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 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. 2002;359:2131. Thrlimann 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/B ER（+）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,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,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、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 （AB Vs. A） ORR TTP OS 或 聯(lián)合 Vs. 序貫 （AB Vs. AB） 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 有廣泛轉(zhuǎn)移或 有臨床癥狀，需要快速控制病情或 腫瘤進展迅速或 威脅生命的轉(zhuǎn)移或 患者的耐受性較好 優(yōu)先考慮單藥化療 無重要臟器轉(zhuǎn)移或 無臨床癥狀或 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、CEF AC、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-Line Doxorubicin 35-50%125-30%1 Epirubicin52-68%28% Paclitaxel29-63%119-57% Docetaxel47-65%139-58% Capecitabine 25%120-27%1 Gemcitabine 23-37%113-41%1 Vinorelbine 40-44%117-36%,1Esteva F et al, Oncologist 2001 (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;23:77947803,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;23:77947803,標準紫杉醇l (n = 224),注射用紫杉醇（白蛋白結(jié)合型） (n = 229),中位時間 = 23.0 周 (19.426.1),中位時間 = 16.9 wks (15.120.9),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. 2005;23:77947803,Capecitabine 1, 250mg/m2 BID days 114 + Docetaxel 175mg/m2 day 1,Docetaxel 100mg/m2 day 1,3-weekly cycles,n=255,n=256,OShaughnessy 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,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,OShaughnessy 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 GEM NVB 希羅達 NVB DDP/CBP GEM DDP/CBP,phase III Spanish Breast Cancer Research Group (GEICAM) trial 療效： 毒副作用： GEMNVB vs. NVB G3/4 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 GEMNVB vs. NVB,Lancet Oncology2007;8:219-225,gemcitabine 1200 mg/m2 days 1 and 8 vinorelbine 30 mg/m2 days 1 and 8 q21d,vinorelbine 30 mg/m2 days 1 and 8 q21d,PD,252 pts MBC pretreated with anthracyclines and taxanes,Epothilone: Ixabepilone (BMS-247550) Bristol-Myers Squibb, New York, NY,Activity in multiple tumor models Low susceptibility to tumor resistance mechanisms MRP and P-gp efflux pumps () tubuiln overexpression tubuiln mutations Antitumor activity in taxane resistance models,S. cellulosum,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 1-14, every 3 wks,Capecitabine 1250 mg/m2 orally BID Days 1-14 every 3 wks,Patients with metastatic or locally advanced breast cancer to anthracyclines PRE/ RESISTANT and taxaneRESISTANT,Stratified by visceral metastases 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% 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,4,0,8,12,16,20,24,0.0,0.2,0.4,0.6,0.8,1.0,28,32,36,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 3/4 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 Capecitabine 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 anti-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 or Doxorubicin (50 mg/m2) d1,every 3 weeks 6-8cycles N=459,CR /PR /SD,Paclitaxel 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, MANTA1 study,Possible Explanationfor MANTA1 study (Paclitaxel maintenance),Use of concurrent endocrine therapy in 60% of hormone receptor-positive patients Control arm patients actual received maintenance hormonal therapy The concurrent of chemo and hormonal may reduce the efficacy Toxicity of paclitaxel Sensory neuropathy grade 2 occurred in 26%, grade 3 in 6% and grade 4 in 2% of the patients in maintenance grade ANC 24%,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：ADM T：TXT PLD：脂質(zhì)體ADM,*Statistically significant; 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 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 HO551g HO650 （關(guān)鍵試驗） （期） （關(guān)鍵試驗） _ N (intent-to-treat) 222 46 114 #CR 8 1 7 #PR 26 4 23 有效率 15 11 26 中位緩解期（月） 9.1 6.6 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,Bontenbal et al. ASCO 2008. Abstract 1014.,99 例 HER2 +,一線 M+ 主要目的: PFS 次要目的: RR 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 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. OShaughnessy J et al. J Clin Oncol 2008: 26 (May 20 Suppl); abs 1015.,PCH 或wPCH,貝伐單抗,Paclitaxel Bevacizumab in MBC (E2100),N=715 Locally recurrent or 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 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 Bevacizumab in MBC (AVADO),N=705 Locally recurrent or 1st-line MBC Stratification: Region Prior taxane/time to relapse since adjuvant chemo Measurable disease HR status,R,Docetaxel 100mg/m2 + Placebo q3w,Docetaxel + Bevacizumab 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 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 and 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 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 28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 12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 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(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 Cancer 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,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 Following AI Failure,Fulvestrant IM injection loading-dose regimen* (n = 351),Exemestane25 mg/day orally (n = 342),Postmenopausal women with hormone receptorpositive, progressing/recurring advanced breast 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 Exemestane,Gradishar W, et al. SABCS 2006. Abstract 12.,Exemestane： 3.7 months Fulvestrant：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,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 Inhibition,BRCA1 BRCA2,1. DNA damage via platinum adducts and DNA crosslinking,2. PARP1 up-regulation Base-excision repair,3. PARP1 inhibition,4. Replication fork collapse Double 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 cross-over to the other treatment arm upon documented disease progression.,RANDOMIZE,21-Day Cycle,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,Gemcitabine (1000 mg/m2, IV, d 1, 8) Carboplatin (AUC 2, IV, d 1, 8) N=62,RESTAGING Post-Cycle 2 Abstract 3.,Phase II Trial of BSI-201 Results: Safety,No differences in hematologic or non-hematologic toxicities No 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用，晚期乳腺癌治療的療效不斷提高 化療與內(nèi)分泌治療是治療晚期乳腺癌的兩種同用有效地治療方法，但分別有各自的適應(yīng)證 對Her-2neu陽性的患者，化療聯(lián)合生物治療能顯著提高療效 通過合理的內(nèi)科治療，能顯著延長患者的生存期，部分患者甚至能夠長期生存,THANK YOU FOR YOUR ATTENTION,