2013 ASCO 乳腺癌内分泌治疗进展 刘冬耕.pptx

1、2013 ASCO 乳腺癌内分泌治疗进展,广州中山大学肿瘤医院 内科 刘冬耕 2013-07-6 湛江,内容,辅助内分泌治疗（延长治疗改善疗效） aTTom ATLAS MA-17 晚期乳腺癌治疗进展（乳腺癌耐药研究进展） BOLERO 2 TANDEM EGF 其他新药 其他研究（包括基础和临床）,Recurrences,Breast Cancer Deaths,超过半数乳腺癌的复发和死亡出现在他莫昔芬结束后,Adapted with permission. Early Breast Cancer Trialists Collaborative Group Meeting, 2000.,Ye

2、ars,85.2,76.1,68.2,73.7,62.7,54.9,68%,55%,0,20,40,60,80,100,0,5,10,15,Tamoxifen Control,15%,17%,0,20,40,60,80,100,0,5,10,15,73%,64%,80.9,73.0,87.8,73.2,64.0,Years,Tamoxifen Control,9%,18%,91.4,% of patients,% of patients,20,187 women with ER-positive or ER-unknown disease randomised in 5 trials of 1

3、0 vs 5 years of tamoxifen:,ECOG, Scottish 381: 805-16,aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer,Richard Gray,Daniel Rea,Kelly Handley381 805-16,10 yrs vs 5 yrs BREAST CANCER MORTALITY IN ER+ rate ratio* by

4、 period in aTTom and ATLAS,p=0.007 #p=0.002 p=0.00004 p=0.1 p=0.004 p=0.001,*Inverse-variance-weighted estimate of the effect in ER+(ATLAS, Lancet 2013),ER+ 10 yrs vs 5 yrs OVERALL SURVIVALrate ratio* by period in aTTom and ATLAS,p=0.0007 p=0.008,*Inverse-variance-weighted estimate of the effect in

5、ER+(ATLAS, Lancet 2013),Conclusions,aTTom and ATLAS together provide proof beyond reasonable doubt that continuing tamoxifen beyond 5 years reduces recurrence over the following years: no effect in years 5-6, benefit mainly after year 7 Continuing tamoxifen beyond 5 years also reduces breast cancer

6、mortality: no effect in years 5-6 ，25% reduction after year 10. 10 years tamoxifen vs no tamoxifen reduces breast cancer mortality by a third in the first decade and a half in the second decade,ATLAS:10 years of tamoxifen vs 5:(Adjuvant Tamoxifen - Longer Against Shorter),6846 women with ER+ disease

7、 completed 5years of tamoxifen, then were randomised to: CONTINUE to year 10, or STOP at year 5 54% node-negative 8 yrs follow-up: compliance, recurrence, death,SABCS 2012,Results：,Recurrence: 617 vs 711 women (2p=0.002) Breast cancer mortality: 331 vs 397 (2p=0.01) Overall mortality: 639 vs 722 (2p

8、=0.01) Recurrence and breast cancer mortality Little effect during years 5-9 benefit mainly after year 10,ATLAS：10 years of tamoxifen vs 5:,ER+：他莫昔芬10年 vs. 5年治疗对副反应与乳腺癌死亡率的作用,Davis C, et al. 2012 SABCS Abstract S1-2.,*EBCTCG. Lancet 2011; 378:771-784. ATLAS=Adjuvant Tamoxifen - Longer Against Shorte

9、r,估计10年他莫昔芬 vs. 0的15年死亡率：绝对获益是绝对损失的30倍,绝经后HR阳性EBC,延长辅助内分泌治疗 MA.17 试验设计,Primary end point: DFS Secondary end points: OS/safety/QOLSubstudies: BMD/bone markers, lipid profile,*n=2575 (efficacy), 2154 (safety); n=2582 (efficacy), 2145 (safety).QOL = quality of life; BMD = bone mineral density.,Goss et

