Trastuzumab emtansine (T-DM1) for HER2-positive breast cancer

Abstract

Background:

Trastuzumab emtansine (T-DM1), a novel drug developed for the treatment of HER2-positive breast cancer, is a human epidermal growth factor receptor (HER2) targeted antibody drug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine). It has been shown that, in preclinical studies, it has anti-tumor activity in trastuzumab refractory cancer cells. In this review, we aim to show the clinical data about trastuzumab-DM1 (T-DM1) therapy and to discuss the therapy advantages for the management of patients with HER2-positive breast cancer.     

拉帕替尼联合曲妥珠单抗治疗HER2阳性乳腺癌的疗效观察

目的探讨拉帕替尼联合曲妥珠单抗治疗HER2阳性乳腺癌患者的临床效果。方法选取2011年1月—2014年3月在宝鸡市妇幼保健院接受治疗的261例乳腺癌患者,随机分为拉帕替尼组(82例)、曲妥珠单抗组(84例)和联合组(95例),3组患者中途各有3、2和1例停止治疗。拉帕替尼组口服拉帕替尼片,6片/次,1次/d;曲妥珠单抗组静脉注射注射用曲妥珠单抗,1次/周,前9周4 mg/kg,后9周2 mg/kg维持;联合组治疗方法是上述两组治疗方法的联用,3组均连续治疗18周。治疗后,观察3组患者临床疗效,同时比较3组治疗前后无进展生存率(PFS)、总生存期(OS)、中枢神经系统(CNS)转移情况、总反应率(ORR)、临床受益反应(CBR)以及不良反应变化情况。结果治疗后,拉帕替尼组治愈率为21.52%,控制率为51.90%;曲妥珠单抗组治愈率为24.39%,控制率为57.32%;联合组治愈率为45.74%,控制率为76.60%,3组治愈率比较差异具有统计学意义(P0.05),控制率比较差异具有统计学意义(P0.01)。治疗后,拉帕替尼组、曲妥珠单抗组和联合组的PFS分别为41、43、55个月,联合组PFS比拉帕替尼组和曲妥珠单抗组均显著延长,差异具有统计学意义(P0.05)。治疗后随访期间拉帕替尼组(72例)、曲妥珠单抗组(76例)和联合组(83例)的PFS分别为24、26、36个月,联合组的PFS比拉帕替尼组、曲妥珠单抗组的均显著延长,差异具有统计学意义(P0.05)。治疗后,拉帕替尼组、曲妥珠单抗组和联合组的CNS转移率分别为32.91%、29.27%、19.15%,联合组的CNS转移率明显低于拉帕替尼组和曲妥珠单抗组,差异具有统计学意义(P0.05)。拉帕替尼组、曲妥珠单抗组和联合组的ORR分别为56.96%、59.76%、76.60%,联合组ORR均高于拉帕替尼组、曲妥珠单抗组,差异具有统计学意义(P0.05)。拉帕替尼组、曲妥珠单抗组和联合组的CBR分别为43.04%、47.56%、69.15%,联合组的均高于拉帕替尼组、曲妥珠单抗组,差异具有统计学意义(P0.05)。联合组的不良反应发生率显著低于拉帕替尼组和曲妥珠单抗组,差异比较具有统计学意义(P0.05)。结论拉帕替尼联合曲妥珠单抗对HER2阳性乳腺癌患者具有较好的临床治疗效果,具有一定的临床推广应用价值。     

Pertuzumab in HER2-positive breast cancer

Abstract

Background:

Lack of response in some patients and relapse during the course of therapy in the treatment of HER2-positive early breast cancer and metastatic breast cancer continue to challenge researchers and clinicians towards a better understanding of the fundamental mechanisms of trastuzumab action and new therapies for HER2. The aim of this review is to discuss current and future treatment options with pertuzumab in the light of new insights into HER2-positive breast cancer.     

