早期乳腺癌輔助化療進(jìn)展

1、早期乳腺癌輔助化療進(jìn)展,,Breast Cancer Incidence Trends Over Time,Cancer Incidence Trends in China 2005 – 2015 Incidence Rates Projection by Cancer Type,Per 100,000,CAGR 2.98%,CAGR 4.5%,CAGR 0.65%,CAGR –2.35%,CAGR 0.99%,CAGR 2.60%,

2、,Source: Estimates of Cancer Incidence in China for 2000 and Projections for 2005, Yang L, et al.,中國乳腺癌發(fā)病概況,每年約有19萬新發(fā)乳腺癌病例 2002年全國乳腺癌年齡標(biāo)化發(fā)病率:18.7/100,000；死亡率: 5.5/100,000發(fā)病率：城市＞農(nóng)村高發(fā)年齡段：45－50歲,近15年來乳腺癌發(fā)病率上升死亡率下降,

3、死亡率下降的原因,,早期診斷 綜合治療,The benefits of chemotherapy data from clinical trails,Early Breast Cancer Trialists' Collaborative Group (EBCTCG).194 randomised trials of adjuvant chemotherapy (CMF,CAF,CEF) or hormonal thera

4、py (TAM) that began by 1995.,Lancet 2005,Placebo53.3%,37.1,47.9,,Time (years),0,5,15,10,,,,,Recurrence(%),15-year gain 12.3% (SE 1.6)Log-rank 2p<0.00001,15-year probabilities of recurrence in women aged <50 year

5、s, with / without polychemotherapy,Polychemotherapy41.1%,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,35.5,24.6,Younger women, 35% node-positive; older women, 70% node-positive;SE=standard error,EBCTCG. Lancet 2005; 365: 1687-1717

6、,Placebo42.4%,20.4,35.0,,,,Breastcancermortality(%),15-year gain 10.0% (SE 1.6)Log-rank 2p<0.00001,Polychemotherapy32.4%,,Time (years),0,5,15,10,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,15.7,27.1,15-year probabilities o

7、f breast cancer mortality in women aged <50 years, with / without polychemotherapy,EBCTCG. Lancet 2005; 365: 1687-1717,Younger women, 35% node-positive; older women, 70% node-positive,15-year gain 4.1% (SE 1.2)Log-

8、rank 2p<0.00001,Placebo57.6%,Polychemotherapy53.4%,48.8,,0,5,15,10,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,35.4,44.1,29.4,15-year probabilities of recurrence in women aged 50-69 years, with / without polychemotherapy,Ti

9、me (years),EBCTCG. Lancet 2005; 365: 1687-1717,Recurrence(%),Younger women, 35% node-positive; older women, 70% node-positive,Placebo50.4%,21.3,38.3,,,,,,,15-year gain 3.0% (SE 1.3)Log-rank 2p<0.00001,Polychemothe

10、rapy47.4%,18.7,,0,5,15,10,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,35.4,15-year probabilities of breast cancer mortality in women aged 50-69 years, with / without polychemotherapy,Time (years),Younger women, 35% node-positive; o

11、lder women, 70% node-positive,EBCTCG. Lancet 2005; 365: 1687-1717,Breastcancermortality(%),Placebo45.0%,38.3,26.5,,15-year gain 11.8% (SE 1.3)Log-rank 2p<0.00001,15-year probabilities of recurrence in women with

12、ER+ (or ER-unknown) disease, with / without ~5 years' tamoxifen,About 5 years' tamoxifen33.2%,,Time (years),0,5,15,10,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,15.1,24.7,,,ER=oestrogen receptor; 10,386 women: 20% ER-un

13、known, 30% node-positive,EBCTCG. Lancet 2005; 365: 1687-1717,Recurrence(%),,,15-year gain 9.2% (SE 1.2)Log-rank 2p<0.00001,Placebo34.8%,About 5 years' tamoxifen25.6%,25.7,,0,5,15,10,,,,,,,,,,,,,,,,,,,,,,,,,,,,

