（刘晓安）乳腺癌分子分型及其治疗策略

乳腺癌分子分型及其治疗策略,王水 刘晓安,乳腺癌分子分型,2000年美国斯坦福大学Perou和Sorlie等通过cDNA微阵列技术分析来自42个乳腺癌患者65份手术切除标本的基因表达特征，将乳腺癌分为5个亚型：,基底细胞样型 (basal-like phenotype, BP),各亚型治疗方法和预后明显不同,Luminal A型,正常乳腺样型,Luminal B型,HER2过表达型,乳腺癌分子亚型分类的基因表达谱与免疫表型特点,三阴性乳腺癌,ER-/PR-/erbB2-乳腺癌 生物学行为不同于其它乳腺癌的分子亚型 每年发病180,000例（全球） 占所有乳腺癌的10-17 首选化疗,三阴性乳腺癌,相对年轻（50岁） 肿瘤发展快 更具侵袭性 治疗后出现复发的时间短，1-3年 脑转移多见 生存期短,Clin Cancer Res. 2007; 13; 44294434.,“三阴性乳腺癌”与“basal-like乳腺癌”,三阴性乳腺癌 （免疫组化分析）,ER-，PR-，erbB2- （cyclinD1-，CK5/6/17+，EGFR+，Vimentin+，nestin+）,Basal-like 乳腺癌 （基因表达芯片分析）,三阴性乳腺癌=Basal-like乳腺癌？,检测方法不同 Basal-like乳腺癌：ER-/PR-/erbB2-/CK5+/CK6+/EGFR+（IHC） 三阴性乳腺癌： 56%-84%表达CK和EGFR,Clin. Cancer Res. 2004; 10; 53675374,BRCA1突变乳腺癌,BRCA1功能,BRCA1突变乳腺癌与basal-like乳腺癌,散发性basal-like乳腺癌具有与BRCA1突变乳腺癌相似的分子表达谱 散发性basal-like乳腺癌中BRCA1通路存在功能缺陷 Basal-like乳腺癌中的60存在BRCA1基因启动子的甲基化 ID4是BRCA1的阴性调节分子，在basal-like乳腺癌中ID4表达升高,BRCA1突变乳腺癌,J of Clinical Oncology,2008;26:4282,BRCA1突变乳腺癌,胚系BRCA1突变 家族聚集性 发病年龄异常年轻 预后差 P53表达 ER-/PR-/erbB2-比例高 对铂类药物相对敏感,TN、BP和BRCA1乳腺癌相关性,Leslie K. et al. Adv. Anat. Pathol. 2007; 14: 419-430,分子分型的临床意义,分子分型对预后的判断 Luminal A型预后最佳，Luminal B型和Normal breast like型预后较好，basal like型和HER2过表达型存活期最短，预后较差 Luminal A型、luminal B型、HER2过表达型、basal like型、Normal breast like型的5年生存率分别为95%、50%、30%、10%、50%,Molecular Typing and Survival,Overall Survival (mon.),Relapse free Survival (mon.),Solie et al. PNAS 2001; 98:10869-10874,Luminal A,Normal breast-like,Luminal B+C,Her-2,Basal type,Cheang, M. C.U. et al. Clin Cancer Res 2008;14:1368-1376 3744 breast cancer cases in British Columbia,Parsing the triple-negative subset of breast cancer,Core basal = TN with + EGFR and/or CK5/6 (2/3rds) 5NP = “five” marker negative phenotype (1/3rd),TNBC早期复发率高,Others,Triple negative,Tischkowitz et al. BMC Cancer 2007;134:7,Canada 456 pts,TNBC远处转移更多,Rebecca Dent et al. CCR 2007;13(15):4429,Despite more patients in TN group received C/T: 48.6 v.s 25.5%,分子分型预测对治疗的反应 Luminal A 型HER2- ，内分泌治疗效果明显优于Luminal B型，但对化疗不敏感 Luminal B 型HER2 + ，对TAM耐药，但对芳香化酶抑制剂敏感 HER2过表达型ER-且PR-，故内分泌治疗效果差，但含有蒽环类的化疗方案以及抗HER2的靶向治疗药物赫赛汀的应用可以显著改善其预后 Basal like型预后较其他亚型差，但化疗可明显改善其预后 Normal breast like型对化疗最不敏感,三阴性乳腺癌的治疗策略,化疗药物 最优化使用已有的化疗药物 新的靶向药物,CALGB 9344 : Response to Taxane by Breast Cancer ER / HER2 status,Hayes D. et al. N Engl J Med, 2007; 357:1496,Triple negative,Luminal B,BCIRG001: Effect in Subsets,Hugh J et al. J Clin Oncol , 2009; 27:1168,HR-/HER2+,Luminal A,Disease-Free Survival ER/HER2 Subgroups Compared in Trials,Adapted from Piccart-Gebhart MJ, ASCO, 2009a,转移性TNBC临床试验,顺铂新辅助化疗在BRCA1突变及三阴性乳腺癌的运用,1Gronwald et al. J Clin Oncol 2009; 27(suppl):7s (abstract 502) 2Garber et al. Breast Cancer Res Treat 2006; 105(suppl1):S149 (abstract 3074) 3Ryan et al. J Clin Oncol 2009; 27(suppl):18s (abstract 551) Leone et al. J Clin Oncol 2009; 27(suppl):37s (abstract 625),*包括 T1 (n = 10) and N0 (n = 18) *包括BRCA1突变 *回顾性研究的亚组分析,高剂量组与剂量密集组对三阴性乳腺癌生存率的影响,随机化（n=236),C600M40F600,E90C600,E90C3000Thiotepa400,E90C600,DD组,HD组,Annals of Oncology 19: 861870, 2008,高剂量组与剂量密集组对三阴性乳腺癌生存率的影响,高剂量组（HD）和剂量密集组（DD）中三阴性乳腺癌的5年生存率分别为71和26。,Annals of Oncology 19: 861870, 2008,Paclitaxel每周方案与三周方案比较,激素受体阴性组（包括三阴性乳腺癌），paclitaxel每周方案可提高DFS 40。 