs P + FEC alone (65.2% vs 26.3%) NOAHPCR: 43% vs 23%tPCR: 38% VS 20%MDACC研究：2
5、/3的患者获病理学完全缓解解26.3%n=1965.2%n=2395% CI(4384%)p=0.016(n=42)pCR (%)P + FEC aloneH + (P FEC)Buzdar A, et al. Proc ASCO 2007NOAH: 更高临床缓解率ORR, %CR, %PR, %SD, %PD, %+ H(n=115)80.960.020.90.94.3- H(n=113)73.451.322.15.36.265.725.240.410.110.1HER2 positiveHER2 negative(n=99)Gianni et al ASCO 2007, poster 53
6、2ORR, overall response rate; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease NOAH：显著提高病理学完全缓解率(pCR) 01020304050+ H- HHER2 negative+ H- HHER2 negativePatients(%)HER2 positiveHER2 positivepCRtpCR43%23%17%38%20%16%p=0.29p=0.002p=0.003p=0.43pCR, pathological comp
7、lete response; tpCR, total pathological complete response in breast and nodesGianni et al ASCO 2007, poster 532NOAH: tumour response赫赛汀联合化疗:新辅助治疗的pCR率pCR (%)PDPAC PVD + cisplatinD + HD + VX + DAC P CMFDP FEC-75P FECStudyHerceptinLapatinibpCR, pathological complete response; AC, doxorubicin, cyclopho
8、sphamide; E, epirubicin; L, lapatinib; V, vinorelbine; X, Xeloda; FEC, 5-fluorouracil, epirubicin, cyclophosphamide; CMF, cyclophosphamide, methotrexate, 5-fluorouracil; D, docetaxel 拉帕替尼（Lapatinib） 酪氨酸激酶抑制剂 有效的选择性ErbB1 (EGFR)和ErbB2 (HER2) 的双重抑制剂 2007年3月13日FDA批准上市与卡培他滨联合，用于既往曾接受过蒽环类、紫杉醇类和曲妥珠单抗治疗的Erb
9、B2过表达的转移性乳腺癌AktLapatinib 作用机制RasRafMAPKPSosShcGrb2ATPAktMAPKPI3KLapatinib增生通路增生通路生存通路生存通路通过通过ATP的的正常活化正常活化Lapatinib阻断其活化阻断其活化生存通路生存通路增生通路增生通路Xia W, et al. Oncogene 2002;21:6255-63.Rusnak DW, et al. Mol Cancer Ther 2001;1:85-94.单克隆抗体与小分子TKI的比较 抑制激酶的胞内区 对突变的ErbB-1 和顶端缺失的 ErbB-2有活性 配体的浓度不会影响其抑制活性 与受体的胞
10、外区结合 不能与突变和顶端缺失的受体结合-无活性 配体的饱和会影响其疗效小分子酪氨酸激酶抑制剂小分子酪氨酸激酶抑制剂单克隆抗体单克隆抗体 MBC单药疗效5.1%， (SD 40%) 难治性MBC单药疗效1.4%，(SD 33%)难治性晚期或转移性乳腺癌应用Lapatinib 卡培他滨 VS 卡培他滨单药治疗的随机、III期研究进展、HER2+转移性乳腺癌或LABC 曾接受过蒽环类、紫杉类和曲妥珠单抗治疗*未接受过卡培他滨治疗患者接受治疗直至疾病进展或出现不可耐受的毒性并进行生存期随访N=528 随随机机卡培他滨2500 mg/m2/d po days 1-14 q 3 wkLapatinib
11、1250 mg po qd + 卡培他滨2000 mg/m2/d po days 1-14 q 3 wk *Trastuzumab must have been administered for metastatic disease Presented by C.E. Geyer et al, ASCO 2006Lapatinib+Capecitabine vs CapecitabinePhase III 复治的MBC（ITT） Time (weeks)010203040506070Cumulative Progression-Free Survival, %01020304050607080
12、901000.001P-value (log-rank, 1-sided)73 (45%)45 (28%)Progressed or died0.49 (0.34, 0.71)Hazard ratio (95% CI)4.48.4Median PFS, mos161160No. of ptsCapecitabineLapatinib + capecitabineGeyer et al, NEJM 2006; 355: 2733-43 Lapatinib在难治性晚期/转移性乳腺癌患者人群患者人群是否是否ErbB-2过表达？过表达？治疗治疗主要终点主要终点EGF20002II期期N=78含曲妥珠单
