Current development of targeted oligonucleotide-based cancer therapies: Perspective on HER2-positive breast cancer treatment

This Review discusses the various types of non-coding oligonucleotides, which have garnered extensive interest as new alternatives for targeted cancer therapies over small molecule inhibitors and monoclonal antibodies. These oligonucleotides can target any hallmark of cancer, no longer limited to so-called “druggable” targets. Thus, any identified gene that plays a key role in cancer progression or drug resistance can be exploited with oligonucleotides. Among them, small-interfering RNAs (siRNAs) are frequently utilized for gene silencing due to the robust and well established mechanism of RNA interference. Despite promising advantages, clinical translation of siRNAs is hindered by the lack of effective delivery platforms. This Review provides general criteria and consideration of nanoparticle development for systemic siRNA delivery. Different classes of nanoparticle candidates for siRNA delivery are discussed, and the progress in clinical trials for systemic cancer treatment is reviewed. Lastly, this Review presents HER2 (human epidermal growth factor receptor type 2)-positive breast cancer as one example that could benefit significantly from siRNA technology. How siRNA-based therapeutics can overcome cancer resistance to such therapies is discussed.     

Docetaxel combined with targeted therapies in metastatic breast cancer

The treatment of metastatic breast cancer (MBC) is essentially palliative and should be based on hormone therapy or optimized chemotherapy designed to delay disease progression and maximize survival with good quality of life. Novel chemotherapeutic agents introduced in the 1990 s include the taxanes (notably docetaxel), which are among the most potent of current anticancer drugs. Current research is also focusing on molecular targeted agents including those against the HER family of transmembrane receptors and vascular endothelial growth factor. Optimal effects are obtained when these compounds are used in combination with chemotherapy, as shown in preclinical models and more recently in clinical trials. Results of a large randomized trial have demonstrated a significant survival advantage for trastuzumab plus docetaxel compared with docetaxel monotherapy. Docetaxel plus bevacizumab combinations have recently been shown to significantly improve progression-free survival and objective response rate compared with docetaxel monotherapy. Overall, docetaxel in combination with novel targeted agents in MBC appears to be highly active in patients with MBC, and such combinations represent promising treatment regimens for clinical investigation.     

Breast cancer clinical practice recommendations from Saint-Paul-de-Vence: excerpts concerning targeted therapies

This article presents excerpts of the conclusions obtained by a working group applying ANAES (Agence nationale d’accréditation et d’évaluation en santé, France) methodology to the following: Treatment of overexpressed HER2 breast cancers.Excerpts translated and reprinted with permission from Oncologie (2005) 7: 342-379.     

Her-2基因与乳腺癌靶向治疗

近年来随着肿瘤分子生物学技术的发展,分子靶向药物治疗已成为众多学者关注的热点领域,对乳腺癌的治疗策略产生了重大影响.其中,人表皮生长因子受体-2(Her-2)已证实为一个有效的分子靶向治疗的靶标,针对乳腺癌Her-2的分子靶向治疗成为近来继化疗和内分泌治疗后又一重要的治疗手段.     

Endometrial cancer—targeted therapies myth or reality? Review of current targeted treatments

Endometrial cancer (EC) is the most common gynaecological malignancy in developed countries and its incidence is increasing related to obesity. EC is divided into histologic subtypes, most frequently endometrioid adenocarcinoma. Options for treatment of advanced or persistent disease remain limited, and survival has not changed in the last decade. No targeted therapy beyond hormonal therapy is approved for EC. Though hormonal therapy has been a ‘standard’ for four decades, prediction of its efficacy with receptor evaluation or understanding mechanisms of resistance remain important challenges. The clinical impact of deregulation of different pathways such as phosphatidylinositide 3-kinase, HER or MAPK warrant further investigation to use in a prognostic or predictive manner. The cell cycle and DNA repair pathways constitute potential targets for the development of precision therapies. Targeting the microenvironment and more recently immune infiltration are promising areas. Advances in the understanding of cell biology have allowed EC to be divided into multiple diseases that respond differently to targeted therapy. Translational clinical trials that link biology with precision targeted therapy are key to improve outcome and will require careful analysis or identification of potential biomarkers in early phase studies and validation in randomised trials. This approach requires collaborative efforts to achieve meaningful improvement in the prognosis of women with EC. This review aims to summarise the latest published trials on targeted therapies in EC and propose future directions.     