10、al. N Engl J Med. 2003;349:1793.,N=5187， MF2.4 year,DFS and OS,首次分析事件数207，中位随访2.4年。 预计4年无复发生存分别为93%和87%（p0.001） 两组死亡分别为42 vs 31(p=0.25)，OS没有区别。 但是来曲唑组轻度潮热，骨关节，肌肉疼痛常见，阴道出血少见。 新发骨质疏松5.8和4.5（p=0.07）,来曲唑稍高。,Goss et al. N Engl J Med. 2003;349:1793.,延长辅助内分泌治疗:Letrozole After 5 Years of Tamoxifen,A similar

11、 reduction in local recurrences, new primaries, and distant recurrences occurred in node-positive and node-negative patients,Goss PE, et al. SABCS 2005. Abstract 16.,Goss PE, et al. SABCS 2005. Abstract 16.,Letrozole After Unblinding of MA.17,Goss PE, et al. SABCS 2005. Abstract 16.,DFS,Distant DFS,

12、OS,Contralateral breast cancer,HR,0.31,0.28,0.53,0.23,0,0.1,0.2,0.3,0.4,0.5,0.6,PLAC-LET to PLAC,P .0001,P .002,P .05,P .012,来曲唑 疗效明显优于安慰剂（ MA.17 ）,The hazard ratios (HRs) of letrozole and placebo from the IPCW analyses(MA17),median follow-up(first interim analysis） 2.5 years. more than 60% of place

13、bo patients crossed over to letrozole after being unblinded Now median follow-up 64 months HR 0.52 (95% CI, 0.45 to 0.61; P .001) for DFS, HR 0.51 (95% CI, 0.42to 0.61; P .001) for distant disease-free survival (DDFS) HR 0.61 (95% CI, 0.52 to 0.71;P .001) for overall survival (OS).,J Clin Oncol 2011

14、 30:718-721,延长辅助内分泌治疗:Exemestane After 5 Years of Tamoxifen,NSABP B-33 2001开始启动， Postmenopausal patients cT1-3N1M0 breast cancer(DFS after 5 yrs of tamoxifen) were random 5 years of exemestane (25 mg/d orally) or 5 years of placebo. And being termination of accrual to B-33 at 2003. Results:At the ti

15、me of unblinding, 1,598 patients, 72% of EXE (exe-exe) and 44% of placebo (place-exe). 30 ms median follow-up, original exemestane group a borderline statistically significant improve in 4-year DFS (91% v 89%; RR 0.68; P .07), and in a statistically significant improvement in 4-year RFS (96% v 94%;

16、RR 0.44; P .004).,J Clin Oncol 26:1965-1971.,NCCN 2013 辅助内分泌治疗,HR+进展期乳腺癌治疗进展,Treatment Guidelines for HR+ Advanced Breast Cancer: Second-Line Endocrine Therapy,Trial of new endocrine therapy,Chemotherapy,Continue endocrine therapy until progression or unacceptable toxicity,No clinical benefit after

17、3 consecutive endocrine therapy regimens Or Symptomatic visceral disease,Yes,No,Progression,NCCN treatment guidelines1 Hormone-receptorpositive advanced breast cancer may benefit from sequential use of ET at time of progression and should receive additional ET for second-line and subsequent therapy

18、Consider the addition of everolimus to exemestane in women who fulfill the eligibility criteria of BOLERO-22,AI, aromatase inhibitor; ET, endocrine therapy; ERD, oestrogen receptor downregulator.1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V

19、.3.2013. 2.WilckenN, et al. Cochrane Database Syst Rev. 2003;2: CD002747; 3. Hurvitz SA, et al. Cancer. 2008;113(9):2385-2397.,34,OBU130607074,PI3K,AKT,Ras,MAPK,Nonnuclear/ nongenomic,E,ER,Src,CoA,ER,P,RTKs: EFGR, HER2, IGF1-R,P,P,P,P,ER,CoA,ER,CoA,AP-1,P,CoA,TFs,EREs,AP-1/SP-1,TFs-REs,P,P,克服HR+乳腺癌的

