轉(zhuǎn)移性乳腺癌的內(nèi)科治療squip

1、轉(zhuǎn)移性乳腺癌的化療,中山醫(yī)科大學(xué)腫瘤醫(yī)院內(nèi)科 劉冬耕,NCCN 2006,,蒽環(huán)類和紫杉類是主要化療方案蒽環(huán)類單藥療效40%左右。紫杉類單藥療效33%-50%。蒽環(huán)類與紫杉類聯(lián)合療效優(yōu)于蒽環(huán)類為主的聯(lián)合化療。首選的聯(lián)合治療方案 CAF/FAC/FEC/CMFAC/EC Paclitaxel+ADRDocetaxel+XelodaPaclitaxel+Gemcitabine首選的單藥和其他有效的藥物蒽環(huán)類 、紫

2、杉類、希羅達(dá)、NVB和健擇。鉑類\VP-16(po)、VLB、5-FU (civ),HER2陰性轉(zhuǎn)移性乳腺癌的一線治療,Anthracyclines （？）TaxanesPaclitaxel / AdriamicineXeloda / Taxotere(XT)Paclitaxel / Gemcitabine（GP）XelodaCMFOther,fitter patients with good performance s

3、tatus and rapidly progressing disease or visceral metastases might derive most benefit from more intensive combinationswhereas less fit patients or those with more indolent disease might derive more benefit from single-

4、agents.,卡培他濱 Capecitabine，Xeloda長春花堿酰胺 Vinorebine吉西他濱 Gemcitabine 鉑類（Cisplatin, Carpoplatin）,蒽環(huán)類與紫杉類失敗后的化療選擇,希羅達(dá)和泰索帝聯(lián)合與泰索帝單藥對照治療蒽環(huán)類失敗的MBC a large phase III trial,Xeloda 1250mg/m2 bid d1-14Taxotere 75mg/m2, day

5、1 q3w,Taxotere 100mg/m2, day 1 q3w,Primary endpoint: TTP,(n=255),(n=256),O’Shaughnessy J et al. J Clin Oncol 2002;20:2812–23,隨機(jī)分組,,,XT與Taxotere對照研究結(jié)果,所有病人用過蒽環(huán)類，80%內(nèi)臟轉(zhuǎn)移，2/3接受過2/3線研究藥物治療。

6、,單Doce更多中粒減少性發(fā)熱，聯(lián)合組更多3/4級腹瀉、胃炎和HFS.住院和SAE發(fā)生率相當(dāng)。,FDA 2001.09 批準(zhǔn)泰素帝/希羅達(dá)聯(lián)合治療轉(zhuǎn)移性乳腺癌,XT T P value Hazard Ratio ORR 42% 30% .006 TTP 6.1m 4.2m .0001OS 14.5m 11.5m .013

7、 0.77,O’Shaughnessy J et al. J Clin Oncol 2002;20:2812–23,Capecitabine in Taxane-pretreated Metastatic Breast Cancer,1. Blum JL et al. Eur J Cancer 2001;37:S190 (Abstract 693)2. Blum JL et al. Cancer 2001;92:

8、1759-1768.3. Reichardt P et al. Ann Oncol. 2003;14:1227-1233. 4. Fumoleau P et al. Eur J Cancer. 2004;40:536-542.,Gemcitabine in Anthracycline/Taxane-Refractory MBC,1. Valerio MR et al. Proc Am Soc Clin Oncol. 2001. A

9、bstract 1953. 2. Rha SY et al. Breast Cancer Res Treat. 2005;90:215-221. 3. Modi S et al. Clin Breast Cancer. 2005;6:55-60.,*Days 1, 8, and 15 every 21 days.,Vinorelbine in Refractory MBC,Multiple phase II studies (OR

10、R, 16%-34%)Degardin et al.1 (N = 100)CR + PR, 16%Median duration of response, 5 mos (range, 3-18) Livingston et al.2 (N = 40)CR + PR, 25%Median TTP, 13 weeksMedian survival, 33 weeks,1. Degardin et al., Ann Oncol.

