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412 专家论坛中国肿瘤临床 2016 年第 43 卷第 10 期 Chin J Clin Oncol 2016. Vol. 43. No. 10 www.cjco.

1 412 专家论坛中国肿瘤临床 2016 年第 43 卷第 10 期 Chin J Clin Oncol Vol. 43. No 张频教授主任医师硕士研究生导师担任北京乳腺病防治学会内科专业委员会副主任委员, 中国老年学会老年肿瘤专业委员会乳腺癌分会副主任委员, 中国女医师协会临床肿瘤学专家委员会常委, 中国医师协会乳腺疾病培训专家委员会常委主要从事乳腺癌的药物治疗综合治疗及抗肿瘤新药临床研究参与临床肿瘤学乳腺癌实用肿瘤内科治疗等多部肿瘤学专著及临床肿瘤内科手册编写 HER-2 阳性晚期乳腺癌治疗策略孙婧张频摘要 HER-2 阳性晚期乳腺癌患者预后差, 以抗 HER-2 靶向治疗为基础的综合治疗显著延长了患者的生存期改善了预后目前多种抗 HER-2 靶向药物已应用于临床, 抑制 HER-2 通路是 HER-2 阳性晚期乳腺癌患者一线治疗及一线治疗进展后的基础治疗本文简要介绍 HER-2 阳性晚期乳腺癌治疗相关的关键临床研究指南推荐及今后的研究方向, 以指导临床实践关键词 HER-2 阳性晚期乳腺癌治疗策略临床研究靶向治疗 doi: /j.issn Therapeutic strategy for HER-2-positive advanced breast cancer Jing SUN, Pin ZHANG Correspondence to: Pin ZHANG; zhang_pin@sina.com Department of Medical Oncology Cancer Institute/Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing , China Abstract Patients with HER-2-positive advanced breast cancer were associated with poor prognosis. Meanwhile, HER-2-targeted therapy has dramatically improved survival and prognosis among breast cancer patients. Over the years, multiple HER-2-targeting drugs stepped into clinical practice, and the targeted agents are now considered as the standard of care in the first-line setting and beyond. This review basically summarizes the importance of HER-2-targeted therapy, the significance of the clinical trial results, and the clinical practice guidelines for the management of patients with HER-2-positive advanced breast cancer. Keywords: HER-2-positive, advanced breast cancer, therapeutic strategy, clinical trials, targeted therapy 人表皮生长因子受体 -2(human epidermal growth factor receptor -2,HER-2) 过表达导致细胞过度增殖分化凋亡减少侵袭转移增加,HER-2 阳性晚期乳腺癌患者的 5 年生存率较 HER-2 阴性者降低 46% [1] 近十年来, 由于多个抗 HER-2 药物成功研发上市,HER- 2 阳性晚期乳腺癌成为证据级别最高治疗方案最成熟的晚期乳腺癌生物学亚型本文结合国内外研究进展及治疗指南 / 共识, 对 HER-2 阳性晚期乳腺癌治疗策略进行综述 1 抗 HER-2 靶向治疗药物 HER-2 是人表皮生长因子受体家族成员之一, 其在信号通路传导中起核心作用 HER-2 受体由细胞外生长因子结合区亲脂的跨膜区胞内区 (HER- 2 功能区具有酪氨酸激酶的活性和 ATP 的结合位点 ) 组成 HER 家族受体只有形成二聚体后才能引起自身磷酸化, 从而激活下游信号传导通路, 导致肿瘤细 [2] 胞增殖和存活目前已上市的抗 HER-2 靶向药物主要为 :1) 针对受体细胞膜外部分的单克隆抗体 : 曲妥珠单抗帕妥珠单抗抗体 - 药物偶联物 (antibody-drug conju gate,adc);2) 针对受体细胞膜内部分的酪氨酸激酶抑制剂 : 拉帕替尼曲妥珠单抗与 HER-2 受体细胞作者单位 : 中国医学科学院肿瘤医院肿瘤内科 ( 北京市 ) 通信作者 : 张频 zhang_pin@sina.com

