早期乳腺癌輔助化療進展課件

1、早期乳腺癌輔助化療進展中國醫(yī)學科學院腫瘤醫(yī)院 徐兵河Breast Cancer Incidence Trends Over TimeCancer Incidence Trends in China 2005 2015 Incidence Rates Projection by Cancer TypePer 100,000 CAGR 2.98%CAGR 4.5%CAGR 0.65%CAGR 2.35%CAGR 0.99%CAGR 2.60% Source: Estimates of Cancer Incidence in China for 2000 and Projections for 20

2、05, 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化發(fā)病率:18.7/100,000；死亡率: 5.5/100,000發(fā)病率：城市農村高發(fā)年齡段：4550歲近15年來乳腺癌發(fā)病率上升死亡率下降死亡率下降的原因早期診斷 綜合治療The benefits of chemotherapy data from clinical trailsEarly Breast Cancer Trialists Collaborative Group (EBCTCG).194 randomised trials of adjuvant chemothera

3、py (CMF,CAF,CEF) or hormonal therapy (TAM) that began by 1995.Lancet 2005Placebo53.3%37.147.90102030405060Time (years)051510Recurrence(%)15-year gain 12.3% (SE 1.6)Log-rank 2p0.0000115-year probabilities of recurrence in women aged 50 years, with / without polychemotherapyPolychemotherapy41.1%35.524

4、.6Younger women, 35% node-positive; older women, 70% node-positive;SE=standard errorEBCTCG. Lancet 2005; 365: 1687-1717Placebo42.4%20.435.00102030405060Breastcancermortality(%)15-year gain 10.0% (SE 1.6)Log-rank 2p0.00001Polychemotherapy32.4%Time (years)05151015.727.115-year probabilities of breast

5、cancer mortality in women aged 50 years, with / without polychemotherapyEBCTCG. Lancet 2005; 365: 1687-1717Younger women, 35% node-positive; older women, 70% node-positive010203040506015-year gain 4.1% (SE 1.2)Log-rank 2p0.00001Placebo57.6%Polychemotherapy53.4%48.805151035.444.129.415-year probabili

6、ties of recurrence in women aged 50-69 years, with / without polychemotherapyTime (years)EBCTCG. Lancet 2005; 365: 1687-1717Recurrence(%)Younger women, 35% node-positive; older women, 70% node-positivePlacebo50.4%21.338.3010203040506015-year gain 3.0% (SE 1.3)Log-rank 2p0.00001Polychemotherapy47.4%1

7、8.705151035.415-year probabilities of breast cancer mortality in women aged 50-69 years, with / without polychemotherapyTime (years)Younger women, 35% node-positive; older women, 70% node-positiveEBCTCG. Lancet 2005; 365: 1687-1717Breastcancermortality(%)Placebo45.0%38.326.5010203040506015-year gain

8、 11.8% (SE 1.3)Log-rank 2p0.0000115-year probabilities of recurrence in women with ER+ (or ER-unknown) disease, with / without 5 years tamoxifenAbout 5 years tamoxifen33.2%Time (years)05151015.124.7ER=oestrogen receptor; 10,386 women: 20% ER-unknown, 30% node-positiveEBCTCG. Lancet 2005; 365: 1687-1

9、717Recurrence(%)010203040506015-year gain 9.2% (SE 1.2)Log-rank 2p0.00001Placebo34.8%About 5 years tamoxifen25.6%25.705151011.98.317.815-year probabilities of breast cancer mortality in women with ER+ (or ER-unknown) disease, with / without 5 years tamoxifenTime (years) 10,386 women: 20% ER-unknown,

10、 30% node-positiveEBCTCG. Lancet 2005; 365: 1687-1717Breastcancermortality(%)010203040506001354Time (years)25-year gain 11.9% (SE 1.0)Log-rank 2p0.00001Nil25.8%About 5 years tamoxifen alone13.9%5-year recurrence in women with ER+ (or ER-unknown) disease with no chemotherapy, with / without 5 years t