13、抗治疗后进展的女性是LapatinibORR 5,1%(SD 40%)EGF20008II期期N=229含蒽环类、紫杉醇类、卡培他滨曲妥珠单抗治疗后进展的女性是/否LapatinibORR 1.4%(SD 33%)EGF100151 III期期N= 399含蒽环类、紫杉醇类及曲妥珠单抗治疗后进展的女性是卡培他滨 lapatinibTTP, RREGF104383III期期一线是紫杉醇+曲妥珠单抗+/- lapatinibTTP, RREGF104535*III期期一线是紫杉醇+/- lapatinib临床受益率EGF104900III期期曲妥珠单抗2个以上疗程治疗后疾病进展是Lapatinib
14、 +/-曲妥珠单抗TTP, RRHER2阳性乳腺癌脑转移 Lapatinib单药治疗脑转移有效， 51例Lapatinib治疗脑放疗后进展，并且已经用过Lapatinib治疗的患者，联合Capecitabin肿瘤缩小20%，占37%肿瘤缩小50%，占20%5例单药Lapatinib达到PR,1例联合Capecitabin又达到PR.20例单药Lapa达SD,加上Capecitabin3例PR,10例SD.辅助治疗临床研究 EGF105485 III期 Lapa vs Placebo ALLTO Study III期 4组 随机对照试验52WEEKSLapatinib Lapatinib+曲妥珠
15、单抗每3周方案共40周Lapatinib+曲妥珠单抗每周方案共12周曲妥珠单抗每周方案共12周Lapatinib52周周曲妥珠单抗每3周方案共40周Lapatinib34 周周紫杉醇每周方案共12周+/-放射治疗放射治疗6周清洗期周清洗期曲妥珠单抗每周方案共12周 在完成任何蒽环类为主的（新-）辅助化疗后，计划靶向治疗与紫杉醇联合使用手术、 完成（新）辅助化疗 (在批准的用药列表中选择)LVEF 50%Max 6 w当地实验室确定的 HER2阳性浸润性乳腺癌中心实验室确定 HER2+; ER and PgR紫杉醇每周方案共12周+/-放射治疗放射治疗紫杉醇每周方案共12周+/-放射治疗放射治疗
16、紫杉醇每周方案共12周+/-放射治疗放射治疗ALLTO StudyLapatinib 腹泻 8个临床试验中1126名使用lapatinib的患者： 50%出现腹泻 分级54%为1级 (轻度)30%为2级 (中度)15%为3级 (重度)1%为4级 (威胁生命) 发作及周期44%的患者在最初6天内出现22%的患者在开始治疗28天后出现每次发作平均持续5天Data on File, GlaxoSmithKline.Lapatinib皮肤事件 8个临床试验中1126名使用lapatinib的患者，46%报告有皮疹(所有级别)*重度皮疹罕见; 4%的患者出现3级皮疹，没有4级皮疹的报告多数皮肤事件出现较
17、早，在治疗前14天内出现中位数周期为29天85%的事件无需干预、剂量调整或治疗中断1%由于皮肤事件终止治疗* Excluding PPE Data on File, GlaxoSmithKline.其它新的抗HER2药物 Pertuzumab阻断异源性二聚体，效力可能比Herceptin更强。 61例三线治疗的安全性报告了该抗体相关的毒性：59%腹泻（G3/4 仅2%），其他G3/4 AE：DV血栓1例，皮疹1例。对心脏功能影响很小，2例33例可评价疗效，ORR 18.2%, CB 39.4%， 进行中研究：联合Herceptin一线MBC.其他新型抗HER2药物(续) HKI-272, 不可
18、逆的全HER2 TKI。N=42 MBCPR 13, SD 20%1例 G3/4腹泻。 Trastuzumab-DM1 HER2+MBCN=16 PR26%贝伐单抗在乳腺癌的临床研究-抗肿瘤血管生成治疗 VEGF 家族和受体家族和受体Neufeld G, et al. FASEB J. 1999;13:9-22.VEGFR-3(Flt-4)VEGFR-2(Flk-1/KDR)VEGFR-1(Flt-1)AngiogenesisLymphangiogenesisAngiogenesisLymphangiogenesis胎盘生长因子胎盘生长因子PIGFVEGF-AVEGF-BVEGF-CVEGF-
19、DBevacizumab (重组人抗VEGF单克隆抗体 ) 贝伐单抗:针对VEGF的人源化单克隆抗体 (93% human, 7% murine),能够识别所有VEGF亚型( Kd=8 x 10-10M),终末半衰期17-21 天.抗血管生成治疗靶点贝伐单抗治疗晚期乳腺癌贝伐单抗治疗晚期乳腺癌I/II期临床研究期临床研究75例化疗过的晚期乳腺癌接受不同剂量贝伐单抗疗效分析例化疗过的晚期乳腺癌接受不同剂量贝伐单抗疗效分析:疗效疗效 3mg/kg(18) 10mg/kg(41) 20mg/kg(16) CR(%) 0 1(2.4) 0PR(%) 1(5.6) 4(9.8) 1(6.8)22周临床获
20、益周临床获益(5) 2(11) 7(17) 3(19)中位有效时间中位有效时间(M) 3.1 5.6 8.0 Cobleigh MA, et al. Semin Oncol 2003;30, 117-24TumorStudyComparisonBev DoseDFSOSBreast 2nd lineMiller et al4zCapecitabine vs Cape + Bev15 mg/kg Q3W=Breast 1st lineE21005Paclitaxel vs Pac + Bev10 mg/kg D1, 15?Breast 1st lineAVADODocetaxel vs Doce
