胰腺癌中HER2状况及曲妥珠单抗临床应用的研究进展

HER2基因及其表达的蛋白质在许多恶性肿瘤的发生、发展过程中起重要作用,是判断癌症预后和指导治疗的重要指标。在乳腺癌和胃癌中,针对HER2蛋白的靶向治疗药物曲妥珠单抗（trastuzumab,商品名为赫赛汀Herceptin）已广泛应用于临床并取得了显著疗效,给其他癌症的治疗带来希望,尤其是对预后极差、几乎无有效干预措施的胰腺癌。     

HER2/neu在胃癌中的作用研究进展

HER2/neu参与了多种肿瘤的发生、发展过程。它通过信号转导途径与多种相关基因协同参与肿瘤细胞的增殖、凋亡、浸润与侵袭作用,出现过表达及高扩增,并可能影响患者的预后。在胃癌治疗中,针对HER2/neu的靶向治疗取得了重要进展。     

应用HER2基因表达评估HER2阳性乳腺癌的靶向治疗效果的研究进展

目的 总结人类表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)基因表达与HER2阳性乳腺癌靶向治疗效果的关系并总结HER2基因拷贝数相关研究的新进展。方法 复习近年来关于HER2阳性乳腺癌与相关靶向治疗的文献并进行综述。结果 HER2基因拷贝数和HER2/17号染色体着丝粒区（centromere on chromosome 17,CEP17）比值与HER2阳性乳腺癌的预后有关,且循环肿瘤DNA测序有望成为靶向治疗效果的预测指标。结论 较高的HER2基因拷贝数可能与HER2阳性乳腺癌较好的预后相关,HER2/CEP17比值和循环肿瘤DNA对有效评估HER2阳性乳腺癌患者对曲妥珠单抗治疗的反应性具有一定意义。     

乳腺癌抗HER2靶向治疗20年历程

2002年曲妥珠单抗获批上市, 开启了我国乳腺癌靶向治疗的新纪元。20年来, 中国乳腺癌抗人表皮生长因子受体2(HER2)治疗经历了单靶向药物、酪氨酸激酶抑制剂、双靶向药物和抗HER2联合抗体-药物偶联物等阶段;抗HER2靶向治疗格局的变化, 不断改变着HER2阳性乃至HER2低表达患者的治疗模式, 显著改善了患者预后。20年来, 中国学者从参与国际临床试验、完成进口产品注册研究, 到结合中国临床实际, 开发中国自主知识产权的产品, 丰富了HER2靶向治疗临床研究证据, 形成了兼具国际标准与中国特色的治疗体系, 《中国临床肿瘤学会乳腺癌诊疗指南》和《靶向HER2乳腺癌临床诊疗中国专家共识》的制定, 更是中国智慧和中国贡献的集中体现。     

精准医学对乳腺癌化疗方案选择的积极意义

2011 年开始,乳腺癌治疗进入分类治疗时代.随着分类治疗理念的不断深入,乳腺癌也进入"精准治疗"时代,体现在针对HER2 靶点的精准靶向治疗,针对HR的内分泌+靶向治疗.而作为乳腺癌治疗基石地位的化疗,即使在靶向治疗时代我们仍不能轻易放弃,例如在 HER2 阳性乳腺癌中,不论是单靶还是双靶,都是在化疗基础上进行联合,...     

HER2阳性早期乳腺癌治疗年度进展

临床治疗指南推荐曲妥珠单抗作为HER2+早期乳腺癌的标准辅助治疗手段之一。在此基础之上,研究者继续尝试新的突破:一方面部分研究者试图通过双靶向治疗、延长用药期限等手段,进一步降低HER2+早期乳腺癌复发率;另一方面,其他研究者也在尝试缩短靶向治疗时间、减少传统化疗药物的使用等,以减少不必要的治疗及其带来的毒副作用。本文将对近期大型临床研究结果进行总结,围绕四个关于早期乳腺癌抗HER2辅助治疗的热点问题:HER2低表达患者是否需要抗HER2治疗?能否缩短抗HER2治疗的疗程?是否需要加强HER2+早期乳腺癌的靶向治疗?是否可以减少化疗药物的使用?为临床医生合理选择抗HER2靶向治疗提供参考。     

HER2阳性乳腺癌分子靶向治疗药物临床应用的研究进展

分子靶向治疗已经成为乳腺癌的有效治疗手段之一。研究表明,HER2阳性乳腺癌恶性程度高,预后差,而应用分子靶向药物能够明显改善此类乳腺癌患者的预后。近年来,针对乳腺癌HER2分子的靶向治疗药物先后批准上市,如曲妥珠单抗、拉帕替尼、帕妥珠单抗、T-DM1等,使HER2阳性乳腺癌患者的生存期显著延长,就这些药物临床应用的研究进展进行综述。     

