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ChemotherapyEndocrine therapyTargeted therapiesTreatmentofBCHIGHLIGHTS IN BREAST CANCER DISEASE BIOLOGYu针对 HER2受体的靶向药物u针对表皮生长因子受体 (EGFR)的靶向治疗u针对肿瘤血管生成的分子靶向药物u其他信号通路抑制剂 mTOR， Ras， MEK等乳腺癌分子靶向药物治疗中位生存期的缩短HER2 扩增 /过度表达 3 年HER2 正常表达 6 - 7 年HER2 受体过度表达受体过度表达HER2 原癌基因扩增HER2在
2、约 20% 30% 的乳腺癌组织中过度表达Slamon DJ et al. Science 1987;235:17782HER2阳性与内分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赫赛汀 (曲妥珠单抗曲妥珠单抗 ): 人源化抗人源化抗 HER2单克隆抗体单克隆抗体l 高度亲和性高度亲和性 (Kd=0.1nM) 和特异性和特异性l 95% 人源化人源化 , 5% 鼠抗，显鼠抗，显著降低免疫原性著降低免疫原性 (HAMA)l 全球第一种治疗实体瘤的单克隆抗体Inhibition of HER2-mediated signalli
3、ngActivation of ADCC赫赛汀的作用机制Additional mechanismsu Prevents formation of truncated HER2 (p95)u Inhibition of HER2-regulated angiogenesisADCC, antibody-dependent cellular cytotoxicity赫赛汀已成为 HER2阳性乳腺癌的基础治疗1st lineHO648gM77001 US OncologyBCIRG 007CHATTAnDEMRHEARelapse2nd+ linesGBG-26BO17929EGF104900Num
4、erous Phase II studiesMBCProgressionHERANSABP B-31NCCTG N9831BCIRG 006AdjuvantNOAHMDACCGeparQuattroNumerous Phase II studiesNeoEBCHER2, human epidermal growth factor receptor 2 EBC, early breast cancer; MBC, metastatic breast cancer13,000 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;
5、 Slamon et al 2006NCCTG N9831 (USA)HERA (ex-USA) BCIRG 006 (global)NSABP B-31 (USA)IHC / FISH (n=5,090)Observation1 year2 yearsIHC / FISH (n=3,505) 1 year1 yearFISH(n=3,222)1 year1 yearIHC / FISH (n=2,030)1 yearDocetaxelDocetaxel + carboplatinDoxorubicin + cyclophosphamide HerceptinStandard CTx Pacl
6、itaxelIHC, 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 2B-31 / N9831 ACPH 3HERA CTxH 1 year 2Median follow-up, yearsOverall survival benefitBCIRG 006 ACDH 3BCIRG 006 DCarboH 3FavoursHerceptinFavours noHerceptinHRSlamon et al 2006 Perez et al 2007
7、; Smith et al 2007H, Herceptin; AC, doxorubicin, cyclophosphamide P, paclitaxel; D, docetaxel; Carbo, carboplatin HR, hazard ratioSize 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 20072-5 cmBCIRG 0062-5 cm5 cm0.0 0.5 2.51.0 1.5 2.00-2 cmN9831 / B-31 0-2 cm5 cmACDH 2 cmDCarboH 2 cm2 cm2 cmFavours Herceptin Favours no HerceptinHRHERADFS, disease-free survival
