上海腫瘤醫(yī)院王中華晚期乳腺癌治療講課

1、轉(zhuǎn)移性乳腺癌內(nèi)科治療進展,王中華2012.05.09講課,Age Distribution,Data from Shanghai Cancer Institute,,,,,,5-yr disease-free,5-yr recurrence,,Gain from adjuvant chemotherapy,70%,30%,70%,10%,20%,Risk reduction: 30%?20%, 10/30=33% Absolute

2、 benefit: 10% 70% always free 20% always recurred,,,,超過 2/3 的乳腺癌復發(fā)為遠處轉(zhuǎn)移,遠處轉(zhuǎn)移(61%-75%)5年生存率 41.3%,對側(cè)乳腺癌(9%-11%)5年生存率83.4%,局部復發(fā)(16%-28%)5年生存率 59.3%,,,,BIG = Breast International Group.Baum et al. Lancet. 200

3、2;359:2131.Thürlimann et al. N Engl J Med. 2005;363:2747.,晚期乳腺癌治療目的,控制疾病，緩解癥狀 提高患者的生活質(zhì)量，延長高質(zhì)量的生存期,,全面評估,,內(nèi)分泌,化療,乳腺癌的分子分型與內(nèi)科治療方法,Luminar A/BER（+）和/或PR（+）,Her-2 陽性,所有類型MBC受體三陰性,全身化療 針對所有類型的晚期乳腺癌,晚期乳腺癌的化療發(fā)展史,,,,

4、,,,,,1955,1965,1975,1985,1995,2005,2015,,,Cyclophosphamide1959,Methotrexate1971,Doxorubicin1974,Gemcitabine2004,Capecitabine1998,Lapatinib 2006,Accessed on-line at http://www.fda.gov/cder/cancer/druglistframe.htm,,

5、,,,,,,,Docetaxel1996,,,Paclitaxel1994,,Trastuzumab2000,,Approved specificallyfor first-line use in MBC,,,Nab paclitaxel2005,,,Ixabepilone 2007,Bevacizumab 2008,5-FU1962,,,,,,Platinums,,,晚期乳腺癌化療適應(yīng)證,病變發(fā)展迅速內(nèi)臟轉(zhuǎn)移，如肝、

6、肺廣泛轉(zhuǎn)移無病生存期（DFS）＜2年ER和PR陰性既往內(nèi)分泌治療無效,化療的應(yīng)用方法,聯(lián)合 Vs. 單藥 （A＋B Vs. A）ORR↑TTP ↑ OS ↑或 —聯(lián)合 Vs. 序貫 （A＋B Vs. A→B）TTP、OS未顯示有明顯優(yōu)勢,聯(lián)合化療 VS.單藥,優(yōu)先選擇聯(lián)合化療①有廣泛轉(zhuǎn)移或②有臨床癥狀，需要快速控制病情或③腫瘤進展迅速或④威脅生命的轉(zhuǎn)移或⑤患者的耐受性較好優(yōu)先考慮單藥化療

7、①無重要臟器轉(zhuǎn)移或②無臨床癥狀或③轉(zhuǎn)移部位少,,輔助,,首選,,蒽環(huán),蒽環(huán)類聯(lián)合紫杉類 AT,蒽環(huán)類CAF、CEFAC、EC,未化療,,,CMF,復發(fā)轉(zhuǎn)移性乳腺癌化療藥物選擇原則,多西他賽聯(lián)合卡培他濱 TX紫杉醇吉聯(lián)合吉西他濱 GP,,或,,蒽環(huán)類及紫杉類治療失敗,卡培他濱、長春瑞濱、吉西他濱、鉑類、伊沙匹隆 、ABX,,,,First-Line Second-LineDoxorubicin 35

8、-50%125-30%1Epirubicin52-68%28%Paclitaxel29-63%119-57%Docetaxel47-65%139-58%Capecitabine 25%120-27%1Gemcitabine 23-37%113-41%1Vinorelbine 40-44%117-36%,1Esteva F et al, Oncologist 2001

9、(6): 133-146,單藥治療MBC有效率,白蛋白結(jié)合型紫杉醇III 期臨床試驗: 試驗設(shè)計,Gradishar et al. J Clin Oncol. 2005;23:7794–7803,MBC,,III 期臨床試驗:注射用紫杉醇（白蛋白結(jié)合型）顯著延長了患者的至腫瘤進展時間,Gradishar et al. J Clin Oncol. 2005;23:7794–7803,標準紫杉醇l (n = 224),注射用紫杉醇（白蛋白

