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。     

伊尼妥单抗联合吡咯替尼二线治疗HER2阳性患者1例

目的:探索伊尼妥单抗联合吡咯替尼治疗HER2阳性乳腺癌患者的安全性及疗效。方法:报道1例右乳腺浸润性导管癌并全身多处转移患者,一线使用多西他赛+卡培他滨+曲妥珠单抗方案3周期后进展,为曲妥珠单抗原发耐药患者,二线使用含伊尼妥单抗联合吡咯替尼方案(伊尼妥单抗首次8 mg·kg^-1,之后6 mg·kg^-1,3周1次+吡咯替尼400 mg·d^-1,qd+长春瑞滨35 mg, d 1,d 8,3周1次),应用此方案共18周期。结果:患者第1次评价疗效即达到部分缓解,在18周期治疗期间,评价疗效为持续部分缓解状态,目前无进展生存期已大于16个月。治疗过程中未出现Ⅲ级及以上不良反应,患者耐受良好。结论:伊尼妥单抗联合吡咯替尼的治疗模式对转移性HER2阳性乳腺癌有一定的临床疗效,安全性良好。     

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。     

伊尼妥单抗联合吡咯替尼治疗原发耐药HER2阳性晚期乳腺癌1例

约10%～30%的乳腺癌患者存在人表皮生长因子受体2(Human epidermal growth factor receptor-2,HER-2)过表达,后者与较差的预后相关。多种抗HER2药物的出现改变了这一现状,其中,曲妥珠单抗仍是一线标准治疗,而曲妥珠单抗治疗失败后的二线及以上治疗靶向药物选择成为新的困难与挑战。伊尼妥单抗是一种优化细胞毒性作用(Antibody-dependent cell-medicated cytotoxicity, ADCC)效应的新型单抗药物,通过改造抗体的Fc段,显示出优于曲妥珠单抗的疾病控制时间及良好的安全性。基础研究显示,小分子酪氨酸激酶抑制剂吡咯替尼在阻断细胞内的HER2 ATP位点的同时,进一步提高了单抗药物的ADCC效应,两药联合的治疗模式具有潜在的临床获益。本文报道了1例曲妥珠单抗原发耐药的HER-2阳性晚期乳腺癌患者,二线治疗失败后应用长春瑞滨联合伊尼妥单抗及吡咯替尼三线治疗,获得了超过19个月的无进展生存期(Progression-free survival, PFS)。     

拉帕替尼加卡培他滨治疗HER2阳性晚期乳腺癌

拉帕替尼是人表皮生长因子受体2型（HER2，也称为HER2／neu）和表皮生长因子受体（EGFR）的酪氨酸激酶抑制剂，在扇曲妥珠单抗基础治疗后病情进展的HER2阳性转移性乳腺癌的妇女中，拉帕替尼和卡培他滨联合使用具有治疗作用。     

吡咯替尼联合化疗在人表皮生长因子受体-2阳性晚期乳腺癌一线及一线以上治疗中的应用效果

目的 探索吡咯替尼联合化疗在人表皮生长因子受体-2(HER-2)阳性晚期乳腺癌（ABC）一线或一线以上治疗中的应用效果。方法 回顾性分析2020年3月至2023年5月福建医科大学附属三明第一医院收治的106例HER-2阳性ABC患者临床资料,依据治疗方法的不同分为对照组（53例）与观察组（53例）,所有患者只需具有一个可测量病灶。对照组采用曲妥珠单抗+帕妥珠单抗+卡培他滨方案治疗,观察组采用吡咯替尼+卡培他滨方案治疗。比较两组的疾病控制率（DCR）及客观缓解率（ORR）、不良反应、肿瘤标志物水平[癌抗原153(CA153)、癌抗原199(CA199)及胸苷激酶1(TK1)]及生活质量。结果 所有患者至少完成两个周期曲妥珠单抗+帕妥珠单抗+卡培他滨或吡咯替尼+卡培他滨治疗。两组ORR、DCR的比较,差异无统计学意义（P>0.05）;两组不良反应包括腹泻、白细胞减少、恶心/呕吐、血小板减少、肝功能损害,不良反应发生率比较,差异无统计学意义（P>0.05）;观察组治疗后的左室射血分数（LVEF）高于对照组,差异有统计学意义（P<0.05)。两组治疗后的CA153、CA199...     

