1、乳腺癌内科治疗新进展,胡夕春,新药 新方案 新理念 新药不良反应及处理,1.1白蛋白结合紫杉醇 (ABX),1.2 EFECT: Evaluation of Treatment Options Following AI Failure,Fulvestrant IM injection loading-dose regimen* (n = 351),Exemestane 25 mg/day orally (n = 342),Postmenopausal women with hormone receptorpositive, progressing/recurring advanced brea
2、st cancer after nonsteroidal AI(N = 693),Progression, death, or withdrawal,*Fulvestrant loading-dose regimen comprised 500 mg on Day 0, 250 mg on Days 14 and 28, and 250 mg monthly thereafter.,Gradishar W, et al. SABCS 2006. Abstract 12.,EFECT: Similar TTP in Patients Treated With Fulvestrant or Exe
3、mestane,Gradishar W, et al. SABCS 2006. Abstract 12.,EFECT: Patient Response and Study Conclusions,Median duration of response to treatment with fulvestrant vs exemestane: 13.5 vs 9.8 months, respectivelyFulvestrant as effective and safe as exemestane in women with hormone receptorpositive breast ca
4、ncer who have progressed on treatment with a nonsteroidal AI,Gradishar W, et al. SABCS 2006. Abstract 12.,Anthracyclin-pretreated and taxane resistant N: 752,R A N D O M I Z C I ,Ixabepilone40 mg/m2 d 1 静脉滴注3h Capecitabine 1000 mg/m2 po. BID x 14,Capecitabine 1250 mg/m2 po. BID x 14,1.3 Ixabepilone+
5、Capecitabine vs Capecitabine,L.T. Vahdat et al. Proc ASCO 2007. Abstr 1006,Ixabepilone+Capecitabine vs Capecitabine,L.T. Vahdat et al. Proc ASCO 2007. Abstr 1006,Ixabepilone+Capecitabine vs Capecitabine,L.T. Vahdat et al. Proc ASCO 2007. Abstr 1006,新药 新方案 新理念 新药不良反应及处理,2.1,Lapatinib oral tyrosine ki
6、nase inhibitor of ErbB1 and ErbB2 Blocks signaling through EGFR and HER2 homodimers and heterodimers May also prevent signaling between ErbB1/ErbB2 and other ErbB family members,Treatment Efficacy: Lapatinib Vs Lapatinib + Trastuzumab,*Confirmed CR+PR CR+PR+SD 6 mo,OShaughnessy J, et al. ASCO 2008.
7、Abstract 1015.,Progression-Free Survival: L Vs L+T,Subjects At Risk,148 148,L L+T,53 73,21 42,13 27,5 8,0 2,6 Mo PFS,Cumulative % Alive Without Progression,13%,28%,0,20,40,60,80,100,0,10,20,30,40,50,60,Time from Randomization (wks),OShaughnessy J, et al. ASCO 2008. Abstract 1015.,Geyer CE, et al. AS
8、CO 2006. Clinical Science Symposium.,EGF100151: Lapatinib + Capecitabine in Advanced Breast Cancer,EGF100151: Lapatinib + Capecitabine in Advanced Breast Cancer (contd),Addition of lapatinib to capecitabine in women with treatment-refractory, advanced metastatic breast cancer associated with Longer
9、time to progression 36.9 vs 19.7 wks (P = .00016) Longer progression-free survival 36.9 vs 17.9 wks (P = .000045) Fewer progressions or deaths 38% vs 48% Response (independent review) Overall: 22.5% vs 14.3% (P = .113),Geyer CE, et al. ASCO 2006. Clinical Science Symposium.,Docetaxel + Avastin 15mg/
10、kg every 3 weeks,Phase III trial of Avastin plus docetaxel in first-line MBC (AVADO),Recruitment commenced March 2006 and completed in March 2007 Primary endpoint: PFS secondary endpoints: ORR, OS, safety, QoL Trial met primary endpoint; data will be presented mid-2008,Previously untreated HER2-nega
11、tive locally recurrent or MBC (n=705),Docetaxel 100mg/m2 every 3 weeks + placebo,Docetaxel + Avastin 7.5mg/kg every 3 weeks,PI: David Miles,Treat to disease progression,Treat to disease progression,Treat to disease progression,R,HR + 95% CI (unstratified),Bev 7.5 + Docetaxel (n = 248),Mos,AVADO Tria
12、l Progression-Free Survival: By Bevacizumab Dose,*Data censored for non-protocol therapy prior to PD mg/kg Q3W,HR + 95% CI (stratified*),.69 (.54.89) P = .0035,.79 (.63.98) P = .0318,Placebo + Docetaxel (n = 241),Median, mos,8.7,8.0,HR + 95% CI (stratified*),.61 (.48.78) P .0001,Median, mos,8.8,8.0,
13、.72 (.57.90) P = .0036,HR + 95% CI (unstratified),Bev 15 + Docetaxel (n = 247),Placebo + Docetaxel (n = 241),PFS estimate,0,0.2,0.4,0.6,0.8,1.0,0,6,12,18,Mos,PFS estimate,0,0.2,0.4,0.6,0.8,1.0,0,6,12,18,Miles D, et al. ASCO 2008. Abstract LBA1011.,Miller et al. ASCO 2005. Oral presentation during sy
