1、乳腺癌的化学治疗乳腺癌的化学治疗 50%的乳腺癌会复发或出现转移，中位生存时间2年左右。几乎所有病人都需要化学治疗，通常需要2-4线方案，直至肿瘤无法控制。治疗主要包括化疗和内分泌治疗和生物靶向治疗等。化学治疗是激素受体阴性或激素耐药乳癌，以及快速进展肿瘤的主要治疗方法。蒽环类治疗复发或转性乳腺癌蒽环类治疗复发或转性乳腺癌 研究目的：PFS不差于ADR的等效性研究，心脏毒性明显低于ADR。脂质体脂质体ADR与传统与传统ADR一线治疗一线治疗MBC的的Phase III 临床研究临床研究N=509 MBC，心脏功能正心脏功能正常常16%ADRRPLD 50mg/m2 q4wADR 60mg/m2
2、 q3w心脏事件：心脏事件：LVEF下降与药物剂量的关系下降与药物剂量的关系病人情况结果结果M-PFSOSPLD6.9HR1.095%CI0.82-1.2221HR0.9495%CI0.74-1.19ADR7.822心脏安全性分析心脏安全性分析累积累积ADR剂量与心脏毒性剂量与心脏毒性亚组分析亚组分析ADR剂量累积与剂量累积与LVEF改变的关系改变的关系结论 PFS和OS与ADR相当，毒性不同：PLD有更好的心脏安全性，在ADR治疗过的患者（16%）中显示心脏毒性发生率更低。脱发呕吐都比ADR少见；但掌跖红斑和黏膜炎更多见。可以用于年龄65岁，有心脏危险因素，以及过去已经用过ADR的MBC。紫
3、杉类治疗紫杉类治疗MBC现状现状 单药 一线治疗疗效25-50%，中位TTF3.5-6月。与蒽环类联合一线疗效：55-63%，中位TTF 7.8月。紫杉类单药或与蒽环类联合是转移性乳腺癌的标准一线化疗方案。紫杉类尤其是紫杉特尔已经成为新的药物临床研究和新药开发的参考药物。常用方案：AT/ET/TAC等 研究进展：紫杉类与非蒽环类联合（DX/D；GT/T）两个紫杉对照研究（TAX311）每周方案与3周方案对照（CALGB 9840）单药序贯与联合对照（GEICAM-9903）紫杉类和非蒽环类联合化疗紫杉类和非蒽环类联合化疗TTP总生存总生存05101520251.00.80.60.40.20.0
4、4.26.11.00.80.60.40.20.0051015202530Months卡培他滨卡培他滨/泰索帝泰索帝 泰索帝泰索帝PriorMedianOverallnCT,%ORRTTPsurvivalOShaughnessy(JCO 2019)511 100泰索帝 100 mg/m2 30%4.2 mo11.5 mo泰索帝 75 mg/m2+卡培他滨 2500 mg/m2 D11442%6.1 mo14.5 mop0.0060.00010.0126Months泰索帝+卡培他滨 vs 泰索帝单药(III期期)卡培他滨卡培他滨/泰索帝泰索帝 泰索帝泰索帝 XT 与与Taxotere比较明显改善比
5、较明显改善 RR(42%与与 30%),TTP(6.1 与与 4.2月月)。XT较较 Taxotere 延长生存（延长生存（14.5与与11.5月月），），是蒽环类治疗过是蒽环类治疗过MBC患者的标准治疗。患者的标准治疗。XT 不损害不损害QoL。方便的剂量调整可以用于方便的剂量调整可以用于XT副作用的处理副作用的处理。XT与与Taxotere对照研究结论对照研究结论 OShaughnessy J et al.J Clin Oncol 2019;20:281223GEMZAR+Paclitaxel vs.Paclitaxel in Patients as frontline therapy f
6、or MBCTreat until documented PDAll sites of disease assessed every 8 weeks GT arm Q3W T arm Q3W Day 1:Paclitaxel 175 mg/m 2(3 hr)Gemcitabine 1250 mg/m2Day 8:Gemcitabine 1250 mg/m2 Day 1:Paclitaxel 175 mg/m2(3 hr)RANDOM KS.Albain et al.ASCO 2019Interim analysisEndopoint GT T P-valueRR(95%C.I.)40.8%22
7、.1%.0001 (34.9,46.7)(17.2,27.2)M-TTP(95%C.I.)5.2 2.9 .0001 (4.2,8.6)(2.6,3.7)6-month 37%23%.0027(progression free)KS.Albain et al.ASCO 2019Interim overal survivalDeaths 160 183Censored 40.1%30.2%M-OS(m)18.5 15.8 (95%C.I.)(16.5,21.2)(14.4,17.4)12-mon survival 70.7%60.9%18-mon survival 50.7%41.9%KS.Al
8、bain et al.ASCO 2019Log rank P=.018 Hazard ratio 0.78(0.63,0.69)Endopoint GT(267)T(262)FDA 2019/5随机化随机化(3周方案周方案)泰索帝泰索帝 75 mg/m2 d 1卡培他滨卡培他滨 1250 mg/m2 bid d 114泰索帝泰索帝 75 mg/m2 d 1 吉西他滨吉西他滨 1000 mg/m2d 1,d 8 蒽环类失败后一线或二线 主要终点:PFS,ORR,TtTF 治疗至治疗失败或出现不可接受的毒性研究在 2019 年3月结束n=305S.Chan etc.ASCO 2019 Abs.58
9、1泰索帝泰索帝+吉西他滨吉西他滨 vs 泰索帝泰索帝+卡培他滨卡培他滨(III期临床期临床)S.Chan etc.ASCO 2019 Abs.581泰索帝泰索帝+吉西他滨吉西他滨 vs 泰索帝泰索帝+卡培他滨卡培他滨(III期临床期临床)GD CDn=150 n=145 ORR27%31%(P=0.4537)治疗周期数治疗周期数754cycles642cycles手足综合症手足综合症0%24%腹泻腹泻7%17%粘膜炎粘膜炎4%16%PFS,ORR,TtTF all efficacy parameters are similar患者特征：预后较差，患者特征：预后较差，50%器官患者有器官患者有3