21、 + Bev7.5-15 mg/kg Q3w? Breast 1st line RIBBON-1CT+Bev vs CT + Place15 mg/kg Q3W= Breast 2st line RIBBON-2CT+Bev vs CT + Place15 mg/kg Q3WNANA1 2. Kabbinavar F, et al. J Clin Oncol. 2003;21:60-65. 3. Giantonio B, et al. ASCO 2005. Abstract 2. 4. Miller KD, et al. J Clin Oncol. 2005;23:792-799. 5. Mi
22、ller KD. SABCS 2005. Abstract 3. 6. Sandler AB, et al. ASCO 2005. Abstract LBA4. 7. Kindler HL, et al. ASCO GI 2007. Abstract 108. 8. Available at: http:/www.clinicaltrials.gov.Bevacizumab Phase III Trials MBCCapecitabine vs. Capecitabine + Beva 治疗晚期乳腺癌治疗晚期乳腺癌Adverse Event, %Capetabine(230) Avast+Ca
23、pe(232)P valueORR研究者19.130.20.006独立评估委员会9.119.20.001中位PFS, 月4.24.9NS中位生存14.515.1NS KD Miller. J Clin Oncol, 2005Capecitabine vs. Capecitabine + Beva 不良反应不良反应不良事件 Capetabine(215)Avast+Cape(229)高血压0.517.9蛋白尿00.9血栓3.75.6手足综合症24.227.5出血0.50.419.2CHF/心肌病13恶心1.92.6 KD Miller. J Clin Oncol, 2005No grade 4B
24、est response (%)Phase III trial of bevacizumab plus paclitaxelin first-line mBC (E2100): 有效率All patientsPatients withmeasurable disease49.2%25.2%21.2%36.9%PaclitaxelBevacizumab + paclitaxelCR + PRp0.001CR + PRp0.001CR = complete responsePR = partial responseMiller, et al. NEJM 2007605040302010011.40
25、61218243036PFS estimateHR=0.48Paclitaxel (n=354)Bevacizumab + paclitaxel (n=368)PFS by investigator 5.811.3HR=0.42PFS by IRF*5.8Months1.00.80.60.40.20*Scans available for 90% of patients Phase III trial of bevacizumab plus paclitaxel in first-line mBC (E2100): PFSAdapted from Cameron. EJC Suppl. 200
26、8 withpermission from Elsevier; Avastin SmPC 2008AVADO: response (patients with measurable disease), %Placebo+ docetaxel(n=207)Bev 7.5 + docetaxel (n=201)Bev 15 + docetaxel (n=206)Overall response rate p value (vs control)44550.0295630.0001Best responseCRPRSD PD 1443912 35235 5 16225 4mg/kg q3wMiles
27、, et al. ASCO 2008 (Abstract LBA1011)Bev 15 +docetaxel (n=247)HR + 95% CI (unstratified)Bev 7.5 +docetaxel (n=248)1.00.80.60.40.20MonthsPFS estimate061218MonthsPFS estimate1.00.80.60.40.20 061218AVADO: progression-free survival(ITT population)*Data censored for non-protocol therapy before PD; mg/kg
28、q3wHR + 95% CI (stratified*)0.69 (0.540.89)p=0.00350.79 (0.630.98)p=0.0318Placebo +docetaxel (n=241)Median8.78.0HR + 95% CI (stratified*)0.61 (0.480.78)p0.0001Median8.88.00.72 (0.570.90)p=0.0099HR + 95% CI (unstratified)Placebo +docetaxel (n=241)Miles, et al. ASCO 2008 (Abstract LBA1011)43RIBBON-1:
