1、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,相对年轻（
2、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%-
3、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BRC
4、A1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
5、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 Colu
6、mbia,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,Desp
7、ite 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
8、 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
9、 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
10、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
11、。,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, 2008Paclitaxel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（
12、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
13、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 207
14、9 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 Assessm
15、ent 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
16、=0.0009,EBC patientsaHER2 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 2009Amar 2007 Gonzalez-Angulo 2009 Joensuu 2003 Press 1997,T1a,bT1a,b T1a,b T1b T1a,b,5-year DFS35-month RFS 5-year RFS 9-year RFS 3-year
17、 BCSS,0.091 0.013 0.007 0.0001 0.003 0.0002,Study,150270 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
18、-,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
19、 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,http:/www
20、.fda.gov/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; Kauf
21、man 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: continuatio
22、n 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 (m
23、onths),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,
24、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 si
25、tu 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 conf
26、ounded 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
27、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 tu
28、mours 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
29、et al 2009; Goldhirsch et al 2009; Kataja et al 2009; NCCN 2010, www.nccn.org,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,aMedia
30、n 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 + X
31、eloda 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 (%),0,20,40,60,80,100,0,10,20,25,5,15,30,35,14.0a,9.5a,
32、Herceptin + lapatinib (n=146) Lapatinib (n=145),Hazard ratio=0.74 p=0.026,Not within EMEA-approved indication for Herceptin,正在进行的临床验证: 与拉帕替尼的联合,Lapatinib + trastuzumab 52 weeks,Design 1a: no concurrenttaxaneDesign 2: concurrent taxaneb (12 weeks),Lapatinib 34 weeks,Trastuzumab 52 weeks,Surgery +Comp
33、letion of 4 cycles (neo)adjuvant anthracycline-based chemotherapy,HER2- positive EBC n=8000,aDesign 1 is now closed to enrolment; bpaclitaxel 6984 patients recruited as of 31 Dec 2009,Trastuzumab 12 weeks,RANDOMISATION,Lapatinib 52 weeks,Wash out 6 weeks,ALTTO,正在进行的临床验证: 与贝伐单抗的联合,Chemotherapy + tras
34、tuzumab + bevacizumab,Chemotherapy + trastuzumab,Resected node-positive or high-risk node-negative HER2-positive EBC n=3500 (maximum),Trastuzumab continued q3w until 1 year total,Trastuzumab + bevacizumab continued q3w until 1 year total,2040 patients recruited as of 16 March 2010,BETH,结 语,乳腺癌分子分型的理念以及近10年在该领域所取得的成就是对乳腺癌病理形态学分型是一个有力的补充，针对不同亚型的临床回顾性及前瞻性研究的数据可为乳腺癌的预后判断和个体化治疗提供重要依据和新的启示,谢 谢,