10、个以上发生转移个以上发生转移 Docetaxel and Paclitaxel 直接比较直接比较治疗转移性乳腺癌治疗转移性乳腺癌-Phase III (TAX 311)Ravdin P,Eur J Cancer 2019;1(Suppl 5):s201.Abstract 670 Docetaxel 100mg/m2（1h）q3wPaclitaxel 175mg/m2（3h）q3wR至肿瘤至肿瘤进展进展蒽环类治疗过的MBCN=449N=225N=224Objective Response in ITT population Docetaxel Paclitaxel P value-ORR(CR+
11、PR)32%25%0.10SD 38.2%39.7%M-TTP(m)5.7 3.6 .0001 95%C.I.4.6-6.9 3.1-4.2OS(m)15.4 12.7 0.03 95%C.I.13.3-18.6 10.6-14.8 Objective Response in Evaluable Population Doce Pacli P valueORR 37.0%25.9%0.02SD 42.9%42.9%TAX 311 研究结论研究结论Weekly Paclitaxel Superior to Standard Every-Three-Week Schedule for MBC CA
12、LGB 9840 MBC根据一线或二线治疗以及HER2状态，随机分4组standard paclitaxel (q3w)weekly paclitaxelstandard paclitaxel+H q3wBweekly paclitaxel+H结果结果 RR明显以weekly paclitaxel 优于3weekly,分别为40%和28%(p=0.017;odds ratio,1.61)。增加trastuzumab对HER2-negative患者不增加疗效。Weekly paclitaxel TTP更长，(p=0.0008;adjusted hazard ratio,1.45).trastuz
13、umab 同样对HER2-negative没有明显作用。患者对患者对Weekly Paclitaxel耐受性更好，血液毒性轻，神经毒耐受性更好，血液毒性轻，神经毒性高。性高。Higher-Dose Paclitaxel 没有改善没有改善转移性乳腺癌治疗效果转移性乳腺癌治疗效果 CALGB trial 9342Eric P.JCO V22 N11 June 1 2019 确定确定Paclitaxel 3小时输注的最佳剂量。小时输注的最佳剂量。474例例MBC,过去接受过过去接受过0-1个方案化疗。个方案化疗。随机分随机分3个剂量组：个剂量组：175/210/250/mg/m2 3h q3w。结果
14、和结论：结果和结论：RR分别为 23%,26%,和21%for the three regimens。剂量与疗效没有显示明显相关。剂量与TTP相关性有统计学意义，(P=.04)但是多因素分析差异不显著。生存分析没有统计学意义。高剂量组神经毒和血液毒性更多见，3组生存质量没有明显区别。OR:31.8%(14 of 44;95%CI 17.5-46.1),no CR.7/14 docetaxel抗药抗药者有效。者有效。M-DR 6.1 months(2.1-12.7).M-TTP 5.0 months临床SAE(3/4):neutropenia(27.2%),leukopenia(25.0%),n
15、europathy-sensory(13.6%),febrile neutropenia(6.8%),anemia(2.2%),constipation(2.2%),and edema(2.2%).Weekly Paclitaxel治疗治疗 docetaxel抗药抗药MBC:a single-center study.每周凯素治疗紫杉类耐药每周凯素治疗紫杉类耐药MBC 两个两个Phase II TrialOShaughnessy JA凯素是纳米白蛋白紫杉醇,是第一个通过受体介导通道(gp60),使 肿瘤细胞紫杉醇浓度更高。凯素 100 mg/m2/W 3 doses,1 week of res
16、t ORR 15%PFS 12ms 13%1yr SR 38%凯素 125 mg/m2/W 3 doses,1 week of rest 安全性：G3/4：中粒减少，感觉神经异常，血小板减少，黏膜炎在在MBC维持治疗的作用维持治疗的作用Paclitaxel(200 mg/m2）Epirubicin(90 mg/m2)every 3 weeks 8cycleN=550(215)CR/PR/SDRPaclitaxel(175 mg/m2）no further chemotherapyevery 3 weeks 8cycle*HR+HTStudy FindingsMaintenance Paclit
17、axelNo MaintenanceNumber109106Median TTP8.0 months8.9 monthsMedian OS28 months29 monthsTable:Results of Maintenance Therapy联合和单药序贯化疗 ADR和和Doce序贯和同时给药序贯和同时给药一线治疗一线治疗 MBC:(GEICAM-9903)Phase III Study AT：ADR 50 mg/m2+Docetaxel 75 mg/m2,每 21 天.2019 ASCO(Abstract 27).R 疗效和安全性分析安全性分析 中粒减少中粒减少：A-T arm AT a
18、rm P 29.3%47.8%=.02 （Asthenia,diarrhea,and fever more in the AT arm）ORR:61%51%M-DR 8.7 m 7.6 m M-TTPs 10.5 m 9.2 m M-OS 22.3 m 21.8 m NS 单药序贯与联合化疗 Phase IIIJCOG 9802AC 40/500mg/m2 6Doce 60mg/m26AC/Doce 交替交替6RMBCN=441 AC或Doce组PD后交换到对侧方案治疗,AC/D组PD后继续原方案再次治疗.JCOG 9802临床研究结果NRR%Cro RR%M-TTP（m）M-OS（m）AC1
