转移性乳腺癌的内科治疗(Squip)

转移性乳腺癌的化疗,中山医科大学肿瘤医院内科 刘冬耕,NCCN 2006,蒽环类和紫杉类是主要化疗方案蒽环类单药疗效40%左右。紫杉类单药疗效33%-50%。蒽环类与紫杉类联合疗效优于蒽环类为主的联合化疗。首选的联合治疗方案 CAF/FAC/FEC/CMFAC/EC Paclitaxel+ADRDocetaxel+XelodaPaclitaxel+Gemcitabine首选的单药和其他有效的药物蒽环类 、紫杉类、希罗达、NVB和健择。铂类VP-16(po)、VLB、5-FU (civ),HER2阴性转移性乳腺癌的一线治疗,Anthracyclines （？）TaxanesPaclitaxel / AdriamicineXeloda / Taxotere(XT)Paclitaxel / Gemcitabine（GP）XelodaCMFOther,fitter patients with good performance status 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-agents.,卡培他滨 Capecitabine，Xeloda长春花碱酰胺 Vinorebine吉西他滨 Gemcitabine 铂类（Cisplatin, Carpoplatin）,蒽环类与紫杉类失败后的化疗选择,希罗达和泰索帝联合与泰索帝单药对照治疗蒽环类失败的MBC a large phase III trial,Xeloda 1250mg/m2 bid d1-14Taxotere 75mg/m2, day 1 q3w,Taxotere 100mg/m2, day 1 q3w,Primary endpoint: TTP,(n=255),(n=256),OShaughnessy J et al. J Clin Oncol 2002;20:281223,随机分组,XT与Taxotere对照研究结果,所有病人用过蒽环类，80%内脏转移，2/3接受过2/3线研究药物治疗。,单Doce更多中粒减少性发热，联合组更多3/4级腹泻、胃炎和HFS.住院和SAE发生率相当。,FDA 2001.09 批准泰素帝/希罗达联合治疗转移性乳腺癌,XT T P value Hazard Ratio ORR 42% 30% .006 TTP 6.1m 4.2m .0001OS 14.5m 11.5m .013 0.77,OShaughnessy J et al. J Clin Oncol 2002;20:281223,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;92:1759-1768.3. 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. Abstract 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 (ORR, 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. 1994;5:423-426.2. Livingston RB et al., J Clin Oncol. 1997;15:1395-1400.,蒽环类和紫杉类方案失败后的治疗选择，XeloNVBGEM的疗效大致相当，但是毒性不同。三种药物之间没有直接对照的研究，选择时更注重避免毒性重叠。,After Anthracyclines and Taxanes: Multiple Options,CapecitabineVinorelbineGemcitabineIrinotecanVinflunineXRP 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.,Albumin-bound paclitaxel, nanoparticle formulationPhase II trial, taxane-refractory MBC (N = 106)中国注册研究已经完成II、III期临床FDA已经批准用于MBC治疗,每周凯素治疗紫杉类耐药MBC 两个Phase II Trial,OShaughnessy JA,凯素是纳米白蛋白紫杉醇, 是第一个通过受体介导通道(gp60),使 肿瘤细胞紫杉醇浓度更高。,紫杉类耐药MBC，n=106,凯素 100 mg/m2 /W 3 doses, 1 week of rest,ORR 15%PFS 12ms 13%1yr SR 38%,凯素 125 mg/m2 /W 3 doses, 1 week of rest,紫杉类耐药MBC，n=75,安全性：G3/4：中粒减少，感觉神经异常，血小板减少，黏膜炎,Vinflunine（长春富宁） After Anthracycline 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 = 60)PR 30.0%, disease control (PR+SD) 63.3%PR 36.8%, disease control 57.9% in taxane-refractory (PFI 40 months,Forbes JF, et al. ASCO 2006. Abstract 516.,BCIRG 007: First-Line Trastuzumab + Docetaxel Carboplatin HER2+ MBC,Different toxicity profiles 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联合化疗的首选方案,Paclitaxel+/-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 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: 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 family 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.,EGF100151: Lapatinib + Capecitabine in Advanced Breast Cancer (contd),Addition of lapatinib to capecitabine in women with treatment-refractory, advanced metastatic breast cancer associated withLonger time to progression36.9 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. ASCO 2006. Clinical Science Symposium.,EGF100151: Lapatinib + Capecitabine in Advanced Breast Cancer (contd),Geyer CE, et al. ASCO 2006. Clinical Science Symposium.,EGF103009: Lapatinib Monotherapy in Relapsed/Refractory 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 clinical 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 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. 