抗体偶联药物在乳腺癌治疗中的研究进展

抗体偶联药物(ADC)是一类治疗乳腺癌的新型靶向药物,由连接子将化疗药物同单克隆抗体(单抗抗偶联而成,以单抗作为载体将化疗药物靶向运输至目标肿瘤细胞内发挥抗肿瘤作用。根据ADC作用于不同靶点的抗原,分为靶向人表皮生长因子受体2(HER2)、人滋养细胞表面抗原2 (Trop-2)及其他分子等类型。目前,全球范围内已有3种ADC获批治疗乳腺癌,除用于HER2阳性乳腺癌的曲妥珠单抗-美坦新偶联物(T-DM1)、曲妥珠单抗-德鲁替康(T-DXd)外,还有可使三阴性乳腺癌(TNBC)获益的戈沙妥珠单抗(SG)。ADC在HER2阳性乳腺癌治疗中疗效显著,同时在治疗晚期TNBC和部分HER2低表达的乳腺癌中也取得了重要进展,为不同乳腺癌分子分型的人群提供了更多选择。     

HER2阳性的进展期胃癌目前和未来的靶向治疗

目前对胃癌中人表皮生长因子受体(2HER2)的预测价值存有争议。当前的治疗指南已经把检测胃癌中HER2状态作为标准化操作。最近,在治疗HER2阳性进展期胃癌中,曲妥珠单抗已经成为一线靶向治疗用药,而原发与继发性药物抵抗则成为主要问题,需要新的治疗策略来克服这种抵抗。许多HER2阳性进展期胃癌患者在接受曲妥珠单抗治疗后都出现疾病进展,必须接受二线方案治疗。新的靶向药物,诸如酪氨酸激酶抑制剂(TKI)拉帕替尼、哺乳动物雷帕霉素靶蛋白(mTOR)通路抑制剂依维莫司、热休克蛋白90(HSP90)抑制剂AUY922、HER二聚化抑制剂帕妥珠单抗以及抗体-药物偶联物曲妥珠单抗-emtansine(T-DM1),在以曲妥珠单抗为基础的一线治疗失败时可以成为二线治疗用药。     

辅助化疗联合曲妥珠单抗治疗人表皮生长因子受体-2阳性晚期或转移性乳腺癌的系统评价

目的：系统评价辅助化疗联合曲妥珠单抗治疗人表皮生长因子受体-2（HER2）阳性晚期或转移性乳腺癌的临床效果。方法：检索国内外公开发表的关于辅助化疗联合曲妥珠单抗治疗HER2阳性晚期或转移性乳腺癌的中英文文献,对纳入的研究进行比较。结果：共纳入6篇随机对照试验（RCT）研究。辅助化疗联合曲妥珠单抗治疗HER2阳性晚期或转移性乳腺癌的反应率和病理完全缓解率的风险比（RR）分别为1.46（P=0.02）和0.98（P=0.91）。结论：尽管研究存在一定的局限性,但在不考虑治疗成本的情况下,辅助化疗联合曲妥珠单抗治疗要优于标准治疗,临床上具有较强的可替代性。     

HER2阳性晚期乳腺癌治疗新药——曲妥珠单抗共轭复合物

摘要 曲妥珠单抗共轭复合物（T DM1）是抗体和药物的复合物,结合了曲妥珠单抗的抗肿瘤活性和DM1对HER 2有针对性的结合,有效地将曲妥珠单抗运送到靶点。临床试验表明,对于曲妥珠单抗、帕妥珠单抗耐药的HER2阳性晚期乳腺癌有效,对于接受过曲妥珠单抗和紫杉烷类药物治疗的HER2阳性晚期乳腺癌的患者,T DM1比拉帕替尼联合卡培他滨显著延长无进展生存期。对曲妥珠单抗耐药的HER2阳性乳腺癌患者,其耐受性更好并且更为有效,同时不会导致脱发,不良反应在可接受的范围内。     

