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三阴性乳腺癌的治疗现状

三阴性乳腺癌的治疗现状. 湖北省肿瘤医院乳腺科 吴 新 红. 2011 年 St Gallen 共识乳腺癌亚型. 亚型 定义 Luminal A 型 ER 和（或） PR 阳性， HER2 阴性， Ki67 低表达（＜ 14% ） Luminal B 型 Luminal B （ HER2 阴性）， ER 和（或） PR 阳性， HER2 阴性， Ki67 高表达（≥ 14% ） Luminal B （ HER2 阳性）， ER 和（或） PR 阳性， HER2 过表达或增殖， Ki67 任何水平

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三阴性乳腺癌的治疗现状

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  1. 三阴性乳腺癌的治疗现状 湖北省肿瘤医院乳腺科 吴 新 红

  2. 2011年St Gallen共识乳腺癌亚型 亚型 定义 Luminal A型 ER和（或）PR阳性，HER2阴性，Ki67低表达（＜14%） Luminal B型 Luminal B（HER2阴性），ER和（或）PR阳性，HER2阴性，Ki67高表达（≥14%） Luminal B（HER2阳性），ER和（或）PR阳性，HER2过表达或增殖，Ki67任何水平 HER-2过表达型 HER2阳性（非Luminal），ER和PR缺失，HER2过表达或增殖 基底样型 三阴性（导管），ER和PR缺失，HER2阴性

  3. 一、三阴性乳腺癌（TNBC） : 概念 • ER- / PgR- / HER2- Triple negative andbasal-like • Basalbut not triple negative • 15-40% are ER+, PR+ or HER2+ Triple negativebut not basal Clinical assay(IHC) Gene arrays

  4. BRCA1、Basal-Like 、TNBC乳腺癌的关系 BRCA1 Basal-like Triple Negative Leslie K. et al. Adv. Anat. Pathol. 2007; 14: 419-430

  5. 二、TNBC的风险因素(排除 BRCA 状态) • Younger age at menarche • Higher parity • Younger age at full term pregnancy • Shorter duration of breast feeding • High body mass index (BMI) • High waist to hip ratio • Lack of exercise Fulford et al, Histopathology 2006; Livasy et al, Mod Pathol, 2006, Bauer KR Cancer 2007 Carey JAMA 2006

  6. 三、TNBC预后因素 • Large tumor size • Presence of nodal metastasis • Presence of distant metastasis • Presence of central necrosis • Absence of androgen receptor • Basal phenotype • EGFR • Age < 40 ? (Liedtke et al. ASCO 2010)

  7. 四、TNBC－流行病学 • 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%。

  8. 五、TNBC－分子病理特征 • 组织学分级多为Ⅲ级, • 细胞增殖比例较高, • 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。

  9. 六、TNBC－临床特征 • 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。

  10. TNBC: Shorter Median Time fromDistant Relapse to Death “Triple Negative” 9 months Other Breast Cancer 22 months Dent R, Trudeau M, Pritchard K, Hana W, Narod S. et al. Clinical Cancer Res 2007

  11. TNBC与Non-TNBC的生存比较

  12. TNBC: Recurrence and Survival • Increased likelihood of distant recurrence • Visceral metastases to brain, lung, and distant nodal sites common • Metastases to bone and liver less common • Relapse most likely during the first 3 y after therapy • Majority of deaths within first 5 y • By 10 years, OS differences between TNBC & non-TNBC are minimal Kim et al. SABCS 2009. Abstract 4065.

  13. 七、TNBC的治疗策略 • TNBC paradox: chemosensitive, but relapse more aggressive with worse OS • Cannot treat with standard targeted therapies (hormonal therapy or anti-HER2 agents) • Question of bevacizumab open • Limited data available from prospective trials in this population • Best available data mostly retrospective subpopulation analyses • No specific recommendations within recognized treatment guidelines • Manage same as other BCs with same grade & stage Anthracycline Taxanes Ixabepilone Platinum agents Biologic agents

  14. (1) 三阴性乳腺癌对标准化疗的疗效

  15. (2) 转移性TNBC较快发生化疗耐药

  16. （3）TNBC对新辅助化疗有较高的pCR率 • Compared with ER+ luminal disease, TNBC and HER2+/ER- BC pts had: • Decreased DFS (p=0.04) • Decreased OS (p=0.02)

  17. 早期TNBC化疗CR者预后好

  18. TNBC对新辅助化疗有较高的pCR率 • 1118 pts received T-FAC • Note Paradox: Despite increase in pCR rate, TNBC had worse outcome (OS) Liedtke et al. J Clin Oncol. 2008;26:1275-1281.

  19. (4) AdjuvantAnthracycline + Taxane for TNBC DFS (BCIRG 001): TAC vs FAC (n=192) OS: ACT vs ATT (N=378) Loesch et al. J Clin Oncol.2010; 28: 2958-2965 Hugh et al. J Clin Oncol. 2009;27:1168-1176.

