乳腺癌临床研究进展

2008乳腺癌临床研究进展,中山大学肿瘤医院 内科刘冬耕20090424,内分泌治疗（Big 1-98）辅助化疗（NSABP B30, BCIRG 005）分子靶向治疗(HERA 4年)双磷酸盐（ABCSG 12 ）新抗癌药物,Big 1-98,2008 SABCS 最新报告核心分析61个月随访；单药组分析76个月随访；序贯组与来曲唑单药组71个月比较分析；,BIG 1-98 Overall Design,Summary of previous analysesPrimary core analysis and monotherapy analyses showed that 5-year DFS and time to distant recurrence significantly superior with upfront letrozole vs upfront tamoxifenPrimary core analysis; median follow-up: 26 mosMonotherapy arm analysis; median follow-up: 51 mos,2,0,5,Yrs,Tamoxifen,Letrozole,Tamoxifen,Letrozole,Tamoxifen,Letrozole,A,B,2-Arm Option,4-Arm Option,n = 911,n = 917,n = 1548,n = 1546,n = 1548,n = 1540,N = 1828enrolled1998-2000,N = 6182enrolled1999-2003,N = 8010*,*ITT excludes 18 patients who withdrew consent and did not receive study treatment.,A,B,C,D,SURGERY,StratifyInstitutionCT (adjuvant/neoadjuvant) Prior None Concurrent,RANDOMIZE,RANDOMIZE,Letrozole,Tamoxifen,Mouridsen HT, et al. SABCS 2008. Abstract 13.,BIG 1-98: Primary Core Analysis (PCA),Is 5 years of letrozole superior to 5 years of tamoxifen as initial adjuvant therapy?For arms C and D, events and follow-up beyond switch are excludedPrimary end point: DFS,0,2,5,Years,TAM,LET,TAM,LET,LET,TAM,A,B,C,D,RANDOMIZE,6182 patients,8010 patients,TAM,LET,A,B,RANDOMIZE,0,2,5,Years,1828 patients,2-Arm Option,Enrolled 1998-2000,Enrolled 1999-2003,Thrlimann et al. N Engl J Med. 2005;353:2747.,N=911,N=917,N=1548,N=1546,N=1548,N=1540,4-Arm option,BIG 1-98: Primary Core Analysis,St. Gallen (January 2005) PCA 25.8 months follow upASCO 2005 PCA 25.8 months follow up After medical reviewSt. Gallen 2009 PCA 60.5 months follow up,Does Letrozole x 5 years improve outcome compared with tamoxifen x 5 years?,T,0,20,40,60,80,100,0,1,2,3,4,5,Percent Alive and Disease-Free,Years from Randomization,BIG 1-98: 26 month Disease-Free Survival,Primary Core Analysis: Key End Points at a Median Follow-up of 26 Months,N = 8010.,1.0,0.5,0.75,1.33,Hazard Ratio,*Time from randomization to invasive regional recurrence, distant metastases, or death from any cause. Thrlimann B et al. N Engl J Med. 2005;353:2747.,Primary Core Analysis:Safety at Median Follow-up of 26 Months,Thrlimann et al. N Engl J Med. 2005;353:2747.,BIG 1-98: PCA Updateat 61 Months Median Follow-Up,0,2,5,Years,TAM,LET,TAM,LET,LET,TAM,A,B,C,D,RANDOMIZE,6182 patients,8010 patients,TAM,LET,A,B,RANDOMIZE,0,2,5,Years,1828 patients,2-Arm Option,Enrolled 1998-2000,Enrolled 1999-2003,N=911,N=917,N=1548,N=1546,N=1548,N=1540,4-Arm