靶向HER2胞外结构域Ⅳ的单克隆抗体在乳腺癌中的应用进展

人表皮生长因子受体2(HER2)阳性乳腺癌侵袭性强且易转移,抗HER2靶向药物的应用能显著改善HER2阳性乳腺癌患者的预后。在已上市的HER2靶向药物中,靶向HER2胞外结构域Ⅳ的大分子单克隆抗体是治疗HER2阳性乳腺癌的基础靶向药物,主要包括曲妥珠单抗、伊尼妥单抗和马吉妥昔单抗。曲妥珠单抗用于乳腺癌全线治疗,循证医学证据充分,实践经验充足且安全性可控;伊尼妥单抗与曲妥珠单抗在HER2阳性转移性乳腺癌和新辅助/辅助治疗中疗效相似,且安全性可控;马吉妥昔单抗聚焦于携带CD16A-158F等位基因的患者,是晚期乳腺癌后线治疗的选择。临床上需根据患者具体病情选择最适合的药物。     

HER2阳性乳腺癌的靶向治疗进展

21世纪以来，抗人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)靶向药物的不断发展，为HER2阳性乳腺癌患者提供更多的治疗选择并显著改善了生存预后。当前抗HER2靶向药物主要包括曲妥珠单抗、帕妥珠单抗等单克隆抗体类药物，拉帕替尼、奈拉替尼等小分子酪氨酸激酶抑制剂，T-DM1、T-DXd等抗体药物偶联物，这些药物在不同病程中扮演着极其重要的角色。HER2阳性乳腺癌的治疗是以曲妥珠单抗的靶向治疗为基础，具有高危因素的早期患者可进行强化靶向治疗进一步改善预后，而晚期患者则需要对靶向治疗方案合理排兵布阵以克服耐药，延长生存。本文将从疾病各个阶段的抗HER2靶向治疗现状、最新研究进展以及对抗HER2靶向治疗未来的展望进行综述。     

曲妥珠单抗联合化疗治疗HER2阳性乳腺癌经济性的系统综述

目的：对曲妥珠单抗联合化疗治疗HER2阳性乳腺癌的药物经济学进行系统分析。方法： 计算机检索PubMed、ScienceDirect、SpringerLink等数据库2003—2013年间已发表的药物经济学文献,按照一定标准进行筛选,根据药物经济学方法,进行系统综述。结果：曲妥珠单抗治疗的增量成本效果比（ICER）值美国在34307~126933美元每QALY之间,瑞典为35975~52753欧元每QALY,挪威每一个LYS需要多付出8148~162417欧元,日本为17000欧元每LYG。结论：曲妥珠单抗联合化疗治疗HER2阳性乳腺癌是否具有经济性的研究结论不一致。在15篇研究中,有4篇研究认为曲妥珠单抗联合化疗方案不具有成本效果。     

德曲妥珠单抗在乳腺癌治疗的研究进展

德曲妥珠单抗(trastuzumab deruxtecan, T-DXd)是抗体药物偶联体,由曲妥珠单抗、连接子、效应分子三部分构成,通过曲妥珠单抗识别表皮生长因子2(HER2)表达的肿瘤细胞后,经过胞吞胞饮进入细胞,在溶酶体酶作用下降解连接子,释放效应分子拓扑异构酶I抑制剂伊沙替康衍生物,从而发挥抗肿瘤作用。在乳腺癌治疗领域,对于经治的无法切除、转移的HER2阳性患者,T-DXd与恩美曲妥珠单抗无进展生存期(PFS)分别为28.8和6.8个月;在经治的无法切除、转移HER2低表达患者中,T-DXd与医生选择的化疗相比,激素受体阳性人群的PFS分别为10.1和5.4个月。对于脑转移人群,研究显示T-DXd的颅内病灶反应率约70%,中位PFS为14个月。骨髓抑制、肝功能损伤、胃肠道反应是该药物常见的不良反应;间质性肺病/肺炎是其特殊的不良反应,对患者生活质量影响大,需要勤监测、早发现、早治疗。T-DXd在研的临床研究覆盖乳腺癌治疗全程,主要探索药物在乳腺癌晚期一线、二线以及在新辅助、辅助阶段的治疗价值。本文对T-DXd的作用机制、药效学、药动学、重要临床试验及不良反应等进展进行了综述。     