14、mposium, Advances in Monoclonal Antibody Therapy for Breast Cancer.,Bevacizumab 10 mg/kg Days 1, 15+ Paclitaxel 90 mg/m2 Days 1, 8, 15 (n = 365),Paclitaxel 90 mg/m2 Days 1, 8, 15 (n = 350),Patients with locally recurrent or metastatic breast cancer,ECOG performance status score 0-1 (N = 715),Stratif
15、ied by disease-free interval, number of metastatic sites, adjuvant chemotherapy, and estrogen receptor status,Bevacizumab Paclitaxel for Locally Recurrent or Metastatic Disease,Eastern Cooperative Oncology Group (ECOG) 2100 trial First planned interim analysis of randomized, first-line, phase 3 tria
16、l,Miller et al. ASCO 2005. Oral presentation during symposium, Advances in Monoclonal Antibody Therapy for Breast Cancer.,Bevacizumab Paclitaxel for Locally Recurrent or Metastatic Disease,PFS significantly longer with combination therapy 10.97 months vs 6.11 months HR = 0.498 (95% CI, 0.401-0.618),
17、 P .001 Overall survival significantly higher for patients receiving bevacizumab + paclitaxel vs paclitaxel alone HR = 0.674 (95% CI, 0.495-0.917), P = .01 Overall response significantly better for patients treated with bevacizumab +paclitaxel 28.2% vs 14.2% for paclitaxel alone cohort (P .0001),Xe
18、1000 mg/m2 BID PTX 175 mg/m2 (n = 431),EPI 60 mg/m2 PTX 175 mg/m2 (n = 431),Patients with locally recurrent or metastatic breast cancer,2.2 Phase III study of Paclitaxel+Xeloda (XP) vs Paclitaxel+EPI (EP),advanced breast cancer, lueck et al,Phase III study of Paclitaxel+Xeloda (XP) vs Paclitaxel+EPI
19、 (EP),EP vs XP Time to progression 11.8 m vs 12.3 m Response 41.0 vs 41.5,2.3 NSABP B-33,Placebo,X 2 years,Randomization,Opened to Accrual: May 2001,Years After Surgery,% Event-Free,0,1,2,3,4,5,0,20,40,60,80,100,Group N Events,Placebo 779 37,Exemestane 783 17,B-33: Relapse-Free Survival*,RR=0.44 p=0
20、.004,96%,94%,*Eligible pts with follow-up,2.4 TAnDEM 研究设计,Crossover to receive trastuzumab was actively offered to all patients who progressed on anastrozole alone,HER2-positive, HR-positive MBC (n=208),R,Anastrozole 1 mg daily + Trastuzumab 4 mg/kg loading dose 2 mg/kg qw until disease progression,
21、Anastrozole 1 mg daily until disease progression,HR, hormone receptor; MBC, metastatic breast cancer; R, randomisation,Progression-free survival,103,48,31,17,14,13,11,9,4,1,1,0,0,A + H,No. at risk,104,36,22,9,5,4,2,1,0,0,0,0,0,A,Probability,1.0,0.8,0.6,0.4,0.2,0,5,10,15,20,25,30,35,40,45,50,55,60,Mo
22、nths,CI, confidence interval PFS = time from randomisation to date of progressive disease or death,0.0,2.5 HTX:HT Time to progression,101 88,57 57,36 32,22 17,14 9,6 7,5 6,3 4,1 1,0 0,Probability,1.0,0.0,0.2,0.4,0.6,0.8,13.8,18.2,HTX HT,55 68,0.697,0.045,0.488, 0.995,ap=0.035 for exploratory analysi
23、s correcting for imbalance in ER / PgR status and duration of primary disease,p valuea,HR,95% CI,Events,0,5,10,15,20,25,30,35,40,45,50,Months from randomisation,No. at risk HTX HT,112 110,新药 新方案 新理念 新药不良反应及处理,3.1攻克血脑屏障的新手段,TransATAC central laboratory analysis indicates benefit of anastrozole over t
24、amoxifen similar for ER-positive patients with or without being PR positive, according to central analysis All patients HR: 0.72 ER-positive/PR-positive patients HR: 0.72 ER-positive/PR-negative patients HR: 0.66,Dowsett M, et al. SABCS 2006. Abstract 48.,3.2 TransATAC Central Laboratory Analysis: A
25、 vs T for ER and PR Status,Benefit of anastrozole over tamoxifen better for patients with no HER2 expression, but confidence intervals of relative benefits with 2 treatments overlapped All patients HR: 0.72 HER2-negative patients HR: 0.66 HER2-positive patients HR: 0.92,Dowsett M, et al. SABCS 2006.