10、結(jié)合型） (n = 229),中位時間 = 23.0 周(19.4–26.1),中位時間 = 16.9 wks(15.1–20.9),無進展百分比,,,,,,,,,,,,,,,,,,,,P = 0.006風險比 = 0.75,,周,0816243240485664 72 80 88 96,104,112,120,III 期臨床試驗: 毒性,Gradishar et al. J Clin Oncol. 20

11、05;23:7794–7803,Capecitabine 1, 250mg/m2 BID days 1–14 + Docetaxel 175mg/m2 day 1,Docetaxel 100mg/m2 day 1,3-weekly cycles,n=255,n=256,O’Shaughnessy et al. J Clin Oncol. 2002;20:2812-2823,SO14999研究：多西他賽聯(lián)合希羅達 vs. 多西他賽,,

12、R,,主要研究終點: TTP,,Gemzar 1, 250mg/m2 BID days 1，8 + Paclitaxel 175mg/m2 day 1,Paclitaxel 175mg/m2 day 1,3-weekly cycles,n=529,O’Shaughnessy et al. J Clin Oncol. 2002;20:2812-2823,JHQG 研究設(shè)計紫杉醇聯(lián)合吉西他濱 vs. 紫杉醇,,R,,主要

13、研究終點: TTP,,蒽環(huán)類和紫杉類均耐藥乳腺癌的化療,希羅達 伊沙匹隆 (Ixabepilone)＋希羅達 （2B）NVB ＋ GEMNVB ± 希羅達NVB ± DDP/CBPGEM ± DDP/CBP,phase III Spanish Breast Cancer Research Group (GEICAM) trial 療效：毒副作用： GEM＋NVB vs. NV

14、BG3/4 ANC下降 66％ vs. 44％ （p = 0.0074 ） ANC減少性發(fā)熱 11％ vs. 6％ （p = 0.15 ）非血液學毒性兩組無顯著差異,蒽環(huán)和紫杉類治療失敗 — GEM＋NVB vs. NVB,Lancet Oncology 2007; 8:219-225,,,gemcitabine 1200 mg/m2 days 1 and 8 vinorelbine

15、 30 mg/m2 days 1 and 8 q21d,vinorelbine 30 mg/m2 days 1 and 8 q21d,,PD,252 pts MBCpretreated with anthracyclines and taxanes,,,,Epothilone: Ixabepilone (BMS-247550)Bristol-Myers Squibb, New York, NY,Ac

16、tivity in multiple tumor modelsLow susceptibility to tumor resistance mechanisms MRP and P-gp efflux pumps? (Ⅲ) tubuiln overexpression? tubuiln mutationsAntitumor activity in taxane resistance models,S. cellulosum,

17、Epothilone B,Ixabepilone,,,,59%,36%,23%,,22%,35%,12%,41%,Study Design: International, Randomized, Phase III trial, BMS 046,Ixabepilone 40 mg/m2 IV over 3 hrs Day 1, every 3 wks +Capecitabine 1000 mg/m2 orally BID Days

18、 1-14, every 3 wks,Capecitabine 1250 mg/m2 orally BID Days 1-14 every 3 wks,Patients with metastatic or locally advanced breast cancerto anthracyclines PRE/ RESISTANT and taxaneRESISTANT,,,Stratified by visceral met

19、astases previous MBC chemotherapy anthracycline resistance study site,,PD,Ixabepilone Plus Capecitabine vs Capecitabine Alone,,,Ixabepilone Plus Capecitabine vs Capecitabine Alone,Overall response rate*I + C vs C: 35

20、% vs 14% (P < .0001)PFS benefit for combination arm* (5.8 vs 4.2 mos)輔助化療后快速復發(fā) （5.6 vs. 2.8 mos） — 2008 SABCS,*As determined by independent radiologic review,Months,Proportion Progression Free,4,0,8,12,16

21、,20,24,0.0,0.2,0.4,0.6,0.8,1.0,,,,,,,28,32,36,PFS by Independent Radiologic Review,,,,,Capecitabine,Ixabepilone + Capecitabine,HR: 0.75 (95% CI: 0.64-0.88)P = .0003,,Vahdat LT, et al. ASCO 2007. Abstract 1006.,Grade 3/

22、4 peripheral neuropathy: 23% for ixabepilone plus capecitabine vs 0% for capecitabine alone 感覺神經(jīng) / 累積性 / 可逆性中位恢復至 G1 or 基線: 6 weeks,More hematologic toxicity observed in ixabepilone arm,,Ixabepilone Plus Capecita