11、amoxifenEBCTCG. Lancet 2005; 365: 1687-1717Recurrence(%) 7056 women: 19% node-positive01020304050600135425-year gain 10.6% (SE 1.5)Log-rank 2p0.00001Chemotherapy alone28.1%Chemotherapy + about 5 years tamoxifen17.5%5-year recurrence in women with ER+ (or ER-unknown) disease with chemotherapy, with /

12、 without 5 years tamoxifenTime (years)EBCTCG. Lancet 2005; 365: 1687-1717Recurrence(%) 3330 women: 53% node-positiveChemotherapy versus endocrine therapy in the treatment of breast cancerIn premenopausal women, polychemotherapy improves 15-year recurrence by 12.4% and survival by 10.0%In postmenopau

13、sal women, 15-year gains in recurrence and survival are smaller (4.2% and 3.0%, respectively) anthracycline-based polychemotherapy reduces the annual death rate by 38% for women 50 years and by 20% for those of age 50-69 yearsEBCTCG. Lancet 2005; 365: 1687-1717Chemotherapy versus endocrine therapy i

14、n the treatment of breast cancerIn patients with ER+ 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 chemotherapyEBCTCG. Lancet 2005; 365: 1687-1717乳腺癌輔助化療進展1960s 1970s 1980s 1990s 2000 2002手術CMF1蒽環(huán)

15、類藥物AC2, CAF3,FEC4Dose5,6CEF1207, 15FEC1008EC9Meta-analysis12紫杉類藥物10,11,13DI14 Sequene 生物治療 1 Bonadonna 1976 2 B-15, B-23 1990, 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, 200013 TAC vs FAC14 CALGB 9741

16、15 MA.05 10 years!評估紫杉類乳腺癌輔助化療的隨機臨床試驗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 ACTPACS 01 FEC vs FEC TECOG 2197 AT vs ACECOG 1199 ACP3 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局指標: OS次要結局指標: DFS,

17、 毒性11項隨機對照試驗, 17056名患者平均中位隨訪54.6個月總結果有利于紫杉烷OS: HR 0.81 (95% CI, 0.75-0.88; 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 effectiveHudis C, Citron M, Berry D, Cirrincione C, Gradishar W, Davidson N,

18、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/NCCTGinvestigatorsHER2+ Breast Cancer and Adjuvant TherapyHer-2Her-2是一種原癌基因，該基因與乳腺癌細胞增殖有關。 約2530%的乳腺癌Her-2過度表達。 Her-2的過度表達的乳腺癌患者生存期短，預后差。成為乳腺癌治療的理想靶點。 HER2陽性對生

19、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67 年Slamon DJ et al. Science 1987;235:17782HER2 狀態(tài): 預示腫瘤對治療的反應 內分泌治療 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% 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

20、完整的muMAB 4D5抗原決定簇的人類IgG1的人體球蛋白Killer cellMacrophageHerceptin stimulates ADCC(antibody-dependent cell-mediated cytotoxicity)Fc receptorHerceptin : 作用機制Trastuzumab in adjuvant , phase III studies赫賽汀輔助治療循證醫(yī)學證據新英格蘭雜志2005年10月北美研究結果發(fā)表新英格蘭雜志2005年10月HERA研究結果發(fā)表新英格蘭雜志2006年2月FinHER結果發(fā)表1703159114341127742383140

21、169815351330984639334127100806040200Patients(%)Months from randomisation12361 year trastuzumabObservation0186No. at risk 赫賽汀輔助治療HERA研究無進展生存時間(ITT)2430EventsHR95% CIp value0.640.54, 0.760.00013-yearDFS80.674.32183216.3%HERA研究DFS風險(ITT)觀察組和赫賽汀一年治療組Months since randomisation1703162714981190794407146100

22、806040200Patients(%)Months from randomisationObservationNo. at risk 1698160814531097711366139赫賽汀輔助治療HERA研究總生存時間(ITT)1 year trastuzumabEventsHR95% CIp value0.660.47, 0.910.01153-yearOS92.489.71236018624305990Median FU 2 yrs2.7%赫賽汀輔助治療北美臨床N9831/B31無進展生存時間隨機分組后年Romond et al N Engl J Med 2005; 353: 1673