  20. (5) sequential chemotherapy for TNBC PACS 01试验（Ⅲ期随机临床试验） 　　针对淋巴结阳性乳腺癌患者 • FEC × 6 VS FEC × 3 序贯 D × 3， • 序贯治疗组中,基底样乳腺癌患者的无病生存(DFS)率(P=0.05)和总生存(OS)率(P=0.005)较好。 因此,虽然基底样乳腺癌的预后较差,但对FEC序贯多西他赛化疗有较好的反应。

  21. 高危乳腺癌术后辅助化疗的Ⅲ期临床试验 (2007年ASCO报告) • A组：AC × 4 序贯 P (175 mg/m2,Q3W) × 4 • B组：AP × 4序贯 P (80 mg/ m2,QW) ×12 结论: 对于三阴性乳腺癌, AP序贯P组五年OS优势更加明显(87%对79%, P=0.037)。 • 紫杉类药物对TNBC有一定的疗效,序贯方式也可能是其获得较好疗效的方式之一。 • 研究结果均来自试验的亚组分析或回顾性分析, 尚需前瞻性研究的证实。

  22. (6) Platinum Agents for TNBC Carbo=carboplatin; Cis=cisplatin; D=docetaxel; E=epirubicin; F=5-FU; H=trastuzumab; P=paclitaxel; retro=retrospective.

  23. (7) High dose chemotherapy(HDC ) for TNBC • WSG AM 01试验 • 9个以上淋巴结阳性的乳腺癌患者分为两组 • A组：密集EC× 2 序贯 HDC × 2 ( EPI 90 mg/m2,CTX 3 g/m2,塞替派400 mg/m2) • B组：密集EC × 4 序贯 密集CMF × 3 • 结果表明,年轻的三阴性乳腺癌患者从HDC中获益最多。

  24. (8) Molecular targeted therapies for TNBC dasatinib, sunitinib cetuximab EGFR tyrosine kinase c-KIT tyrosine kinase MAPK, Notch inhibitors MAP Kinase Pathway Akt Pathway Angiogenesis Trabedectin, brostacillin bevacizumab Transcriptional Control DNA Repair pathway- platinum agents, PARP inhibitors Cell Cycle Microtubule stabilization ixabepilone

  25. Bevacizumab for TNBC OS in TNBC population showed no difference between bev and non-bev treated groups (HR=0.96; 95% CI: 0.79-1.16) O’Shaughnessy et al. ASCO 2010 *Median PFS vs non-TNBC subgroup. Thomssen, et al. SABCS 2009. Abstract 6093. O’Shaughnessy J, et al. SABCS 2009. Abstract 207.

  26. EGFR Inhibition for TNBC Efficacy data from phase II trials NR=not reported; PFS=progression-free survival; RR=response rate; TBCRC=Translational Breast Cancer Research Consortium • TNBC strongly associated with EGFR expression • EGFR inhibitors combined with platinum • Current data conflicting Carey et al. ASCO 2008; abstr 1009; O’Shaughnessy et al. SABCS 2007; abstr 308.

  27. Other Targets for TNBC Adapted from Tan and Swain. Cancer Journal. 2008;14.

  28. 700 600 500 400 PARP1 mRNA level 99.9%UCL 300 99%UCL 95%UCL 90%UCL 200 Mean 100 0 IDC Normal PARP1 in Breast Cancer • Infiltrating ductal carcinoma (IDC) is a highly invasive tumor, accounting for 70-80% of all breast malignancies • IDC shows statistically significant PARP1 upregulation in comparison with normal breast tissues: p = 2x10-27 • PARP1 is upregulated in TNBC *defined by percentage of samples exceeding the 95% UCL of normal tissue distribution

  29. The rate of clinical benefit from 34% to 56% (P=0.01) • The rate of overall response from 32% to 52% (P=0.02). • PFS：3.6 M to 5.9 M (hazard ratio for progression, 0.59; P=0.01) • OS： 7.7 M to 12.3 M (hazard ratio for death, 0.57; P=0.01).

  30. (9）Radiotherapy for TNBC • Haffty等对442（100TNBC)例保乳手术乳腺癌进行了分析,比较局部复发和远处转移 • TNBC的OS(67%对75%,P=0.096)、无远处转移生存率(61%对75%,P=0.002)、特异性生存率(67%对78%,P=0.03)和无淋巴结转移生存率(93%对99%,P=0.021) • 局部控制率方面没有差异(均为83%),证明了其对放射线的敏感性

  31. （10）TNBC: Ongoing Clinical Trials • Numerous prospective trials ongoing to evaluate various therapeutic options specifically in TNBC population • 57 open trials currently listed on clinicaltrials.gov • Most include TNBC populations only • Studies include targeted agents, vaccines • Across stages of disease

  32. （11）TNBC: Conclusions • TNBC is a distinct subtype of BC and is associated with treatment challenges due to its aggressive nature • TNBC has no specific target…yet • Antracycline and taxane work (but not very well…) • Molecular pathways that control tumor development could determine treatment • Platinum-based chemotherapy is emerging as backbone of new treatments • Introduction of novel agents (PARPi) is showing promise—iniparib • Results from ongoing phase III trials will help determine the best treatment strategy

  33. Treat ment choices in TNBC TODAY TOMORROW Chemotherapy Tailored chemotherapy Chemotherapy Chemotherapy Molecular targeted therapies

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