2 中国肿瘤临床 2016 年第 43 卷第 10 期 Chin J Clin Oncol Vol. 43. No 膜外 Ⅳ 区结合, 阻断肿瘤细胞信号传导帕妥珠单抗结合于 HER-2 受体胞外 Ⅱ 区, 抑制 HER-2 同源或异源二聚体形成, 继而阻止下游信号传导两药可以互补增强对 HER-2 通路的抑制 [3] T-DM1(trastu zumab emtansine) 是新型的 ADC, 由曲妥珠单抗和细胞毒药物 DM1(derivative of maytansine 1) 连接而成, 与细胞表面 HER-2 受体结合后内吞入细胞, 释放 DM1 抑制微管聚集, 发挥细胞毒作用, 同时曲妥珠单抗发挥抗肿瘤作用拉帕替尼是 HER-1 和 HER-2 受体酪氨酸激酶抑制剂, 可同时抑制 HER-1 HER-2, 从而阻断下游信号传导 [4] 2 HER-2 阳性晚期乳腺癌一线治疗策略 2.1 以曲妥珠单抗为基础的一线化疗方案曲妥珠单抗是最早研发上市的抗 HER-2 药物, 可以有效抑制 HER-2 阳性乳腺癌进展, 与多种化疗药物 [5] 联合具有协同增效作用 Slamon 等首次证实了一线曲妥珠单抗联合化疗 ( 包括蒽环类或紫杉类药物 ) 与单独化疗相比, 能提高 HER-2 阳性晚期乳腺癌的 ORR(50% vs. 32%,P<0.001), 明显延长 TTP(7.4 个月 vs. 4.6 个月, P<0.001) 及 OS(25.1 个月 vs 个月,P=0.046), 但化疗联合曲妥珠单抗增加心脏毒性, 因此目前临床治疗不推荐蒽环类药物联合曲妥珠单抗 ( 临床研究除外 ),Marty [6] 等进一步肯定了上述研究的结果紫衫类多西他赛联合曲妥珠单抗优于多西他赛在曲妥珠单抗联合紫 [7] 衫类药物基础上,Robert 等发现曲妥珠单抗紫杉醇联合卡铂较安慰剂提高 ORR(52% vs. 36%,P=0.04) 和 PFS(7.1 [8] 个月 vs 个月,P=0.03);Wardley 等研究证明曲妥珠单抗多西他赛联合卡培他滨较安慰剂延长 PFS(17.9 个月 vs 个月,P=0.045), 提高 2 年生存率 (75% vs. 66%) 以上均为一线治疗可选择的方案 2.2 曲妥珠单抗联合帕妥珠单抗作为一线治疗 [9] Baselga 等发现曲妥珠单抗联合帕妥珠单抗能增加信号阻断效应, 这与两药从不同作用位点上抑制 HER-2 信号通路有关研究发现, 曲妥珠单抗多西他赛联合帕妥珠单抗与非联合组相比, 双靶向联合化疗延长 PFS 6.1 个月,OS 延长 15.7 个月 (P= ); 亚组分析发现, 辅助或新辅助化疗激素受体状态及检测 HER-2 过表达的方法均不影响生存获益 [10-11] 目前双靶向联合多西他赛是 HER-2 阳性晚期乳腺癌一线治疗的优选方案 2.3 激素受体阳性 HER-2 阳性晚期乳腺癌一线内分泌治疗约 50%HER-2 阳性乳腺癌患者激素受体 (hor mone receptor,hr) 阳性, 雌激素受体 (estrogen recep tor,er) 与 HER-2 信号通路存在细胞内相互交联, HER-2 过表达可导致内分泌治疗耐药绝经后患者 HR 阳性 HER-2 阳性晚期乳腺癌一线内分泌治疗研 [12] 究中,Kaufman 等证明曲妥珠单抗联合阿那曲唑较阿那曲唑延长 PFS 1 倍 (4.8 个月 vs. 2.4 个月,P= ), 提高临床获益率 (CBR)(42.7% vs. 27.9%,P=0.026); [13] Johnston 等证明拉帕替尼联合来曲唑较来曲唑提高 ORR(37.9% vs. 14.8%,P=0.021), 延长 PFS(8.2 个月 vs. 3.0 个月,P=0.019) 两项研究说明双通路抑制能提高疗效, 恢复内分泌药物敏感性, 延缓疾病进展 2.4 其他靶向药物的一线治疗 [14] Gianni 等表明曲妥珠单抗多西他赛联合贝伐珠单抗一线治疗 HER-2 阳性晚期乳腺癌较标准治疗无明显获益,PFS 为 16.5 个月 vs 个月,P= ) Gelmon [15] 等研究发现一线治疗中曲妥珠单抗联合紫杉类药物优于与拉帕替尼联合紫杉类药物,PFS 为 11.3 个月 vs. 9.0 个月 (P=0.01) PTEN 缺失,PIK/AKT/mTOR 通路激活是曲妥珠单抗耐药的原因之一,mTOR 抑制剂可逆转 [16] [17] 曲妥珠单抗耐药 Hurvitz 等在曲妥珠单抗联合紫杉醇基础上, 联合依维莫司或安慰剂, 结果证明 HER-2 阳性晚期乳腺癌一线治疗中 mtor 抑制剂无优势,PFS 为个月 vs 个月 (P=0.1166), 同时不良反应增加 HER-2 阳性晚期乳腺癌一线治疗关键临床研究见表国内外指南一线治疗的推荐 [18] [19] NCCN(2015 年 ) Giordano 等及 Cardoso 等推荐曲妥珠单抗帕妥珠单抗联合紫杉类药物作为 HER-2 阳性晚期乳腺癌一线治疗优选方案曲妥珠单抗联合不同化疗药物 ( 紫杉类等 ) 为备选方案 HER-2 阳性 HR 