23、-168487%85%67%75%HR=0.48; p0.000110090807060500123452-year median follow-up AC PAC PHnEventsACPH1672133ACP1679261Patients (%)18%Romond et al N Engl J Med 2005; 353: 1673-168401234020406080100120Rate per 1000 Women /Yr隨機分組后年ACTHACTN9831/B31遠處轉移風險赫賽汀輔助治療北美臨床N9831/B31總生存時間ACTH94%91%87%92%ACTNDeathsACT1

24、67992ACTH167262HR=0.67, 2P=0.015Years From RandomizationPatients (%)Years10090807001234593%86%84%80%80%91%86%77%73%n107410751073Events7798147ACDHDCarboHACD6050HR=0.49HR=0.61BCIRG 006研究DFSSlamon et al 2005 SABCS (abstract #1) 無病生存率總生存率HR (95% CI)P值HR (95% CI)P值N9831/B-310.48 (0.410.57)0.000010.65 (0.

25、510.84)0.0007HERA 0.54 (0.430.67)0.00010.76 (0.471.23)0.26FinHER0.42 (0.210.83)0.010.41 (0.161.08)0.07BCIRG AC-TH TCH0.61 (0.480.86)0.67 (0.540.83)1 cm輔助內分泌治療+輔助化療+曲妥珠單抗（1類）淋巴結陽性（指1個或多個同側腋窩淋巴結有1個或多個轉移灶2 mm）輔助內分泌治療+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

26、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）聯合非格司亭支持ACMF（多柔比星序貫環(huán)磷酰胺/甲氨喋呤/氟尿嘧啶）ECMF（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）AC4 （多柔比星/環(huán)磷酰胺）序貫紫杉醇4，每2周1次，聯合非格司亭支持ATC（多柔比星序貫紫杉醇再序貫環(huán)磷酰胺）每2周1次，聯合非格司亭支持FECT（ 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：ACT同步曲妥珠單抗（多柔比星/環(huán)磷酰胺序貫紫杉醇曲妥珠單抗

27、)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-JAdverse event profiles of chemotherapy vs tamoxifenTamoxifenChemotherapy(CMF / FAC / FEC)Hot flushesVaginal drynessVaginal dischargeThromboembolic eventsEndometrial cancerNauseaVomi

28、tingFatigueHair lossPainCNS problemsImmune system problemsEBCTCG. Lancet 2005; 365: 1687-1717CMF=cyclophosphamide, methotrexate and fluorouracilFAC=fluorouracil, doxorubicin and cyclophosphamideFEC=fluorouracil, epirubicin and cyclophosphamideThe rise of AIs in the treatment of breast cancerThe adju

29、vant 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 AIs have been investigated innewly diagnosed patientspatients who have started adjuvant tamoxifenp

30、atients who have completed 5 years tamoxifen treatmentAI=aromatase inhibitor;HR+=hormone receptor-positive芳香化酶抑制劑用于乳腺癌術后輔助治療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年輔助內分泌治療輔助內分泌治療絕經后芳香化酶抑制劑5年（1類）他莫昔芬23年芳香化酶抑

31、制劑直至5年（1類）或更久(2B類）他莫昔芬4.56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輔助內分泌治療輔助內分泌治療絕經前他莫昔芬23年（1類）卵巢抑制/切除（2B類）絕經后絕經前BINV-I輔助內分泌治療絕經后他莫昔芬直至5年（1類）芳香化酶抑制劑直至5年（1類）或更久（2B類）芳香化酶抑制劑5年（1類）絕經前絕經后芳香化酶抑制劑5年（1類）絕經前不進行進一步內分泌治療BINV-I 他莫昔芬直至5年（1類）ConclusionsEndocrine therapy is an effe

32、ctive and well-tolerated long-term treatment strategy in reducing the risk of recurrence after primary surgeryThird-generation AIs are becoming the new gold standard in endocrine therapyNovel Treatments The erbB familyTargeting Her2 and EGFR in breast cancerAnti-angiogenesisTargeting VEGF signaling pathways 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 Studies Used To Select 21 Gene PanelPROLIFERATIONKi-67STK15Survi