Engl J Med 358:1663-1671, 2008 Paclitaxel每周方案使激素受体阴性乳腺癌的pCR绝对值提高25，从而总生存率提高6.5%。 J Clin Oncol 23:5983-5992, 2005,新的化疗药物,埃博霉素（epothilone） 新一代抗有丝分裂药物 机制类似于taxane 不受多药耐药蛋白的影响 可用于蒽环类和紫杉类耐药的患者,新的化疗药物,伊沙匹隆（ixabepilone） epothiloneB内酰胺类似物 新辅助化疗II期试验，单药40mg/m2，4次 对各种分型的乳腺癌有效，尤其是三阴性乳腺癌 原发肿瘤pCR 29%（三阴性） vs 18% 淋巴结pCR 19%（三阴性）vs 11%,J Clin Oncol 2008,27:526-534.,靶向治疗,PARP抑制剂 ADP聚合酶抑制剂 PARP是DNA损伤修复的关键酶 临床前研究表明BRCA1/2突变细胞株对PARP抑制剂非常敏感,Nature. 2005 Apr 14;434(7035):913-7.,BRCA1功能丢失,PARP1与DNA修复,TNBC分子靶向药物,HER2阳性乳腺癌的治疗策略,HER2的检测,Positive 3+,Reported as HER2 positive,Eligible for treatment,IHC,Equivocal 2+,ISH,HER2在乳腺癌中的阳性率,Study,n,Stage,HER2 positive, %,Acosta 2001 Ross 2003 Owens 2004a Press 2005b Francis 2007 Gown 2008a Ferno 2007 Penault-Llorca 2008 UK NEQAS 2007,9307 5227 16,092 2502 6512 6604 5043 2079 30,720,I-IV I-III I-IV I-IV NS NS NS I-III I-IV,20 24 23 26 17 20 14 16 15,aData from high-throughput laboratories; bBCIRG reference laboratory EBC, early breast cancer; IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation; NS, not specified; NEQAS, National External Quality Assessment Scheme; BCIRG, Breast Cancer International Research Group,Method,IHC / FISH NS FISH only FISH only IHC IHC / FISH IHC / FISH IHC / FISH FISH,HER2在早期乳腺癌中的阳性率,HER2 阳性提示预后不良,Pauletti et al 2000,总生存率 (%),时间 (months),0,12,60,96,120,100,90,80,70,60,50,40,24,36,48,72,84,108,Log-rank p=0.0004 Wilcoxon p=0.0009,EBC patientsa HER2 negative (n=771) HER2 positive (n=189),aUnselected stage I, II and III breast cancer patients,HER2 阳性在早期乳腺癌中提示预后不良，甚至是 1 cm的肿瘤,Curigliano 2009 Amar 2007 Gonzalez-Angulo 2009 Joensuu 2003 Press 1997,T1a,b T1a,b T1a,b T1b T1a,b,5-year DFS 35-month RFS 5-year RFS 9-year RFS 3-year BCSS,0.091 0.013 0.007 0.0001 0.003 0.0002,Study,150 270 965 65 232,n,Tumour size,End point,p value,DFS, disease-free survival; RFS, recurrence-free survival; BCSS, breast cancer-specific survival; HR, hormone receptor,92 vs 99 91a vs 92a 92.6 vs 98.6 77.1 vs 93.7 67 vs 95 70.5 vs 91.5,HER2+ vs HER2-,aHR-positive group,赫赛汀改善 HER2阳性病人的生存,Patients with HER2-positive MBC now have comparable outcomes with HER2-negative MBC,Dawood et al 2010,aIHC 3+ population; ns, not significant,Smith et al 2001; Marty et al 2005; Robert et al 2006; Pegram et al 2007,赫赛汀作为一线方案 在转移性乳腺癌治疗（MBC）中有生存优势,D H+D,P H+P,H+D DCarboH,H+P PCarboH,HO648ga,M77001,BCIRG007,US Oncologya,OS (months),p0.05,ns,p=0.033,ns,化疗,Herceptin + 化疗,赫赛汀在IHC 3+ FISH-乳腺癌中的应用,H0648g data,Risk ratio=0.40 95% confidence interval=0.19, 0.87 n=43,Patients (%),Time (months),Herceptin + chemotherapy,Chemotherapy alone,Time to progression,/ohrms/dockets/ac/01/slides/3815s1_07_Jerian/sld001.htm,Ana Ana H,2.4 4.8,6.8 20.3,Trial,Median PFS, months,ORR, %,赫赛汀与AIs 在激素受体及HER2阳性的转移性乳腺癌病人中的应用,0.018,p value,TAnDEM,Let Let H,3.3 14.2,13 27,0.018,eLEcTRAb,Patients, n,Study drug,104a 103,31 26,Huober et al 2009; Johnston et al 2009; Kaufman et al 2009,AI, aromatase inhibitor; Ana, anastrozole; Let, letrozole; Lap, lapatinib; PFS, progression-free survival; ORR, overall response rate; TTP, time to