阳性的绝经后晚期乳腺癌患者可采用曲妥珠单抗联合芳香化酶抑制剂治疗中国抗癌协会乳腺癌专业委员会推荐, 在帕妥珠单抗国内尚未上市的情况下, 曲妥珠单抗联合紫杉醇或多西他赛可以作为首选的一线方案, 也可加用卡铂进一步提高疗效, 其他可联合药物包括长春瑞滨卡培他滨等 [20-21] 3 一线治疗后疾病进展的治疗策略 3.1 继续抑制 HER-2 通路抗 HER-2 治疗过程中出现疾病进展, 后续靶向治 [22] 疗仍有应用价值 von Minckwitz 等发现曲妥珠单抗治疗中对于疾病进展患者, 后续曲妥珠单抗联合卡培他滨的疗效优于改用卡培他滨单药 (TTP:5.6 个月 vs. 8.2 个月,P= ;ORR:27% vs. 48.1%,P= ), 说明继续使用曲妥珠单抗仍可提高疗效, 可能与曲妥 [23] 珠单抗增加化疗敏感性有关 Geyer 等发现, 对于曲妥珠单抗一线治疗后疾病进展的患者改用拉帕替尼联合卡培他滨优于卡培他滨单药 (TTP:8.4 个月 vs. 4.4 个月, P<0.001), 但腹泻和皮疹的发生率增加

3 414 中国肿瘤临床 2016 年第 43 卷第 10 期 Chin J Clin Oncol Vol. 43. No 表 1 HER-2 阳性晚期乳腺癌患者一线治疗关键临床研究 Table 1 Pivotal clinical trials for HER-2-positive advanced breast cancer first-line treatment Author Treatment arm ORR Median TTP/PFS Median OS Slamon et al. [5] (phase Ⅲ, n=469) Chemotherapy (anthracycline+ctx or paclitaxel)+h (loading dose 4 mg/kg, then 2 mg/kg, qw) vs. chemotherapy 50% vs. 32% 7.4 months vs. 4.6 months 25.1 months vs months (P=0.046) Marty et al. [6] (phase Ⅱ, n=186) HT (H: loading dose 4mg/kg, then 2 mg/kg, qw; T: 100 mg/ m 2 q3w 6 cycles) vs. T 63% vs. 34% (P=0.0002) 11.7 months vs. 6.1 months (P=0.0001) 31.2 months vs months (P=0.0325) Robert et al. [7] ( phase Ⅲ, n=196) H+Tax+C (H: loading dose 4 mg/kg, then 2 mg/kg, qw; Tax: 175 mg/m 2 q3w; C: AUC=6 mg/ml/min) vs. H+Tax 52% vs. 36% (P=0.04) 10.7 months vs. 7.1 months (P=0.03) 56.8 months vs months (P=0.76) Wardley et al. [8] HTX (X: 950 mg/m 2 bid d1-d14, every 3 weeks) vs. HT (phase Ⅱ, n=222) 70.5% vs. 72.7% (P=0.717) 17.9 months vs months (P=0.045) Baselga et al. [10], Swain et al. [11] (phase Ⅲ, n=808) HTP (P: 840 mg, d1, followed by 420 mg x1 cycle) vs. HT+ placebo 80.2% vs. 69.3% (P=0.001) 18.5 months vs months 56.5 months vs months (P=0.0002) Kaufman et al. [12] Anastrozole+H (n=103) vs. anastrozole (n=104) (phase Ⅲ, n=207) 4.8 months vs. 2.4 months (P=0.0016) 28.5 months vs months (P=0.325) Johnston et al. [13] Letrozole+lapatinib (1500 mg qd) vs. letrozole+placebo (phase Ⅲ, n=219) 37.9% vs. 14.8% (P=0.021) 8.2 months vs. 3.0 months (P=0.019) 33.3 months vs months (P=0.113) Gianni et al. [14] (phase Ⅲ, n=424) BTH (B: 15 mg/kg; H: loading dose 8 mg/kg, 6 mg/kg; T: 100 mg/m 2, every 3 weeks) vs. TH 74.3% vs. 69.6% (P=0.3492) 16.5 months