乳腺癌临床研究进展ppt课件

2008乳腺癌临床研究进展乳腺癌临床研究进展1n 内分泌治疗（内分泌治疗（ Big 1-98）n 辅助化疗（辅助化疗（ NSABP B30, BCIRG 005）n 分子靶向治疗分子靶向治疗 (HERA 4年年 )n 双磷酸盐（双磷酸盐（ ABCSG 12 ）n 新抗癌药物新抗癌药物2Big 1-98 n 2008 SABCS 最新报告最新报告n 核心分析核心分析 61个月随访；个月随访；n 单药组分析单药组分析 76个月随访；个月随访；n 序贯组与来曲唑单药组序贯组与来曲唑单药组 71个月比较分析；个月比较分析；3BIG 1-98 Overall DesignSummary of previous analysesn Primary core analysis and monotherapy analyses showed that 5-year DFS and time to distant recurrence significantly superior with upfront letrozole vs upfront tamoxifenn Primary core analysis; median follow-up: 26 mosn Monotherapy arm analysis; median follow-up: 51 mos20 5YrsTamoxifenLetrozoleTamoxifenLetrozoleTamoxifenLetrozoleAB2-Arm Option4-Arm Optionn = 911n = 917n = 1548n = 1546n = 1548n = 1540N = 1828enrolled1998-2000N = 6182enrolled1999-2003N = 8010*ITT excludes 18 patients who withdrew consent and did not receive study treatment.ABCDSURGERYStratify Institution CT (adjuvant/neoadjuvant) Prior None ConcurrentRANDOMIZERANDOMIZELetrozoleTamoxifenMouridsen HT, et al. SABCS 2008. Abstract 13. 4BIG 1-98: Primary Core Analysis (PCA)n Is 5 years of letrozole superior to 5 years of tamoxifen as initial adjuvant therapy?n For arms C and D, events and follow-up beyond switch are excludedn Primary end point: DFS0 2 5 YearsTAMLETTAM LETLET TAMABCDRANDOMIZE6182 patients8010 patientsTAMLETABRANDOMIZE0 2 5 Years1828 patients2-Arm OptionEnrolled 1998-2000Enrolled 1999-2003Thrlimann et al. N Engl J Med. 2005;353:2747.N=911N=917N=1548N=1546N=1548N=15404-Arm option5BIG 1-98: Primary Core Analysisn St. Gallen (January 2005) n PCA 25.8 months follow upn ASCO 2005 n PCA 25.8 months follow up After medical reviewn St. Gallen 2009 n PCA 60.5 months follow upDoes Letrozole x 5 years improve outcome compared with tamoxifen x 5 years?6T0204060801000 1 2 3 4 5Percent Alive and Disease-FreeYears from RandomizationBIG 1-98: 26 month Disease-Free SurvivalL97.797.6YearlyDFS %95.193.490.589.086.884.684.081.4No. at Risk38923896296429261261123889286640034007567544N HR (95% CI) p8010 0.81 (.70-.93) 0.003Events7797Primary Core Analysis: Key End Points at a Median Follow-up of 26 MonthsN = 8010.Favors LETFavorsTAMNumber of Events (LET:TAM)Hazard Ratio (LET:TAM)(CI) P ValueDFS 351 428 0.81 (0.70-0.93) 0.003Overall survival 166 192 0.86 (0.70-1.06) 0.16Systemic DFS* 323 383 0.83 (0.72-0.97) 0.02DFS (w/o 2nd malignancy) 296 3690.79 (0.68-0.92) 0.002Time to distant recurrence 184 2490.73 (0.60-0.88) 0.001Time to recurrence 228 310 0.72 (0.61-0.86) 2 cm (35% vs. 26%) compared with those who remained on TAM11Both ITT and Censored Analysis are Likely to be BiasedITT: Against LetrozoleCensored: Against Tamoxifen (survival)Against Letrozole (recurrence events)RANDOMIZETamoxifenLetrozole0 2 5ITT Censored for crossoverRANDOMIZETamoxifenLetrozole0 2 512Cumulative Incidence of DFS Events (ITT)* 619 patients received letrozole after the tamoxifen-alone arm was unblinded201510500 2 4 6Breast cancer recurrenceYears from RandomizationSecond (non-breast) primaryDeath without prior cancer eventLetrozoleTamoxifen*Percent1 3 5 713Endpoints: ITT and Censored* Results1. 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 crossoverFavors LET Favors TAMLETN=4003TAM*N=4007 HR (95% CI) PNo. of Events0.50 0.75 1.00 1.25Disease-Free SurvivalITT 585 664 0.86 (0.770.96) 0.008Censored 643 0.83 (0.740.93)Overall SurvivalITT 330 374 0.87 (0.751.01) 0.07Censored 330 369 0.81 (0.700.94)Time to Distant RecurrenceITT 287 0.79 (0.680.92) 0.003Censored 287 351 0.78 (0.670.92)357585DFS no 2nd MalignancyITT 503 577 0.85 (0.750.96) 0.008Censored 503 564 0.81 (0.720.92)Time to Recurrence (TTR)ITT 368 0.82 (0.710.94) 0.004Censored 368 0.79 (0.680.90)441430Endpoint Hazard Ratio14*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 LETPCA- 26 months PCA- 61 months ITT* Censored DFSHR95% CIP-value0.810.70-0.930.0030.860.77-0.960.0080.830.74-0.93NRTDRHR95% CIP-value0.730.60-0.880.0010.790.68-0.920.0030.780.67-0.92NROSHR95% CIP-value0.860.70-1.060.160.870.75-1.010.070.810.70-0.94NRBIG 1-98: PCA Efficacy ResultsPCA, Primary core analysis; MAA, Monotherapy arms analysis; DFS, Disease free survival; TDR, Time to distant recurrence; OS, overall survival 15BIG 1-98: Safety Results OvertimeGRADE 1-5 (%)PCA- 26 mosLET TAM(N=3975) (N=3988)PCA- 61 mosLET TAM(N=3975) (N=3988)CVA/ TIA 1.0 1.0 1.4 1.5Thromboembolic events 1.5 3.5* 2.0 4.1Cardiac event (Ischemic heart disease MAA, Monotherapy arms analysis; CVA/TIA, Cerebrovascular accident/ Transient Ischemic attack ; TAM, tamoxifen; LET, letrozole, NR, not reported *P 50 yrs 50 yrsER negativeER positivePost-menoHRTPre-menoNo HRTLN 1-3LN 4+0-2 cm2 cm+0.7 0.8 0.9 1 1.10.840.840.810.820.840.880.830.790.880.770.860.78HRFactorSwain SM, et al. SABCS 2008. Abstract 75.In Favor of AC T In Favor of TAC 28BCIRG 005: Study Design4 x AC 4 x Docetaxel60/600 mg/m2 100 mg/m26 x TAC75/50/500 mg/m2Dexamethasone premedication: 8 mg BID, 3 daysProphylactic ciprofloxacin: 500 mg BID, Days 5-14Eiermann W, et al. SABCS 2008. Abstract 77.HER2 normal(FISH)(N = 3298)Stratification: Nodes: 1-3 4+ HR