Early primary breast cancer in the elderly - Pattern of presentation and treatment

Introduction

The incidence of primary breast cancer in elderly patients is increasing. However, little is known about their biological profile and most appropriate clinical management, as most studies have been conducted in the younger population. This study aimed to identify a profile of characteristics in elderly women with operable primary breast cancer and investigate the dynamics influencing the treatment decision-making process.

Methods

A review of 268 consecutive female patients >70 years of age, diagnosed with early operable primary breast cancer (<5 cm) over a 30-month period at the Nottingham Breast Institute, was conducted. Age, co-morbidity, cancer characteristics, treatment offered and undertaken, and reason for patient choice were recorded and analysed.

Results

The median age was 78 (range 70-100) years. In our study, 82% of the patients had one or more co-morbidities, with 34% of them having three or more co-morbidities. The commonest pathological diagnosis (from needle core biopsies) was invasive ductal carcinoma of no special type (76%) with histological grade 2 (64%). Majority of them were oestrogen receptor (ER)-positive (84%) and had a high histochemical (H)-score (83% with H-score >200).Most of the patients (60%) underwent primary surgical management, of which 45.4% received breast-conserving surgery. Among the patients who had breast-conserving surgery, 68% of them received adjuvant radiotherapy. When offered genuine choice in treatment options, most patients chose non-operative treatment. Patients who underwent non-operative treatment were on average seven years older and had significantly more co-morbidities than those who had surgery.

Conclusion

The elderly population evidently have demographic and cancer characteristics distinct from their younger counterparts, with less patients receiving surgical management. Further work is underway to correlate this with their clinical outcomes and to examine the factors behind the treatment decision-making process.     

三阴性乳腺癌分子靶向治疗的研究进展

三阴性乳腺癌(TNBC)是雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体2(HER-2)均阴性的乳腺癌,具有独特的病理和分子生物学特性,表现为复发早、进展快、生存期短和预后较其他类型乳腺癌差的特点。除手术治疗外,化疗是其主要的全身治疗手段。目前靶向治疗正逐步应用于乳腺癌的临床治疗中,对TNBC靶向治疗的深入研究,将有助于临床采取有效的治疗方法以提高其疗效。     

A systematic review of generic and breast cancer specific life expectancy models in the elderly

Introduction

The use of primary endocrine therapy (PET) in managing breast cancer in the elderly has become common practice. Whilst there appears to be no difference in overall survival in comparison with surgery, PET has been found to be inferior in local disease control with a limited duration of efficacy (2–3 years). The International Society of Geriatric Oncology (SIOG) state that PET may be considered in patients with a short life expectancy (<2 years) or considered unfit for surgery. Frequently, decision making for PET allocation is a subjective process by the clinician.

microRNAs in breast cancer development and treatment

microRNAs (herein after miRNAs) represent a recently uncovered class of small and endogenous non-coding RNAs. miRNAs play a well conserved and crucial role in normal biological processes, such as cell differentiation, proliferation and apoptosis through a complicated gene regulation networking. The recent rise of interest in miRNAs in cancer research is ascribed to the breakthrough of their role in many pathological processes, including malignant transformation. miRNAs signatures have been clearly defined for certain types of cancer, with correlation to tumor aggressiveness, therapy response and patient outcome. Furthermore, the use of miRNAs as therapeutic targets for cancer is currently under investigation. The aim of this review is to focus on the role of miRNAs in breast cancer development and to summarize the evidence for their potential diagnostic and therapeutic applications in clinical practice.     

乳腺癌干细胞信号转导通路及以其为靶点的干细胞治疗

20世纪以来,乳腺癌的发病率在世界范围内呈逐年上升趋势,且发病年龄日趋年轻化.据估计,2009年美国有192 370名女性被诊断患有乳腺癌,40 170名女性因乳腺癌而死亡.在我国,乳腺癌亦位居女性恶性肿瘤发病率首位.     