表没食子儿茶素没食子酸酯联合曲妥珠单抗对HER2过表达乳腺癌细胞增殖的影响及其机制

目的 研究表没食子儿茶素没食子酸酯(EGCG)联合曲妥珠单抗对人表皮生长因子受体2(HER2)过表达乳腺癌细胞增殖的影响及其作用机制.方法 表达纯化曲妥珠单抗;用CCK-8细胞增殖检测试剂盒(CCK8)检测不同浓度EGCG、曲妥珠单抗及两药联用对HER2过表达乳腺癌细胞BT474、SK-BR-3的增殖抑制作用;用Wes...     

曲妥珠单抗治疗乳腺癌患者的观察及护理

<正>乳腺癌的分子靶向治疗是继化疗和内分泌治疗后的又一种有效内科治疗手段,曲妥珠单抗是第1个用于治疗乳腺癌的人源化的单克隆抗体药物,选择性地作用于人表皮生长因子受体2(HER2)细胞外部位,抑制肿瘤细胞的增值,阻断肿瘤细胞的信号传递,曲妥珠单抗对HER2蛋白具有高亲和力和高特异性,该药与多种化疗药和内分泌药物     

HER2阳性乳腺癌靶向治疗药物的临床研究进展

乳腺癌已成为全球最常见的癌症,人表皮生长因子受体2（HER2）阳性乳腺癌恶性程度较高,早期易复发和转移,总体预后较差。HER2阳性乳腺癌的治疗因靶向药物的不断问世而呈现更多可能,这类药物包括单克隆抗体（曲妥珠单抗、帕妥珠单抗）、酪氨酸激酶抑制剂（奈拉替尼、拉帕替尼、吡咯替尼、图卡替尼）、抗体药物偶联物（T-DM1、DS-8201）。对HER2阳性乳腺癌靶向治疗药物的最新临床试验结果进行综述,以期为该类乳腺癌的临床用药提供参考。     

Hitting multiple targets in HER2-positive breast cancer: proof of principle or therapeutic opportunity?

INTRODUCTION: Pharmacological targeting of the tyrosine kinase receptor HER2 with the monoclonal antibody trastuzumab has dramatically changed the outlook of HER2-positive breast cancer patients. However, HER2 is part of a more complex biological network that, when deregulated, plays a central role in sustaining the cancer phenotype. These interactions account for primary or acquired resistance to drugs that hit a single biological target, like trastuzumab. Several preclinical models suggest that simultaneous targeting of crucial metabolic pathways has the potential to circumvent or delay the onset of resistance phenomena in HER2-positive breast cancer cells. AREAS COVERED: This review describes the rationale and results of clinical trials using biologically targeted agents in HER2-positive breast cancer patients. Single drugs that hit multiple targets and cocktails of biologically targeted agents are considered, whereas combinations with chemotherapy are not addressed. EXPERT OPINION: Most of the studies using biological agents to hit multiple targets in HER2-positive breast cancer patients confirm that resistance to single-agent HER2-targeting can be overcome. Further developments will include combination of multi-targeting strategies with chemotherapy in patients with earlier-stage disease. In addition, it is possible that newer molecular predictive factors may allow a more rationale choice of the most appropriate targeting for each individual patient.     