vs months (P>0.05) (P=0.0775) Gelmon et al. [15] (phase Ⅲ, n=537) LTax/L (L: mg/d; Tax: paclitaxel 80 mg/m 2 once per week on days 1, 8, and 15 of a 28-day schedule or docetaxel 75 mg/m 2 once every 3 weeks) vs. HTax/H 55% vs. 54% (P>0.05) ITT PFS 9.0 months vs (P>0.05) months (P=0.01) Hurvitz et al. [17] H+Tax+everolimus (10 mg qd) vs. H+Tax+placebo (phase Ⅲ, n=719) 69% vs. 67.1% (P>0.05) months vs months (P=0.1166) T: docetaxel, H: trastuzumab(herceptin), CTX: cyclophosphamidum, C: carboplain, X: capecitabine (Xeloda), L: lapatinib, Tax: taxol (or Paclitaxel), B: bevacizumab, P: pertuzumab Major adverse event Cardiac dysfunction (n=63): anthracycline + CTX+H (27%) vs. anthracycline+ctx (8%), Tax+ H (13%) vs. Tax (1%) Grade 3, 4 leukopenia and neutropenia, 32% vs. 22%; fibrile neutropenia 23% vs. 17% Well tolerable Fibrile neutropenia 27% vs. 15%; Grade 3/4 leukopenia and neutropenia 77% vs. 54% Nausea: 42.3% vs. 41.6%; rash 33.7% vs. 24.2; mucosal inflammation 27.8% vs. 19.9%; fibrile neutropenia 13.8% vs. 7.6%; left ventricular systolic dysfunction 1.2% vs. 2.8% Grade 3, 4 adverse effect 23% vs. 15%, 5% vs. 1% Grade 3, 4 diarrhea 10% vs. 1% BTH group grade 3 febrile neutropenia 11.6% vs. 8.7%; hypertension 11.6% vs. 0.5% Grade 3, 4 diarrhea 19% vs. 1%; rash 8% vs. 0 Grade 3, 4 neutropenia 25% vs. 15%; stomatitis 13% vs. 1%; anaemia 10% vs. 3%; diarrhea 9% vs. 4%

4 中国肿瘤临床 2016 年第 43 卷第 10 期 Chin J Clin Oncol Vol. 43. No 拉帕替尼与曲妥珠单抗因作用于 HER-2 受体的不同位点, 提示二者有协同作用曲妥珠单抗治疗后疾病进展的患者中, 比较拉帕替尼联合曲妥珠单抗与拉帕替尼单药的疗效, 结果联合组 PFS 延长 4 周 (12.0 周 vs. 8.1 周,P=0.008), 中位 OS 延长 4.5 个月 (14.0 个月 vs. 9.5 个月,P=0.026),CBR 提高 1 倍 (24.7% vs. 12.4%, P=0.01), 不良反应两组相似 [24-25] 该研究为 HER-2 阳性晚期乳腺癌患者提供了无化疗的双靶向治疗选择 3.2 T-DM1 在二线治疗中的作用 [26] Verma 等评价了 T-DM1 在曲妥珠单抗治疗后疾病进展患者中的应用价值该研究中曲妥珠单抗紫杉类治疗 HER-2 阳性晚期乳腺癌疾病进展患者, 随机行 T-DM1 或拉帕替尼联合卡培他滨治疗结果表明,T- DM1 组有疗效优势 (ORR:43.6% vs. 30.8%,P<0.001;PFS:9.6 个月 vs. 6.4 个月,P<0.001; OS:30.9 个月 vs 个月,P<0.001) 可见 T-DM1 疗效明显优于拉帕替尼联合卡培他滨, 且总体耐受性更好, 为二线治疗的优选药物, 但该药物目前尚未在国内批准上市 3.3 抑制 mtor 通路 [27] André 等首次在 HER-2 阳性晚期乳腺癌 Ⅲ 期临床试验中, 证明 mtor 通路抑制剂依维莫司在二线治疗中获益该研究对曲妥珠单抗联合紫杉醇类药物治疗失败的晚期乳腺癌患者, 进行曲妥珠单抗长春瑞滨联合依维莫司或安慰剂的疗效比较, 依维莫司组 PFS 延长 (7.00 个月 vs 个月,P= ), 但 3~4 级不良反应增加该研究虽为 HER-2 