14、,11.9,8.3,17.8,,,,,,,15-year probabilities of breast cancer mortality in women with ER+ (or ER-unknown) disease, with / without ~5 years' tamoxifen,Time (years),10,386 women: 20% ER-unknown, 30% node-positive,EBCTCG

15、. Lancet 2005; 365: 1687-1717,Breastcancermortality(%),,0,1,3,5,4,Time (years),2,,,,,,,5-year gain 11.9% (SE 1.0)Log-rank 2p<0.00001,Nil25.8%,About 5 years' tamoxifen alone13.9%,,,,,,,,,,,,,5-year recurrence

16、 in women with ER+ (or ER-unknown) disease with no chemotherapy, with / without ~5 years' tamoxifen,EBCTCG. Lancet 2005; 365: 1687-1717,Recurrence(%),7056 women: 19% node-positive,,,0,1,3,5,4,2,,,,,,,5-year gain 10

17、.6% (SE 1.5)Log-rank 2p<0.00001,Chemotherapy alone28.1%,Chemotherapy + about 5 years' tamoxifen17.5%,,,,,,,,,,,,5-year recurrence in women with ER+ (or ER-unknown) disease with chemotherapy, with / without ~5

18、 years' tamoxifen,Time (years),EBCTCG. Lancet 2005; 365: 1687-1717,Recurrence(%),3330 women: 53% node-positive,Chemotherapy versus endocrine therapy in the treatment of breast cancer,In premenopausal women, polychem

19、otherapy improves 15-year recurrence by 12.4% and survival by 10.0%In postmenopausal women, 15-year gains in recurrence and survival are smaller (4.2% and 3.0%, respectively) anthracycline-based polychemotherapy reduc

20、es the annual death rate by 38% for women ＜50 years and by 20% for those of age 50-69 years,EBCTCG. Lancet 2005; 365: 1687-1717,Chemotherapy versus endocrine therapy in the treatment of breast cancer,In patients with ER+

21、 disease, tamoxifen improves 15-year recurrence by 11.8% and survival by 9.2%Gains made with tamoxifen treatment appear to be irrespective of adjuvant chemotherapy,EBCTCG. Lancet 2005; 365: 1687-1717,乳腺癌輔助化療進(jìn)展,,1960’s

22、 1970’s 1980’s 1990’s 2000 2002～,手術(shù),CMF1,蒽環(huán)類藥物AC2, CAF3,FEC4,Dose5,6,CEF1207, 15FEC1008EC9,Meta-analysis12,紫杉類藥物10,11,13,DI14 Sequene 生物治療,1 Bonadonna 1976 2 B-15, B-23 1990

23、, 2000 3 SECSG 1994 4 Coombes 1996,5 Bonadonna 1995 6 Wood 1994 7 MA-05 1998 8 FASG 2001,9 Belgium 2001 10 CALGB 200011 B-28 200012 EBCTCG 1998, 2000,13 TAC vs FAC14 CALGB 974115 MA.05 10 years!,,,評估紫杉類乳腺癌

24、輔助化療的隨機(jī)臨床試驗,CALGB 9344 AC vs AC? PNSABP B-28 AC vs AC? P*ECTO A ?CMF vs AP ?CMFBCIRG 001 TAC vs FACNSABP B-27 AC vs AC?TPACS 01 FEC vs FEC ?TECOG 2197 AT

25、 vs ACECOG 1199 AC→P3 vs P1 vs D3 vs D1……..,T=多西他賽 P=泰素* 在化療時同時給予三苯氧胺,紫杉烷輔助化療薈萃分析:方法,目的: 比較含紫杉烷輔助化療方案與不含紫杉烷輔助化療方案主要結(jié)局指標(biāo): OS次要結(jié)局指標(biāo): DFS, 毒性11項隨機(jī)對照試驗, 17056名患者平均中位隨訪54.6個月總結(jié)果有利于紫杉烷OS: HR 0.81 (95% CI, 0.7