Trastuzumab induces gastrointestinal side effects in HER2-overexpressing breast cancer patients

Summary   Purpose: To characterise the gastrointestinal toxicities associated with Trastuzumab administration in HER2-overexpressing breast cancer patients. Methods: All patients (n = 46) who received Trastuzumab as a single agent or in conjunction with conventional anti-cancer treatment within the Royal Adelaide Hospital Cancer Centre from 2002–2007 were included in this study. A retrospective analysis of case-notes was conducted to investigate the toxicities associated with Trastuzumab. Results: Trastuzumab as a single agent induced toxicities following 22% of administrations. Gastrointestinal toxicities were observed following 12% of administrations and included nausea and vomiting, diarrhoea, abdominal pain and bloating. However, other prominent toxicities that were not related to the gastrointestinal tract were also observed including fatigue and lung symptoms (10.4%). Elderly patients (≥60 years) and those with metastatic disease experienced the highest frequency of toxicity. Conclusion: Trastuzumab induces a range of gastrointestinal toxicities in HER2-overexpressing breast cancer patients. These toxicities are separate to those caused by concurrent chemotherapy and/or radiotherapy.     

HER2蛋白在乳腺癌靶向治疗中的作用及意义

近年来,分子生物学在医学领域得到了充分的发展,分子靶向治疗成为治疗肿瘤的一个新方向。酪氨酸激酶受体家族调控着细胞增殖、分化以及凋亡,与肿瘤的发生与发展密切相关,是一个较为理想的特异性靶点。约有30%的乳腺癌患者出现了人表皮生长因子受体2（HER2）过表达,而HER2受体的活化直接导致了其下游的PI3K/AKT和丝裂原活化蛋白激酶（MAPK）通路被激活,而通过靶向HER2过表达的细胞对肿瘤进行控制成为了一种新的乳腺癌的治疗手段。     

Label-free LC-MS analysis of HER2+ breast cancer cell line response to HER2 inhibitor treatment

Background

Human epidermal growth-factor receptor (HER)-2 is overexpressed in 25 % of breast-cancers and is associated with an aggressive form of the disease with significantly shortened disease free and overall survival. In recent years, the use of HER2-targeted therapies, monoclonal-antibodies and small molecule tyrosine-kinase inhibitors has significantly improved the clinical outcome for HER2-positive breast-cancer patients. However, only a fraction of HER2-amplified patients will respond to therapy and the use of these treatments is often limited by tumour drug insensitivity or resistance and drug toxicities. Currently there is no way to identify likely responders or rational combinations with the potential to improve HER2-focussed treatment outcome.

Methods

In order to further understand the molecular mechanisms of treatment-response with HER2-inhibitors, we used a highly-optimised and reproducible quantitative label-free LC-MS strategy to characterize the proteomes of HER2-overexpressing breast-cancer cell-lines (SKBR3, BT474 and HCC1954) in response to drug-treatment with HER2-inhibitors (lapatinib, neratinib or afatinib).

Results

Following 12 hours treatment with different HER2-inhibitors in the BT474 cell-line; compared to the untreated cells, 16 proteins changed significantly in abundance following lapatinib treatment (1 μM), 21 proteins changed significantly following neratinib treatment (150 nM) and 38 proteins changed significantly following afatinib treatment (150 nM). Whereas following 24 hours treatment with neratinib (200 nM) 46 proteins changed significantly in abundance in the HCC1954 cell-line and 23 proteins in the SKBR3 cell-line compared to the untreated cells. Analysing the data we found that, proteins like trifunctional-enzyme subunit-alpha, mitochondrial; heterogeneous nuclear ribonucleoprotein-R and lamina-associated polypeptide 2, isoform alpha were up-regulated whereas heat shock cognate 71 kDa protein was down-regulated in 3 or more comparisons.

Conclusion

This proteomic study highlights several proteins that are closely associated with early HER2-inhibitor response and will provide a valuable resource for further investigation of ways to improve efficacy of breast-cancer treatment.     

