三阴性乳腺癌基因学分子分型和个体化治疗新进展

目的 三阴性乳腺癌(triple negative breast cancer,TNBC)作为乳腺癌的一种特殊类型,具有高侵袭性,极易出现局部复发和远处转移.近年来关于TNBC进一步亚分类,并且针对各亚型进行相应靶向治疗的基础研究和临床研究均较多.本研究对国内外TNBC的分子分型和个体化治疗新进展进行综述分析.对国内外三阴性乳腺癌(triple negarive breast cancer,TNBC)的分子分型以及个体化治疗新进展进行综述分析.方法 应用PubMed及CNKI期刊全文数据库检索系统,以“三阴性乳腺癌、TNBC、分子分型、治疗”等为关键词,检索2011-01-2016-05相关文献,共检索到英文文献240条,中文文献449条.纳入标准:(1)TNBC的生物学功能;(2)TNBC的分子分型;(3)TNBC的个体化治疗.剔除标准:(1)乳腺癌的分子分型;(2)乳腺癌的个体化治疗.根据剔除标准剔除中文文献130条,英文文献141条,最后纳入分析63篇文献.结果 TNBC从基因学角度分为6个亚型,针对每个亚型均有不同的个体化治疗靶向药物,包括表皮生长因子受体(epidermal growth factor receptor,EGFR)抑制剂、铂类、聚腺苷酸二磷酸核糖转移酶(poly-AD-ribose polymerase,PARP)抑制剂、蒽环/紫衫、免疫治疗、血管内皮生长因子受体(vascular endothelial growth factor receptor,VEGFR)抑制剂、雄激素受体(androgen receptor,AR)拮抗剂以及各靶向治疗手段的联合使用.结论 TNBC是异质性疾病,其分子分型的确定对于理解肿瘤的生物学特征和临床行为,以及发展TNBC个体化治疗都是必需的.由于TNBC肿瘤信号通路之间的交联,发展不同靶向药物的联合应用才有望真正的提高该疾病的总生存.     

三阴性乳腺癌分子分型与异质性的研究进展

三阴性乳腺癌（triple-negative breast cancer ,TNBC）是指ER、PR及HER-2 均为阴性的乳腺癌,占乳腺癌15% ～20% 。随着基因组学的发展,乳腺癌的分型已不仅局限于基于免疫组织化学的传统分子分型,其中TNBC 也被认为是一类异质性疾病,其异质性在分子水平、病理学以及临床特征上也各不相同。因此,对TNBC 进一步行分子分型将为靶向治疗带来极大获益,但TNBC分子分型尚无被广泛认可的统一标准,现就最新相关研究做一综述。      

三阴性乳腺癌的分子分型及靶向治疗进展

摘 要：三阴性乳腺癌(triple-negative breast cancer,TNBC )具有高度侵袭性,组织学分级较高,易发生早期复发转移,对于内分泌治疗及HER2靶向治疗往往不敏感。因此准确识别三阴性乳腺癌有效靶点及积极研制新型靶向治疗药物是临床科研中亟待解决的问题。全文就三性阴乳腺癌的分子分型及靶向治疗最新进展作一综述。     

三阴性乳腺癌的认识与治疗方向

目的:总结国内外对三阴性乳腺癌分子生物学的认识,探讨其可行的治疗手段与研究进展.方法:利用 PubMed数据检索系统,以"三阴性乳腺癌、基底样乳腺癌和治疗"为关键词,检索近5年的相关文献.纳入标准:1)TNBC的来源和分子生物学特征;2)治疗包括化学治疗、放疗及靶向治疗.根据纳入标准分析54篇文献.结果:TNBC本质上起源于BLBC,即分子分型的基底样乳隙癌,恶性程度高,预后差,治疗易耐受.但对许多靶向药物显示出敏感性.结论:TNBC研究前景广阔,无论发病机制还是治疗选择都期待进一步的探讨.     

三阴性乳腺癌精准治疗研究的新进展与未来展望

世界卫生组织国际癌症研究机构最新发布的数据显示,乳腺癌现已取代肺癌成为全球发病率最高的恶性肿瘤。三阴性乳腺癌(triple-negative breast cancer,TNBC)是雌激素受体(estrogen receptor,ER)、孕激素受体(progesterone receptor,PR)和人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)表达均为阴性的乳腺癌,与其他分子分型的乳腺癌相比,TNBC具有易复发转移、整体预后差等特点。TNBC对内分泌治疗及抗HER2治疗不敏感,化疗是其主要的系统治疗手段。随着基因组学、转录组学、代谢组学、蛋白组学、微生物组学的蓬勃发展及对TNBC分子分型的深入研究,针对不同靶点的靶向治疗药物和针对免疫检查点的免疫治疗药物的出现,如多聚腺苷二磷酸核糖聚合酶[poly(ADP-ribose) polymerase,PARP]抑制剂、人滋养细胞表面抗原2(trophoblast cell-surface antigen 2,TROP-2)抗体药物偶联物、pembrolizumab、atez...     