11、 1994;5:423-426.2. Livingston RB et al., J Clin Oncol. 1997;15:1395-1400.,蒽環(huán)類和紫杉類方案失敗后的治療選擇，Xelo\NVB\GEM的療效大致相當(dāng)，但是毒性不同。三種藥物之間沒有直接對照的研究，選擇時(shí)更注重避免毒性重疊。,After Anthracyclines and Taxanes: Multiple Options,CapecitabineVinor

12、elbineGemcitabineIrinotecanVinflunineXRP 9881Ixabepilonenab-paclitaxel,Abraxane (ABI-007，楷素),1. Ibrahim NK et al., J Clin Oncol. 2005;23:6019-26.2. Blum JL et al., Proc Am Soc Clin Oncol. 2004. Abstract 543.,Album

13、in-bound paclitaxel, nanoparticle formulationPhase II trial, taxane-refractory MBC (N = 106)中國注冊研究已經(jīng)完成II、III期臨床FDA已經(jīng)批準(zhǔn)用于MBC治療,每周凱素治療紫杉類耐藥MBC 兩個(gè)Phase II Trial,OShaughnessy JA,凱素是納米白蛋白紫杉醇, 是第一個(gè)通過受體介導(dǎo)通道(gp60),使 腫瘤細(xì)胞紫杉醇濃

14、度更高。,紫杉類耐藥MBC，n=106,,凱素 100 mg/m2 /W 3 doses, 1 week of rest,ORR 15%PFS 12ms 13%1yr SR 38%,凱素 125 mg/m2 /W 3 doses, 1 week of rest,紫杉類耐藥MBC，n=75,安全性：G3/4：中粒減少，感覺神經(jīng)異常，血小板減少，黏膜炎,Vinflunine（長春富寧） After Anthracyc

15、line and Taxane Failure in MBC,Fumoleau et al., Proc Am Soc Clin Oncol. 2004. Abstract 542.,Novel semi-synthetic vinca alkaloid Inhibits tubulin assemblyNo stabilizing effect on assembled microtubulesPhase II study (N

16、 = 60)PR 30.0%, disease control (PR+SD) 63.3%PR 36.8%, disease control 57.9% in taxane-refractory (PFI < 3 mo) patientsGrade 3/4 neutropenia in 63.5% of patients, neutropenic infection in 5.8%,,,,Ixabepilone (BMS-2

17、47550，埃坡霉素),Epothilone B is a natural macrolide produced by the myxobacterium Sorangium cellulosum Ixabepilone is a semisynthetic analog of epothilone B (aza-epothilone B),Epothilone B,,Ixabepilone,,,,,,,,,,,,Antitumor

18、Activity in Taxane-Resistant PAT-21 Breast Cancer Xenografts,PAT-21 breast cancer xenografts are derived from a patient with MBC who received 10 cycles of CMF, then 4 cycles of paclitaxel. MTD=maximum tolerated dose.,M

19、edian tumor wt. (mg),,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,10,100,1000,40,70,100,130,160,Days posttumor implantation,,,Control,,,Ixabepilone (10 mg/kg, MTD),,,Paclitaxel (36 mg/kg, MTD),Control,,,Ixabepilone (13 mg/k

20、g, MTD),,,Docetaxel (20 mg/kg, MTD),,Vinorelbine (9 mg/kg, MTD),Days posttumor implantation,10,100,1000,40,50,60,70,80,90,Median tumor wt. (mg),,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Data on file, Bri

21、stol-Myers Squibb Company.,Clinical Response to Ixabepilone NCI-0229,Low. J Clin Oncol. 2005;23:2726-34.,,,,Phase III Clinical Trials ofIxabepilone Plus Capecitabine,Ixabepilone 40 mg/m2 q3wk plus Capecitabin

22、e 1000 mg/m2 bid x 14 days,Capecitabine 1250 mg/m2 bid x 14 days,,,Randomized,,,Conclusion,Ixabepilone very active in breast cancerAdvantages No steroid premedicationMinimal hypersensitivity reactions and nausea/ vomi

23、ting3%-5% Grade 3 peripheral neuropathyCombinations in progress,分子靶點(diǎn)藥物臨床研究,Hercecptin in Her2 + MBCBevazcizumab in MBC,Targeting Dysregulated Pathways With Novel Agents,HER tyrosine kinase inhibitors,Apoptosis,Ras s

24、ignaling,VEGF signaling,HER signaling,TP,,,,Apoptotic agents,,,Kinase inhibitors,Anti-HER MAbs,Tumor-activatedchemotherapy,Anti-VEGF MAbs and other molecules,Strategies for ErbB Receptor Inhibition,Monoclonal antibodie