option,Median follow-up 60.5 months (2-arm: 99.1 mos., 4-arm monotherapy 70.3 mos., 4-arm switching 25.1 mos.).All patients are off protocol treatment.,Selective Crossover in Tamoxifen-alone Arm,Tamoxifen monotherapy arm (Arm A) unblinded in 2005619 (25.2%) patients on TAM-alone arm selectively crossed over to LETMost patients (612) were from the 4-arm optionMost patients crossed over during years 3-5 as seen in the figure belowMedian duration of LET after selective crossover was 18 monthsPatients who crossed over to LET were more likely to have node-positive disease (47% vs. 29%) and tumors 2 cm (35% vs. 26%) compared with those who remained on TAM,Both ITT and Censored Analysis are Likely to be Biased,ITT: Against LetrozoleCensored: Against Tamoxifen (survival)Against Letrozole (recurrence events),Censored for crossover,RANDOMIZE,Tamoxifen,Letrozole,0,2,5,Cumulative Incidence of DFS Events (ITT),* 619 patients received letrozole after the tamoxifen-alone arm was unblinded,20,15,10,5,0,0,2,4,6,Breast,cancer,recurrence,Y,ears,from,Randomization,Second,(non-breast),primary,Death,without,prior,cancer,event,Letrozole,T,amoxifen*,Percent,1,3,5,7,Endpoints: ITT and Censored* Results,1. N Engl J Med 353:2747-2757, 2005,*Follow-up of the 619 pts who selectively crossed over to receive Let are censored at the time of selective crossover,*ITT included 25.2% of women in TAM arm who crossed over to receive LET during years 3-5 Patients who were censored at the time of cross over from TAM to LET,BIG 1-98: PCA Efficacy Results,PCA, Primary core analysis; MAA, Monotherapy arms analysis; DFS, Disease free survival; TDR, Time to distant recurrence; OS, overall survival,BIG 1-98: Safety Results Overtime,PCA, Primary core analysis; MAA, Monotherapy arms analysis; CVA/TIA, Cerebrovascular accident/ Transient Ischemic attack ; TAM, tamoxifen; LET, letrozole, NR, not reported *P0.001, P 50 yrs, 50 yrs,ER negative,ER positive,Post-meno,HRT,Pre-meno,No HRT,LN 1-3,LN 4+,0-2 cm,2 cm+,0.7,0.8,0.9,1,1.1,0.84,0.84,0.81,0.82,0.84,0.88,0.83,0.79,0.88,0.77,0.86,0.78,HR,Factor,Swain SM, et al. SABCS 2008. Abstract 75.,In Favor of AC T,In Favor of TAC,BCIRG 005: Study Design,4 x AC,4 x Docetaxel,60/600 mg/m2,100 mg/m2,6 x TAC,75/50/500 mg/m2,Dexamethasone premedication: 8 mg BID, 3 daysProphylactic ciprofloxacin: 500 mg BID, Days 5-14,Eiermann W, et al. SABCS 2008. Abstract 77.,HER2 normal(FISH)(N = 3298)Stratification: Nodes:1-34+ HR +/- Center,BCIRG 005 Primary Analysis: DFS,Disease-Free