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.     

纳米靶向给药在三阴性乳腺癌治疗中的研究进展

摘 要：近年来纳米医学作为交叉学科在肿瘤治疗中的运用进展迅速,纳米粒（nanoparticles,NPs）介导的靶向给药系统(drug delivery systems,DDS)已成为研究热点,其在肿瘤治疗中的关键方面是利用纳米载体靶向分子识别标记选择性地靶向肿瘤细胞,而不会对正常细胞或器官造成伤害。三阴性乳腺癌（triple negative breast cancer,TNBC）由于其特殊的分子分型,治疗困难,国际上虽无针对性的指南,但随着个性化肿瘤药物的快速发展,纳米给药平台为TNBC模块化、个性化治疗提供了更多的选择。全文讨论DDS在TNBC治疗中的进展。     

三阴性乳腺癌各亚型精准医疗策略研究进展

三阴性乳腺癌(Triple negative breast cancer,TNBC)约占乳腺癌总数的15%,缺乏明确的靶向治疗及内分泌治疗靶点,治疗手段相对单一,且复发较早,总生存率较差。早期TNBC的主要治疗方法是新辅助化疗和确定性手术,TNBC分子分型的提出使得TNBC个体化治疗进入精准治疗时代。基于TNBC各亚型特点进行精准医疗策略,可使患者获得临床获益,本文旨在对TNBC各亚型的精准医疗策略研究进展及精准医疗临床获益进行综述。     

三阴性乳腺癌的药物治疗进展

三阴性乳腺癌（triple-negative breast cancer,TNBC）是雌激素受体（estrogen receptor,ER）、孕激素受体（progesterone receptor,PR）及人类表皮生长因子受体（human epidermal growth factor-2 ,HER2）均不表达的乳腺癌,因此不能从现有的内分泌治疗、分子靶向治疗中获益。细胞毒性药物化疗是目前TNBC的标准治疗,但其复发率及病死率仍较高。近年来,针对TNBC靶向治疗、内分泌治疗及免疫治疗的研究成为热点,并已有临床试验发现上述药物能使TNBC患者不同程度获益,该文就TNBC药物治疗取得的进展作一综述。     

三阴性乳腺癌分类治疗的机遇与挑战

三阴性乳腺癌（triple-negative breast cancer,TNBC）由于缺乏特异性的治疗靶点及预后判断指标,已逐渐成为乳腺癌研究领域的热点和难点。同时,TNBC高度异质性的特点使其临床个体化治疗存在着极大的盲目性和局限性,这也给疾病的诊治带来更多的挑战。目前,分子生物学技术尤其是基因芯片技术的发展为TNBC的治疗提供了新的机遇。基于基因表达谱分析结果,TNBC可分为六个亚型,这为TNBC的分类治疗奠定了理论基础。化疗作为目前TNBC治疗的主要手段,患者的临床获益十分有限,而根据TNBC分子分型结果展开的相关研究显示,抗雄激素受体的内分泌治疗、以铂类为基础的化疗、多聚二磷酸腺苷核糖聚合酶（poly ADP-ribose polymerase,PARP）抑制剂靶向治疗等手段分别在特定的TNBC亚群患者中疗效明显。此外,已有大量临床试验发现血管内皮生长因子（vascular endothelial growth factor,VEGF）抑制剂、表皮生长因子受体（epidermal growth factor receptor,EGFR）抑制剂等也能使TNBC患者不同程度地获益。因此,从TNBC分子分型着手寻找新的治疗靶点及疗效预测指标,有助于指导临床内分泌、化疗及靶向药物的应用,使TNBC分类治疗成为可能。然而,目前TNBC分子分型及分类治疗的相关研究尚处于探索阶段,其成果应用于临床还有待于更多的试验加以证实。另外,如何将分子分型与易于检测的临床病理指标相结合,还需要做大量的基础-临床间的转化工作。     

Narrowing the focus: Therapeutic cell surface targets for refractory triple-negative breast cancer