26、5-0.88; p<.00001)DFS: HR 0.81 (95% CI, 0.75-0.86; p<.00001),Nowak 等. ASCO 2007. 文摘號 545.,Five Year follow-up of INT C9741: Dose-dense chemotherapy is safe and effective,Hudis C, Citron M, Berry D, Cirrincione C,

27、Gradishar W, Davidson N, Martino S, LivingstonR, Ingle J, Perez E, Abrams J, Schilsky R, EllisM, Carpenter J, Muss H, Norton L, & Winer EOn behalf of CALGB/ECOG/SWOG/NCCTGinvestigators,HER2+ Breast Cancer and A

28、djuvant Therapy,Her-2,Her-2是一種原癌基因，該基因與乳腺癌細(xì)胞增殖有關(guān)。 約25～30%的乳腺癌Her-2過度表達(dá)。 Her-2的過度表達(dá)的乳腺癌患者生存期短，預(yù)后差。成為乳腺癌治療的理想靶點。,,,HER2陽性對生存期的影響,HER2陽性的乳腺癌患者的生存率降低！,中位生存期HER2 陽性3 年HER2 陰性6–7 年,Slamon DJ et al. Science 1987;235:17

29、7–82,HER2 狀態(tài): 預(yù)示腫瘤對治療的反應(yīng),內(nèi)分泌治療 HER2陽性患者相對耐藥 CMF方案 HER2陽性患者相對耐藥 蒽環(huán)類 對蒽環(huán)類相對敏感 紫杉類藥物相對敏感,赫賽汀® (曲妥珠單抗): 人源化抗HER2單克隆抗體,高度親和性 (Kd=0.1nM) 和特異性95% 人源化, 5

30、% 鼠抗，顯著降低免疫原性(HAMA),全球第一種治療實體瘤的單克隆抗體，為HER2癌基因陽性的腫瘤患者帶來了新的希望！Trastuzumab是包含了完整的muMAB 4D5抗原決定簇的人類IgG1κ的人體球蛋白,,Killer cell,Macrophage,,,,,,,,,,,,,,,,Fc receptor,Herceptin® : 作用機(jī)制,Trastuzumab in adjuvant , phase III st

31、udies,,赫賽汀®輔助治療循證醫(yī)學(xué)證據(jù),,,新英格蘭雜志2005年10月北美研究結(jié)果發(fā)表,新英格蘭雜志2005年10月HERA研究結(jié)果發(fā)表,新英格蘭雜志2006年2月FinHER結(jié)果發(fā)表,1703,1591,1434,1127,742,,383,140,1698,1535,1330,984,639,,334,127,100,80,60,40,20,0,Patients(%),,,,,,,,Months from

32、 randomisation,1 year trastuzumab,Observation,0,,No. at risk,赫賽汀輔助治療HERA研究無進(jìn)展生存時間(ITT),,,,,Events,HR,95% CI,p value,0.64,0.54, 0.76,<0.0001,3-yearDFS,80.6,74.3,,,,218,321,6.3%,,HERA研究DFS風(fēng)險(ITT)觀察組和赫賽汀一年治療組,Months s

33、ince randomisation,1703,1627,1498,1190,794,,407,146,100,80,60,40,20,0,Patients(%),,,,,,,,Months from randomisation,Observation,,No. at risk,1698,1608,1453,1097,711,,366,139,赫賽汀輔助治療HERA研究總生存時間(ITT),1 year trastuzumab,,,,

34、,Events,HR,95% CI,p value,0.66,0.47, 0.91,0.0115,3-yearOS,92.4,89.7,,,,0,59,90,Median FU 2 yrs,2.7%,,赫賽汀輔助治療北美臨床N9831/B31無進(jìn)展生存時間,隨機(jī)分組后年,Romond et al N Engl J Med 2005; 353: 1673-1684,,,87%,85%,67%,75%,HR=0.48; p<0.0