20、内分泌治疗耐药,Osborne CK, et al. Annu Rev Med. 2011;62:233-247; Yamnik RL, et al. J Biol Chem. 2009;284:6361-6369.,S6KI,抑制因子失活,转录因子活化,增殖 存活 侵袭,mTOR 抑制剂,基因表达 （GFs RTKS）,II期临床试验(Study 2222):新辅助： 来曲唑 依维莫司,分子标记物研究被证实可用于甄别是否某病人群体具有更高治疗应答可能,AE, adverse event; CR, complete response; ER, oestrogen receptor; PR, p

21、artial response. *1-sided level of significance of 10%. Baselga J, et al. J Clin Oncol. 2009;27(16):2630-2637.,手术,首要终点: 触诊 临床反应,来曲唑 2.5 mg/day 依维莫司 10 mg/day (n = 138),来曲唑 2.5 mg/day 安慰剂 (n = 132),(N = 270) 首诊，未经治疗 ER+ 局限性乳腺癌，可能从内分泌治疗中获益; 触诊肿瘤直径2cm,筛选,36,OBU130607066,TAMRAD: II期临床试验 他莫昔芬+依维莫司在HR+进展期

22、乳腺癌,ABC, advanced breast cancer; AI, aromatase inhibitor; CBR, clinical benefit rate; ER, oestrogen receptor; EVE, everolimus; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; ORR, overall response rate; OS, overall survival; PgR, progesterone receptor; PMW, postmenopausal women

23、; TAM, tamoxifen; TTP, time to progression. Bachelot T, et al. J Clin Oncol. 2012;30(22):2718-2724.,37,OBU130607066,TAMRAD: II期临床试验 他莫昔芬+依维莫司在HR+进展期乳腺癌,TAM + EVE: 14.8 mo TAM: 5.5 mo,PFS: 继发耐药患者 HR = 0.46 (0.26-0.83), P = .0087,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,6,12,18,24,30,TTP Probabil

24、ity,Months,ABC, advanced breast cancer; CI, confidence interval; EVE, everolimus; HR, hazard ratio; HR+, hormone-receptorpositive; ITT, intent to treat; OS, overall survival; PFS, progression-free survival; TAM, tamoxifen; TTP, time to progression. Bachelot T, et al. J Clin Oncol. 2012;30(22):2718-2

25、724.,OS: HR = 0.45 (95% CI of 0.240.81), 探索性 P值：0.007 不良反应: 依维莫司联合他莫昔芬较他莫昔芬单药主要毒性包括: 乏力 (72% vs 53%), 口腔炎 (56% vs 7%), 皮疹 (44% vs 7%), 纳差 (43% vs 18%), 及腹泻(39% vs 11%),HR = 0.54 (0.36-0.81) P = .002 (探索性分析),TAM + EVE: 8.6 months TAM: 4.5 months,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,2,4,6,8,1

26、0,12,14,16,18,20,22,24,26,28,30,32,34,Months,TTP Probability,PFS: ITT 分析,38,OBU130607066,BOLERO-2: NSAI进展的ABC：EXE EVE III期临床试验,随机分层 既往内分泌治疗的敏感程度 有无内脏转移 不允许交叉换药,依维莫司 10 mg/day + 依西美坦 25 mg/day (n = 485),安慰剂 + 依西美坦25 mg/day (n = 239),主要终点: PFS 次要终点: OS, ORR, CBR, safety, QOL, bone markers,ABC, advance

27、d breast cancer; AI, aromatase inhibitor; ANA, anastrozole; CBR, clinical benefit rate; HER2, human epidermal growth factor receptor; HR+, hormone-receptorpositive; LET, letrozole; NSAI, nonsteroidal aromatase inhibitor; ORR; overall response rate; OS, overall survival; PFS, progression-free surviva