阳性晚期乳腺癌二线治疗提供了选择, 但治疗时需权衡利弊 3.4 国内外指南对一线治疗后疾病进展的治疗建议 [18] [19] NCCN(2015 年 ) Giordano 等及 Cardoso 等推荐二线治疗优选 T-DM1, 其他选择包括继续使用曲妥珠单抗同时更换化疗药物改用拉帕替尼同时更换化疗药物, 曲妥珠单抗联合拉帕替尼双靶向治疗继续抑制 HER-2 通路仍为治疗的基础中国晚期乳腺癌诊治专家共识及乳腺癌诊治指南推荐, 在 T-DM1 未上市的情况下, 可选择继续使用曲妥珠单抗同时更换化疗药物拉帕替尼联合卡培他滨曲妥珠单抗联合卡培他滨曲妥珠单抗联合拉帕替尼另外,mTOR 抑制剂依维莫司也可作为二线治疗后的一种选择 [20-21] HER-2 阳性晚期乳腺癌患者一线治疗后疾病进展的主要临床研究见表 2 表 2 HER-2 阳性晚期乳腺癌患者一线治疗后疾病进展的主要临床研究 Table 2 Pivotal clinical trials for disease progression of HER-2-positive advanced breast cancer beyond first-line treatment Author Treatment arm ORR Median TTP/PFS Median OS Major adverse event von Minckwitz et al. [22] H+X vs. X 48.1% vs. 27.0% 8.2 months vs months vs Grade 3, 4 adverse effect (phase Ⅲ, n=156) (P= ) months (P= ) months (P=0.2570) (P=0.865) Geyer et al. [23] L+X (L: mg/d, X: % vs. 14.0% 8.4 months vs weeks vs Diarrhea 60/98 vs. 39/60; (phase Ⅲ, n=399) mg/m 2 ) vs. X (2 500 mg/m 2 ) (P=0.09) months weeks (P=0.206) rash 27/45 vs. 15/23 Blackwell et al. [24-25] (phase Ⅲ, n=296) H+L vs. L CBR 24.7% vs. 12.4% (P=0.01) 12 weeks vs. 8.1 weeks (P=0.008) 14.0 months vs. 9.5 months (P=0.026) Grade 1, 2 diarrhea 60% vs. 48%(P=0.03); symptomatic (2.0% vs. 0.7% ), asymptomatic cardiac events (3.4% vs. 1.4%) Verma et al. [26] (phase Ⅲ, n=991) T-DM1 (3.6 mg/kg q3w) vs. L+X 43.6% vs. 30.8% 9.6 months vs. 6.4 months 30.9 months vs months Grade 3, 4 neutropenia (12.9% vs. 0.2%), increased serum aminotransferase level (2.9% vs. 0.8%) Andre et al. [27] (phase Ⅲ, n=569) H + NVB + everolimus (H: 2 mg/kg, qw; NVB: 25 mg/m 2 ; everolimus: 5 mg/d) vs. H % vs. 37.0% (P= ) 7.00 months vs months (P= ) Grade 3, 4 neutropenia (73%vs. 62%), anemia(19% vs. 6% ), mucosal inflam- NVB+placebo mation (13% vs. 1% ), fatigue (12% vs. 4%) H: trastuzumab (Herceptin), X: capecitabine (Xeloda), L: lapatinib, NVB: vinorelbine

5 416 中国肿瘤临床 2016 年第 43 卷第 10 期 Chin J Clin Oncol Vol. 43. No 结语目前,HER-2 阳性晚期乳腺癌相关的基础转化研究正在不断深入, 有望更多治疗中获益和发现潜在的预后靶点曲妥珠单抗帕妥珠单抗对 PIK3CA 野生型和突变型患者均有效, 但野生型获益更多,T- [28] DM1 对突变型患者获益更多 Avan 等研究发现, HER-2 mrna 高表达是 HER-2 阳性晚期乳腺癌预后良好的独立因素,HER-2 下游的 PIK3CA 突变则提示预后较差但可在治疗中获益多种肿瘤细胞持续表达或可诱导产生 PD-1 配体, 在逃避活化 T 细胞的免疫监视中起关键作用,PD-1 高表达与不良预后和低生存率相关, 是一个引人注目的治疗干预靶点目前正在招募中的 PANACEA 试验, 旨在研究 