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。     

乳腺癌的分子靶向药物及进展

目的：通过文献复习探讨乳腺癌的分子靶向治疗现状和进展。方法：查询近几年国内外乳腺癌分子靶向药物治疗进展的关键性文献并进行分析。结果：在乳腺癌的治疗中有明显疗效的分子靶向药物有人表皮生长因子受体2（HER2）的抗靶点药物曲妥珠单抗、拉帕替尼、帕妥珠单抗和曲妥珠单抗一DMl;有表皮生长因子受体( EGFR)靶向治疗的药物吉非替尼和西妥昔单抗,其他的靶点药物有血管内皮生长因子(VEGF)的靶向治疗(贝伐珠单抗)等。结论：目前不少分子靶向药物进入乳腺癌的临床应用,明显降低了乳腺癌患者的疾病复发风险,延长了晚期乳腺癌患者的生存期,其中抗HER2的靶向药物曲妥珠单抗是乳腺癌治疗最成功的靶向药物。分子靶向治疗是乳腺癌术后辅助治疗和晚期乳腺癌解救治疗中新的重要治疗手段。     

拉帕替尼联合卡培他滨治疗HER-2阳性晚期乳腺癌疗效观察

<正>拉帕替尼(lapatinib)是一种口服的表皮生长因子受体(EGFR)及抑制HER1、HER2双靶点的小分子酪氨酸激酶抑制剂。2007年被美国食品药品管理局(FDA)批准用于HER-2阳性既往接受过曲妥珠单抗治疗的晚期或转移性乳腺癌。本研究回顾性观察了2013年5月至2014年5月就诊于山西省肿瘤医院乳腺科的25例晚期患者,探讨拉帕替尼联合卡培他滨在晚期乳腺癌中的作用。现报告如下。     

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。     

Trastuzumab and chemotherapy after the treatment failure of lapatinib for HER2-positive metastatic breast cancer

We describe a patient with human epidermal growth factor receptor type 2 (HER2/c-erbB-2)-positive metastatic breast cancer who survived for approximately 6 years after the initiation of combination therapy with trastuzumab and varying types of chemotherapeutic agents. The patient was a 48-year-old postmenopausal female who underwent partial mastectomy with axillary node dissection for cancer of the right breast in March 1994. She developed lung metastases 2 years thereafter, but survived free of relapse for 8 years following chemotherapy and pulmonary lobectomy. The patient failed to respond to lapatinib, a HER1 (EGFR)/HER2 tyrosine kinase inhibitor, received during the course of her treatment but then again responded to subsequently administered trastuzumab. Primary treatment with trastuzumab and paclitaxel was initiated in April 2004 when the patient developed hepatic metastases 8 years after undergoing surgery for lung metastases. Long-term combination therapy with continued trastuzumab and a variety of chemotherapeutic agents was administered for 6 years without any significant adverse events. We discuss the treatment strategies for HER2-positive breast cancer and the role of lapatinib, a recently approved anticancer drug.     

曲妥珠单抗辅助化疗治疗HER2阳性乳腺癌有效性和安全性的Meta分析

目的 系统评价曲妥珠单抗辅助化疗治疗HER2阳性乳腺癌的有效性和安全性。方法 计算机检索国内外1996-2013年发表的曲妥珠单抗辅助化疗治疗HER2 阳性乳腺癌的前瞻性随机对照研究,对符合纳入标准的研究以Jadad评分标准进行文献质量评价,并使用Review Manager 5.3进行Meta分析。结果 共纳入4项III 期临床随机对照试验(其中有两项试验为合并分析)。Meta分析结果显示,与单纯化疗相比,曲妥珠单抗联合化疗治疗HER2 阳性乳腺癌可以显著延长患者的无病生存期DFS(HR=0.63,95%CI [0.50,0.81],P<0.001)和总生存期OS(HR=0.69,95%CI [0.56,0.86],P=0.001)。在安全性方面,曲妥珠单抗联合化疗组心脏事件(RR=5.09,95% CI [3.23,8.03],P<0.00001)及充血性心力衰竭(RR=5.32,95% CI [2.28,12.44],P=0.0001)发生率显著高于单纯化疗组,而在心脏事件导致的死亡方面,两组没有显著差异。 结论 曲妥珠单抗联合化疗治疗HER2阳性乳腺癌的疗效显著优于单纯化疗,但心脏事件也显著增加。     

Lapatinib ditosylate: expanding therapeutic options for receptor tyrosine-protein kinase erbB-2-positive breast cancer

Receptor tyrosine-protein kinase erbB-2 (HER2)-positive breast cancer is a specific entity with an aggressive behavior. Trastuzumab, a monoclonal antibody targeting erbB-2 (HER2) deeply transformed the outcome in patients. Nevertheless, resistance to trastuzumab is still a major concern. Lapatinib ditosylate is an orally available, small molecule targeting the tyrosine activity of the HER2 receptor. Lapatinib as a single agent and in combination therapy showed interesting activity in trastuzumab-resistant advanced tumors. In addition, lapatinib use seemed suitable in recurrent locally advanced inflammatory breast cancer and brain metastases. More recently, the Neo-ALTTO (NeoAdjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) trial showed that lapatinib in combination with trastuzumab and paclitaxel significantly improved the pathological complete response in a neoadjuvant setting. Several clinical trials are still ongoing and data that may change current clinical practice are awaited with much interest.     