Tubular adenoma of the breast in a 73-year-old Woman

A 73-year-old woman presenting with a right breast mass is described. The patient underwent lumpectomy under a diagnosis of breast cancer. However, histopathologically the surgical specimen was tubular adenoma of the breast. This is a rare benign tumor that is difficult to differentiate from breast cancer clinically, especially in elderly patients. We describe two reported cases of tubular adenoma in patients older than 65-years in Japan, as well as the present case.     

Pharmacodynamics: biological activity of targeted therapies in clinical trials

Anticancer drug discovery and development in cancer are currently undergoing of fast transformation. The selection of a therapeutic and effective dose using conventional cytotoxic agents has been based on the consecution of the maximally tolerated dose. However, this principle does not apply for new targeted therapies, where the definition of the optimal biologic dose (OBD) should be preferred. The definition of OBD might be established based on pharmacokinetic endpoints and, ideally, on pharmacodynamic assays by demonstrating directly the biological effect on the target and its down-stream molecules in normal or tumor tissues. Normal tissues, such as peripheral blood mononuclear cells, skin or mucosa, may be excellent surrogates for explore the exposure of a drug and the dynamic target inhibition in vivo. In addition, tumor pharmacodynamic assays may determine the biologic effects of a therapy because tumor cells respond in a different way to targeted drugs than normal tissues, and to identify biomarkers that would permit to predict the individual response. In conclusion, these studies provide demonstration of proof of concept for biological and molecular mechanisms of selected drug, to select the appropriate population to be treated, to help the interpretation of clinical data, to inform the identification of optimal dose and schedule, to evaluate the clinical response and to contribute to take decisions for final approval by authorities. Supported by an unrestricted educational grant from Roche Farma S.A.     

HER2阳性乳腺癌治疗的研究进展

人表皮生长因子受体2(HER2)阳性乳腺癌因其侵袭性高、预后差而一直备受关注。随着曲妥珠单抗的应用,早期HER2阳性乳腺癌患者的预后已得到显著改善,由于其仍存在耐药性和不良反应,在标准治疗中加入新的抗HER2药物又成为新的研究重点,这些药物包括帕妥珠单抗、抗体药物偶联物曲妥珠单抗-美坦新(T-DM1)和各种小分子抑制剂(拉帕替尼、来那替尼、吡咯替尼)。同时PD1及PD-L1抑制剂如帕博利珠单抗在HER2阳性乳腺癌中的研究也在进行中,并有部分基础研究和病例报道已经证实了其疗效和安全性。本文旨在对目前HER2阳性乳腺癌的治疗方案和支持HER2阳性乳腺癌治疗的最新证据进行综述。     

MET signaling: novel targeted inhibition and its clinical development in lung cancer

MET is a versatile receptor tyrosine kinase within the human kinome which is activated by its specific natural ligand hepatocyte growth factor (HGF). MET signaling plays an important physiologic role in embryogenesis and early development, whereas its deregulation from an otherwise quiescent signaling state in mature adult tissues can lead to upregulated cell proliferation, survival, scattering, motility and migration, angiogenesis, invasion, and metastasis in tumorigenesis and tumor progression. Studies have shown that MET pathway is activated in many solid and hematological malignancies, including lung cancer, and can be altered through ligand or receptor overexpression, genomic amplification, MET mutations, and alternative splicing. The MET signaling pathway is known to be an important novel target for therapeutic intervention in human cancer. A number of novel therapeutic agents that target the MET/HGF pathway have been tested in early-phase clinical studies with promising results. Phase 3 studies of MET targeting agents have just been initiated. We will review the MET signaling pathway and biology in lung cancer and the recent clinical development and advances of MET/HGF targeting agents with emphasis on discussion of issues and strategies needed to optimize the personalized therapy and further clinical development.     

Network systems biology for targeted cancer therapies

The era of targeted cancer therapies has arrived.However,due to the complexity of biological systems,the current progress is far from enough.From biological network modeling to structural/dynamic network analysis,network systems biology provides unique insight into the potential mechanisms underlying the growth and progression of cancer cells.It has also introduced great changes into the research paradigm of cancer-associated drug discovery and drug resistance.     