26、 Abstract 48.,TransATAC Central Laboratory Analysis: A vs T for HER2 Status,9,022 HR+ patientsRecruitment period: 1987-2001Latest follow-up: 2006Median follow-up: 6.8 yearsMean age: 43.6 years,3.3 LHRHa疗效: Meta-analysis,Chemotherapy ( tam) LHRH (n=2741),RECURRENCE,DEATH AFTER RECURRENCE,0,10,20,30,4
27、0,50,Death after recurrence (%),0,1,2,3,4,5,6,7,8,9,10,Years since randomisation,HR=0.85, 95% CI = 0.73-0.99, p=0.04,13.2% vs. 10.9% 2.3% reduction,0,10,20,30,40,50,Recurrence (%),0,1,2,3,4,5,6,7,8,9,10,Years since randomisation,HR=0.88, 95% CI = 0.77-0.99, p=0.04,29.6% vs. 25.2% 4.4% reduction,3.4,
28、3.5 基因芯片,FDA 批准,Oncotype 21基因芯片 Dutch 70-Gene基因芯片(mammaprint),Oncotype DX,The 21-Gene Recurrence Score (Oncotype DX) is an RT-PCR based gene expression profiling assay that includes 16 cancer genes and 5 reference genes.,PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2,ESTROGEN ER PR Bcl2 SCUBE2,I
29、NVASION Stromelysin 3 Cathepsin L2,HER2 GRB7 HER2,BAG1,GSTM1,REFERENCE GENES Beta-actin, GAPDH, RPLPO GUS, TFRC,CD68,Predicting Tamoxifen Benefit With Recurrence Score (RS) Assay,NSABP B-14: estrogen receptorpositive, nodenegative breast cancer Treated with tamoxifen (n = 290) Treated with placebo (
30、n = 355) RS assay: 21-gene assay including 16 cancer genes 9 proliferative genes 7 estrogen genes RS assay assigned predictive categories according to recurrence risk Low risk: RS 18 Intermediate risk: RS 18, 31 High risk: RS 31,Paik et al. ASCO 2005. Abstract 510.,Prognostic Value of Recurrence Sco
31、re Assay,RS genes correlate with increased recurrence risk in placebo arm 10-year distant recurrence-free survival lower in higher-risk groups (P = .0001) Proliferation genes associated with recurrence in untreated patients CCNB1: HR = 1.55; P = .001 SURV: HR = 1.33; P = .001 MYBL2: HR = 1.28; P = .
32、003 Ki-67: HR = 1.27; P = .020 STK15: HR = 1.42; P = .008,Paik et al. ASCO 2005. Abstract 510.,Prognostic Value of RS Assay in Tamoxifen-Treated Patients,Distant recurrence-free survival following tamoxifen treatment greater in lower RS risk category (P = .060)Greater quantitative ER gene expression
33、 predicts better response to tamoxifen (P .001),Paik et al. ASCO 2005. Abstract 510.,辅助化疗瓶颈,Phase III tAnGo Trial: Study Design,Early breast cancer patients,N = 3,152,Poole CJ, et al. ASCO 2008. Abstract 506.,Epirubicin 90 mg/m2 D1, Q3W x 4Cyclophosphamide 600 mg/m2 D1, Q3W x 4 n = 1,576,Paclitaxel
34、175 mg/m2 D1, Q3W x 4,Epirubicin 90 mg/m2 D1, Q3W x 4Cyclophosphamide 600 mg/m2 D1, Q3W x 4 n = 1,576,R A N D O M I Z A T I O N,Paclitaxel 175 mg/m2 D1, Q3W x 4Gemcitabine 1250 mg/m2 D1 and D8 Q3W x 4,Phase III tAnGo Trial Disease-Free Survival: ECT Vs ECGT,No significant difference between treatmen
35、ts,HR = 1.0 (95% CI 0.8-1.2),DFS (mos),Number at risk, N,ECT,ECGT,1570,1571,1545,1550,1488,1479,1392,1385,1156,1158,813,834,533,531,162,154,% Surviving Disease Free,0,100,50,0,6,12,18,24,30,36,42,ECGT,ECT,P = .96,48,86,88,25,75,Poole CJ, et al. ASCO 2008. Abstract 506.,CMF: C = 100 mg/m2 day 1-14 PO
36、, M = 40 mg/m2 and FU = 600 mg/m2 d1 and d8 Q4W AC: A = 60 mg/m2, C = 600 mg/m2 d1 Q3W X 4 cycles,2000 d1-14 Q3W X 6 cycles (in 2 divided doses),Muss HB, et al. ASCO 2008. Abstract 507.,Stratification Age 65-69,70-80,80+; PS 0-1 vs 2; HER-2 +/-/unk,CMF 6 cycles or AC 4 cycles,Capecitabine for 6 cycl
37、es,Randomize,CALGB 49907 Design: CMF or AC Vs Capecitabine in EBC Pts 65 Yrs,CALGB 49907 Relapse-Free Survival: Multivariate Analysis,Muss HB, et al. ASCO 2008. Abstract 507.,N = 622; 15% events Std, standard chemotherapy (CMF or AC); X, capecitabine,The future of breast cancer management,Prevention,Novel therapies,Detection,Breast cancer in the 21st century,Improving use of current treatments,Tailored therapies,Multidisciplinary approach,