23、bine vs Capecitabine Alone,October 22, 2007 FDA Approves Ixempra (ixabepilone, Bristol-Myers Squibb) for Advanced Breast Cancer PatientsThe U.S. Food and Drug Administration has approved Ixempra (ixabepilone), a new a

24、nti-cancer treatment, for use in patients with metastatic or locally advanced breast cancer who have not responded to certain other cancer drugs.,何時停藥？治療越長越好？,效不更方至病情進展或不可耐受的毒性選擇其中一個藥物用至進展或不可耐受的毒性更換其他一種化療藥希羅達，PLD更換

25、成內(nèi)分泌治療耐受性好，作用機制不同，減少耐藥停止用藥（6-8周期后），觀察定期復查，進展再給予處理,三種不同劑量多西他賽治療MBC,,* P <0.05,,,,Paclitaxel (200 mg/m2 ）d2+Epirubicin (90 mg/m2) d1 orDoxorubicin (50 mg/m2) d1,every 3 weeks 6-8cyclesN=459,CR/PR/SD,Paclit

26、axel 175 mg/m2,no further chemotherapy,every 3 weeks 8cycles,*HR+ HT,Paclitaxel maintenance —— JCO, 2006,R,,,Gennari A, et al, JCO,2006,3912-8,N=215 (255),The primary end point : PFS,Gennari A, et al, JCO,2006,3912-8,,

27、—— MANTA1 study,,Possible Explanationfor MANTA1 study (Paclitaxel maintenance),Use of concurrent endocrine therapy in 60% of hormone receptor-positive patientsControl arm patients actual received maintenance hormonal

28、 therapyThe concurrent of chemo and hormonal may reduce the efficacyToxicity of paclitaxel Sensory neuropathy grade 2 occurred in 26%, grade 3 in 6% and grade 4 in 2% of the patients in maintenancegrade ¾ ANC↓ 2

29、4%,GEICAM 2001-01 Study — Phase III trial,288 pts MBC,,,2008 ESMO,observation,PLD 40mg/m2 q28d × 6,,,一線,,,CR / PR / SD,AT （50/75） × 6,155 pts,78 pts,77 pts,R,A：ADMT：TXTPLD：脂質(zhì)體ADM,,*Statistically significan

30、t; ?assessed in futility analysis.,Randomized Studies of Chemotherapy Duration in MBC,,MBC的化療,為何用？ — 目的何時用？ — 適應(yīng)癥怎么用？ — 方法（聯(lián)合、單藥）用何藥？ — 三級選用（蒽環(huán)，蒽環(huán)耐藥， 蒽環(huán)及紫杉均耐藥）何時停？ — 五種措施,生物靶向治療 －與化療聯(lián)合,Targeted therapies

31、for breast cancer,mTOR,Tam,AI,Her-2陽性MBC －Herceptin－ Lapatinib,HER2陽性定義,IHC 3+,CISH +,FISH +,或,或,免疫組織化學法(IHC)色素原位雜交法(CISH) 熒光原位雜交法(FISH),Hercetpin單藥治療晚期乳腺癌的療效,—————————————————— HO649g

32、HO551g HO650 （關(guān)鍵試驗） （Ⅱ期） （關(guān)鍵試驗）_____________________________________________ N (intent-to-treat) 222 46 114 #CR 8

33、 1 7 #PR 26 4 23 有效率 15％ 11％ 26％中位緩解期（月） 9.1 6.6

34、 18.8中位生存期（月） 13 14 24.4______________________________________________,Herceptin聯(lián)合化療一線治療Her-2陽性MBC,,,H: Herceptin, T: TXT, P: PAX, C: CBP, X: Xeloda,,,曲妥珠單抗聯(lián)合泰索帝：同時還是序貫使用? HERTAX,B

35、ontenbal et al. ASCO 2008. Abstract 1014.,99 例 HER2 +,一線 M+主要目的:PFS次要目的:RR & OS,曲妥珠單抗每周+ 泰索帝 100 mg/m²,曲妥珠單抗 每周,,,隨機,泰索帝 100 mg/m²,序貫,PD,,,Lapatinib —針對Her-2陽性MBCFDA于2007.3.13批準上市規(guī)格250mg/150#,L