35、001,,,100,,90,,80,,70,,60,,50,,0,,1,,2,,3,,4,,5,,2-year median follow-up,AC PH,,n,Events,,ACPH1672133,,ACP1679261,,Patients (%),Romond et al N Engl J Med 2005; 353: 1673-1684,,,,,,,,,,,,,,,,,,,,,,,,,0,1,2,3

36、,4,Rate per 1000 Women /Yr,隨機(jī)分組后年,AC?TH,AC?T,N9831/B31遠(yuǎn)處轉(zhuǎn)移風(fēng)險,赫賽汀輔助治療北美臨床N9831/B31總生存時間,Patients (%),Years,,,100,,90,,80,,70,,,,0,,1,,2,,3,,4,,5,,,,,,,93%,86%,84%,80%,80%,91%,86%,77%,73%,,,,n107410751073,Events7798

37、147,AC?DHDCarboHAC?D,60,50,,,HR=0.49,,,HR=0.61,BCIRG 006研究DFS,Slamon et al 2005 SABCS (abstract #1),曲妥珠單抗輔助治療,Trastuzumab: Adjuvant Breast Cancer,All trials demonstrated an important benefit in disease free survival i

38、n the trastuzumab-treated groupSome trials also demonstrated a striking benefit in overall survivalHowever some concerns exist for cardiac safety,激素受體陽性、HER-2陽性乳腺癌的全身輔助治療,組織學(xué)類型：導(dǎo)管癌小葉癌混合型癌化生性癌,pT1、pT2或pT3；和pN0或pN1m

39、i（腋窩淋巴結(jié)轉(zhuǎn)移灶≤2 mm）,腫瘤≤0.5 cm或微浸潤或腫瘤0.6~1.0 cm，且高分化,pN0 不進(jìn)行輔助治療pN1mi 考慮輔助內(nèi)分泌治療,腫瘤0.6~1.0 cm，且中/低分化或伴預(yù)后不良因素,輔助內(nèi)分泌治療±輔助化療（1類）,腫瘤>1 cm,輔助內(nèi)分泌治療+輔助化療+曲妥珠單抗（1類）,淋巴結(jié)陽性（指1個或多個同側(cè)腋窩淋巴結(jié)有1個或多個轉(zhuǎn)移灶>2 mm）,輔助

40、內(nèi)分泌治療+輔助化療+曲妥珠單抗（1類）,BINV-5,,,,,,,,,,,,,,,,,,,,,,,,輔助化療,不含曲妥珠單抗的化療方案（均為1類）FAC/CAF（氟尿嘧啶/多柔比星/環(huán)磷酰胺）或FEC/CEF（環(huán)磷酰胺/表柔比星/ 氟尿嘧啶）AC（多柔比星/環(huán)磷酰胺）±序貫紫杉醇EC（表柔比星/環(huán)磷酰胺）TAC（多西他賽/多柔比星/環(huán)磷酰胺）聯(lián)合非格司亭支持A→CMF（多柔比星序貫環(huán)磷酰胺/甲氨喋呤/氟尿嘧

41、啶）E→CMF（表柔比星序貫環(huán)磷酰胺/甲氨喋呤/氟尿嘧啶）CMF（環(huán)磷酰胺/甲氨喋呤/ 氟尿嘧啶）AC×4 （多柔比星/環(huán)磷酰胺）＋序貫紫杉醇×4，每2周1次，聯(lián)合非格司亭支持A→T→C（多柔比星序貫紫杉醇再序貫環(huán)磷酰胺）每2周1次，聯(lián)合非格司亭支持FEC→T（ 氟尿嘧啶/表柔比星/環(huán)磷酰胺序貫多西他賽）TC（多西他賽和環(huán)磷酰胺）,含曲妥珠單抗的化療方案（均為1類）首選的輔助方案：AC→T＋同步