胃及胃食道交界处癌中HER2研究进展

在多项研究中,科学家发现在胃及胃食道交界处恶性肿瘤中有人类表皮生长因子受体-2（HER2／neu）基因异常扩增及HER2／neu蛋白的过表达的现象。鉴于这些肿瘤的高病死率,患者期望能够通过对类似于HER2等分子标志物的检测获得诊断和治疗方面的收益。目前,这些伴有HER2高表达的肿瘤诊断率较低且表现出对传统的化疗药物的耐药。抗HER2抗体Trastuzumab靶向治疗具有一定效果。本文简要综述胃及胃食道交界处恶性肿瘤中HER2基因扩增／过表达的研究进展。     

恩美曲妥珠单抗治疗复发转移性乳腺癌一例并文献复习

HER2阳性乳腺癌侵袭性高、易出现复发和转移。恩美曲妥珠单抗（ado-trastuzumab emtansine, T-DM1）是新型抗HER2靶向药物,具有靶向性和细胞毒杀伤双重抗肿瘤作用,2020年2月国家药品监督管理局正式批准其上市,而国内的应用报道较少。本文报道了1例局部晚期HER2阳性的乳腺癌患者使用T-DM...     

HER-2/neu基因在肿瘤组织中的表达及其临床价值

癌基因及其表达是近年来人们研究的热点 ,HER - 2 neu基因自被发现以来 ,已有大量的研究报道问世 ,对其在肿瘤中的基因状态、表达情况及其意义已有一定程度的了解 ,且已有抗HER - 2 neu基因的药物 (herceptin trastuzumab)应用于乳腺癌的临床治疗并取得了明显的效果 ,为近年来肿瘤治疗中引人注目。现就HER - 2 neu基因在肿瘤恶变中的作用、检测方法等作一综述介绍 ,并展望其临床应用前景。1　HER - 2 neu基因简介　　HER - 2 neu又称erbB - 2基因 ,是编码第二人表皮生长因子受体 (humanepidermalgrowthfactorreceptor,HER - 2 …     

Neoadjuvant treatment of HER2 and hormone-receptor positive breast cancer – Moving beyond pathological complete response

Pathologic complete response (pCR) was noted to be prognostic in all but hormone receptor-positive (HR) breast cancer cases even when HER2 is overexpressed. Evocative data suggest that HER2-positive breast cancer patients are a heterogeneous population and a subset of HER2-positive and HR-positive tumors biologically behave more like HER2-negative. Identification and targeted monitoring of these patients is crucial to consolidate data aiming to optimize combination treatment with new agents, thereby avoiding overtreatment with chemotherapy. The questions surrounding HER2-positive and HR-positive breast cancer patients treatment as well as the potential direction towards development of surrogate markers alternative to pCR are discussed.     

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??Japanese gastric cancer treatment guidelines-the 4th Edition 2014 update message HU Xiang. Department of General Surgery??the First Affiliated Hospital??Dalian Medical University??Dalian 116011??China
Abstract The launch of Japanese gastric cancer treatment guidelines ( the following as guide) -the 3rd Edition in 2010 has produced a great effect on the surgical treatment of gastric cancer. The treatment of gastric cancer is more standardized, rationalized and normalized. In recent years, new research results made "guide" revised and reedited. In the new "guide" of the 4th Edition 2014, seven major problems were revised on the basis of the previous “guide”. New evidence and standards were introduced (the definition of gastric operation was updated; temporary provisions and flow chart were enacted for the lymph node dissection when the size of esogastric junction adenocarcinoma is smaller than 4cm; laparoscopic distal gastrectomy was considered to be the conventional treatment for stage I gastric cancer; the relevant standards under gastroscope therapy; the recommended degree of chemotherapy ; the recommended scheme and flow chart for HER2-negative and HER2-positive gastric carcinoma; the relevant provisions of the operation, chemotherapy and follow-up for gastric cancer of stage M1). The "guide"- the 4th edition has acquired the latest scientific achievements, which makes the basic principles for the treatment of gastric cancer and the concept more scientific and accurate. It will provide important guidance for the future clinical practice.     