HER-2阳性早期乳腺癌辅助治疗的研究进展

人表皮生长因子受体-2(HER-2)阳性乳腺癌是具有较强侵袭性、预后较差的一类肿瘤,曲妥珠单抗抗Her-2靶向的问世,改变了Her-2阳性乳腺癌的预后.除了曲妥珠单抗这个药物,一系列抗Her-2靶向治疗药物的相继用于临床研究及治疗,包括小分子酪氨酸激酶抑制剂拉帕替尼、来那替尼;抗Her-2分子异源二聚化的药物帕妥珠单抗以及曲妥珠单抗-细胞毒性的共轭药物(T-DM1).本文就是对HER-2阳性早期乳腺癌的辅助治疗进行综述评价.     

Ectopic pregnancy in a breast cancer patient receiving trastuzumab

Cervico-isthmic pregnancy is a rare form of ectopic pregnancy with a poor obstetrical prognosis, whose mechanism remains unclear. Preclinical data indicate that HER-2 plays a major role in embryo implantation. We report a case of cervico-isthmic pregnancy occurring during treatment with trastuzumab (Herceptin™, a monoclonal antibody to HER-2). A 43-year-old woman presented with abnormal vaginal bleeding, while she was receiving trastuzumab for the last 14 months as an adjuvant therapy for a node-positive, HER-2 positive breast cancer. The diagnosis of evolutive cervico-isthmic pregnancy was confirmed by iterative ultrasonographic examinations. Given the poor obstetrical prognosis, the patient underwent voluntary abortion. The use of trastuzumab during pregnancy is still poorly documented, and its safety is not yet established. Given the importance of HER-2 in embryo implantation and fetal development, its putative role in this abnormal embryo implantation should be discussed.     

Pharmacologic inhibition of mTOR improves lapatinib sensitivity in HER2-overexpressing breast cancer cells with primary trastuzumab resistance

Lapatinib, a dual EGFR/HER2 kinase inhibitor, is approved for use in patients with trastuzumab-refractory HER2- overexpressing breast cancer. Increased PI3K signaling has been associated with resistance to trastuzumab, although its role in lapatinib resistance remains unclear. The purpose of the current study was to determine if PI3K/mTOR activity affects lapatinib sensitivity. Reduced sensitivity to lapatinib was associated with an inability of lapatinib to inhibit Akt and p70S6K phosphorylation. Transfection of constitutively active Akt reduced lapatinib sensitivity, while kinase-dead Akt increased sensitivity. Knockdown of 4EBP1 also increased lapatinib sensitivity, in contrast to p70S6K knockdown, which did not affect response to lapatinib. Pharmacologic inhibition of mTOR using rapamycin or ridaforolimus increased lapatinib sensitivity and reduced phospho-Akt levels in cells that showed poor response to single-agent lapatinib, including those transfected with hyperactive Akt. Finally, combination mTOR inhibition plus lapatinib resulted in synergistic inhibition of proliferation, reduced anchorage-independent growth, and reduced in vivo tumor growth of HER2- overexpressing breast cancer cells that have primary trastuzumab resistance. Our data suggest that PI3K/mTOR inhibition is critical for achieving optimal response to lapatinib. Collectively, these experiments support evaluation of lapatinib in combination with pharmacologic mTOR inhibition as a potential strategy for inhibiting growth of HER2-overexpressing breast cancers that show resistance to trastuzumab and poor response to lapatinib.     

