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。     

转移性乳腺癌治疗药Trastuzumab Emtansine的Ⅲ期临床试验取得进展

美国基因泰克(GENENTECH)公司于2012年8月27日宣布,其在研药物Trastuzumab Emtansine(曾用名:T-DM1)用于人表皮生长因子受体2(HER2)阳性转移性乳腺癌(mBC)的Ⅲ期临床试验取得进展。Trastuzumab Emtansine是一种抗体-药物偶联物(ADC),由抗体药物曲妥珠单抗和化疗药Emtansine组     

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。     

帕妥珠单抗、曲妥珠单抗联合白蛋白紫杉醇治疗1例转移性乳腺癌患者致指甲脱落案例报道

<正>帕妥珠单抗于2018年12月18日在我国正式上市,帕妥珠单抗联合曲妥珠单抗和紫杉醇类药物可能作为人表皮生长因子受体-2(human epidermal growth factor receptor-2,HER2)阳性晚期乳腺癌患者的一线治疗选择~([1-4]),未来会有越来越多的转移性乳腺癌患者使用曲妥珠单抗、帕妥珠单抗联合紫杉醇类药物的治疗方案,其不良反应也可能越来越常见。本文报道1例转移性乳腺癌患者采用曲妥珠单抗、帕妥珠单抗联合白蛋白     

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。     

帕妥珠单抗联合曲妥珠单抗和长春瑞滨治疗老年人表皮生长因子受体2阳性转移性乳腺癌的临床效果

目的 探讨帕妥珠单抗联合曲妥珠单抗和长春瑞滨治疗老年人表皮生长因子受体2(HER-2)阳性转移性乳腺癌的临床效果.方法 采用回顾性分析方法,收集2018年4月至2020年4月海南省海口市人民医院收治的86例老年HER-2阳性转移性乳腺癌患者的临床资料.根据治疗方法不同将其分为观察组(35例,接受帕妥珠单抗联合曲妥珠单抗...     

针对HER2靶点的抗体药物研究与肿瘤靶向治疗

人类表皮生长因子受体2(HER2)属于跨膜酪氨酸激酶受体家族的成员,在肿瘤细胞中存在过表达。研究显示在乳腺癌、卵巢癌、胃癌、肺癌、前列腺癌中均存在不同程度的HER2过表达。抗体靶向治疗与传统化疗相比,特异性强,毒副作用小。本文介绍了曲妥珠单抗和帕妥珠单抗的单药治疗效果和与化疗药物、激素治疗、疫苗的联合治疗效果,以及偶联药物策略,阐述了其他新型抗HER2抗体药物,特别是双特异抗体、免疫毒素以及抗体融合蛋白等研究近况,为相应的HER2抗体药物开发和临床应用提供参考。     

人表皮生长因子受体2阳性乳腺癌在研靶向新药——trastuzumab deruxtecan

人表皮生长因子受体2 (human epidermal growth factor receptor 2,HER2)靶向疗法的出现已明显提高了HER2阳性转移性乳腺癌患者的生存期,但目前针对HER2靶向治疗无效的患者尚无有效的治疗手段。曲妥珠-依沙替康衍生物(以下称为DS-8201a)是由第一三共(Daiichi Sankyo)公司正在开发的一种新型抗体偶联药物,临床前研究表明对乳腺癌等多种肿瘤均体现出显著活性,并对曲妥珠单抗-美坦新偶联物(T-DM1)耐药的肿瘤细胞也具有抑制活性。Ⅰ期临床试验中期分析显示,DS-8201a对既往接受HER2靶向药物治疗后耐药的患者具有治疗效果,其2017年8月被美国食品药品监督管理局授予突破性疗法、快速通道和快速审批资格,有望为HER2耐药及HER2低表达乳腺癌带来新的治疗方案。本文就DS-8201a的基本信息、作用机制和临床试验情况作一概述。     