HER-2 阳性晚期乳腺癌中曲妥珠单抗耐药应用抗 PD-1 单克隆抗体的价值 MK-3475 是一种高效的高选择性的直接阻断 PD-1 的人源性单克隆抗体, 明显增加 T 细胞免疫应答, 同时调节 IL-2 TNF-α IFN-γ 及其他细胞因子此外该研究将评估 MK-3475 是否可以逆转曲妥珠单抗耐药, 提高 HER-2 阳性乳腺癌临床预后肿瘤微环境作为预后和预测性指标也正在被认识, 基于肿瘤的异质性, 对患者进行的个体化治疗将进一步提高 HER-2 阳性晚期乳腺癌的治疗效果由此可见,HER-2 晚期乳腺癌未来治疗将更加精准化个体化参考文献 [1] Dawood S, Broglio K, Buzdar AU, et al. Prognosis of women with metastatic breast cancer by HER-2 status and trastuzumab treatment: an institutional-based review[j]. J Clin Oncol, 2010, 28(1): [2] Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network [J]. Nat Rev Mol Cell Biol, 2001, 2(2): [3] De Mattos- Arruda L, Cortes J. Use of pertuzumab for the treatment of HER- 2 positive metastatic breast cancer[j]. Adv Ther, 2013, 30(7): [4] Segovia-Mendoza M, González-González ME, Barrera D, et al. Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib, lapatinib and neratinib in the treatment of HER- 2 positive breast cancer: preclinical and clinical evidence[j]. Am J Cancer Res, 2015, 5(9): [5] Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER-2 for metastatic breast cancer that overexpresses HER-2[J]. N Engl J Med, 2001, 344(11): [6] Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2- positive metastatic breast cancer administered as first- line treatment: the M77001 study group[j]. J Clin Oncol, 2005, 23(19): [7] Robert N, Leyland- Jones B, Asmar L, et al. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER- 2- overexpressing metastatic breast cancer[j]. J Clin Oncol, 2006, 24(18): [8] Wardley AM, Pivot X, Morales-Vasquez F, et al. Randomized phase II trial of first- line trastuzumab plus docetaxel and capecitabine compared with trastuzumab plus docetaxel in HER-2-positive metastatic breast cancer[j]. J Clin Oncol, 2010, 28(6): [9] Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2- positive metastatic breast cancer that progressed during prior trastuzumab therapy[j]. J Clin Oncol, 2010, 28(7): [10] Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer[j]. N Engl J Med, 2012, 366(2): [11] Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER- 2- positive metastatic breast cancer[j]. N Engl J Med, 2015, 372(8): [12] Kaufman B, Mackey JR, Clemens