25、s (MAbs) against erbB receptorsSmall-molecule tyrosine kinase inhibitors (SMTKIs),Her2 過表達(dá)的MBC的治療,,人類表皮生長因子 (HER2), 也稱做 c-erbB-2 和HER2/neu, 能促進(jìn)細(xì)胞生長和腫瘤發(fā)生。在原發(fā)性乳腺癌患者中 25% to 30%有 HER2 蛋白過度表達(dá)，這些患者通常具有早期復(fù)發(fā)和生存期較短的臨床特征。Trastu

26、zumab 是一種人源化的重組 DNA 單克隆抗體，能夠選擇性與細(xì)胞表面 HER2決定簇結(jié)合。有 HER2 過度表達(dá)的轉(zhuǎn)移性乳腺癌患者，赫賽丁單藥治療具有抗腫瘤療效 。與單純化療比較，與化療聯(lián)合應(yīng)用時(shí)能提高療效、并且能延長生存。,赫賽丁單藥治療的客觀療效Study H0649g,赫賽丁單藥一線治療MBC Study H0650 Response Rate,N=114 patients 2mg/

27、kg Vs 4mg/kg Complete responses7ptPartial responses23 ptOverall response rate30 pt (26%)Time to response 1.8moResponse duration 11-22mo,赫賽丁與化療聯(lián)合一線治療MBC ORR (HO648g),Design and enrolment,No prior anthracycl

28、ines,Prior anthracyclines,Paclitaxel(n=96),Herceptin® + paclitaxel(n=92),AC(n=138),Herceptin® + AC(n=143),Eligible patients (n=469),Comparative Study HO648gOverall ORR,P - value 0.1038 0.0001,Co

29、mparative Study HO648gTime-to-Disease Progression,H + P (n = 92)median = 6.9 moP (n = 96)median = 3.0 mo,,,H + AC (n = 143)median = 8.1 moAC (n = 138)median = 6.1 mo,,,p = 0.0003,p = 0.0001,Overall survival,C

30、T patients treated withHerceptin® after disease24%62%65%progression,,1.00.80.60.40.20,0515253545,H + CTCT,Probability of survival,25.4 months (?25%),20.3 months,,,RR=0.76p=0.025,Time (months),Mean c

31、ombination index values for chemotherapeutic drug/Herceptin® combinations in vitro,*5'-dFUrd is a metabolite of Xeloda®; Herceptin® plus Xeloda® demonstrates additive activity in vivo3,1Konecny G,

32、 et al. Breast Cancer Res Treat 1999;57:114 (Abstract 467)2Pegram M, et al. Oncogene 1999;18:2241–513Fujimoto-Ouchi K, et al. Cancer Chemother Pharmacol 2002;49:211–16,Herceptin與每周paclitaxel (n=95),Phase II trial of He

33、rceptin® plus weekly paclitaxel (90mg/m2)RRs in 70–80% range in HER2-positive patients169% (DAKO) 67% (PAb1) 76% (CB11) 81% (TAB250) 75% (FISH) Used by Intergroup to develop adjuvant designWidely used in the

34、 clinical setting in the USA and Australia,1Seidman AD, et al. J Clin Oncol 2001;19:2587–95,Herceptin 聯(lián)合 docetaxel Phase II trials,Herceptin® was administered as a 4mg/kg initial dose followed by 2mg/kg weekly unti

35、l progression,Herceptin 與 vinorelbine聯(lián)合,1Burstein H, et al. J Clin Oncol 2001;19:2722–302Jahanzeb M, et al. Breast Cancer Res Treat 2001;69:284 (Abstract 429),Herceptin與 gemcitabine聯(lián)合,Phase II study (n=59) of Herceptin&

36、#174; plus gemcitabine (1,200mg/m2 day 1 and 8 q3-weekly)RR = 33% (22/59)In patients with IHC 3+ disease, RR = 45% (17/38),O’Shaughnessy JA, et al. Breast Cancer Res Treat 2001;69:302 (Abstract 523),Herceptin與 docetaxe

37、l和platinum 聯(lián)合（First-line）,Herceptin® in combination with docetaxel and cisplatin (BCIRG 101)RR = 79% (49/62)Herceptin® in combination with docetaxel and carboplatin (BCIRG 102)RR = 56% (31/55)This regimen