29、Study DesignPreviously untreated MBC (n=1237)Stratification factors:l Disease-free intervall Previous adjuvant chemotherapyl Number of metastatic sitesl Cape., T or Anthra.Capecitabineor TaxaneorAnthracyclineChemo +Bevacizumabq3wChemo +placeboq3wTreatuntilPDOptional2nd-line chemo+ bevacizumab21CHOIC
30、E OF CHEMORobert et al. ASCO 2009. Abstract 1005.Primary endpoint: l l PFS as assessed by investigatorSecondary endpoints: l l Overall Survival (OS) & 1-year OS rate l l Objective response rate (ORR); l l PFS by independent review committee (IRC); l l SafetyCapecitabine (1000 mg/m2 BID x 14d)Taxane
31、(docetaxel or protein- bound paclitaxel)Anthracycline-based chemotherapy (AC, EC, FAC, FEC)Placebo or bevacizumab (15 mg/kg)4444RIBBON-1: Patient CharacteristicsCapecitabineTaxane/AnthracyclinePL (n=206)BV (n=409)PL (n=207)BV (n=415)Median age, years ECOG PS 05753565355535553HR positive Triple negat
32、ive7425772277237624Disease-free 3 metastatic sitesMeasurable diagnosis4579438045864583All data as %, unless otherwise noted.Robert et al. ASCO 2009. Abstract 1005.45RIBBON-1: Objective Response RatePLBVPLBV23.635.437.951.3Capecitabinep=0.0097Taxane/Anthracyclinep=0.0054%Measurable*Disease, %79808683
33、*Includes only patients with measurable disease at baselineCRPRRobert et al. ASCO 2009. Abstract 1005.45th Asco 200946RIBBON-1: Exploratory Secondary Endpoint:PFS by Chemotherapy SubgroupsTaxaneAnthracyclinePL (n=104)BV (n=203)PL (n=103)BV (n=212)mPFS, mo8.29.27.99.2HR (95% CI)P-value0.75 (0.56-1.01
34、)0.05470.55 (0.40-0.74)3 AEsCapecitabineTaxaneAnthracyclinePL (n=201)BV (n=404)PL (n=102)BV (n=203)PL (n=100)BV (n=210)Bleeding eventsFebrile neutropeniaGI perforationHypertensionLV systolic dysfunctionNeutropeniaProteinuriaSensory neuropathyVTE0.5001.00.51.000.53.50.2009.41.01.22.23.04.802.01.02.00
35、4.908.84.95.48.42.58.92.09.43.48.42.000.50004.0001.003.8010.02.94.31.90.52.9VTE=Venous ThromboEmbolismRobert et al. ASCO 2009. Abstract 1005.49RIBBON-1: Authors Summary For the pre-specified capecitabine and taxane/anthracycline cohorts, the addition of bevacizumab led to a statistically significant
36、 improvement in:PFS (by investigator)PFS (by IRC)ORR No difference was noted in OSSafety:Incidence of bevacizumab-related adverse events consistent with prior studiesNo new bevacizumab-related safety signals in each of the chemotherapy groupsRobert et al. ASCO 2009. Abstract 1005.贝伐单抗临床研究方向 (III期临床试