36、apatinib: Targeting EGFR and HER2,Lapatinib oral tyrosine kinase inhibitor of ErbB1 and ErbB2Blocks signaling through EGFR and HER2 homodimers and heterodimersMay also prevent signaling between ErbB1/ErbB2 and other Er

37、bB family members,Rusnak DW, et al. Mol Cancer Ther. 2001;1:85-94.Xia W, et al. Oncogene. 2002;21:6255-6263.,Geyer CE, et al. ASCO 2006. Clinical Science Symposium.,EGF100151: Lapatinib + Capecitabine in Advanced Breast

38、 Cancer,到疾病進展時間（ITT Population）,70,20,40,60,80,0,100,,,,,,,,,10,20,30,40,50,60,,,,,,,,,,0,,,,,,Time (weeks),,Patients Progression Free* (%),EGF100151,Geyer CE, et al. N Engl J Med 2006 ;355(26):2733-2743.,GBG-26：曲妥珠單抗加希羅

39、達 vs. 希羅達，延長TTP近3個月（8.2m vs. 5.6m P<0.05)EGF104900：曲妥珠單抗加拉帕替尼 vs. 拉帕替尼，顯著延長TTP（2.8m vs. 1.9m P=0.008）,含曲妥珠單抗一線治療Her-2陽性MBC進展后,von Minckwitz G et al. J Clin Oncol 2008: 26 (May 20 Suppl); abs 1025. O’Shaughnessy J e

40、t al. J Clin Oncol 2008: 26 (May 20 Suppl); abs 1015.,,,,PCH 或wPCH,貝伐單抗,Paclitaxel ± Bevacizumab in MBC (E2100),N=715Locally recurrentor 1st-line MBC,值得關(guān)注的是貝伐單抗組有更多感染、 3/4 級的高血壓、蛋白尿、頭痛、 心腦血管局部缺血,Miller et al. N

41、Engl J Med. 2007;357:2666-2676,Results,,Paclitaxel 90 mg/m2 d 1, 8, 15 q4w,,Paclitaxel 90 mg/m2 d 1, 8, 15 q4w + bevacizumab 10 mg/kg d1, 15,Yellow text indicates statistically significant values.,,,R,Docetaxel ± Be

42、vacizumab in MBC (AVADO),N=705Locally recurrentor 1st-line MBCStratification:RegionPrior taxane/time to relapse since adjuvant chemoMeasurable diseaseHR status,,,R,Docetaxel 100mg/m2 + Placebo q3w,Docetaxel + Beva

43、cizumab 7.5mg/kg q3w,Docetaxel + Bevacizumab 15mg/kg q3w,Bevacizumab continued to disease progression; all pts given option to receive bevacizumab with 2nd-line chemo; docetaxel administered for maximum of 9 cycles,Miles

44、 et al. ASCO 2008. Late-Breaking Abstract 1011.,Phase III Studies: E2100 and AVADO,*Miller et al. N Eng J Med. 2007; **Miles et al. ASCO 2008 (LBA#1011).,Yellow text indicates statistically significant values.,,E2100 an

45、d AVADO Safety data,*Miller et al. N Eng J Med. 2007; **Miles et al. ASCO 2008 (LBA#1011).***VTE: no increase in bevacizmab arm in either study.,,,,,,,,,,,Ongoing Phase III Trials Evaluating Bevacizumab in First-Line

46、MBC,GEICAM 2006-11,AVEREL,HER2+ DiseaseTrastuzumab-containingregimens,Hormonal therapy,,RIBBON 1,RIBBON 1,RIBBON 1,Capecitabine,,AVADO,Single-agenttaxane therapy,Anthracycline-based chemotherapy,Bevacizumab,晚期乳腺癌的內(nèi)分

47、泌治療 —針對Luminal A/B 的 MBC ER（+）PR（+）ER（+）或 PR（+）,內(nèi)分泌治療與化學治療,內(nèi)分泌改變腫瘤的內(nèi)環(huán)境來抑制其生長對正常細胞影響小，副作用小2～8周起效，緩解期長不需要升白、止吐等支持治療治療費用較低,化療阻斷腫瘤復制來殺死腫瘤細胞對正常細胞有殺傷，副作用大1～2周起效，緩解期短常需要升白、止吐等支持治療治療費用一般較高,晚期乳腺癌內(nèi)分泌治療適應(yīng)證,患者年齡＞35歲