乳腺癌细胞的HER2过表达降低其对紫杉醇的药物敏感性

目的紫杉醇的耐药性由多种因素引起,本文研究乳腺癌细胞中的HER2蛋白水平是否影响细胞对紫杉醇的药物敏感性。方法以HER2低表达的MCF-7/pcDNA3.1细胞和经稳定转染获得的HER2高表达的MCF-7/HER2细胞为研究对象,MTT方法测定紫杉醇对这两种细胞的生长抑制作用,流式细胞仪测定紫杉醇对细胞周期分布的影响,An-nexin V-FITC/PI实验测定紫杉醇诱导的细胞凋亡,两种细胞的裸鼠移植瘤实验测定紫杉醇的抑瘤率。结果紫杉醇对MCF-7/HER2细胞的IC50值是MCF-7/pcDNA3.1细胞的6.2倍;紫杉醇诱导细胞G2/M期阻滞,且是HER2非依赖性的;0.01、0.1和1.0μmol.L-1紫杉醇诱导MCF-7/pcDNA3.1细胞凋亡的百分比分别是15.1%±2.1%、21.0%±2.9%和35.7%±3.8%,诱导MCF-7/HER2细胞凋亡的百分比分别是7.5%±1.7%、14.1%±2.3%和24.2%±3.4%,同一浓度的紫杉醇诱导两细胞的凋亡百分比差异有显著性;5、10和20 mg.kg-1的紫杉醇对裸鼠移植MCF-7/pcDNA3.1肿瘤生长抑制率分别是36.9%、58.7%和75.4%,对裸鼠移植MCF-7/HER2肿瘤生长抑制率分别是20.1%、33.3%和67.3%。在相同剂量下紫杉醇对裸鼠移植的两种肿瘤的抑瘤率差异有显著性。结论HER2蛋白的高表达可降低乳腺癌细胞对紫杉醇的药物敏感性。     

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.     

Quality-adjusted survival analysis of first-line treatment of hormone-receptor-positive HER2+ metastatic breast cancer with letrozole alone or in combination with lapatinib

Abstract

Aim:

Compare first-line lapatinib plus letrozole (L?+?Let) versus letrozole monotherapy (Let) in hormone-receptor-positive HER2?+?metastatic breast cancer, employing Q-TWiST (quality-adjusted time without symptoms and toxicity) analysis to account for differences in progression times, with offsets for the impact of adverse events during the treatment period.     

紫杉醇联合曲妥珠单抗治疗表皮生长因子受体-2阳性可手术乳腺癌

目的 探讨紫杉醇联合曲妥珠单抗治疗表皮生长因子受体-2( Her-2)阳性可手术乳腺癌的临床疗效及其安全性.方法 22例Her-2阳性浸润性乳腺癌患者给予紫杉醇联合曲妥珠单抗每3周新辅助化疗方案治疗,并行根治性手术治疗,评价临床疗效及毒副反应.结果 22例患者治疗后,完全缓解13例,部分缓解3例,稳定4例,进展2例,有效率为72.7％(16/22),疾病控制率为90.9％( 20/22);病理完全缓解12例(54.6％).毒副反应主要表现为骨髓抑制和消化道反应.结论 紫杉醇联合曲妥珠单抗治疗Her-2阳性可手术治疗的乳腺癌疗效较好,且安全,具有较高的病理完全缓解率及有效率.     

Nanoparticles (NPs)-mediated systemic mRNA delivery to reverse trastuzumab resistance for effective breast cancer therapy

Monoclonal antibody-based therapy has achieved great success and is now one of the most crucial therapeutic modalities for cancer therapy.The first monoclonal antibody authorized for treating human epidermal growth receptor 2(HER2)-positive breast cancer is trastuzumab.However,resistance to trastuzumab therapy is frequently encountered and thus significantly restricts the therapeutic outcomes.To address this issue,tumor microenvironment(TME) p H-responsive nanoparticles(NPs) were herein develope...     

