乳腺癌内分泌治疗

乳腺癌的内分泌治疗乳腺癌是一古老的疾病古埃及3000多年前已经描述乳腺肿瘤；公元前400年Hippocrates描述过乳腺癌。我国宋代已经有关于乳腺癌的描述。清《医宗金鉴》称“乳癌由肝脾两伤，气郁凝结而成”。乳癌内分泌治疗历史1896年卵巢切除术治疗复发转移乳癌1922年放疗卵巢去势1939年雄性激素1944年人工合成雌激素1951年孕激素1953年肾上腺切除和下丘脑切除1973年三苯氧胺1981年芳香化酶抑制剂1990‘s新一代的芳香化酶抑制剂近代乳癌内分泌治疗●1971年发现ER，选择阳性病人效果好●1973年研制TAM，逐步成为标准治疗——抵消雌激素作用●1981年应用第一代抗芳香化酶制剂——切断绝经后妇女雌激素来源●1995年推出第三代抗芳香化酶制剂——向标准治疗挑战三苯氧胺雌激素受体结合脂肪肌肉肾上腺雄激素芳香化酶雌激素雌激素受体三苯氧胺雌激素雌激素受体结合抑制肿瘤生长肿瘤生长抑制肿瘤生长抗芳香化酶制剂抗芳香化酶制剂与芳香化酶结合三苯氧胺70年代后期以来公认的乳腺癌术后ER(+)患者一线辅助治疗的金标准服用三苯氧胺的时间及ER状态对于复发的影响Lancet,20050%20%40%ReductioninAnnualOddsofRecurrence1-2年11%22%26%5年-4%31%41%ER阴性ER未知ER阳性三苯氧胺辅助治疗乳腺癌的临床获益ER阳性或ER未知Lancet365,2005化疗对使用5年三苯氧胺的影响Lancet,20050%20%40%60%ReductioninAnnualOdds死亡31%39%复发41%40%TamvnilTam+ChemovChemo三苯氧胺治疗5年后累计的复发危险仍然存在2.14.67.810.2024681012year6year7year8year9复发病人％HortobagyiGN,etal.procAmSocClinOncol.2004;23:23复发死亡Adaptedwithpermission.EarlyBreastCancerTrialists’CollaborativeGroupMeeting,2000.Years85.276.168.273.762.754.968%55%020406080100051015TamoxifenControl15%17%02040608010005101573%64%80.973.087.873.264.0YearsTamoxifenControl9%18%91.4生存病人％生存病人％NSABPB-14:延长三苯氧胺无益Fisheretal.JNatlCancerInst.2001;93:684.无病生存率1009080706050%ofpatients510安慰剂三苯氧胺Years12总生存率510Years100908070605012%ofpatients安慰剂三苯氧胺82%78%94%91%P=0.03P=0.07679118687911他莫昔芬显示了增加子宫内膜癌的发生率，增加心脑血管疾病的危险重视芳香化酶抑制剂(AI)在乳腺癌治疗中的地位适用于绝经后ER和/或PR(+)患者按作用机制分两大类:非甾体类AI：与雄激素竞争芳香化酶,并与芳香化酶以离子键形式可逆性结合,阻止雄激素底物与酶结合,即“竞争性抑制”。第一代：氨鲁米特（AG）第二代：法曲唑(fadrozole)第三代：来曲唑（弗隆），阿那曲唑（瑞宁德）甾体类AI：结构与雄激素相似，但与芳香化酶的结合力比雄激素强，它以共价键与芳香化酶不可逆结合，造成酶的永久失活，即“自杀性抑制”。第一代：睾内酯(Testolactone)第二代：福美斯坦（兰他隆）第三代：依西美坦NCCN的绝经定义•双侧卵巢切除；•年龄≥60岁；•年龄60岁，停经≥12月；（除外化疗、TAM或卵巢抑制，FSH、E2在绝经后范围）•化疗、TAM、托瑞米芬治疗者，且年龄60岁，FSH、E2在绝经后范围；•正接受LHRH激动/抑制剂者，不能确定其绝经状态。第三代AI的优点明显降低雌激素水平对芳香化酶选择性高，不良反应少，患者耐受性明显提高口服生物利用度好，可每日一次给药，治疗方便抗芳香化酶制剂（AIs)作用机理醛固酮肾上腺皮质皮质类固醇雄烯二酮雌二醇芳香化酶新AIs睾酮雌酮●特异抑制芳香化酶●对醛固酮、皮质醇没影响●快速稳定降低雌二醇及雌酮水平第一代AI（氨鲁米特）NSABP-B33Tamx5yExemestanex5yN=1598(atclosure)已经发表和未发表的芳香化酶抑制剂的大规模辅助试验ATACN=6241IESN=4742MA-17N=5187TEAMtrialN=7000Exemestanex5yABCSG8N=4000Tam2-3yAnastrozole3-2yBIG1-98N=8028Letrozolex5yTam2-3yLetrozole3yLetrozole3yTam3yMA-27N=6830(targetaccrual)ExemestaneCelecoxiborAnastrozoleCelecoxibTOTAL=16,170(published)TOTAL=27,456(unpublished)辅助性AI治疗Aromataseinhibitors(AIs)(postmenopausal)ATACIESITAABCSG8和ARNO95NCICMA-17BIG1-98Combination(n=3125)DiscontinuedfollowinginitialanalysisasnoefficacyortolerabilitybenefitcomparedwithtamoxifenarmATACtrialdesign9366postmenopausalwomenwithinvasivebreastcancerSurgery+radiotherapy+chemotherapyRandomisation1:1:1for5yearsAnastrozole(n=3125)Tamoxifen(n=3116)Regularfollow-upPrimarytrialendpoints:•Disease-freesurvival•Safety/tolerabilitySecondarytrialendpoints:•Incidenceofcontralateralbreastcancer•Timetodistantrecurrence•Overallsurvival•TimetobreastcancerdeathATAC:disease-freesurvival(HR+population)Medianfollowup68monthsIncludesnonbreastcancerdeaths;HR+=hormonereceptorpositiveFollow-uptime(years)05101520250123456Absolutedifference:1.6%2.6%2.5%3.3%Patients(%)AnastrozoleTamoxifenHR0.830.87HR+ITT95%CI(0.73–0.94)(0.78–0.97)p-value0.0050.01ATACTrialists’Group.Lancet2005;365:60-62ATAC:recurrence(HR+ve)Medianfollowup68monthsPatients(%)Follow-uptime(years)05101520250126Absolutedifference:1.7%2.4%2.8%3.7%Atrisk:A261825402448235522682014830T259825162398230421891932774Anastrozole(A)Tamoxifen(T)3HR0.740.79HR+veITT95%CI(0.64,0.87)(0.70,0.90)p-value0.00020.000545CI=confidenceintervals;HR=hazardratioITT=intent-to-treatATACTrialists’Group.Lancet2005;365:60-62Anastrozoleismoreeffectivethantamoxifeninreducingtheincidenceofnew(contralateral)breastprimariesTamoxifen(n=2598)Anastrozole(n=2618)21invasiveNo.cases48invasive6DCIS5DCIS26total54total0102030405060ATAC:timetodistantrecurrence(HR+ve)Medianfollowup68monthsATACTrialists’Group.Lancet2005;365:60-62Patients(%)HR0.840.86HR+veITT95%CI(0.70,1.00)(0.74,0.99)p-value0.060.04Follow-uptime(years)Atrisk:AT26182550246423862309205184525982533233823612257200581605101520250123456Anastrozole(A)Tamoxifen(T)ATAC:efficacyanalysis(ITTandHR+ve)HR(A:T)and95%CIDisease-freesurvivalTimetorecurrenceTimetodistantrecurrenceOverallsurvivalTimetobreastcancerdeathContralateralbreastcancer0.20.40.60.81.01.21.52.0ITTpopulationHR+vepopulationAnastrozole(A)betterTamoxifen(T)betterATACTrialists’Group.Lancet2005;365:60-620.870.790.860.970.880.58ITTHR+0.830.740.840.970.870.47*Patients1fractureoccurringbeforerecurrence,includingpatientsnolongerontreatmentPre-specifiedadverseevents(%)T40.910.213.20.82.84.529.47.75.1A35.75.43.50.22.02.835.611.01.3HotflashesVaginalbleedingVaginaldischargeEndometrialcancerIschemiccerebrovascularVenousthromboembolicJointsymptomsFractures*Hysterectomyp-value0.00010.00010.00010.020.030.00040.00010.00010.0001SummaryAnastrozole–•demonstratessuperiorefficacytotamoxifen-reducesrecurrence,distantrecurrenceandcontralateralbreastcancer•isbettertoleratedoverall•benefitinthefirst3yearsjustifiesofferingtreatmentasearlyaspossibleConclusionAnastrozole–•theinitialtreatmentofchoiceforhormonereceptorpositiveearlybreastcancerinpostmenopausalwomen辅助性AI治疗Aromatas