37、验) 转移性乳腺癌: 一线RIBBON1: 化疗+/-贝伐单抗, (1239例)AVEREL: Docetaxel+Herceptin+/- 贝伐单抗 (462例) 辅助治疗:BEATRICE(三阴): 辅化+/-贝伐单抗, (2530例)BETH（NSABP B-44）: HER2+: 辅化/Herceptin+/-贝伐单抗 (5400例)E5103:AC-T+/-B,BEVA 短程.长程NSABP B-46 1 TAC/TC/ TC+B 新辅助化疗:NSABP B40: AC/TX/DG+贝伐单抗(1200例)研究中的抗血管生成新靶点治疗药物 抗VEGF 贝伐单抗VEGF Trap（可溶性
38、受体,已经进入3期临床）小分子配体阻断剂 TKISutent单药临床获益16%，与Taxan联合进行中。 阿那曲唑+/-Sorafenib（ER+ 和/或PR+MBC）AxitinibPazopanib 选择性更强的VEGF抑制剂。 抗VEGFRAxitinib治疗晚期乳腺癌 Axitinib+Docetaxel vs Docetaxel N=168例M-TTP: 8.2m vs 7.0mORR: 40% vs 23%AE(G3/4):ADDFN (16%/7%)Stomatitis(13%/2%)Diarrhea(11%/0%)Hypertension(5%/2%)受体酪氨酸激酶抑制剂Sun
39、itinib Phase III Trial MBCSUN 1064 Doce+/-Sunitinib in her2- MBC(一线)SUN 1094 Pacli+beva vs Pacli+Sunitinib LA/MBCSUN 1099 Xelo+/-Sunitinib in her2+ MBC(hercep or lapa treated) EBC HER2阴性乳腺癌新辅助化疗后：SUN vs PLACEBO 1年其他新型分子靶向治疗以及研究 PARP1 Olaparib AZD2281口服PARP 1 抑制剂 I期 Inhibitor BSI-201 NF-kB受体活化因子的配体（R
40、ANKL）抑制剂Denosumab抑制RANKL的活性，减少骨吸收。Addition of PARP1 Inhibitor BSI-201 to Gemcitabine/Carboplatin Improves Outcomes in Metastatic TNBC Randomized, multicenter, open-label phase II trial Poly (ADP-ribose) polymerase-1 (PARP1) Critical enzyme in DNA repair and cell proliferation Involved in non-BRCAdep
41、endent DNA repair pathwaysUpregulated in most TNBC BSI-201 potent PARP1 inhibitor OShaughnessy J et.al, 2009 ASCO, Abs NO.3Study Design OShaughnessy J et.al, 2009 ASCO, Abs NO.3Results-ORR/CBROutcome, n (%)Gemcitabine/Carboplatin(n = 44)BSI-201 +Gemcitabine/Carboplatin(n = 42)P ValueClinical benefit
42、 rate9 (21)26 (62).0002Objective response rate7 (16)20 (48).002OShaughnessy J et.al, 2009 ASCO, Abs NO.3Results-PFS/OSSurvival, mosGemcitabine/Carboplatin(n = 59)BSI-201 +Gemcitabine/Carboplatin(n = 57)HR (95% CI)P ValueMedian PFS3.36.90.342 (0.200-0.584) .0001Median OS5.79.20.348 (0.189-0.649).0005
43、OShaughnessy J et.al, 2009 ASCO, Abs NO.3Results-SafetyAdverse Event, %Gemcitabine/Carboplatin(n = 59)BSI-201 +Gemcitabine/Carboplatin(n = 57)Grade 3/4 hematologicThrombocytopenia20.422.8Neutropenia52.543.9G-CSF use15.310.6Grade 2 nonhematologicNausea16.912.3Vomiting15.37.0Fatigue16.917.5OShaughness
44、y J et.al, 2009 ASCO, Abs NO.3Denosumab对双磷酸盐治疗过的骨转移乳腺癌 随机开放 Phase II 活性对照，N=111 研究目的：评估Denosumab在经过8周以上双磷酸盐治疗的骨转移乳腺癌uNTX仍然高的患者，疗效和安全性分析。 主要发现：静脉双磷酸盐无反应患者，Denosumab比继续双磷酸盐能降低uNTX(77% vs 34% p0.1)治疗两周后，中位uNTX降低达80，且维持25周。在25周时其他骨标志改变百分比，Denosumab也更大。骨相关事件更少：13 vs 10常见安全性事件：骨痛，恶心，贫血等。Gralow SABCS 2008 AB 1155谢谢