Lapatinib: a novel EGFR/HER2 tyrosine kinase inhibitor for cancer

Lapatinib is an oral dual tyrosine kinase inhibitor that targets epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2), both frequently overexpressed in human cancer. Preclinical data have shown that lapatinib is a potent and selective inhibitor of the tyrosine kinase domain of EGFR and HER2, and tumor cells that overexpress these receptors are growth inhibited by lapatinib both in vitro and in vivo. Phase I clinical trials have shown that lapatinib is well tolerated, with mild diarrhea and rash the most frequent toxicities, and early evidence of clinical efficacy has been reported especially in HER2-positive breast cancer. Phase II studies have shown activity for lapatinib in trastuzumab-refractory breast cancer either alone or in combination with trastuzumab. When used as first-line monotherapy for advanced breast cancer, objective tumor responses have been seen in 28% of patients with untreated HER2-positive advanced breast cancer. An extensive phase III program in advanced breast cancer is now in progress both for refractory disease and as first-line therapy in combination with chemotherapy with and without trastuzumab, and with endocrine therapy. Phase II studies have also been conducted in a variety of other tumors, including renal cell cancer. Parallel biomarker studies are starting to elucidate predictive molecular phenotypes that may indicate likelihood of response to lapatinib, and these may direct future trials with this oral tyrosine kinase inhibitor.     

Overcoming treatment resistance in HER2-positive breast cancer: potential strategies

Human epidermal growth factor receptor (HER)-2 overexpression or amplification occurs in about 20% of all breast cancers and results in a worse prognosis. Nevertheless, anti-HER2 treatments have recently been developed, resulting in dramatic improvements in the clinical outcome of patients with HER2-positive breast cancer. Trastuzumab has shown efficacy in early and advanced breast cancer treatment and lapatinib is currently approved for the treatment of advanced disease. Other anti-HER2 agents are being investigated. Mechanisms of resistance to trastuzumab treatment include crosstalk with heterologous receptors and amplification of HER2 signalling; amplification of the phosphoinositide 3-kinase (PI3K)/AKT pathway; alteration in binding of trastuzumab to HER2; and loss of HER2 expression. Proposed mechanisms of resistance to lapatinib involve derepression and/or activation of compensatory survival pathways through increased PI3K/AKT or estrogen receptor (ER) signalling. Several strategies to overcome resistance to anti-HER2 treatment are in different phases of development and include treatment with pertuzumab, T-DM1 and mammalian target of rapamycin (mTOR) inhibitors.     

Trastuzumab: a review of its use in the management of HER2-positive metastatic and early-stage breast cancer

Trastuzumab (Herceptin) is a humanised monoclonal antibody used in the treatment of breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2), which is associated with clinically aggressive disease and a poor prognosis. The addition of intravenous trastuzumab to first-line chemotherapy improved the time to disease progression, objective response rate, duration of response, and overall survival in randomised, multicentre trials in women with HER2-positive metastatic breast cancer. As such, trastuzumab has become the standard of care in this setting, despite its high acquisition cost and potential for cardiac events, and is licensed for use in combination with paclitaxel (Europe and the US) or docetaxel (Europe). In addition, trastuzumab monotherapy is approved for use in patients with HER2-positive metastatic breast cancer who have previously received chemotherapy for their metastatic disease. Recent data from large phase III trials with trastuzumab in the adjuvant setting revealed significant improvements in disease-free and overall survival. Thus, trastuzumab is also rapidly becoming a standard component of adjuvant therapy for patients with HER2-positive early-stage breast cancer.     

Role of trastuzumab in adjuvant therapy for locally invasive breast cancer.

