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1、乳腺癌分子靶向药物治疗进展,张清媛哈尔滨医科大学附属肿瘤医院,Chemotherapy,Endocrine therapy,Targeted therapies,Treatment of BC,HIGHLIGHTS IN BREAST CANCER,DISEASE BIOLOGY,针对HER2受体的靶向药物针对表皮生长因子受体(EGFR)的靶向治疗针对肿瘤血管生成的分子靶向药物其他信号通路抑制剂mTOR，Ras， MEK等,乳腺癌分子靶向药物治疗,HER2在约20% 30%的乳腺癌组织中过度表达,Slamon DJ et al. Science 1987;235:17782,HER2阳性与内分
2、泌治疗及部分化疗耐药密切相关，是重要的预后指标 HER2成为乳腺癌治疗的理想靶点，是预测赫赛汀疗效的重要指标,赫赛汀(曲妥珠单抗): 人源化抗HER2单克隆抗体,高度亲和性 (Kd=0.1nM) 和特异性 95% 人源化, 5% 鼠抗，显著降低免疫原性(HAMA),全球第一种治疗实体瘤的单克隆抗体,Inhibition of HER2-mediated signalling,Activation of ADCC,赫赛汀的作用机制,Additional mechanisms Prevents formation of truncated HER2 (p95) Inhibition of HER2
3、-regulated angiogenesis,ADCC, antibody-dependent cellular cytotoxicity,赫赛汀已成为HER2阳性乳腺癌的基础治疗,1st line,HO648g M77001 US Oncology BCIRG 007 CHAT TAnDEM RHEA,Relapse,2nd+ lines,GBG-26 BO17929 EGF104900 Numerous Phase II studies,MBC,Progression,HERA NSABP B-31 NCCTG N9831 BCIRG 006,Adjuvant,NOAH MDACC Ge
4、parQuattro Numerous Phase II studies,Neo,EBC,HER2, human epidermal growth factor receptor 2 EBC, early breast cancer; MBC, metastatic breast cancer,13,000 患者入组的赫赛汀四大辅助临床研究,Piccart-Gebhart et al 2005 Romond et al 2005; Slamon et al 2006,NCCTG N9831 (USA),HERA (ex-USA),BCIRG 006 (global),NSABP B-31 (U
5、SA),IHC / FISH (n=5,090),Observation,1 year,2 years,IHC / FISH (n=3,505),1 year,1 year,FISH (n=3,222),1 year,1 year,IHC / FISH (n=2,030),1 year,Doxorubicin + cyclophosphamide,IHC, immunohistochemistry FISH, fluorescence in situ hybridisation CTx, chemotherapy,赫赛汀可减少三分之一的死亡风险,0,1,2,B-31 / N9831 ACPH,
6、3,HERA CTxH 1 year,2,Median follow-up, years,Overall survival benefit,BCIRG 006 ACDH,3,BCIRG 006 DCarboH,3,Favours Herceptin,Favours no Herceptin,HR,Slamon et al 2006 Perez et al 2007; Smith et al 2007,H, Herceptin; AC, doxorubicin, cyclophosphamide P, paclitaxel; D, docetaxel; Carbo, carboplatin HR
7、, hazard ratio,Size of square represents sample size; horizontal bars indicate 95% confidence intervals,无论肿瘤大小，赫赛汀均显示DFS获益,Slamon et al 2006 Perez et al 2007; Smith et al 2007,2-5 cm,BCIRG 006,2-5 cm,5 cm,0.0,0.5,2.5,1.0,1.5,2.0,0-2 cm,N9831 / B-31,0-2 cm,5 cm,ACDH,2 cm,DCarboH,10+ nodes,DCarboH,N-,
8、N+,N+,BCIRG 006,N-,ACDH,N-,HERA,HR,Slamon et al 2006 Perez et al 2007; Smith et al 2007,无论年龄大小，赫赛汀均显示DFS获益,35-49 years,0.0,0.5,2.5,1.0,1.5,2.0,HERA,35 years,50-59 years,60 years,N9831 / B-31,40 years,60 years,40-49 years,50-59 years,Favours Herceptin,Favours no Herceptin,HR,Perez et al 2007; Smith e
9、t al 2007,赫赛汀的新辅助治疗研究进展,1st line,HO648g M77001 US Oncology BCIRG 007 CHAT TAnDEM RHEA,Relapse,2nd+ lines,GBG-26 BO17929 EGF104900 Numerous Phase II studies,MBC,Progression,HERA NSABP B-31 NCCTG N9831 BCIRG 006,Adjuvant,NOAH MDACC GeparQuattro Numerous Phase II studies,Neo,EBC,NOAH study: neoadjuvant
10、 Herceptin for LABC,aHormone receptor-positive patients receive adjuvant tamoxifen AP, doxorubicin 60 mg/m2, paclitaxel 150 mg/m2; H, Herceptin 8 mg/kg loading then 6 mg/kg P, paclitaxel 175 mg/m2; CMF, cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, 5-fluorouracil 600 mg/m2 LABC, locally advance
11、d breast cancer; q3w, every 3 weeks; q4w, every 4 weeks,HER2-positive LABC (IHC 3+ and/or FISH+),n=113,H + AP q3w x 3,H + P q3w x 4,H q3w x 4 + CMF q4w x 3,Surgery followed by radiotherapya,H continued q3w to Week 52,n=115,P q3w x 4,CMF q4w x 3,Surgery followed by radiotherapya,AP q3w x 3,AP q3w x 3
12、,P q3w x 4,CMF q4w x 3,Surgery followed by radiotherapya,n=99,HER2-negative LABC (IHC 0/1+),p=0.002,p=0.004,pCR (%),Baselga et al 2007; Gianni et al 2007,HER2 positive (n=228),HER2 positive (n=62),NOAH研究中赫赛汀新辅助显著提高了pCR率,Without Herceptin With Herceptin,90,80,70,60,50,40,30,20,10,0,HER2 negative (n=9
13、9),HER2 negative (n=14),23,43,17,19,55,29,Total population,IBC population,pCR, pathological complete response in the breast IBC, inflammatory breast cancer,新辅助化疗中加入赫赛汀明显提高疗效(16个相关研究, 1,226例患者入组),aX was given either concurrently or sequentially with D + H EC, epirubicin, cyclophosphamide; FEC, 5-fluo
14、rouracil, epirubicin, cyclophosphamide My, Myocet; X, Xeloda,0,10,20,30,40,50,60,70,80,90,100,pCR (%),赫赛汀已成为HER2阳性乳腺癌的基础治疗,1st line,HO648g M77001 US Oncology BCIRG 007 CHAT TAnDEM RHEA,Relapse,2nd+ lines,GBG-26 BO17929 EGF104900 Numerous Phase II studies,MBC,Progression,HER2, human epidermal growth factor receptor 2 EBC, early breast cancer; MBC, metastatic breast cancer,EBC,HERA NSABP B-31 NCCTG N9831 BCIRG 006,Adjuvant,NOAH MDACC GeparQuattro Numerous Phase II studies,Neo,一线赫赛汀治疗显著延长患者的生存时间,Median survival (months),