28、l; PMW, postmenopausal women; QOL, quality of life. Piccart M, et al. Presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium. Poster P6-04-02.,N = 724 ER+ HER2来曲唑或阿那曲唑治疗失败的绝经后晚期乳腺癌患者 在辅助治疗期间或结束后12个月内复发 或者晚期治疗期间或结束后1个月内疾病进展的患者,39,OBU130607066,BOLERO-2: 患者基线特征,ECOG, Eastern Cooperative On

29、cology Group; EVE, everolimus; EXE, exemestane; PBO, placebo.*All other patients had 1 mainly lytic bone lesion; Prior therapies include those used in the adjuvant setting or to treat advanced disease. Piccart M, et al. Presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium. Poster P6-0

30、4-02.,40,OBU130607066,BOLERO-2: PFS最终分析结果(A) 当地评估(B) 中央评估,CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo. Piccart M, et al. Presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium. Poster P6-04-02.,41,时间（周）,OBU130607066,亚洲女性乳腺癌的发病特点,Huang CS, et

31、 al. J Steroid Biochem Mol Biol. 2010;4:300-303; Toi M, et al. Jpn J Clin Oncol. 2010;40:i13-i18.,luminal A型比例更高,42,OBU130607066,BOLERO-2 (18个月随访): PFS在亚洲及非亚洲患者中均延长2 倍以上,亚洲患者: HR = 0.62; 95% CI, 0.41-0.94 非亚洲患者: HR = 0.41; 95% CI, 0.33-0.50,亚洲患者,非亚洲患者,n/N = 67/98 n/N = 35/45,n/N = 243/387 n/N = 165/

32、194,CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival; pts, patients. Data from Noguchi S, et al. Breast Cancer. 2013. Epub ahead of print,依维莫司联合依西美坦对于亚洲及非亚洲的HR+/HER2NSAI治疗失败的进展期乳腺癌患者 提供一致疗效,43,OBU130607066,BOLERO-2: PFS 亚组分析,CI

33、, confidence interval; ECOG, Eastern Cooperative Oncology Group; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival; PgR, progesterone receptor.Piccart M, et al. Presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium. Poster P6-04-02.,44,Med

34、ian PFS, mo,Median PFS, mo,OBU130607066,BOLERO-2: PFS 亚组分析（续）,EVE, everolimus; EXE, exemestane; HR, hazard ratio; NSAI, nonsteroidal aromatase inhibitor; PBO, placebo; PFS, progression-free survival.Piccart M, et al. Presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium. Poster P6-04-0

35、2.,45,依维莫司+依西美坦治疗 在所有预先定义的亚组中均临床获益,OBU130607066,BOLERO-2: PFS 亚组分析(A) 内脏转移, (B) 无内脏转移, (C) 仅有骨转移,CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival. Piccart M, et al. Presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symp

36、osium. Poster P6-04-02.,46,OBU130607066,BOLERO-2: PFS 当地评估辅助治疗期间复发*,依维莫司+依西美坦治疗改善新辅助及辅助治疗期间疾病进展患者的PFS，证明了作为进展期一线治疗的有效性,CI, confidence interval; CT, chemotherapy; EVE, everolimus; EXE, exemestane; HR, hazard ratio; NSAI, nonsteroidal aromatase inhibitor; PBO, placebo; PFS, progression-free survival.

37、*33个患者接受了新辅助治疗. Piccart M, et al. Presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium. Poster P6-04-02.,0,20,40,60,Probability of Event, %,80,100,Time, wk,0,6,12,18,24,30,36,42,66,72,78,84,90,96,102,108,Kaplan-Meier medians,EVE + EXE: 11.50 mo,PBO + EXE: 4.07 mo,HR=0.39 (95% CI, 0.25