PURPOSE: The role of trastuzumab in adjuvant therapy for locally invasive breast cancer is discussed. SUMMARY: Trastuzumab is a humanized monoclonal antibody that binds to the extracellular domain of human epidermal growth factor receptor-2 (HER2). Currently, trastuzumab is indicated for use in HER2-positive patients with metastatic breast cancer. Because trastuzumab specifically targets a receptor that is overexpressed in tumor cells, it is less likely to cause the cytotoxic adverse effects of traditional chemotherapy. Cardiotoxicity has been a major concern, however. Several trials were started to evaluate trastuzumab in the adjuvant setting in patients diagnosed with early-stage breast cancer. The interim results of these trials have shown a promising effect of adjuvant therapy with trastuzumab in improving overall survival, disease-free survival, relapse-free survival, and distant-disease-free survival. CONCLUSION: The use of trastuzumab as adjuvant therapy in patients with HER2-positive breast cancer can lead to increased survival. The appropriateness of trastuzumab therapy should be considered based on HER2 status, cost, and risk of toxicity.     

New protein kinase inhibitors in breast cancer: afatinib and neratinib

Introduction: Human epidermal growth factor receptor (HER) 2 is overexpressed in 20 – 25% of breast cancers, and has historically been a poor prognostic marker. The introduction of trastuzumab, the first fully humanized monoclonal antibody targeting HER2, has drastically changed the outcomes of metastatic breast cancers. However, despite initial response, most patients develop resistance. Recent data suggest that strategies targeting more than one member of HER family may circumvent trastuzumab resistance and confer synergistic effects.

Areas covered: Following a literature search on PubMed, national meetings and clinicaltrials.gov using ‘afatinib’, ‘neratinib’, ‘HER2’ and ‘breast cancer’ as keywords, we critically analyzed the different HER2-targeted therapies for their drug development and evidence-based therapeutic strategies. Afatinib and neratinib, two second-generation tyrosine kinase inhibitors (TKIs) that irreversibly inhibit more than one HER family member, are being actively investigated in clinical trials either as monotherapy or in combination. We reviewed the efficacy and optimal use of these agents in various settings, such as systemic therapy for advanced breast cancer including brain metastases, and neoadjuvant therapy in early-stage breast cancer.

Expert opinion: HER2-targeted therapies have been widely used and greatly improved the outcome of HER2-positive breast cancer. Despite the accelerated advancement in recent years, several crucial questions remain unanswered, such as how to treat a prior resistance or affect a sanctuary site, that is, CNS metastasis. The novel next-generation TKIs, afatinib and neratinib, were rationally designed to overcome the resistance by targeting multiple HER family members and irreversibly binding the targets. In spite of the encouraging results of the afatinib and neratinib monotherapies, they have not been proven more efficacious in the combination therapies yet, even though multicenter international trials are still ongoing. The key tasks in the future are to study resistance pathways, design novel strategies to more efficiently test combinations for synergistic effects and identify biomarkers and novel imaging tools to guide individualized therapies.     

晚期HR阳性/HER2阳性乳腺癌的治疗进展

激素受体（HR）阳性伴人表皮生长因子受体2（HER2）阳性乳腺癌（HR+/HER2+乳腺癌）是相对特殊的分子亚型。由于针对HR+/HER2+乳腺癌的临床证据相对较少,在其治疗决策的制定上也存在一定的不确定性。本文将针对多项晚期乳腺癌临床研究的数据进行分析,权衡HR+/HER2+乳腺癌患者治疗的获益以及不良反应,以期为寻找更合适的HR+/HER2+乳腺癌治疗策略提供依据。     

New target therapies for brain metastases from breast cancer

Central nervous system (CNS) metastases from breast cancer (BC) represent an important cause of disease-related morbidity and mortality. For BC patients who develop CNS metastases, local control measures (both surgery and radiation) are essentially palliative and usually poorly effective, with systemic therapies often failing to achieve optimal control mainly due to the presence of the blood-brain barrier which hampers adequate penetration of therapeutic agents into the brain. However, recent evidence suggests that the status of the human epidermal growth factor receptor-2 (HER2) strongly influences the incidence of CNS metastases and the survival of BC patients from the time of development of CNS metastases, with HER2-positive (HER2+) patients generally experiencing higher rates of CNS metastases and prolonged overall survival compared to patients with HER2-negative disease. This phenomenon likely reflects the difficult CNS drug-penetration and improved control of extra-CNS disease following the clinical use of the anti-HER2 monoclonal antibody trastuzumab. Importantly, this HER2-based survival difference has important implications when planning the optimal treatment of BC patients with CNS metastases. To date, although no systemic therapy has been specifically approved for the treatment of CNS metastases from BC, several targeted agents are being clinically developed for this purpose. In the present review we will discuss the targeted therapies that are under investigation for the treatment of CNS metastases from BC, highlighting the different implications based on whether a given agent is being developed to target CNS metastases from HER2+ or HER2-negative breast cancer.