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。     

伊尼妥单抗治疗人表皮生长因子受体2阳性转移性乳腺癌伴胃肠功能紊乱1例

乳腺癌是女性常见的肿瘤,如今乳腺癌实体肿瘤通过相应的治疗可取得较好的疗效,但人表皮生长因子受体2(HER2)阳性乳腺癌侵袭性较强、恶性程度高,需引起患者及医务人员的重视。本文回顾性分析1例激素受体阴性、HER2阳性伴胃肠功能紊乱的乳腺癌患者诊治经过。患者初诊为局部晚期炎症乳腺癌伴腋窝淋巴结转移,给予新辅助化疗及手术治疗。术后3年后病情进展,予以伊尼妥单抗联合白蛋白紫杉醇,后续伊尼妥单抗单独靶向治疗,病情持续缓解。提示对于HER2阳性晚期乳腺癌,伊尼妥单抗是个很好的单抗类药物选择。     

Sacituzumab for the treatment of triple-negative breast cancer: the poster child of future therapy?

Introduction: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that disproportionately impacts younger women and is associated with a poor prognosis. Systemic treatment options for metastatic TNBC (mTNBC) are limited to cytotoxic chemotherapy agents with low response rates. This encouraged the clinical development of sacituzumab govitecan (IMMU-132), an antibody-drug conjugate targeting Trop-2, a potential target in epithelial cancer such as TNBC.

Areas covered: We summarize the key features, pharmacokinetics, and the safety and efficacy data of sacituzumab govitecan. We also discuss the future directions of this novel therapeutic agent for mTNBC.

Expert opinion: Based on the efficacy and tolerability observed in the phase 1/2 clinical trial, sacituzumab govitecan was granted breakthrough therapy designation by the Food and Drug Administration as ≥3^rd line therapy for mTNBC. Novel treatment modalities for the management of mTNBC are necessary to improve the care of this aggressive disease. Sacituzumab govitecan represents an important advance in the treatment of mTNBC because of its efficacy and tolerability.     

三阴性乳腺癌新型靶向治疗药物研究进展

三阴性乳腺癌（TNBC）即雌激素受体（ER）、孕激素受体（PR）和人表皮生长因子受体-2（HER-2）表达均为阴性的乳腺癌,是一种异质性疾病,通常具有较高的组织学级别,较激素受体阳性乳腺癌更具侵袭性,且易发生内脏转移。目前,临床对TNBC多采用细胞毒性药物进行常规化疗,但极易产生骨髓抑制、神经毒性等不良反应,导致患者不耐受。使用铂类药物治疗转移性TNBC,药效持续时间短、毒性大,中位总生存期仅9～12个月。鉴于TNBC的化疗效果欠佳,临床迫切需要寻找新的靶向治疗药物,从而根据患者的肿瘤分子亚型制定有效的治疗方案。本文主要就TNBC新型靶向治疗药物的研究进展作一综述。     

Triple negative breast cancer: a brief review of its characteristics and treatment options

Triple negative breast cancer (TNBC), an aggressive variant of breast cancer, is characterized by lack of expression of the estrogen (ER) and progesterone receptors (PRs) and the human epidermal growth factor receptor (HER-2) that are commonly observed in other breast cancer subtypes. The TNBC subtype primarily occurs in younger women of African American or Hispanic descent and tumors tend to be high grade and initially responsive to chemotherapy. However, TNBC is characteristically aggressive with high recurrence, metastatic, and mortality rates. Treatment options are limited since the hormonal receptor and HER-2 antagonists typically used for other breast cancers are ineffective. As such, the mainstay of treatment of TNBC is traditional systemic cytotoxic chemotherapy. Potential future therapies for TNBC include targeted molecular strategies including poly (adenosine diphosphate ribose) polymerase (PARP) and epidermal growth factor receptor (EGFR) inhibitors and antiangiogenic agents. Further research aimed at identifying unique genetic characteristics of TNBC may allow development of other targeted molecular chemotherapy treatment options.     