2014年第4版日本《胃癌治疗指南》更新要旨

2010年第3版日本《胃癌治疗指南》（以下为“指南”）发行以来,对胃癌外科治疗产生了巨大影响,胃癌治疗更为标准化、合理化、规范化。近年来,新的科学研究成果的问世,两次促使“指南”修订、再版。2014年第4版“指南”在原来的基础上,对7个大的问题进行了修订,引进了新的证据和标准（更新胃手术的定义;制定食管胃结合部癌＜4 cm时淋巴结清扫的暂行规定和流程图;确定Ⅰ期胃癌腹腔镜下远端胃切除术为常规性治疗;胃镜下治疗的相关标准;化疗方案推荐度;HER2阴性、阳性胃癌的推荐方案、流程图;M1胃癌的手术、化疗问题以及术后随访的相关规定）。第4版“指南”汲取了最新的科学成就,将胃癌治疗的基本原则、概念更为科学化、精准化,为今后的临床实践提供了重要的指导作用。     

The MicroRNA-21/PTEN Pathway Regulates the Sensitivity of HER2-Positive Gastric Cancer Cells to Trastuzumab

Background

The ToGA trial demonstrated the significant efficacy of trastuzumab in addition to chemotherapy in patients with HER2-positive gastric cancer (GC). Although trastuzumab has become a key drug in breast cancer treatment, resistance to trastuzumab is a major problem in clinical practice. The aim of the current study was to identify the micro-RNA (miR)/gene pathway regulating the sensitivity of HER2-positive GC cells to trastuzumab.

Methods

Correlations between the expression levels of miR-21, PTEN, and p-AKT were analyzed by real-time PCR and Western blot test in HER2-positive GC cell lines. The effects of overexpression or suppression of miR-21 on the sensitivity of GC cells to trastuzumab were also analyzed in vitro.

Results

Overexpression of miR-21 down-regulated PTEN expression, increased AKT phosphorylation, and did not affect HER2 expression. Inversely, suppression of miR-21 increased PTEN expression and down-regulated AKT phosphorylation, but still did not affect HER2 expression. Overexpression of miR-21 decreased the sensitivity of GC cells to trastuzumab, while suppression of miR-21 expression restored the resistance of GC cells to trastuzumab. Overexpression of miR-21 significantly suppressed trastuzumab-induced apoptosis.

Conclusions

To our knowledge, this study was the first reveal the miR-21/PTEN pathway regulated the sensitivity of HER2-positive GC cell lines to trastuzumab through modulation apoptosis. These findings suggest that this pathway may be crucial to the mechanism of resistance to trastuzumab in GC, which may lead to the development of individualized treatment in clinical practice.     

Palliative systemic therapy and overall survival of 1,395 patients with advanced breast cancer – Results from the prospective German TMK cohort study

Data on treatment and outcome of advanced breast cancer in routine practice are rare, especially concerning recurrent disease, but important to complement the results from clinical trials and to improve the standard of care. We present data on choice of systemic first-line treatment, number of treatment lines, and survival of patients treated by medical oncologists in Germany.1395 patients recruited by 124 sites at start of first-line therapy into the ongoing, prospective German clinical cohort study TMK (Tumour Registry Breast Cancer) between February 2007 and October 2015 were analysed.The median OS was 33.8 months (95% CI 30.2–40.2) for HR-positive/HER2-negative, 38.2 months (95% CI 31.3–43.0) for HER2-positive and 16.8 months (95% CI 11.5–22.0) for triple negative breast cancer. Patients with triple negative tumours more often died before start of a third-line therapy than patients with HR-positive or HER2-positive tumours (44% vs. 25%). Use of taxane-based chemotherapies has increased since 2007, with 65% of all first-line chemotherapy-treatments containing taxanes in 2013–15 (60% HR-positive/HER2-negative, 75% HER2-positive, 56% triple negative). 52% of the patients with HR-positive/HER2-negative tumours received first-line endocrine therapy in 2013–15; when restricted to patients with only non-visceral metastases this percentage increased to 63%.To our knowledge, this is the first cohort study showing systemic first-line therapy for all subtypes of advanced breast cancer. Overall survival in the TMK is comparable to that reported by clinical trials despite the inclusion of older and comorbid patients.     

Current challenges and unmet needs in treating patients with human epidermal growth factor receptor 2-positive advanced breast cancer

Human epidermal growth factor receptor 2 oncogene (HER2-positive) overexpression/amplification occurs in less than 20% of breast cancers and has traditionally been associated with poor prognosis. Development of therapies that target HER2 has significantly improved outcomes for patients with HER2-positive advanced breast cancer (ABC). Currently available HER2-targeted agents include the monoclonal antibodies trastuzumab, pertuzumab, and margetuximab, the small-molecule inhibitors lapatinib, tucatinib, neratinib, and pyrotinib, as well as the antibody-drug conjugates trastuzumab emtansine and trastuzumab deruxtecan. Optimal sequencing of these agents in the continuum of the disease is critical to maximize treatment outcomes. The large body of clinical evidence generated over the past 2 decades aids clinicians in treatment decision-making. However, patients with HER2-positive ABC and specific disease characteristics and/or comorbidities, such as leptomeningeal disease, brain metastases, or cardiac dysfunction, are generally excluded from large randomized clinical trials, and elderly or frail patients are often underrepresented. In addition, there is great inequality in the accessibility of approved drugs across countries. This article addresses various challenging clinical situations when treating patients with HER2-positive ABC. The objective is to provide guidance to clinicians on how and when HER2-targeted therapies and additional treatments can be best implemented in routine clinical practice, on the basis of existing clinical evidence and expert opinion where needed.     