Sentinel node biopsy in elderly breast cancer patients

INTRODUCTION: Even if an increasing body of data suggests that sentinel node biopsy is a safe and accurate method of screening the axillary nodes for metastasis, there is a tendency to perform less extensive or no axillary surgery in older breast cancer women. The aim of this study therefore was to assess the safety of the procedure as well as the rate of axillary recurrences after sentinel node biopsy in this older population. METHODS: Between May 1997 and March 2003, 241 consecutive elderly patients (>or=70 years) with operable breast cancer up to 3 cm and clinically negative axillary lymph nodes were entered into this study. Sentinel node was identified using 5-10 MBq of 99 mTc-labeled colloidal particles and examined with immediate complete intraoperative frozen-section. RESULTS: The sentinel node identification rate was 100%. Ninety-seven percent of the patients underwent breast-conserving surgery. In 90 out of 241 patients (37.3%) the sentinel node was positive for metastasis and complete axillary dissection was immediately performed. In 56.7% of these patients the sentinel node was the only lymph node involved. Micrometastasis in the sentinel node was detected in 30 of the 90 (33.3%) patients. A total of 151 patients (62.7%) were sentinel node negative and no further surgical treatment was done. There were no axillary recurrences at a median followup of 29.7 months (range 3-87 months). The overall survival of this group of patients was 97.9%. CONCLUSIONS: Sentinel node biopsy is a safe and accurate method of screening the axillary nodes for elderly women with operable breast cancer less than 3 cm. The absence of axillary recurrences after sentinel node biopsy without complete axillary dissection supports the hypothesis.     

三阴性乳腺癌分子分型与个体化靶向治疗现状

目的 三阴性乳腺癌(triple-negative breast caner,TNBC)异质性大,恶性程度高,预后差,对内分泌治疗及抗HER2治疗均不敏感.本研究总结TNBC的分子分型及靶向治疗的临床研究进展,以明确TNBC靶向治疗的研究现状和前景.方法 应用PubMed及CNKI数据库检索系统,以"TNBC、分子分型、和靶向治疗"等为关键词,检索2011-04-2016-04的相关文献.纳入标准:TNBC的分型与靶向治疗.根据纳入标准,最后纳入分析66篇文献.结果 根据基因表达谱,TNBC可分为多种分子亚型,主要为"基底细胞样亚型、间充质/间充质干细胞亚型、免疫调节亚型、管腔雄激素受体亚型".TNBC主要的靶向治疗方式分为5大类:针对DNA修复缺陷的靶向药物、酪氨酸激酶抑制相关的靶向药、PI3K-AKT-mTOR通路抑制剂、免疫检查点抑制剂和雄激素受体抑制剂.其中PARP抑制剂、铂类、PD-L1抑制剂、AKT抑制剂的研究均已进入Ⅲ期临床试验;酪氨酸酶抑制相关靶向药物及PI3K/AKT/mTOR通路抑制剂单药使用的价值有限,可能更适宜多药联合或与传统化疗药物联合应用;雄激素受体抑制剂的治疗价值尚需进一步临床试验的验证.结论 TNBC有多种分子亚型,多种靶向治疗药物处于临床研究阶段,其中PARP抑制剂、铂类、PD-L1抑制剂最具有研究前景.     

Current and emerging targeted therapies for metastatic breast cancer

The success of endocrine therapies for hormone receptor-positive breast cancer and trastuzumab and lapatinib for targeting human epidermal growth factor receptor 2 (HER2)-positive tumors has paved the way for the clinical development of several other metastatic breast cancer (MBC)-targeted therapies. Although the benefit of the anti-VEGF (vascular endothelial growth factor) monoclonal antibody bevacizumab in the MBC setting has become a topic of debate, clinical trial results are accumulating, and phase 3 evaluations are ongoing for newer HER2-targeted agents (pertuzumab and trastuzumab-maytansine immunoconjugate) and VEGF-targeted agents (aflibercept), as well as dual, epidermal growth factor receptor/HER2-targeted agents (afatinib [BIBW 2992] and neratinib), multitargeted tyrosine kinase inhibitors (sunitinib and pazopanib), and mammalian target of rapamycin (everolimus) and poly (ADP-ribose) polymerase 1 inhibitors (iniparib, olaparib). These agents as well as other novel classes of anticancer agents are being tested in clinical trials with the potential of addressing unmet therapeutic needs in the MBC patient population.