新型靶向HER2的抗体偶联药物:trastuzumab deruxtecan

trastuzumab deruxtecan(DS-8201a)是新型靶向人表皮生长因子受体2 (HER2)的抗体偶联药物,于2019年12月20日获美国食品和药物管理局加速批准上市,用于治疗有转移性疾病且已接受过2种及以上抗HER2药物治疗方案的HER2阳性、不可切除或转移性乳腺癌成人患者。临床研究表明,DS-8201a在多种恶性肿瘤中均具有较好的抗癌活性,且安全性良好。     

HER-2-positive metastatic breast cancer: trastuzumab and beyond

Background: The recognition achieved in the late 1980s of human epidermal growth factor receptor 2 as an appealing therapeutic target for breast cancer has led to the development of targeted therapies for patients with human epidermal growth factor receptor 2-overexpressing breast tumors. Objectives: The aim of the present review is to address the standard treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer patients, which is currently based on the humanized monoclonal antibody trastuzumab and to describe the new treatment options available for patients progressing on trastuzumab-based therapies. Methods: A broad literature research was performed in order to review treatments, starting from the developmental phase of trastuzumab to the most recent biologic agents being tested in human epidermal growth factor receptor 2-positive disease. Results: Trastuzumab combined with a taxane represents the first therapeutic option for human epidermal growth factor receptor 2-positive metastatic breast cancer. However, novel combinations of trastuzumab and chemotherapy still hold great interest for their remarkable activity and good tolerability. On the other hand, the dual epidermal growth factor receptor/human epidermal growth factor receptor 2 inhibitor lapatinib has been the first drug to be approved in combination with capecitabine for the treatment of patients who progress on trastuzumab-based therapies. Moreover, in the near future, trastuzumab plus another biologic agent targeting human epidermal growth factor receptor 2, either directly or indirectly, may represent an effective ‘chemotherapy-free’ combination for trastuzumab-refractory patients.     

Palbociclib and beyond for the treatment of HR + HER2- metastatic breast cancer: an Asian-Pacific perspective and practical management guide on the use of CDK4/6 inhibitors

Abstract

Breast cancer is the most frequent cancer amongst women worldwide including in Asia where the incidence rate is rapidly increasing. Even with treatment, around 30% of patients with early breast cancer progress to metastatic disease, with hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer the most common phenotype. First-line endocrine therapy targeting the estrogen receptor signaling pathway provides a median progression-free survival or time to progression of 6–15?months in HR?+?HER2- metastatic breast cancer. Recently, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, combined with endocrine therapy, have achieved more than two years median progression-free survival in HR?+?HER2- metastatic breast cancer. However, the characteristics of the Asian breast cancer population differ from those of Western populations and need to be considered when selecting a suitable treatment. Breast cancer is diagnosed at a younger age in Asian populations and late stage at presentation is generally more common in low-/middle-income countries than high-income countries. Consequently, the proportion of premenopausal women with metastatic breast cancer is higher in Asian compared with Western populations. While CDK4/6 inhibitors have been approved in the USA (FDA) since 2015, experience with them in Asia is more limited. We review the experience with the CDK4/6 inhibitor palbociclib in Asian patients with HR?+?HER2- metastatic breast cancer and provide guidance on the use of palbociclib in these patients.     

Triple-negative breast cancer and poly(ADP-ribose) polymerase inhibitors

Recent gene profiling studies have identified at least 5 major subtypes of breast cancer, including normal type, luminal A type, luminal B type, human epidermal growth factor receptor (HER)-2 positive type, and basal-like type. Triple-negative breast cancer (TNBC), showing no or low expressions of estrogen receptor (ER), progesterone receptor (PgR), and HER2, considered important clinical biomarkers, accounts for 10% to 20% of all breast cancers. Hormonal therapy and molecular targeted therapy are not indicated for the management of TNBC, resulting in poor outcomes. Because TNBC lacks clear-cut therapeutic targets, effective treatment strategies remain to be established. However, TNBC is known to share similar biologic characteristics with basal-like type breast cancer and is often accompanied by loss of functional BRCA, a gene-modifying enzyme. Breast cancer with BRCA1 or BRCA2 mutations is accompanied by activation of the enzyme poly(ADP-ribose) polymerase (PARP). PARP, a DNA base-excision repair enzyme, is known to play a central role in gene repair, along with BRCA. Because some breast cancers with BRCA1 or BRCA2 mutations are TNBC, the suppression of PARP has attracted attention as a new treatment strategy for TNBC. In this article, we review the clinical characteristics of TNBC, discuss problems in treatment, and briefly summarize the international development status of PARP inhibitors.     