基于HER2的多肽疫苗抗肿瘤作用研究进展

人类表皮生长因子受体2属于跨膜酪氨酸激酶受体家族,该受体在乳腺癌、卵巢癌、胃癌、肺癌、前列腺癌中均存在不同程度的过表达现象,可作为抗肿瘤药物的靶点。对目前研究较多的基于人类表皮生长因子受体2的多肽疫苗的抗肿瘤作用研究进展进行综述,为其进一步开发和临床使用提供参考。     

HER2基因突变晚期非小细胞肺癌治疗进展

肺癌是全球范围内一种高发病率和高死亡率的恶性肿瘤,非小细胞肺癌（NSCLC）是最常见的亚型,发生率约85%。人表皮生长因子受体2（HER2）是受体酪氨酸激酶（RTK）的重要成员之一,NSCLC中HER2基因主要表现为HER2突变、HER2扩增和HER2过表达三种形式。目前,靶向HER2突变的酪氨酸激酶抑制剂、单克隆抗体和抗体偶联药物在HER2突变的NSCLC中显示出一定的临床疗效,但相关免疫治疗疗效有限。本文就HER2突变相关NSCLC的治疗进展进行综述,以期为进一步完善HER2突变晚期NSCLC临床诊疗策略提供理论依据。     

Anti-erbB-2 antibody trastuzumab in the treatment of HER2-amplified breast cancer

Human epidermal growth factor receptor-2 (HER2/erbB-2) is a member of a family of four transmembrane receptor tyrosine kinases that regulate cell growth, survival and differentiation via multiple signal transduction pathways. Amplification of the HER2 gene occurs in 20–25% of human breast cancers. This amplification event is an independent adverse prognostic factor as well as a predictive factor for increased response to doxorubicin-based combination chemotherapy, response to trastuzumab and decreased response to hormonal therapy. Methods for detecting protein overexpression or gene amplification in clinical tumor specimens include immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) techniques, with the latter considered by some to be more accurate. Trastuzumab (Herceptin) is a recombinant humanized monoclonal antibody which targets an epitope in the extracellular domain of the HER2 protein. Preclinical models demonstrated that this antibody has significant anti-tumor activity as a single agent and has synergy with certain chemotherapeutic drugs. Phase II and III clinical trials performed in women with metastatic breast cancer that overexpress HER2 have shown that trastuzumab has clinical activity when used as first-, second- or third-line monotherapy, and improves survival when used as first-line therapy in combination with chemotherapy. Newer combinations with numerous chemotherapeutic drugs have also shown significant clinical activity in phase II studies. In all of these trials, trastuzumab was generally well-tolerated, but cardiac toxicity (particularly when the antibody was combined with anthracyclines) was an unexpected adverse effect. Although trastuzumab is currently usually administered on a weekly intravenous schedule, evidence suggests that a triple dose of the drug given once every three weeks has a pharmacokinetic profile expected to be equally efficacious. Neither the optimal schedule nor the optimal duration of trastuzumab therapy has yet been clearly defined in controlled clinical trials. Current clinical investigations of trastuzumab include its use in both the adjuvant and neoadjuvant settings as well as in combination with other chemotherapy drugs or new biologic targeted agents.     

Efficacy and safety of trastuzumab

The human epidermal growth factor receptor (HER) 2 is overexpressed in ～ 20 – 25% of human breast cancers and is an independent adverse prognostic factor. Targeted therapy directed against this receptor has been developed in the form of a humanised monoclonal antibody, trastuzumab. This antibody has shown activity as a single agent in metastatic breast cancer both prior to chemotherapy and in heavily pretreated patients. A pivotal Phase III trial has demonstrated that its use in combination with an anthracycline or paclitaxel results in a significant improvement in survival, time to progression, and response. This has recently been reinforced by another trial with docetaxel. The HER2 status of a tumour is a critical determinant of response to trastuzumab-based treatment. Those that express HER2 at the highest level on immunohistochemistry (IHC), 3+, derive more benefit from treatment with trastuzumab than those with overexpression at the 2+ level. Benefit correlates best with tumours that are positive on fluorescence in situ hybridisation for HER2, regardless of IHC status. Treatment with trastuzumab is generally well tolerated with a low incidence of adverse events. Some patients may experience fever, chills, dyspnoea and pain, particularly with the first administration. Unexpectedly, cardiac toxicity has developed in some patients treated with trastuzumab, and this has a higher incidence in those treated in combination with an anthracycline. ‘Cross-talk’ between the oestrogen receptor and HER2 pathway has stimulated interest in using trastuzumab in combination with endocrine therapy. Current clinical trials are investigating the role of this agent in the adjuvant setting.     