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。     

Intrathecal trastuzumab (Herceptin) and methotrexate for meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer: a case report

Leptomeningeal carcinomatosis represents a rare manifestation of metastatic breast cancer (MBC). We herewith report on a patient suffering from HER2 overexpressing MBC who received intrathecal methotrexate and trastuzumab for meningeal carcinomatosis. A 48-year-old woman was diagnosed with breast cancer in December 2002. Following surgery, six cycles of adjuvant FE100C plus irradiation and, subsequently for 1 year, trastuzumab were given. As a result of disseminated metastatic spread in October 2005, the patient received whole-brain radiotherapy for symptomatic central nervous system involvement, and was put on several trastuzumab-based combination regimens (capecitabine, vinorelbine, paclitaxel). In June 2006, the patient developed clinical signs of terminal cone involvement with overflow incontinence and paraparesis of the legs. Immediate radiation led to partial relief from clinical symptoms. Subsequently, the patient was put on the tyrosine kinase inhibitor lapatinib and capecitabine (August to October 2007), but on November 6th the patient suffered again from overflow incontinence and weakness of the legs. Failing to respond to lapatinib, the patient received gemcitabine/cisplatin and, additionally, was recommenced on intravenous trastuzumab. Owing to progressive leptomeningeal disease, the patient received repeated doses of intrathecal methotrexate and trastuzumab. Within 2 weeks and four intrathecal treatments, cerebrospinal fluid cytology showed the absence of tumor cells. Moreover, a striking clinical improvement with resolution of the paraparesis of the legs and overflow incontinence was observed. This case report gives details regarding the clinical course of a breast cancer patient who received intrathecal trastuzumab and methotrexate via lumbar puncture for meningeal carcinomatosis of HER2-overexpressing MBC.     

Level of HER2/neu gene amplification as a predictive factor of response to trastuzumab-based therapy in patients with HER2-positive metastatic breast cancer

Summary  To explore the clinical significance of the level of HER2/neu gene amplification in a homogenous cohort of 33 patients with HER2-positive metastatic breast cancer (MBC) and available tumor samples treated with a trastuzumab-based regimen, we retrospectively performed dual-color fluorescence in-situ hybridization test and correlated them for each patient with time-to-progression (TTP) and overall survival (OS). We obtained values of HER2/chromosome 17 centromere (CEP17) ratio ranging from 2.5 to 21 (median 7.2). At the Cox model there is indication that patients whose tumors have high-level HER2/CEP17 ratio have shorter TTP and OS than those with lower ratio, when treated with a trastuzumab-based regimen. Correlations do not reach the limits of statistical significance but no formal sample size calculation was performed due to the explorative nature of the study. If confirmed in larger cohorts of patients, HER2/CEP17 ratio could represent a reliable and economical predictor of response to trastuzumab-based therapy in MBC. All Authors declare that they do not have conflict of interests.     

曲妥珠单抗联合长春瑞滨或吉西他滨对人类表皮生长因子受体2阳性乳腺癌患者的临床观察

目的 探讨曲妥珠单抗联合长春瑞滨或吉西他滨对人类表皮生长因子受体2（HER-2）阳性乳腺癌患者的临床研究。方法 选择2012年1月-2015年12月汉中市三二〇一医院收治的103例HER-2阳性乳腺癌患者,根据随机数字表法,分为A组（49例）及B组（54例）,A组给予曲妥珠单抗联合长春瑞滨,B组给予曲妥珠单抗联合吉西他滨,21 d为1个疗程,共用4~6个疗程。观察两组的实体瘤疗效、健康生存质量、治疗后1、2年生存率、总生存时间、无进展生存时间及毒副反应。结果 A组部分缓解率及客观有效率明显高于B组,差异有统计学意义（P<0.05）;两组完全缓急、疾病稳定及病情进展对比无统计学意义。A组的健康生存质量评分明显高于B组,差异有统计学意义（P<0.05）。A组治疗后1、2年的生存率高于B组,A组的总生存期及无进展生存时间长于B组,但差异无统计学意义。两组毒副反应对比无统计学意义。结论 与吉西他滨联合曲妥珠单抗对比,长春瑞滨联合曲妥珠单抗治疗HER-2阳性乳腺癌患者的部分缓解率、客观有效率及健康生存质量较高,且毒副反应患者可耐受,值得临床推广应用。