Probability,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,12,24,36,48,60,72,84,96,HR = 1.002(95% CI: 0.86-1.16),Log rankP = .98,78.9%,78.6%,Mos,Eiermann W, et al. SABCS 2008. Abstract 77.,TACACT,BCIRG 005 Primary Analysis: Overall Survival,Survival Probability,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,12,24,36,48,60,72,84,96,HR = 0.91(95% CI: 0.75-1.11),Log rankP = .37,88.9%,88.1%,Eiermann W, et al. SABCS 2008. Abstract 77.,TACACT,Mos,双磷酸盐抗肿瘤临床研究,氯曲膦酸帕米磷酸唑来磷酸,DFS 无病生存率; OS = 总生存率. 1. Diel IJ, et al. N Engl J Med. 1998;339:357-363; 2. Diel IJ, et al. Proc Am Soc Clin Oncol. 2000;19:82a. Abstract 314; 3. Powles T, et al. Breast Cancer Res. 2006;8:R13; 4. Saarto T, et al. Acta Oncol. 2004;43:650-656.,2年试验令人鼓舞的结果(N=1,371)1-3 治疗期间延缓骨转移在一项试验中提高DFS 在两项试验中提高OS10年试验结果分析无效 (N=299)4未能延缓骨病进展未能延长DFS或OS,氯曲膦酸在乳腺癌辅助治疗的研究：相互矛盾的研究结果,17,口服帕米膦酸未能改善乳腺癌疾病终点,LNBC患者随机分组接受口服PAM (150mg bid，治疗2年; n=460) 或不使用PAM (n=493)帕米膦酸显示出预防骨质丢失的作用(n=27)骨转移复发: HR, 1.03 (95%CI, 0.75-1.40; P= .86),骨转移,骨转移+其他转移,患者数, n,PAM,未使用PAM,LN, 淋巴结；BC, 乳腺癌；PAM, 帕米膦酸.,20,Kristensen B, et al. Acta Oncol. 2008;47:740-746.,他莫昔芬 20 mg/day,阿那曲唑 1 mg/day,n = 1,803 绝经前乳腺癌患者 I/II期(骨亚组研究, n=404)分层: ER+ 和/或PR+年龄 分期 分级 淋巴结,治疗3年,研究终点主要终点: 无病生存率 (DFS) 次要终点: 无复发生存率 (RFS), 总生存率 (OS), 骨密度 (BMD), 安全性,四组均使用戈舍瑞林 3.6 mg28天一次,TAM: Tamoxifen, ANA: Anastrozole,他莫昔芬+唑来膦酸 4 mg 6个月一次,阿那曲唑 + 唑来膦酸 4 mg 6个月一次,随机分组,长期监测5年复发和生存率(DFS, OS),3年BMD,5年BMD,ABCSG-12,34,ABCSG-12: 无病生存率,患者数,904,832,713,537,407,241,145,47,899,848,730,555,414,257,123,54,未使用ZOL,ZOL,Gnant M et al. NEJM 2009; 360 (7): 679-691,35,首次DFS 事件数 (ITT 人群),患者首次事件数, n,(n = 904),(n = 899),Gnant M et al. NEJM 2009; 360 (7): 679-691,36,N=83,N=46,ABCSG-12: 需要治疗的患者数 (NNT),使1例患者获得无病生存（DFS）临床益处所需治疗的患者数- NNT = 1 / 绝对风险降低唑来膦酸与其他治疗药物(如紫杉醇) DFS疗效相似,*Bria E, et al. Cancer. 2006;106:2337-2344, *Gnant M et al. NEJM 2009; 360 (7): 679-691,37,小结,与单纯内分泌治疗相比，唑来膦酸显著延长DFS和RFS 36%DFS事件风险 (HR = 0.64; P = .01) 35%RFS事件风险 (HR = 0.65; P = .015)无论在骨内还是在骨外，唑来膦酸均显示了获益：降低对侧乳腺癌复发降低局部复发降低非骨转移仍需要开展进一步的临床研究探讨最佳剂量、给药方法和给药间隔。应考虑将唑来膦酸列入辅助治疗以改善绝经前乳腺癌妇女的治疗,ZOL = 唑来膦酸; DFS = 无病生存率; RFS = 无复发生存率; OS = 总体存活率; HR 风险比.,来曲唑,Z- FAST / ZO- FAST / E-ZO-FAST: 择泰+ 弗隆 辅助协同研究预防或延迟给药,研究终点主要终点：骨密度次要终点：骨标记物; 骨折; 至复发时间,来曲唑 + 唑来膦酸4 mg，6个月一次,n=2,194 乳腺癌患者 I - IIIa 期绝经后或因抗癌治疗闭经ER+ 和/或 PR+ T值 2,如存在下列一项，延迟唑来膦酸用药 BMD T 值 2 临床骨折 36个月时无症状骨折,治疗5 年,随机分组,BMD = 骨密度；ER = 雌激素受体; PR = 孕激素受体;,31,Z-FAST腰椎和髋骨： 与基线比较和个月BMD的平均变化,24月,腰椎,髋骨,Mean (SEM) Percentage Change BMD,P .0001*,P .0001*,*P values correspond to INTERGROUP comparisons所有组内12个月或24个月和基线的比较均有统计学意义 (P.0001) ，SEM=standard error of the mean. Brufsky A, et al. Presented at: The 29th Annual SABCS Dec. 14 17, 2006. Abstract 5060.,P .0001*,P .0001*,12月,24月,12月,ZO-FAST 36个月主要研究终点：早期治疗组BMD显著提高,P0.0001,P0.0001,BMD 平均变化 (%),Z-FAST / ZO-FAST 综合分析,1. Brufsky A, et al. Oncologist. 