Growth differentiation factor 15 (GDF15)-mediated HER2 phosphorylation reduces trastuzumab sensitivity of HER2-overexpressing breast cancer cells

Resistance to the anti-HER2 monoclonal antibody trastuzumab is a major problem in the treatment of HER2-overexpressing metastatic breast cancer. Growth differentiation factor 15 (GDF15), which is structurally similar to TGF beta, has been reported to stimulate phosphorylation of HER2. We tested the hypothesis that GDF15-mediated phosphorylation of HER2 reduces the sensitivity of HER2-overexpressing breast cancer cell lines to trastuzumab. Gene microarray analysis, real-time PCR, and ELISA were used to assess GDF15 expression. Growth inhibition and proliferation assays in response to pharmacologic inhibitors of HER2, TGF beta receptor, or Src were performed on cells stimulated with recombinant human GDF15 or stable GDF15 transfectants. Western blotting was performed to determine effects of GDF15 on HER2 signaling. Cells were infected with lentiviral GDF15 shRNA plasmid to determine effects of GDF15 knockdown on cell survival in response to trastuzumab. Cells with acquired or primary trastuzumab resistance showed increased GDF15 expression. Exposure of trastuzumab-sensitive cells to recombinant human GDF15 or stable transfection of a GDF15 expression plasmid inhibited trastuzumab-mediated growth inhibition. HER2 tyrosine kinase inhibition abrogated GDF15-mediated Akt and Erk1/2 phosphorylation and blocked GDF15-mediated trastuzumab resistance. Pharmacologic inhibition of TGF beta receptor blocked GDF15-mediated phosphorylation of Src. Further, TGF beta receptor inhibition or Src inhibition blocked GDF15-mediated trastuzumab resistance. Finally, lentiviral GDF15 shRNA increased trastuzumab sensitivity in cells with acquired or primary trastuzumab resistance. These results support GDF15-mediated activation of TGF beta receptor-Src-HER2 signaling crosstalk as a novel mechanism of trastuzumab resistance.     

New perspectives on anti-HER2/neu therapeutics

HER2/neu and the epidermal growth factor receptor (EGFR) are significantly overexpressed in several cancer cells. Overexpression of these two receptors accounts for progression of many types of cancer: breast, ovarian, skin, pancreas and brain. In recent years, several approaches to disable the receptor complexes have shown promise. Antibody-based therapy, kinase inhibitors and other inhibitors of signaling molecules are the major approaches. Our group developed the concept that an anti-p185HER2/neu monoclonal antibody might represent a therapeutic for cancer and this has culminated in a clinically useful therapeutic, the humanized monoclonal antibody Herceptin (trastuzumab). We have now developed a small-molecule form of an anti-HER2/neu peptidomimetic (AHNP) that exhibit functions comparable to those of the monoclonal antibody Herceptin. This approach may be considered a new paradigm in receptor-specific tumor therapeutics. A brief review of our approach in developing receptor-specific therapeutic agents for HER2/neu-related cancer is presented.     

Cardiac dysfunction associated with trastuzumab

The HER2/neu gene is amplified in ～ 25% of breast cancers, leading to HER2 protein overexpression and shortened overall survival and time to relapse. Trastuzumab is a humanised, monoclonal antibody against HER2, which improves survival for women with metastatic HER2-overexpressing breast cancer and reduces the risk of recurrence in women with early stage HER2-overexpressing breast cancer. Cardiac toxicity was an unexpected finding in the pivotal Phase III trial leading to the approval of trastuzumab, and prospective cardiac monitoring has, therefore, been incorporated into more recent clinical trials of trastuzumab. This article reviews the cardiac toxicity findings in key trastuzumab clinical trials and clinical characteristics of trastuzumab-associated cardiac toxicity.