42、曲妥珠單抗（多柔比星/環(huán)磷酰胺序貫紫杉醇＋曲妥珠單抗)其他輔助方案：多西他賽＋曲妥珠單抗→ FECTCH（多西他賽、卡鉑、曲妥珠單抗）化療后序貫曲妥珠單抗AC→多西他賽＋曲妥珠單抗新輔助化療：T＋曲妥珠單抗→CEF+曲妥珠單抗（紫杉醇＋曲妥珠單抗序貫環(huán)磷酰胺/表柔比星/ 氟尿嘧啶＋曲妥珠單抗）,BINV-J,,,Adverse event profiles of chemotherapy vs tamoxifen

43、,Tamoxifen,Chemotherapy(CMF / FAC / FEC),Hot flushesVaginal drynessVaginal dischargeThromboembolic eventsEndometrial cancer,NauseaVomitingFatigueHair lossPainCNS problemsImmune system problems,EBCTCG. Lancet 2

44、005; 365: 1687-1717,CMF=cyclophosphamide, methotrexate and fluorouracilFAC=fluorouracil, doxorubicin and cyclophosphamideFEC=fluorouracil, epirubicin and cyclophosphamide,,,,The rise of AIs in the treatment of breast

45、cancer,The adjuvant treatment of HR+ early breast cancer has been revolutionised in the last 5 yearsAIs have challenged 5 years’ tamoxifen use as the optimum adjuvant treatment for postmenopausal women in this setting

46、AIs have been investigated innewly diagnosed patientspatients who have started adjuvant tamoxifenpatients who have completed 5 years’ tamoxifen treatment,AI=aromatase inhibitor;HR+=hormone receptor-positive,芳香化酶抑制劑用于

47、乳腺癌術(shù)后輔助治療,MA17試驗：三苯氧胺5年＋來曲唑5年 vs 三苯氧胺5年IES031試驗：三苯氧胺＋依西美5年 vs 三苯氧胺5年ATAC試驗：阿那曲唑5年 vs 三苯氧胺5年Big-198試驗：三苯氧胺5年 vs 來曲唑5年 vs 三苯氧胺2年?來曲唑3年 vs 來曲唑2年?三苯氧胺3年,輔助內(nèi)分泌治療,輔助內(nèi)分泌治療,絕經(jīng)后,芳香化酶抑制劑5年（1類）,,他莫昔芬2~3年,芳香化酶抑制劑直至5年（1類）或更久(2B類）,

48、他莫昔芬4.5~6年,芳香化酶抑制劑5年（1類）,患者有芳香化酶抑制劑禁忌證或不能接受芳香化酶抑制劑，或不能耐受芳香化酶抑制劑，可以服用他莫昔芬5年（1類）,,,,,,,,,,BINV-1,輔助內(nèi)分泌治療,輔助內(nèi)分泌治療,絕經(jīng)前,他莫昔芬2~3年（1類）±卵巢抑制/切除（2B類）,絕經(jīng)后,絕經(jīng)前,BINV-I,,,,,,,,,,,輔助內(nèi)分泌治療,絕經(jīng)后,他莫昔芬直至5年（1類）,芳香化酶抑制劑直至5年（1類）或更久（2B類

49、）,芳香化酶抑制劑5年（1類）,絕經(jīng)前,絕經(jīng)后,芳香化酶抑制劑5年（1類）,絕經(jīng)前,不進(jìn)行進(jìn)一步內(nèi)分泌治療,BINV-I,,,,,他莫昔芬直至5年（1類）,,,,,,,,Conclusions,Endocrine therapy is an effective and well-tolerated long-term treatment strategy in reducing the risk of recurrence after

50、primary surgeryThird-generation AIs are becoming the new ‘gold standard’ in endocrine therapy,Novel Treatments,The erbB familyTargeting Her2 and EGFR in breast cancerAnti-angiogenesisTargeting VEGF signaling pathways