2008;13:503-514; 2. Frassoldati et al. Ann Oncol. 2008; 19 (suppl 8): viii. Abstract 185PD).,P = .0183,P = .0401,Z/ZO-FAST 24个月综合分析2,Z/ZO-FAST 12个月综合分析1,复发率, %,32,复发率, %,0,10,20,30,40,50,60,70,80,90,100,0,5,10,15,20,25,30,35,DFS，%,时间，月,早期使用ZOL延迟使用ZOL,HR = 0.588P = .0314,ZO-FAST 36个月分析: 早期使用唑来膦酸显著提高DFS 41%,a 同一患者可能有多个转移位点，包括：骨、脑、肝、肺、皮肤、淋巴结和其他,患者数, n,(n = 532),(n = 532),疾病复发a,DFS,33,Adapted from Eidtmann H, et al. Presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, TX. Abstract 44.,结 论,使用AI辅助治疗的早期乳腺癌患者早期使用择泰（4mg IV 1次/6个月）能够预防骨质丢失；早期使用择泰和延迟使用择泰在骨折发生率方面无显著差异；早期使用择泰显著提高无病生存率(提高41%)；药物安全性结果与以往一致这些结果进一步证明择泰治疗早期乳腺癌具有预防骨质丢失和抗肿瘤活性并延长无病生存期。,研究终点主要终点: 无病生存率其他终点: 至骨转移/远处转移的时间；SREs；总生存率,标准治疗,标准治疗唑来膦酸 4 mg 给药 6 次 (3-4周一次)给药8 次 (3个月一次)给药5 次(6个月一次),N=3,360乳腺癌 II/III 期分层: N+/N- T 分期 ER 状况 辅助全身化疗 绝经前/绝经后,随机分组,治疗后随访5年：复发和生存,治疗5年,AZURE : 乳腺癌,38,AZURE: 新辅助治疗患者的亚组分析,206 (6.1%) 接受新辅助化疗唑来膦酸基线特征两组平衡肿瘤大小，ER，HER2，月经状态，化疗类型残余浸润性肿瘤大小（RITS)和中位残余淋巴结数量比较,ZOL = Zoledronic acid; ER = Estrogen receptor; HER2 = Human epidermal growth factor receptor 2; RITS = Residual invasive tumour size. Winter et al. Cancer Treat Rev. 2008;34:S55-S56.,39,新辅助治疗 AZURE,平均RITS , mm,相对 33% (14 mm),42.4,5.8,28.2,10.9,0,10,20,30,40,50,60,70,单纯化疗,化疗+唑来膦酸,P = .03,a 多元分析 (N=171). RITS： 残余浸润性肿瘤大小 Winter MC, et al. SABCS, 2008 (Abst #5101), SABCS 2008,0,10,20,30,40,50,病理学完全缓解 %,P = .002,40,AZURE新辅助化疗亚组：结论,与单纯新辅助治疗相比，新辅助治疗+择泰能缩小肿瘤体积，并提高病理学完全应答率；这些结果显示择泰可能有直接的抗肿瘤作用。,现有双膦酸盐辅助治疗临床研究,44,HERA试验,1年与无治疗的最新分析失去OS获益的解读以及临床意义1年与2年的分析尚未有正式报告2011年证实发布分析结果,HERA 研究设计,赫赛汀 q3w x 1 年,观察组,HER2-阳性可手术乳腺癌 (IHC 3+ 和 / 或 FISH+)n=5102,赫赛汀q3w x 2 年,手术 + (新)辅助化疗 + 放疗,IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation,赫赛汀的研发历程,I期安全性临床研究开始,鼠 HER2 / neu 基因成功克隆,人 HER2 基因克隆,单抗4D5研发,发现HER2与临床预后差相关,紫杉醇 + 赫赛汀 和赫赛汀单药 适应症美国批准,紫杉醇 + 赫赛汀 和赫赛汀单药 适应症欧盟批准,HERA研究第一次中期分析,1992,1985,1990,1981,1987,2000,1998,2005,2006,HERA 入组开始,HERA 研究2年组随访,赫赛汀辅助适应症治疗批准,2008,HERA研究1年组 4年随访结果 vs 2年组中期分析,2011,HERA 1年组与2年组终期分析,HER2, human epidermal growth factor receptor 2; H, Herceptin; IA, interim analysis,HERA 研究终点,首要终点无病生存期1-年赫赛汀治疗组 vs 观察组2-年赫赛汀治疗组 vs 观察组次要终点总生存, 无复发生存, 无远处转移生存, 安全性 1-年赫赛汀治疗组 vs 观察组2-年赫赛汀治疗组 vs 观察组比较无病生存,总生存, 无复发生存,无远处转移生存, 安全性1-年赫赛汀治疗组 vs 2-年赫赛汀治疗组,DFS, disease-free survival; OS, overall