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1、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 analyses Primary core analysis and monotherapy analyses showed tha
2、t 5-year DFS and time to distant recurrence significantly superior with upfront letrozole vs upfront tamoxifen Primary core analysis; median follow-up: 26 mos Monotherapy arm analysis; median follow-up: 51 mos,2,0,5,Yrs,Tamoxifen,Letrozole,Tamoxifen,Letrozole,Tamoxifen,Letrozole,A,B,2-Arm Option,4-A
3、rm Option,n = 911,n = 917,n = 1548,n = 1546,n = 1548,n = 1540,N = 1828 enrolled 1998-2000,N = 6182 enrolled 1999-2003,N = 8010*,*ITT excludes 18 patients who withdrew consent and did not receive study treatment.,A,B,C,D,S U R G E R Y,Stratify Institution CT (adjuvant/ neoadjuvant)PriorNoneConcurrent
4、,R A N D O M I Z E,R A N D O M I Z E,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 excluded Primary
5、 end point: DFS,0,2,5,Years,TAM,LET,TAM,LET,LET,TAM,A,B,C,D,R A N D O M I Z E,6182 patients,8010 patients,TAM,LET,A,B,R A N D O M I Z E,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
6、-Arm option,BIG 1-98: Primary Core Analysis,St. Gallen (January 2005) PCA 25.8 months follow up ASCO 2005 PCA 25.8 months follow up After medical review St. 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
7、,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
8、 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 Update at 61 Months Median Follow-Up,0,2,5,Years,TAM,LET,TAM,LET,LET,TAM,A,B,C,D,R A N D O M I Z E,6182 patients
9、,8010 patients,TAM,LET,A,B,R A N D O M I Z E,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
10、 protocol treatment.,Selective Crossover in Tamoxifen-alone Arm,Tamoxifen monotherapy arm (Arm A) unblinded in 2005 619 (25.2%) patients on TAM-alone arm selectively crossed over to LET Most patients (612) were from the 4-arm option Most patients crossed over during years 3-5 as seen in the figure b
11、elow Median duration of LET after selective crossover was 18 months Patients 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
12、Letrozole Censored: Against Tamoxifen (survival)Against Letrozole (recurrence events),Censored for crossover,R A N D O M I Z E,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,
13、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 a
14、t 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
15、 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, P0.05,Notes: Fix num
16、bers based on reference,Conclusions,BIG 1-98 核心分析证实来曲唑优于TAM,并且: 本次分析显示总生存获益（ LET compared to TAM ） 来曲唑明显延长DFS和TTDR（尽管 619例患者，占25.2转成来曲唑） 各亚组均有获益，淋巴结阳性者更明显。 本次分析时所有患者都已经完成治疗，安全性显示与两药既往已知毒性相似。,BIG 1-98 Monotherapy Comparison: Arms A vs B (Median Follow-Up 51 Months),Does initial adjuvant monotherapy with letrozole continue to be superior to initial adjuvant monotherapy with tamoxifen with longer follow-up?,