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: 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 trastuzumab 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. Abstract 501.,单药紫杉醇 vs lapatinib+紫杉醇一线治疗Her2过表达MBCPhase III,首次复发的 转移性乳腺癌有可测量病灶Her2过渡表达（IHC+ or FISH +）,抗血管生成因子治疗,Targeting Dysregulated Pathways With Novel Agents,HER tyrosine kinase inhibitors,Apoptosis,Ras signaling,VEGF signaling,HER signaling,TP,Apoptotic agents,Kinase inhibitors,Anti-HER MAbs,Tumor-activatedchemotherapy,Anti-VEGF MAbs and other molecules,Agents Targeting the VEGF Pathway,Podar and Anderson. Blood. 2005;105:1383,VEGFR-2,VEGFR-1,Endothelial cell,Small-moleculeVEGFR inhibitors (PTK787, SU11248, ZD6474, BAY 43-9006),Anti-VEGFR antibodies(IMC-1121b),VEGF,Anti-VEGF antibodies(bevacizumab),Soluble VEGFRs(VEGF-TRAP),Capecitabine Bevacizumab for MBC,Significantly increased response in combination arm19.8% vs 9.1%; P = .001No significant difference in PFS or OS, combination vs single agentPFS, 4.86 vs 4.17 mos, HR = 0.98; OS 15.1 vs 14.5 mos,Miller KD et al. J Clin Oncol. 2005;23:792-799.,Capecitabine (n = 230),Capecitabine + Bevacizumab (n = 232),Patients with MBCPreviously treated with A/T,Capecitabine Bevacizumab for MBC,Miller KD et al. J Clin Oncol. 2005;23:792-799.,Eligible patients had received anthracycline and taxane treatment1 or 2 prior chemotherapy regimens for MBC, orRelapse within 12 months of completing anthracycline- and taxane-containing adjuvant therapyStudy regimen included bevacizumab 15 mg/kg IV q3w, capecitabine 1250 mg/m2 po BID x 14d q3w,Bevacizumab的其他研究,Miller and colleagues2 比较capecitabine with and without bevacizumabIn 462 patients 一线MBC capecitabine 2500 mg/m2/day 14 d q 21day alone capecitabine 2500 mg/m2/day+ bevacizumab 15 mg/kg d1虽然RR在XB组较高（19.8%) vs X alone (9.1%)，但是 PFS (XB 4.86 m vs 4.17 ms X alone) 或 OS (XB 15.1 ms vs X 14.5 ms )都没有改善。 与Herceptin+Paclitaxel在改善PFS vs OS的疗效十分相似，是以往细胞毒方案所不能比拟的，显示十分重要的前景。有可能成为Her2阴性乳癌的一线治疗。,Miller et al. ASCO 2005. Oral presentation during symposium, Advances in Monoclonal Antibody Therapy for Breast Cancer.,Bevacizumab 10 mg/kg Days 1, 15 + Paclitaxel 90 mg/m2 Days 1, 8, 15(n = 365),Paclitaxel 90 mg/m2 Days 1, 8, 15(n = 350),Patients with locally recurrent or metastatic breast cancer, ECOG performance status score 0-1(N = 715),Stratified by disease-free interval, number of metastatic sites, adjuvant chemotherapy, andestrogen receptor status,Bevacizumab Paclitaxel 1st linefor Locally Recurrent or Metastatic Disease,Eastern Cooperative Oncology Group (ECOG) 2100 trialFirst planned interim analysis of randomized, first-line, phase 3 trial,Miller et al. ASCO 2005. Oral presentation during symposium, Advances in Monoclonal Antibody Therapy for Breast Cancer.,Bevacizumab Paclitaxel for Locally Recurrent or Metastatic Disease,PFS significantly longer with combination therapy10.97 months vs 6.11 months HR = 0.498 (95% CI, 0.401-0.618), P .001Overall survival significantly higher for patients receiving bevacizumab + paclitaxel vs paclitaxel aloneHR = 0.674 (95% CI, 0.495-0.917), P = .01Overall response significantly better for patients treated with bevacizumab +paclitaxel2