survival; RFS, relapse-free survival,100,80,60,40,20,0,患者(%),随机分组后月,12,36,赫赛汀1年治疗组（n=1703) 事件数218,观察组（n=1698)事件数321,0,18,6,24,30,HR=0.64,P0.0001,80.6%,74.3%,6.3%,HERA 23-month follow-up data at ASCO on June 3rd, 2006,HERA研究:无病生存时间(DFS)显著改善复发风险降低36%,100,80,60,40,20,0,HR=0.66,P=0.0115,92.4%,89.7%,0,2.7%,HERA研究:生存时间(OS)显著改善死亡风险降低34%,随机分组后月,HERA 23-month follow-up data at ASCO on June 3rd, 2006,患者(%),赫赛汀1年治疗组（n=1703) 事件数59,观察组（n=1698)事件数90,HERA: 不同随访时间的无病生存和总生存,死亡事件数 赫赛汀 1 年 vs 观察组,0,1,2,倾向赫赛汀 治疗,倾向非赫赛汀治疗,HR,OS 获益,29 vs 37p=0.26,200511 年(0%),59 vs 90p=0.0115,中位随访时间 (% 选择入组后随访时间,200622 年(4.1%),200511 年 (0%),中位随访时间 (% 选择入组后随访时间),200622 年 (4.3%),无病生存事件数赫赛汀1年 vs 观察组,127 vs 220p0.0001,218 vs 321p0.0001,0,1,2,倾向赫赛汀 治疗,倾向非赫赛汀治疗,HR,DFS 获益,1Piccart-Gebhart et al 2005; 2Smith et al 2007,HERA 研究设计,HER2-阳性可手术乳腺癌 (IHC 3+ and / or FISH+)n=5102,手术 + (新)辅助化疗 + 放疗,赫赛汀 q3w x 1 年,观察组,2005/5观察组患者数据情况,1698 例患者初始分配至观察组,1354 例患者无病生存,5月16日,2005,344 例患者出现DFS事件或失访 198 例出现DFS 事件后仍生存,344 例不符合交叉赫赛汀治疗标准,885 例交叉 接受赫赛汀治疗,469 继续留在观察组,交叉接受赫赛汀治疗的时间 (n=885),0.6,0.5,0.4,0.3,0.2,0.0,16 May 2005,22 Aug 2005,28 Nov 2005,6 Mar 2006,12 Jun 2006,18 Sep 2006,25 Dec 2006,1354,1193,596,209,116,71,30,0.1,转至赫赛汀治疗组,No. at riskObservation,比例,随机至第一次治疗时间诊断至第一次治疗时间第一次治疗后开始随访时间,中位时间 (区间), 月数22.8 (1-52.7)30.9 (9.1-58.3)29.1 (0.8-34.5),观察组患者中52%选择赫赛汀治疗，打破了1年赫赛汀治疗组和观察组的随机分组，能导致意向性治疗分析数据（ITT）结果的偏差吗？,特殊问题 1,无病生存期 (ITT分析): 4-年中位随访时间,100,80,60,40,20,0,0,6,12,18,24,30,48,36,42,随机分组后月,16981703,15641619,14401552,13631485,12971414,12401352,712854,11801280,9921020,No. at risk,事件数458369,4-年DFS72.278.6,风险系数0.76,95% 可信区间0.66, 0.87,p 值0.0001,1-年赫赛汀组,观察组,6.4%,患者(%),总生存 (ITT分析): 4年中位随访,0,6,12,18,24,30,48,36,42,Months from randomisation,16981703,16421660,16011640,15561615,15191577,14711524,828953,13981447,11751149,时间数213182,4-年DFS87.789.3,HR0.85,95% CI0.70, 1.04,p 值0.1087,1.6%,1-年赫赛汀治疗组,观察组,100,80,60,40,20,0,患者 (%),No. at risk,HERA: 不同随访时间的无病生存和总生存,死亡事件数 赫赛汀1 年 vs 观察组,0,1,2,倾向赫赛汀 治疗,倾向非赫赛汀治疗,HR,OS 获益,29 vs 37p=0.26,200511 年 (0%),59 vs 90p=0.0115,182 vs 213p=0.1087,中位随访时间 (% 选择入组后随访时间),200622 年(4.1%),20084 年 (30.9%),200511 年 (0%),中位随访时间 (% 选择入组后随访时间),200622 年 (4.3%),20084 年(33.8%),无病生存事件数赫赛汀1年 vs 观察组,127 vs 220p0.0001,218 vs 321p0.0001,369 vs 458p0.0001,0,1,2,倾向赫赛汀 治疗,倾向非赫赛汀治疗,HR,DFS 获益,1Piccart-Gebhart et al 2005; 2Smith et al 2007,观察组中无病生存的患者1354例,其中885例 (65%) 在2005年5月16日后接受了赫赛汀交叉治疗问题:观察组中未接受赫赛汀治疗的患者疾病的进程如何呢？延迟赫赛丁治疗有效吗？,总生存 (ITT分析): 4年中位随访,0,6,12,18,24,30,48,36,42,Months from randomisation,16981703,16421660,16011640,15561615,15191577,