51、 with monoclonal antibodies and TKIsOther important pathways Potential benefits through inhibition of PARP, SRC and other pathwaysTailored therapy,個體化治療（Tailored Therapy),化療,,,,化療,化療,Three Breast Cancer

52、 Studies Used To Select 21 Gene Panel,PROLIFERATIONKi-67STK15SurvivinCyclin B1MYBL2,ESTROGENERPRBcl2SCUBE2,INVASIONStromolysin 3Cathepsin L2,HER2GRB7HER2,BAG1,GSTM1,REFERENCEBeta-actinGAPDHRPLPOGUSTFRC

53、,CD68,16 Cancer and 5 Reference Genes,Best RT-PCR performance and most robust predictions,Paik S, et al: NEJM 2004,Recurrence Score (RS) Algorithm,,,Scale: 0 to 100,Paik S, et al: SABCS 2003,21-基因 RT-PCR 檢測的應(yīng)用,限于ER+、淋巴結(jié)陰

54、性腫瘤僅對接受初次化療和他莫昔芬治療的患者有效絕大多數(shù)HER-2陽性的患者RS較高因而主要應(yīng)用于ER+、HER-2陰性、淋巴結(jié)陰性腫瘤。,激素受體陽性、HER-2陰性乳腺癌的全身輔助治療,組織學(xué)類型：導(dǎo)管癌小葉癌混合型癌化生性癌,pT1，pT2，或pT3；和pN0或pN1mi（腋窩淋巴結(jié)轉(zhuǎn)移灶≤2 mm）,淋巴結(jié)陽性（1個或多個同側(cè)腋窩淋巴結(jié)有1個或多個轉(zhuǎn)移灶>2 mm）,腫瘤≤0.5 cm或微浸潤或腫瘤0

55、.6~1.0 cm，且高分化，無不良預(yù)后因素,pN0 不進(jìn)行輔助治療pN1mi 考慮進(jìn)行輔助內(nèi)分泌治療,腫瘤0.6~1.0 cm，中/低分化或伴不良預(yù)后因素腫瘤>1cm,考慮21-基因RT-PCR分析（2B類）,未做,復(fù)發(fā)評分為低危（<18）,,復(fù)發(fā)評分為中危（18~30）,復(fù)發(fā)評分為高危（≥31),輔助內(nèi)分泌治療±輔助化療（1類）,輔助內(nèi)分泌治療（2B類

56、）,輔助內(nèi)分泌治療±輔助化療（2B類）,輔助內(nèi)分泌治療+輔助化療（2B類）,輔助內(nèi)分泌治療+輔助化療（1類）,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,BINV-6,,,,,,,,激素受體陽性、HER-2陰性乳腺癌的全身輔助治療,BINV-6,腫瘤0.6~1.0 cm，中/低分化或伴不良預(yù)后因素腫瘤>1cm,考慮21-基因RT-PCR分析（2B類）,未做,復(fù)發(fā)評分為低危（<18）

57、,復(fù)發(fā)評分為中危（18~30）,復(fù)發(fā)評分為高危（≥31),輔助內(nèi)分泌治療±輔助化療（1類）,輔助內(nèi)分泌治療（2B類）,輔助內(nèi)分泌治療±輔助化療（2B類）,輔助內(nèi)分泌治療+輔助化療（2B類）,,,,,,,,,,,,,,,,,,,Sensitivity ( + ),Sensitivity ( - ),,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Responder Probable

58、survival benefit,Non-RespondersToxicity without survival benefitDelay in effectivetreatment,Anti-cancer agent,Today - One Size Fits All Therapy,,,,Sensitivity ( + ),Sensitivity ( - ),,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

59、,,,ResponderSurvival benefit,Non-RespondersToxicity without survival benefitDelay in effectivetreatment,The Future - Tailored Therapy,,,,Molecular profiling,1,2,2,,,,Right therapy for right patient,,,3,,,,,,,乳腺癌輔助化療