对比三阴和HER-2阳性乳腺癌新辅助化疗中病理完全缓解率的荟萃分析

目的 对比三阴乳腺癌（TNBC）和人表皮生长因子受体2（HER-2）阳性乳腺癌在新辅助化疗（NAC）中获得的病理完全缓解（pCR）率,为循证医学提供更为确切的数据.方法 检索PubMed和Cochrane Collaboration Library数据库,纳入乳腺癌NAC中包含TNBC和HER-2阳性病例的文献,应用相对危险度（RR）对比TNBC和HER-2阳性两组患者获得的pCR率.结果 共纳入11篇文献,病例数量为1076,其中TNBC组获得28.2%的pCR率,HER-2阳性组为20.0%,两组RR为1.62,95%置信区间（confidence interval,CI）：1.30-2.03,无明显异质性和发表偏倚.结论 TNBC较HER-2阳性乳腺癌在NAC中获得更高pCR率.     

Antiproliferation and apoptosis studies of estrone pharmacophores in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that shows high metastatic capability and poor prognosis. The aggressive behavior of TNBC may involve amplified EGFR expression. Currently, no targeted therapy has been approved for treating TNBC, which urgently needs novel treatment options. In this study, we report that estrone analogs with novel pharmacophores exhibited high potency toward TNBC cells through multiple mechanisms, inhibition of cell proliferation via EGFR receptor, and induction of mitochondrial apoptosis. Molecular docking studies revealed that hit analogs MMA307 and MMA321 were potent against the EGFR receptor (pdb code: 1M17) in silico and were over 10-fold more potent than sorafenib (positive control) when dosed against MDA-MB-468 cells in vitro. MMA307 and MMA321 induced mitochondrial apoptosis as characterized by condensed nuclei with fragmented chromatin, phosphatidylserine flip and modulated expressions of Apaf1, cytochrome c, and caspases 3 and 9. MMA307 and MMA321 inhibited TNBC proliferation through suppression of EGFR and activated EGFR (Y1068) expressions. Similarly, EGFR signaling pathways, RAF/ERK and AKT/mTOR, were inhibited as pARaf, pERK1/2 (characterizes RAF/ERK pathway) and pAKT, pmTOR, p70S6Kα (characterizes AKT/mTOR pathway) were all suppressed. Moreover, MMA307 and MMA321 inhibited TNBC cell growth through downregulation of cyclin D1 expression and arresting TNBC cells in the G₁ phase of cell cycle. This study reports for the first time that estrone congeners with novel pharmacophores may be an effective therapy for TNBC. Findings from this research provide a solid foundation for further preclinical and clinical studies in developing estrone derivatives as novel TNBC therapeutics.     

消癌平注射液联合化疗治疗转移性三阴型乳腺癌临床疗效观察

目的：观察消癌平注射液联合化疗治疗转移性三阴型乳腺癌（ triple-negative breast cancer,TNBC）的疗效及安全性。方法选择2012年12月—2014年12月共101例患者纳入此项研究,均经病理诊断为转移性 TNBC,转移部位主要包括肺、肝、骨、肾上腺、淋巴结等。所有患者需接受消癌平注射液联合化疗4~6周期。应用 RECIST 1.1实体瘤评价标准对患者进行疗效判定。并检测疗效与临床病理因素之间的相关性。应用 NCI-CTCAE 3.0毒性评价标准评估药物相关性不良反应。结果患者中位随访时间为22个月,疗效评估显示：完全缓解4例,部分缓解33例,疾病稳定45例和疾病进展19例。全组患者的客观有效率和疾病控制率分别为36.6%和81.2%。转移部位、转移灶数量和美国东部肿瘤协作组评分与 TNBC 患者的疗效有显著相关性（ P ﹤0.01）。1年总生存率（ overall survival,OS）为81.2%,中位 OS 未达到。常见不良反应多为轻中度,经对症治疗后均有效缓解,患者均可耐受。结论消癌平注射液联合化疗治疗转移性 TNBC 具有较好的疗效和安全性。