19、4630246.422.4Doce14741196.425.7AC/D14835226.725.0P=NSNSNSNSNS2019ASCO Updated OS,初始Doce优于初始AC组,P=.04 单药序贯与联合化疗比较,显示相同的ORR和TTP,以及OS。单药序贯组不良反应发生率较低，耐受性更好。Her2 过表达的过表达的MBC的治疗的治疗仍然需要进一步解决的问题 Herceptin 的最佳剂量和给药方法？单药Herceptin（H0650）与细胞毒药物联合（HO648g）联合1个还是2个药物？(BCIRG101/102)Herceptin治疗进展后还能再用吗？每3周还是每周给药？什么患
20、者获益最大？可用于辅助治疗吗？Trastuzumab First Line Monotherapy Study H0650 Response Rate N=114 patients 2mg/kg Vs 4mg/kg Complete responses7pt Partial responses 23 pt Overall response rate30 pt(26%)Time to response 1.8mo Response duration 11-22moComparative Study HO648gOverall Objective Response Rate H +AC(n=143
21、)AC(n=138)H +Paclitaxel(n=92)Paclitaxel(n=96)Com plete Response 8%7%7%2%Partial Response 44%36%35%14%O verall Response Rate(CR+PR)52%43%42%16%95%CI(44,61)(34,51)(32,52)(8,23)P-value 0.1038 0.0001Comparative Study HO648gTime-to-Disease ProgressionAC Stratum00.20.40.60.810510152025MonthsProbabilityPac
22、litaxel Stratum00.20.40.60.8105101520MonthsProbabilityH+P(n=92)median=6.9 moP (n=96)median=3.0 moH+AC (n=143)median=8.1 moAC (n=138)median=6.1 mop=0.0003p=0.0001Overall survivalCT patients treated withHerceptin after disease24%62%65%progression1.00.80.60.40.200515253545H+CTCTProbability of survival2
23、5.4 months(25%)20.3 monthsRR=0.76p=0.025Time(months)Phase II trials of Herceptin plus docetaxelHerceptin was administered as a 4mg/kg initial dose followed by 2mg/kg weekly until progressionTrialDocetaxel scheduleRR(%)Kuzar et al.200075mg/m2 q3-weekly7/16(44)Malik et al.200033mg/m2 weekly5/6(83)Uber
24、 et al.200135mg/m2 weekly12/19(63)Esteva et al.200135mg/m2 weekly19/30(63)Medan et al.200135mg/m2 weekly6/12(50)Herceptin in combination with vinorelbine1Burstein H,et al.J Clin Oncol 2019;19:2722302Jahanzeb M,et al.Breast Cancer Res Treat 2019;69:284(Abstract 429)Vinorelbine schedulePatientsRR(%)25
25、mg/m2 weekly1All30/40(75)IHC 3+24/30(80)First line16/19(84)30mg/m2 weekly2All(first line)29/37(78)IHC 3+18/22(82)FISH+10/12(83)Herceptin plus gemcitabine Phase II study(n=59)of Herceptin plus gemcitabine(1,200mg/m2 day 1 and 8 q3-weekly)RR=33%(22/59)In patients with IHC 3+disease,RR=45%(17/38)OShaug
26、hnessy JA,et al.Breast Cancer Res Treat 2019;69:302(Abstract 523)Herceptin in metastatic breast cancerSumaryEvidence supports Herceptin therapy in HER-2overexpressing metastatic breast cancer1.Herceptin with chemotherapy in first line improved time to treatment failure increased response rates impro
27、ved survival2.Herceptin monotherapy active in first line and in second/third line favourable safety profile survival data in first line not inferior to combination therapyMiller et al.ASCO 2019.Oral presentation during symposium,Advances in Monoclonal Antibody Therapy for Breast Cancer.Bevacizumab 1