38、-0.62),Censoring times,EVE + EXE (n/N = 56/100),PBO + EXE (n/N = 30/37),EVE + EXE 在NSAI辅助治疗失败后立即使用，将中位PFS延长至将近1年,47,OBU130607066,骨代谢的生化标记物(骨丢失的监测),骨形成,BSAP 骨钙素 P1NP,骨吸收,NTX, CTX 钙 羟脯氨酸,BSAP, bone-specific alkaline phosphatase; CTX, C-telopeptide of type I collagen; EVE, everolimus; P1NP, procollagen

39、 type 1 amino-terminal propeptide; NTX, N-telopeptide of type l collagen. Choi Y, et al. Nat Rev Rheumatol. 2009;5:543-548.,48,成骨细胞,破骨细胞,OBU130607066,M-CSF,TNF/RANKL,p85,S6K,生存因子的转录/抑制凋亡,下游因子,MEK1/2,MAPK,改善骨健康 抑制破骨细胞生存,aAlthough RAS/RAF are the canonical upstream activators of MEK1/2-MAPK, their inv

40、olvement in the RANKL axis is not clearly established. Glantschnig H, et al. Cell Death Differ. 2003;10(10):1165-1177; Ross FP. Ann. N.Y. Acad. Sci. 2006;1068: 110116.,RASa,RAFa,BOLERO-2: 骨标记物(18个月随访),6 周,12 周,BSAP, bone-specific alkaline phosphatase; CTX, C-telopeptide of type I collagen; EVE, ever

41、olimus; EXE, exemestane; P1NP, procollagen type 1 amino-terminal propeptide; PBO, placebo. Gnant M, et al. J Natl Cancer Inst. 2013;105:654-663.,50,OBU130607066,BOLERO-2: 骨病灶进展(18个月随访),EVE, everolimus; EXE, exemestane; PBO, placebo. Gnant M, et al. J Natl Cancer Inst. 2013;105:654-663.,总人群 基线骨转移患者,5

42、1,OBU130607066,BOLERO-2: 总生存（OS）,OS数据在中期分析尚不成熟1,2 最终OS分析将在398死亡事件发生后进行，预计2013年底,EVE, everolimus; EXE, exemestane; OS, overall survival; PBO, placebo; PFS, progression-free survival. 1. Baselga J, et al. N Engl J Med. 2012;366(6):520-529; 2. Hortobagyi GN, et al. SABCS 2011. Abstract S3-7; 3. Piccart

43、 M, et al. Presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium. Poster P6-04-02.,52,OBU130607066,BOLERO-2: 安全性,AE, adverse event; EVE, everolimus; EXE, exemestane; PBO, placebo. *发生率25%, 但值得特殊关注 Piccart M, et al. Presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium. Po

44、ster P6-04-02.,53,OBU130607066,BOLERO-2: 亚洲亚组中的常见不良反应,最常见3/ 4级不良反应在亚洲及非亚洲人群中发生率类似,ALT, alanine aminotransaminase; EVE, everolimus; EXE, exemestane; Gr, grade; ILD, interstitial lung disease; LDH, lactate dehydrogenase; PBO, placebo. Data from Noguchi S, et al. Breast Cancer. 2013. Epub ahead of prin

45、t,依维莫司+依西美坦安全性结果在亚洲与非亚洲人群中相似，仅存在个别可管理差异,54,OBU130607066,至EORTC QLQ-30 GHS定义评分恶化时间, MID = 5%,BOLERO-2: 健康相关生活质量（HRQOL ）（18个月随访）,尽管依维莫司+依西美坦联合使用导致3/4不良发生率增加，但较对照组， 至EORTC QLQ-C30 GHS定义的HRQOL恶化 时间延长（最小重要性差异（MID）=5%）,CI, confidence interval; EORTC QLQ, European Organisation for Research and Treatment of

46、 Cancer Quality of Life Questionnaire; EVE, everolimus; EXE, exemestane; GHS, Global Health Scale; HRQOL, health-related quality of life; MID, minimal important difference; PBO, placebo; TTD, time to definitive deterioration. Beck JT, et al. ASCO 2012. Abstract 539.,55,OBU130607066,BOLERO-2: 接受依维莫司+

