1、1三阴性乳腺癌治疗及进展三阴性乳腺癌治疗及进展 江苏省肿瘤医院内科江苏省肿瘤医院内科冯继锋冯继锋2三阴性乳腺癌定义(triple negative breast cancer,TNBC)指乳腺癌雌激素受体(ER)阴性孕激素受体(PR)阴性表皮生长因子受体2(Her-2)阴性3占所有乳腺癌病理类型的 10.0%20.8%；具有特殊的生物学行为和临床病理特征；预后较其他类型差；多发生于绝经前年轻女性；尤其是非洲裔美国妇女：50岁以下非洲裔美国妇女的发病率甚达39%；白种人则仅为16%。三阴性乳腺癌流行病学(triple negative breast cancer,TNBC)4组织学分级多为级,细
2、胞增殖比例较高,c-kit、p53、EGFR表达多为阳性,基底细胞标志物细胞角蛋白(CK)5/6、17也多为阳性。三阴性乳腺癌病理特征 (triple negative breast cancer,TNBC)5Brenton J.J Clin Oncol.2005;23:7350-7360.Basal-likeERBB2+Normal Breast-LikeLuminal CLuminal ALuminal B6根据乳腺癌基因特征分为：导管A型(luminal-A)起源于腔上皮细胞，ER阳性导管B型(luminal-B)起源于腔上皮细胞，ER阳性HER-2过表达型(HER-2 overexpr
3、ession)基底细胞型(basal-like)起源于导管基底层细胞，高表达基底上皮细胞分子标志物（细胞角蛋白即CK5/6、17），且ER、PR、HER-2均表达缺失。正常细胞型(nomal-like)三阴性乳腺癌病理特征 (triple negative breast cancer,TNBC)7三阴性乳腺癌的一些临床特征直接或间接来源于基底样乳腺癌。但三阴性乳腺癌是基底样乳腺癌的一个亚型,二者不完全同义,不能完全互换。有研究表明,80%90%的BRCA1相关性乳腺癌为三阴性乳腺癌。三阴性乳腺癌病理特征 (triple negative breast cancer,TNBC)8BRCA1BRC
4、A1、Basal-Like Basal-Like、TN乳腺癌的关系Leslie K.et al.Adv.Anat.Pathol.2007;14:419-430Basal-likeTriple NegativeBRCA1 9临床表现为侵袭性病程；远处转移风险较高,内脏转移几率较骨转移高,脑转移几率也较高。预后较差,死亡风险较高。三阴性乳腺癌临床特征 (triple negative breast cancer,TNBC)10三阴性乳腺癌与非三阴性乳腺癌的生存比较三阴性乳腺癌与非三阴性乳腺癌的生存比较11X CensoredLum ALum B+CNorB-likeERBB2+BasalProba
5、bilityP0.010.00.80.60.40.2024489672survival months1 Sorlie T,Perou CM,Tibshirani R et al.Proc Natl Acad Sci USA.2001;98:10869-10874.不同亚型乳腺癌的生存比较不同亚型乳腺癌的生存比较13乳腺癌的治疗选择Hormone-receptor positive(ER/PR)TamoxifenAromatase InhibitorsHER2 positiveHER2-targeted therapiesTrastuzumabLapatinibER/PR/HER2 negati
6、veChemotherapiesDent R,et al.Clin Cancer Res.2007;13:4429-4434;Altundag K,Ibrahim N.The Oncologist.2006;11:553-562;Reis-Filho JS,Tutt ANJ.Histopathology.2008;52:108-118.14Clinical Response toClinical Response to Anthracycline-Based Chemotherapy Anthracycline-Based ChemotherapyCarey L,et al.Clin Canc
7、er Res.2007;13:2329-2334Entire Entire populationpopulationBasal-like Basal-like(n=34)(n=34)HER2(n=11)HER2(n=11)Luminal B Luminal B(n=26)(n=26)Luminal A Luminal A(n=36)(n=36)P P value valueClinical response to ACClinical response to AC Complete response Complete response15(14%)10(29%)1(10%)2(8%)2(6%)
8、0.0001 Partial response Partial response50(47%)19(56%)6(60%)13(50%)12(33%)Stable disease Stable disease40(38%)5(15%)3(30%)11(42%)21(58%)Progressive disease Progressive disease1(1%)0001(3%)Complete response+partial Complete response+partial responseresponse65(61%)29(85%)7(70%)15(58%)14(39%)2cm if nod
9、e neg,or any node+N=188Primary endpoint:clinical and path responseRandomized phase II35 Carboplatin PaclitaxelQw x12 NoneBevacizumab Carboplatin PaclitaxelQw x12 NoneStage IIA-IIIATriple negative(ER-,PR-HER2-)N=3621ary endpoint:pathCRTN CALGB 40603 Basal-like Neoadjuvant TN CALGB 40603 Basal-like Ne
10、oadjuvant TrialTrialSURGERYAC q2w x4PI.W SikovRandomized phase II36BEATRICE:Phase III Adjuvant for BEATRICE:Phase III Adjuvant for Triple Negative Breast CancerTriple Negative Breast CancerPrimary end point:invasive progression-free survivalPrimary end point:invasive progression-free survival Anthra
11、cycline+cyclophosphamide+/-taxane,or taxane+bevacizumab 5mg/kg qw equivalentAnthracycline+cyclophosphamide+/-taxane,or taxane+placeboRhttp:/clinicaltrials.gov/ct/show/NCT00528567 N=2530Triple negative(ER-,PR-,HER2-)37Several Ongoing Studies Targeting PARP,Several Ongoing Studies Targeting PARP,DNA G
12、roove,othersDNA Groove,others MBC,MBC,NeoadjuvantNeoadjuvant Adjuvant?Adjuvant?PARP:Involved in repair of DNA strand breaksInhibition of PARP-1 prevents recruitment of DNA repair enzymes,leads to failure of single stand DNA break repair Ongoing or planned single agent and combination studies with ci
13、splatin for triple negative diseaseOther gents that impair DNA repairBrostacillinTrabadectinEtc,etcDNA repair38 BRCA1在DNA复制过程中与多种基因协作以维持基因组的稳定性。BRCA1功能缺失可导致DNA合成期(S期)检测点和DNA合成后期(G2期)-分裂期(M期)转变异常,BRCA1功能缺失细胞对放射线敏感。三阴性乳腺癌放疗(triple negative breast cancer,TNBC)39 研究显示，经保乳手术和放疗,三阴性乳腺癌的局部复发率并没有显著升高,证明了其对放
14、射线的敏感性,表明放疗对局部控制有一定的作用,应制订一些新的治疗策略来降低远处转移的几率。三阴性乳腺癌放疗(triple negative breast cancer,TNBC)40三阴性乳腺癌具有特殊的生物学特性、病理特征及临床病程。其 CK 5/6、17等基底细胞标志物阳性,EGFR等表达多为阳性,具有高增殖比例、分化差等特点。与基底样乳腺癌和BRCA1相关性乳腺癌有较多相似特征。三阴性乳腺癌结语(triple negative breast cancer,TNBC)41此亚型乳腺癌对放疗尚比较敏感,但常规标准治疗后其预后较差。由于此类肿瘤的BRCA1基因异常、EGFR高表达及其他信号传导通路异常,目前已开展了针对这些靶点的相关研究,我们期待着这些临床研究结果能改善三阴性乳腺癌的预后。三阴性乳腺癌结语(triple negative breast cancer,TNBC)424344