28、0 mg/kg Days 1,15+Paclitaxel 90 mg/m2 Days 1,8,15(n=365)Paclitaxel 90 mg/m2 Days 1,8,15(n=350)Patients with locally recurrent or metastatic breast cancer,ECOG performance status score 0-1(N=715)Stratified by disease-free interval,number of metastatic sites,adjuvant chemotherapy,andestrogen receptor
29、statusBevacizumab Paclitaxel 1st linefor Locally Recurrent or Metastatic Disease Eastern Cooperative Oncology Group(ECOG)2100 trial First planned interim analysis of randomized,first-line,phase 3 trialMiller et al.ASCO 2019.Oral presentation during symposium,Advances in Monoclonal Antibody Therapy f
30、or Breast Cancer.Bevacizumab Paclitaxel for Locally Recurrent or Metastatic Disease PFS significantly longer with combination therapy 10.97 months vs 6.11 months HR=0.498(95%CI,0.401-0.618),P .001 Overall survival significantly higher for patients receiving bevacizumab+paclitaxel vs paclitaxel alone
31、 HR=0.674(95%CI,0.495-0.917),P=.01 Overall response significantly better for patients treated with bevacizumab+paclitaxel 28.2%vs 14.2%for paclitaxel alone cohort(P .0001)Grade 3/4 EventBevacizumab+Paclitaxel,%(n=342)Paclitaxel,%(n=330)P ValueHypertension13.30.0001Thromboembolism1.21.2NSBleeding0.90
32、NSProteinuria2.40.0004Neuropathy20.514.2.01Fatigue5.0 2.7NSNeutropenia5.33.0 NSDecreased LVEF0.30.0NSMiller et al.ASCO 2019.Oral presentation during symposium,Advances in Monoclonal Antibody Therapy for Breast Cancer.Bevacizumab Paclitaxel for Locally Recurrent or Metastatic Disease Bevacizumab+pacl
33、itaxel regimen associated with more grade 3/4 adverse events vs paclitaxel alone结论 Bevacizumab improves PFS when added to paclitaxel for treatment of locally recurrent or metastatic disease Improved overall survival and overall response Increased hypertension,proteinuria,neuropathy with bevacizumabR
34、eceptor Tyrosine Kinase Inhibitor SU11248 for Heavily Treated MBC Phase II trial，N=64，重度复治的MBC SU11248 6周方案：50 mg/d28 d,休2周。PR 14%，SD 2%。近一半患者由于毒副作用需要调整剂量 Dose reduction,17%Dose interruption,31%Neutropenia(39%)是最常见3级毒性。最常见1-2级非血液毒性 Diarrhea,56%Mouth pain,49%Fatigue,47%Nausea,44%Miller et al.ASCO 201
35、9.Abstract 563.小结 细胞毒药物仍然是MBC的主要治疗手段，PLD显示与ADR 等效，但是心脏毒性更轻。紫杉类每周用药比3周方案疗效更好，而且具有更好的耐受性。新型紫杉类显示对紫杉类难治性MBC具有长的肿瘤控制期，值得进一步确定其意义。提高紫杉醇剂量或维持化疗没有改善临床疗效。单药序贯与联合化疗清楚证明具有同等疗效，但是患者的耐受性更好。Herceptin 单药和联合方案具有十分显著的疗效，是Her2+MBC的首选治疗。针对VEGF受体的人源化单抗-Bevacizumab，联合Paclitaxel，对Her2阴性MBC一线治疗改善PFS和OS。是首个在乳癌显示显著疗效的这类药物，特别是对Her2 患者，具有及其重要的意义。MBC的治疗仍然是肿瘤医师面临的最大挑战,开发新药和新的治疗方法是目前主要方向.CCI-779(雷帕霉素类似物)Ixabepilone(Epothilone类似物)谢谢 Thank you