47、依西美坦亚洲患者生活质量未受影响,EVE + EXE较对照组 未影响 至EORTC QLQ-C30 and BR23 定义的生活质量恶化时间*,*Note that TTD was used as the abbreviation for time to definitive deterioration for consistency with the Noguchi publication. However, the main HRQOL manuscript uses the abbreviation TDD for time to definitive deterioration. EO

48、RTC QLQ-C30 BR23, European Organisation for Research and Treatment of Cancer Quality of Life and Breast Cancer Module Questionnaires; EVE, everolimus; EXE, exemestane; PBO, placebo; TTD, time to definitive deterioration. Noguchi S, et al. Breast Cancer. 2013. Epub ahead of print,n = 98 n = 45,56,HOR

49、IZON: 替西罗莫司+来曲唑进展期乳腺癌III期临床试验,接受替西罗莫司联合治疗的患者较来曲唑单药组 发生3级以上不良反应机率明显增加 (37% vs 24%)1,替西罗莫司 30 mg/天 *5天 每2周一次 + 来曲唑 2.5 mg/天 (n = 493),安慰剂 + 来曲唑 2.5 mg/天 (n = 499),N = 992 绝经后HR+晚期BC 晚期治疗阶段未使用内分泌治疗 入组前12个月内未接受过辅助AI治疗,首要终点: PFS 次要重点: CBR, ORR,Months,56% 未接受过既往内分泌治疗2,CBR, clinical benefit rate; CI, confi

50、dence interval; LABC, locally advanced breast cancer; LET, letrozole; m, metastatic; ORR, overall response rate; PFS, progression-free survival; PMW, postmenopausal women; TEM, temsirolimus. *Months from first dose of temsirolimus to progressive disease or death. 1. Wolff AC, et al., J Clin Oncol. 2

51、013;31(2):195-202; 2. Johnston SR. Breast Cancer Res. 2012 Jun 19;14(3):311.,57,OBU130607066,如何评价HORIZON 试验的阴性结果？,替西罗莫司用于HR+进展期乳腺癌患者的临床试验结果为阴性1 ，然而BOLERO-2显示依维莫司联合依西美坦明确获益2 。 此结果可能与以下原因相关：,1. Baselga J, et al. N Engl J Med. 2012;366(6):520-529; 2. Wolff AC, et al. J Clin Oncol. 2013;31(2):195-202.,5

52、8,BOLERO-2: 结论,依维莫司+依西美坦联用用于NSAIs治疗失败的HR+ HER2 进展期乳腺癌，显著延长PFS1 依维莫司+依西美坦疗效在各预先设计的亚组分析中一致获益1 依维莫司+依西美坦在辅助治疗期间复发患者中降低61% PFS事件风险 依维莫司+依西美坦无论有无内脏转移或骨转移均延长PFS超过4个月 1 依维莫司+依西美坦较对照组死亡事件发生数较少1 依维莫司+依西美坦不良反应的构成与其他既往依维莫司临床试验相似2,1. Piccart M, et al. Presented at the 2012 CTRC-AACR San Antonio Breast Cancer Sy

53、mposium. Poster P6-04-02; 2. Motzer RJ, et al. Cancer. 2010;116(18):4256-4265.,59,a Line of therapy refers to the advanced setting only. Abbreviations: AI, aromatase inhibitor; ANA, anastrozole; BC, breast cancer; CBR, clinical benefit rate; ET, endocrine therapy; EVE, everolimus; EXE, exemestane; F

54、UL, fulvestrant; HR+, hormone-receptor positive; NR, not reached; NSAI, nonsteroidal aromatase inhibitor; OL, open-label; ORR, overall response rate; PBO, placebo; PFS, progression-free survival; PMW, postmenopausal women; pts, patients; Rand, randomized; TAM, tamoxifen; TTP, time to progression. 1.

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