38、is being investigated in phase III trials in the adjuvant (006) and metastatic (007) settings,Nabholtz J-M, et al. Eur J Cancer 2001;37:S190 (Abstract 695),Herceptin與 Xeloda聯(lián)合,In patients pretreated for metastatic brea

39、st cancerRR = 62% (8/13) when Xeloda® was administered at a dose of 1,125mg/m2 b.i.d.1RR = 53% (9/17) when Xeloda® was administered at a dose of 1,000mg/m2 b.i.d.2The combination was well toleratedAdditiona

40、l trials to further examine this combination include a randomised phase II trial of Herceptin® plus docetaxel ± Xeloda®,1Bangemann N, et al. Ann Oncol 2000;11:143 (Abstract 653P)2Bangemann N, et al. Breas

41、t Cancer Res Treat 2000;64:123 (Abstract 530),M77001: trial design,HER2-positive MBC (IHC 3+ and/or FISH+) n=188,Docetaxel*100mg/m2 q3w x 6,Docetaxel100mg/m2 q3w x 6,Herceptin®4mg/kg loading,? 2mg/kg weekly un

42、til PD,+,*Patients progressing on docetaxel alone could crossover to receive Herceptin®,,,Two patients did notreceive study medication n=92,n=94,M77001: efficacy summary,*Kaplan-Meier estimate,Intent-to-treat popu

43、lation, 12-month cut-off,Herceptin in metastatic breast cancer,Evidence supports Herceptin therapy in HER-2overexpressing metastatic breast cancer1.Herceptin with chemotherapy in first lineimproved time to treatment

44、failureincreased response ratesimproved survival2.Herceptin monotherapy active in first line and in second/third linefavourable safety profilesurvival data in first line not inferior to combination therapy,3藥聯(lián)合治療

45、Her2 Overexpress MBC Weekly VS 3weekly---NCCTG,,Chemotherapy + Trastuzumab x 6 mo ® Trastuzumab q3w,1st Line HER2+ MBC,PI: Perez EA,Response to Therapy(Interim Analysis),50%,Overall Response,56%,27%,1-year PFS,13.4

46、 mo,8.8 mo,Median PFS,61%,39%,Partial Response,78%,11%,Complete Response,weekly(n=18),q3w(n=18),,,,,,,,,,,,,,,,,,,,,,Survival(Interim Analysis),81%,50%,2- year OS,,100%,89%,1- year OS,weekly(n=18),q3w(n=18),,,,,,,,

47、,,,,,,,,,,,Adverse Events: Hematologic(70 Evaluable Patients),-,-,3%,15%,Febrile Neutropenia,-,6%,-,29%,RBC Transfusion,-,3%,-,18%,Anemia,-,3%,-,35%,Thrombocytopenia,11%,44%,71%,18%,Neutropenia,4,3,4,3,NCI Grade,weekly

48、(n = 36),q3w(n = 34),,,,,,,,,,,,,,,,,,p*,0.003,0.01,0.005,0.05,0.01,* p-value from Fisher’s Exact test; post-hoc analysis,,,,,,,,,Adverse Events: Non-Hematologic(70 Evaluable Patients),-,-,-,9%,-,3%,-,24%,-,47%,-,68%,A

49、lopecia (grade 2),,,,,Neuropathy,-,3%,-,18%,Myalgia,-,8%,6%,6%,Hypersensitivity,-,11%,-,12%,Fatigue,-,8%,-,15%,Arthralgia,4,3,4,3,NCI Grade,weekly(n=36),q3w(n=34),,,,,,,,,,,,,,,,,,,,,,,,,,,,p*,0.47,1.0,0.71,0.05,0.11,0

50、.012,0.10,* p-value from Fisher’s Exact test; post-hoc analysis,Motor,Sensory,,,,,,,,,,Conclusions,Both q3w and weekly regimen of carboplatin, paclitaxel, and trastuzumab are highly active in HER2+ MBC Weekly regimen is

51、 better tolerated Therapeutic ratio of carboplatin, paclitaxel, and trastuzumab in HER2+ MBC is improved with weekly regimen,Forbes JF, et al. ASCO 2006. Abstract 516.,BCIRG 007: First-Line Trastuzumab + Docetaxel ±