MR, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2- positive, hormone receptor- positive metastatic breast cancer: results from the randomized phase III TAnDEM study[j]. J Clin Oncol, 2009, 27(33): [13] Johnston S, Pippen J Jr, Pivot X, et al. Lapatinib combined with letrozole versus letrozole and placebo as first- line therapy for postmenopausal hormone receptor- positive metastatic breast cancer [J]. J Clin Oncol, 2009, 27(33): [14] Gianni L, Romieu GH, Lichinitser M, et al. AVEREL: a randomized phase III trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER-2-positive locally recurrent/ Metastatic breast cancer[j]. J Clin Oncol, 2013, 31(14): [15] Gelmon KA, Boyle FM, Kaufman B, et al. Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2- positive advanced breast cancer: final results of NCIC CTG MA.31 [J]. J Clin Oncol, 2015, 33(14): [16] O'Brien NA, McDonald K, Tong L, et al. Targeting PI3K/mTOR overcomes resistance to HER2- targeted therapy independent of feedback activation of AKT[J].Clin Cancer Res, 2014, 20(13): [17] Hurvitz SA, Andre F, Jiang Z, et al. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER-2-positive advanced breast cancer (BOLERO-1): a phase 3, randomized, double-blind, multicentre trial[j]. Lancet Oncol, 2015, 16 (7): [18] Giordano SH, Temin S, Kirshner JJ, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2- positive breast cancer: American Society of Clinical Oncology clinical practice guideline[j]. J Clin Oncol, 2014, 32(19): [19] Cardoso F, Costa A, Norton L, et al. ESO- ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2)[J]. Breast, 2014, 23(5): [20] Chinese Anti-Cancer Association Committee of Breast Cancer Society. Chinese expert consensus for diagnosis and treatment of advanced breast cancer (2015 edition)[m]. Beijing: People's Medical Publishing House, 2015.[ 中国抗癌协会乳腺癌专业委员会. 中国晚期乳腺癌诊治专家共识 (2015 版 )[M]. 北京 : 人民卫生出版社,2015.] [21] Chinese Anti-Cancer Association Committee of Breast Cancer Society. Chinese Anti- Cancer Association Committee guidelines and

中国肿瘤临床 2016 年第 43 卷第 10 期 Chin J Clin Oncol 2016. Vol. 43. No. 10 www.cjco.cn 417 standards for breast cancer diagnosis and treatment(2015 edition) [J]. Chin Oncol, 2015, 25(9):641-703.

Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study[j].

6 中国肿瘤临床 2016 年第 43 卷第 10 期 Chin J Clin Oncol Vol. 43. No standards for breast cancer diagnosis and treatment(2015 edition) [J]. Chin Oncol, 2015, 25(9): [ 中国抗癌协会乳腺癌专业委员会. 中国抗癌协会乳腺癌诊治指南与规范 (2015 版 )[J]. 中国癌症杂志,2015,25(9): ] [22] von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group study[j]. J Clin Oncol, 2009, 27(12): [23] Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER-2-positive advanced breast cancer[j]. N Engl J Med, 2006, 355(26): [24] Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer[j]. J Clin Oncol, 2010, 28(7): [25] Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF Study[J]. J Clin Oncol, 2012, 30(21): [26] Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER-2- positive advanced breast cancer[j]. N Engl J Med, 2012, 367(19): [27] André F, O'Regan R, Ozguroglu M, et al. Everolimus for women with trastuzumab- resistant, HER- 2- positive, advanced breast cancer (BOLERO-3): a randomized, double-blind, placebo-controlled phase 3 trial[j]. Lancet Oncol, 2014, 15(6): [28] Avan A, Maftouh M, Ghayour Mobarhan M, et al. Biomarker analysis in CLEOPATRA: searching for a sensitive prognostic factor in breast cancer[j]. J Clin Oncol, 2015, 33(15): ( 收稿 ) ( 修回 ) ( 编辑 : 张抿亻校对 : 杨红欣 ) 作者简介孙婧专业方向为肿瘤内科临床与基础研究 legendsun001@163.com 读者作者编者西达本胺治疗外周 T 细胞淋巴瘤中国专家共识 (2016 版 ) 外周 T 细胞淋巴瘤 (PTCL) 是一组高度异质性的淋巴细胞异常恶性增殖性疾病, 其发病率具有明显的地域差异在中国,PTCL 发病例数约占非霍奇金淋巴瘤 (NHL) 的 25%~30%, 显著高于欧美国家的 10%~15% 传统化疗方案对于 PTCL 的疗效并不理想, 组蛋白去乙酰化酶 (HDAC) 抑制剂作为一种新型抗肿瘤药物, 已在复发或难治性 PTCL 治疗中取得了显著成果近年来已有 3 个 HDAC 抑制剂上市用于此适应证, 包括美国 FDA 批准的罗米地辛 (romidepsin) 和贝利司他 (belinostat), 以及中国 CFDA 批准的西达本胺 (chidamide, 爱谱沙 ) 本期专家共识栏目刊出了由马军石远凯朱军教授等执笔, 由中国临床肿瘤学会 (CSCO) 中国抗淋巴瘤联盟 (UCLI) 等多个学术组织中的权威专家审阅, 结合我国的临床研究结果制定的西达本胺治疗外周 T 细胞淋巴瘤中国专家共识 (2016 版 ) 阅读本文请登录网站或关注本刊微信公告号 ( 扫描文章下方二维码 ) 查看本刊编辑部

二 Her-2 阳性复发转移性乳腺癌的治疗原则 1. 治疗总则 : 对于 Her-2 阳性晚期复发转移性乳腺癌, 首选含曲妥珠单抗为基础的治疗. 根据患者激素受体状况以及既往 ( 新 ) 辅

二 Her-2 阳性复发转移性乳腺癌的治疗原则 1. 治疗总则 : 对于 Her-2 阳性晚期复发转移性乳腺癌, 首选含曲妥珠单抗为基础的治疗. 根据患者激素受体状况以及既往 ( 新 ) 辅人表皮生长因子受体 2 阳性乳腺癌临床诊疗专家共识江泽飞邵志敏徐兵河肿瘤分子靶向治疗是利用肿瘤细胞表达而正常细胞很少或不表达的特定基因或基因的表达产物作为治疗靶点, 最大程度杀死肿瘤细胞, 而对正常细胞杀伤较小的