progression,EGF30008,a73 patients crossed over to receive H; breported as TTP,Let Let Lap,108 111,3.0 8.2,15 28,0.021,GBG-26: continuation of Herceptin beyond progression provides clear benefits,von Minckwitz et al 2009,aMedian TTP in months (time between randomisation and documented disease progression or disease-related death) Median follow-up: 15.6 months,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,40,0,0,20,100,80,60,40,Time (months),10,20,30,77 74,55 40,29 15,12 8,4 5,3 3,1 2,1 1,1 1,Hazard ratio=0.69 p=0.034,8.2a,5.6a,Herceptin + Xeloda (n=78) Xeloda (n=78),Not within EMEA-approved indication for Herceptin,Probability of progression (%),赫赛汀辅助治疗（13,000 病人）,Piccart-Gebhart et al 2005; Romond et al 2005; Slamon et al 2006,NCCTG N9831 (USA),BCIRG 006 (global),NSABP B-31 (USA),IHC / FISH n=3505,1 year,FISH n=3222,IHC / FISH n=2006,Doxorubicin + cyclophosphamide,Standard chemotherapy,HERA (ex-USA),IHC / FISH n=5102,Observation,2 years,1 year,1 year,1 year,1 year,1 year,IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation,赫赛汀辅助治疗总生存（OS）长期随访结果,Perez et al 2007; Smith et al 2007; Gianni et al 2009; Slamon et al 2009,0,1,2,HERA CTx H 1 year,NSABP B-31 / N9831 AC TH H,Favours trastuzumab,Favours no trastuzumab,HR,BCIRG 006 AC TH H,BCIRG 006 TCH,4,3,Median follow-up, years,5,5,HERA CTx H 1 year,2,Not confounded by crossover,Confounded by crossover,EBC, early breast cancer; ITT, intent to treat,Weisgerber-Kriegl et al 2008,Patients (n),20,000,Year,18,000,16,000,14,000,12,000,10,000,8,000,6,000,4,000,2,000,0,2000,2005,2010,2015,MBC, metastatic breast cancer,赫赛汀（trastuzumab）有效预防复发 欧洲28,000 病人超过10年的随访,主要的方案: 序贯治疗 (ChemotherapyH) 与含蒽环类方案联合运用 (ACTHH) 与不含蒽环类化疗方案联合运用 (TCH) 根据肿瘤的性质和病人自身特点选择治疗方案 获益率/风险 病人的选择,治疗策略,赫赛汀在HER2阳性病人中的应用指南,EBC NCCN Consider Herceptin for node-negative tumours 0.6-1 cm Use Herceptin for node-negative tumours 1 cm or node-positive tumours ESMO Treat HER2-positive node-negative tumours 1 cm or node-positive tumours with Herceptin St Gallen Treat HER2-positive tumours 1 cm and HER2-positive, node-positive tumours with Herceptin,MBC Both NCCN and ESMO recommend 1st line: Herceptin + chemotherapy Beyond progression: maintain HER2 suppression with Herceptin or lapatinib,Cardoso et al 2009; Goldhirsch et al 2009; Kataja et al 2009; NCCN 2010, ,正在进行的临床验证: 治疗时间,Treatment duration,6 months vs 1 year PHARE Persephone,9 weeks vs 1 year SHORT-HER SOLD,1 year vs 2 years HERA,Results expected 2011 onwards,EMEA lapatinib SmPC; US lapatinib PI 2007; Ryan et al 2008,aMedian TTP (months) Patients had all received previous taxanes, anthracyclines and Herceptin,Lapatinib + Xeloda in HER2-positive MBC improves PFS after taxanes, anthracyclines and Herceptin,1.3 months,Investigator assessment,Time (weeks),10,0,20,40,50,60,70,80,100,30,18.3 (4.2)a,23.9 (5.5)a,Lapatinib + Xeloda Xeloda,Hazard ratio=0.72 p=0.008,90,0,20,40,60,80,100,Probability of progression (%),EGF104900: Herceptin + lapatinib,Blackwell et al 2010,aMedian OS (months),Time (months),148 148,88 65,43 28,1,25 13,64 47,121 102,Probability of survival (%),0,20,40,60,80