52、; Carboplatin HER2+ MBC,BCIRG 007: First-Line Trastuzumab + Docetaxel ± Carboplatin HER2+ MBC,Median follow-up: 27.6 monthsTime to progression equivalent between arms (P = .57)TH: 11.07 monthsTCH: 10.35 monthsSi

53、milar overall responseTH: 72.5%TCH: 72.7%Median survival: > 40 months,Forbes JF, et al. ASCO 2006. Abstract 516.,BCIRG 007: First-Line Trastuzumab + Docetaxel ± Carboplatin HER2+ MBC,Different toxicity profile

54、s noted with each treatmentTH: neuropathy, myalgia, rash, nail changes, neutropeniaTCH: thrombocytopenia, nausea, vomiting,Forbes JF, et al. ASCO 2006. Abstract 516.,CerbB2 Over-expressed MBC Herceptin聯(lián)合化療的首選方案,Paclita

55、xel+/-CarboplatinDocetaxel +/-CarboplatinVinorebine,NCCN 2004,Tykerb (lapatinib)—A Dual Receptor Tyrosine Kinase Inhibitor,Potent, oral, reversible dual tyrosine kinase inhibitorBinds to ATP site of erbB-1 and erbB-2

56、receptor kinases, blocking kinase activity and downstream signaling,Strategies for ErbB Receptor Inhibition,Monoclonal antibodies (MAbs) against erbB receptorsSmall-molecule tyrosine kinase inhibitors (SMTKIs),Lapatinib

57、: 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 ErbB famil

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

59、EGF100151: Lapatinib + Capecitabine in Advanced Breast Cancer (cont’d),Addition of lapatinib to capecitabine in women with treatment-refractory, advanced metastatic breast cancer associated withLonger time to progressio

60、n36.9 vs 19.7 wks (P = .00016)Longer progression-free survival36.9 vs 17.9 wks (P = .000045)Fewer progressions or deaths38% vs 48%Response (independent review)Overall: 22.5% vs 14.3% (P = .113),Geyer CE, et al. AS

61、CO 2006. Clinical Science Symposium.,EGF100151: Lapatinib + Capecitabine in Advanced Breast Cancer (cont’d),Geyer CE, et al. ASCO 2006. Clinical Science Symposium.,EGF103009: Lapatinib Monotherapy in Relapsed/Refractory

62、IBC,58 women with relapsed or refractory inflammatory breast cancer given lapatinib 1500 mg/day in phase II studyMedian prior chemotherapy regimens: 4.5 (range: 0-21)Response rates in ErbB2 overexpressers: 62% All cl

63、inical respondersErbB2 (IHC 3+/FISH+)p-ErbB2+Response rates in ErbB1 overexpressers: 8.3%,Spector NL, et al. ASCO 2006. Abstract 502.,Targeting HER2 via HSP-90,Heat shock protein-90 (HSP-90) is a chaperone protein for

64、 a variety of oncogenic proteins, including HER2, ER/PR, AKT, MET, and Raf kinase17-AAG (KOS-953), an inhibitor of HSP-90, suppresses tumor growth in mouse xenograft models of HER2+ human breast cancers,Modi S, et al.

65、ASCO 2006. Abstract 501.,17-AAG + Trastuzumab,Partial response: 159% ↓ in lung metastasisTumor regression: 4All HER2+ MBC who progressed on trastuzumabDecreases in lung, nodal, breast metastases notedStable disease:

66、 4 (≥ 4 months)Phase II trial of 17-AAG (450 mg/m2) + trastuzumab in HER2+ metastatic breast cancer ongoing,Data from phase I trial of 17-AAG + trastuzumab reportedWeekly 17-AAG (various doses) + standard weekly tra

67、stuzumab 25 patients with various solid tumor types evaluatedLargest proportion had HER2+ overexpressing breast cancerMaximum 450 mg/m2 dose well tolerated1 grade 2 thrombocytopenia,Modi S, et al. ASCO 2006. Abstrac

68、t 501.,單藥紫杉醇 vs lapatinib+紫杉醇一線治療Her2過表達(dá)MBCPhase III,首次復(fù)發(fā)的 轉(zhuǎn)移性乳腺癌有可測量病灶Her2過渡表達(dá)（IHC+++ or FISH +）,抗血管生成因子治療,Targeting Dysregulated Pathways With Novel Agents,HER tyrosine kinase inhibitors,Apoptosis,Ras signaling,V