48、無病生存期（DFS) ＞2年骨和軟組織轉(zhuǎn)移；無癥狀的內(nèi)臟轉(zhuǎn)移ER和／或PR陽性,晚期乳腺癌的內(nèi)分泌治療,月經(jīng)狀況 治療藥物 絕經(jīng)前 戈舍瑞林 (Goserelin， zoladex） 亮丙瑞林 (Leuprolide acetate） 絕經(jīng)后 瑞寧得

49、(Anastrozole ) 來曲唑( Letrozole) 依西美坦 各種年齡 他莫昔芬，孕激素,阿那曲唑的一線療效優(yōu)于TAM,‘Arimidex’ (anastrozole) versus Tamoxifen for the First-line Treatment of Advanced Breast Cance

50、r in Postmenopausal Womenfrom Trials 0030 and 0027 Known to be Receptor-positive,025試驗設(shè)計 :來曲唑 vs. 他莫昔芬 作為晚期一線治療,Mouridsen et al. J Clin Oncol. 2001;19: 2596.,試驗人群: 絕經(jīng)后; 局部晚期或局部復發(fā)或轉(zhuǎn)移的乳腺癌; ER 和/或 PgR陽性或未知,來曲唑的一線療效優(yōu)于TAM,

51、非甾體類 AI 失敗后的內(nèi)分泌治療MBC,芳香化酶抑制劑作用機理: 非甾體 VS 甾體,,,,雄激素,非甾體類（抑制劑）(eg, anastrozole, letrozole),芳香化酶,甾體類（滅活劑）(eg, exemestane),,,,,,,,,,,,,Geisler et al. Clin Cancer Res. 1998;4:2089-93.,EFECT: Evaluation of Treatment Options

52、 Following AI Failure,Fulvestrant IM injection loading-dose regimen* (n = 351),Exemestane25 mg/day orally (n = 342),Postmenopausal women with hormone receptor–positive, progressing/recurring advanced breast cance

53、r 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.

54、 Abstract 12.,EFECT: Similar TTP in Patients Treated With Fulvestrant or Exemestane,Gradishar W, et al. SABCS 2006. Abstract 12.,Exemestane： 3.7 monthsFulvestrant：3.7 months P=.65,絕經(jīng)后MBC的內(nèi)分泌治療,一線,二線,三線,TAM,孕激素

55、,雄激素,AI,TAM,孕激素,,輔助,AI,孕激素 ?,氟維司群 ?,TAM ?,,,,,,,1985~,2002~,,新方向 靶向聯(lián)合內(nèi)分泌,2008 SABCS,,EGF30008：拉帕替尼聯(lián)合來曲唑 隨機Ⅲ期臨床,2008 SABCS,PFS,,,,,P：拉帕替尼，L:來曲唑 T：TAM,絕經(jīng)后 ER/PR陽性 MBC一線,受體三陰性乳腺癌,Triple-Negative BC and PARP Inhibitio

56、n,BRCA1BRCA2,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

57、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

58、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

59、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

60、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,1. DNA damage via platinum adducts and DNA crosslinking,2. PARP1 up-regulation Base-excision repair,3. PARP1 inhibition,4. Replica

61、tion fork collapseDouble strand DNA break,CELL SURVIVAL,CELL DEATH,PARP1,PARP1,BSI-201,Pt,Pt,Pt,Pt,Pt,,,,,,,,,PARP1,PARP: 聚腺苷二磷酸核糖聚合酶,Phase II Trial of BSI-201: Schema,Patients receiving gemcitabine/carboplatin could

62、cross-over to the other treatment arm upon documented disease progression.,,,,RANDOMIZE,21-DayCycle,,BSI-201 (5.6 mg/kg, IV, d 1, 4, 8, 11)Gemcitabine (1000 mg/m2, IV, d 1, 8)Carboplatin (AUC 2, IV, d 1, 8)N=61,Ge

63、mcitabine (1000 mg/m2, IV, d 1, 8)Carboplatin (AUC 2, IV, d 1, 8)N=62,RESTAGINGPost-Cycle 2 & every 6-8 wks,Metastatic TNBCN = 120,Phase II Trial of BSI-201 Results: Efficacy,O’Shaughnessy et al. ASCO 2009;Abst

64、ract 3.,Phase II Trial of BSI-201 Results: Safety,No differences in hematologic or non-hematologic toxicitiesNo differences in GC dose reductions between arms,轉(zhuǎn)移性乳腺癌內(nèi)科治療共識,晚期乳腺癌的主要治療目的是提高患者的生活質(zhì)量，延長高質(zhì)量的生存期由于新藥的不斷問世以及合理使