Comparative Study on Overexpression of HER2/neu and HER3 in Gastric Cancer

Background  

Owing to the special importance of the HER family in tumorigenesis, the downstream signaling pathways and effectors have become the key molecules in the strategy of carcinoma-targeted therapy. Recent evidence that HER3 is responsible for tumor resistance to therapeutic agents targeting EGFR or HER2/neu, along with the new findings that HER3 is involved in the process of dedifferentiation of gastric cancer (GC) have highlighted the critical role of HER3 in cancer research. HER3 is becoming a new targeted molecule in cancer treatment. Here, we comparatively investigated the expression of HER2/neu and HER3 in gastric cancer of two pathologic types (intestinal type and diffuse type) using immunohistochemistry (IHC) and analyzed the correlation between overexpression of HER2 and HER3 and clinicopathologic parameters.     

Neoadjuvant Therapy – What Have We Achieved in the Last 20 Years?

Neoadjuvant chemotherapy is the standard of care for patients with large, inoperable tumors or inflammatory breast cancer, but it is also increasingly considered for women with operable disease. Several randomized trials have demonstrated that anthracycline- and taxane-containing regimens in operable breast cancer were equally effective in terms of disease-free or overall survival regardless of whether they were administered postoperatively or preoperatively. Further neoadjuvant treatment allows for a higher rate of breast conserving surgery. Tumor responses in terms of pathologic complete remission after short-term chemotherapy will probably only serve as a surrogate marker for long-term outcome in some molecular breast cancer subtypes like the triple-negative, HER2-positive, and some luminal B subsets. Recent trials showed that in HER2-positive disease pCR rates were as high as 70% when 2 HER2-targeted agents were added to chemotherapy.     

Central nervous system disease in phase III studies for advanced HER2 positive breast cancer: A review

ImportanceThe introduction of human epidermal growth factor receptor 2 (HER2) directed therapy has transformed the outcomes of patients with advanced breast cancer (BC). However, HER2 positive breast cancer has a predilection for the central nervous system (CNS) which is associated with significant morbidity and mortality. Understanding the intracranial activity of novel HER2 directed agents is key to developing treatments as well as possible preventative strategies for HER2-positive CNS disease.ObservationsUsing protocols and data from published phase III clinical trials for locally advanced/metastatic HER2-positive breast cancer since the licensing of single agent trastuzumab for advanced BC we review the central nervous system related aspects. This includes CNS related entry criteria, use of baseline and on study cross-sectional imaging of the CNS and protocol and non-protocol defined CNS end points and reported data.Conclusionsand Relevance: This review found heterogeneity between studies with regard to the entry criteria, use of CNS imaging and reported end points within the pivotal phase III studies. Based on these data, a standardisation of both entry criteria and end points with regard to the CNS should be developed and applied to future studies of HER2-positive advanced BC. Such an approach would enable the generation of comparable data and allow a meaningful analysis of different treatment approaches with regard to the CNS. This in turn would allow the development of the most optimal treatment approaches for HER2 positive CNS disease and ultimately the development of preventative strategies.     

Evolving landscape of human epidermal growth factor receptor 2-positive breast cancer treatment and the future of biosimilars

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer comprises approximately 15%–20% of all breast cancers and is associated with a poor prognosis. The introduction of anti-HER2 therapy has significantly improved clinical outcomes for patients with HER2+ breast cancer, and multiple HER2-directed agents (ie, trastuzumab, pertuzumab, lapatinib, and ado-trastuzumab emtansine [T-DM1]) are approved for clinical use in various settings. The treatment landscape for patients with HER2+ breast cancer is continuing to evolve. While novel agents and therapeutic strategies are emerging, biologic therapies, particularly trastuzumab, are likely to remain a mainstay of treatment. However, access issues create barriers to the use of biologics, and there is evidence for underuse of trastuzumab worldwide. A biosimilar is a biologic product that is highly similar to a licensed biologic in terms of product safety and effectiveness. Biosimilars of trastuzumab are in development and may soon become available. The introduction of biosimilars may improve access to anti-HER2 therapies by providing additional treatment options and lower-cost alternatives. Because HER2-targeted drugs may be administered for extended periods of time and in combination with other systemic therapies, biosimilars have the potential to result in significant savings for healthcare systems. Herein we review current and emerging treatment options for, and discuss the possible role of biosimilars in, treating patients with HER2+ breast cancer.