Triple-negative breast cancer (TNBC) is defined as a type of breast cancer with lack of expression of estrogen receptor, progesterone receptor and human epidermal growth factor 2 protein. In comparison to other types of breast cancer, TNBC characterizes for its aggressive behavior, more prone to early recurrence and a disease with poor response to molecular target therapy. Although TNBC is identified in only 25%-30% of American breast cancer cases annually, these tumors continue to be a therapeutic challenge for clinicians for several reasons: Tumor heterogeneity, limited and toxic systemic therapy options, and often resistance to current standard therapy, characterized by progressive disease on treatment, residual tumor after cytotoxic chemotherapy, and early recurrence after complete surgical excision. Cell-surface targeted therapies have been successful for breast cancer in general, however there are currently no approved cell-surface targeted therapies specifically indicated for TNBC. Recently, several cell-surface targets have been identified as candidates for treatment of TNBC and associated targeted therapies are in development. The purpose of this work is to review the current clinical challenges posed by TNBC, the therapeutic approaches currently in use, and provide an overview of developing cell surface targeting approaches to improve outcomes for treatment resistant TNBC.     

Triple-negative breast cancer: A run-through of features,classification and current therapies

Breast cancer is the most prevalent cancer in women worldwide. Triple-negative breast cancer (TNBC) is characterized by the lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. It is the most aggressive subtype of breast cancer and accounts for 12–20% of all breast cancer cases. TNBC is associated with younger age of onset, greater metastatic potential, higher incidence of relapse, and lower overall survival rates. Based on molecular phenotype, TNBC has been classified into six subtypes (BL1, BL2, M, MES, LAR, and IM). TNBC treatment is challenging due to its heterogeneity, highly invasive nature, and relatively poor therapeutics response. Chemotherapy and radiotherapy are conventional strategies for the treatment of TNBC. Recent research in TNBC and mechanistic understanding of disease pathogenesis using cutting-edge technologies has led to the unfolding of new lines of therapies that have been incorporated into clinical practice. Poly (ADP-ribose) polymerase and immune checkpoint inhibitors have made their way to the current TNBC treatment paradigm. This review focuses on the classification, features, and treatment progress in TNBC. Histological subtypes connected to recurrence, molecular classification of TNBC, targeted therapy for early and advanced TNBC, and advances in non-coding RNA in therapy are the key highlights in this review.     

三阴性乳腺癌的临床病理特征及分子研究进展

三阴性乳腺癌(triple negative breast cancer,TNBC)是具有特殊生物学及临床病理学特征的乳腺癌亚型,以雌激素受体(estrogen receptor,ER)、孕激素受体(progesterone receptor,PR)和人类表皮生长因子受体2(human epidermal growth factor receptor 2,HER-2)均不表达为主要特征。该型乳腺癌组织学分级较高,侵袭性强,除浸润性导管癌外,还包括一些特殊的组织学亚型。TNBC的免疫表型和分子特征与基底样乳腺癌(basal-like breast cancer,BLBC)存在一定相似性。与其他亚型乳腺癌相比,TNBC因缺乏相应靶点而失去了内分泌和靶向治疗的机会,目前以蒽环类为基础的化疗为主,但疗效欠佳,早期局部复发和远处转移率较高,无病生存和总生存率较低,预后较差。同时该组肿瘤具有高度异质性,虽然免疫表型均为三阴性,但形态学、预后及对治疗的反应有很大差别。近年来,TNBC受到乳腺癌临床和病理学界的广泛关注,针对其分子分型以及多种信号通路的靶向药物得到广泛研究。     

Clinicopathological and immunohistochemical characteristics of breast cancer patients from Northeast India with special reference to triple negative breast cancer: A prospective study

Background: Molecular pathogenesis of Triple-negative breast cancer (TNBC) is inconclusively documented from resource limited countries and hence there is a lack of available targeted therapy for clinical interventions. Compared to other breast cancer subtypes, TNBC is more aggressive, higher recurrence rate, and higher prevalence in younger premenopausal women. Sporadic literature indicates predominance of TNBC in all reported breast cancer cases from Northeast India.Aim: This study was conducted to evaluate the candidature of panel of key molecular markers involved in the development and progression of TNBC for prognosis and futuristic tailored targeted therapy.Materials and Methods: We analyzed the clinicopathological characterized and immunohistochemically screened the differential expression of key molecular markers involved in the development and progression of in TNBC cases vis-a-vis non-TNBC and autopsy-based control samples.Results: TNBC tends to display at an early reproductive age and is more aggressive in nature. Further, the differential expression of 2 specific markers viz., epidermal growth factor receptor (EGFR) and FolR1 was higher in TNBC cases compared to controls and non-TNBC (both in terms of susceptibility and specificity), clinical staging in TNBC cases (severity) and mortality (outcome). Although Ki67 and vascular endothelial growth factor expression also correlated with severity and outcome of the disease but their differences in non-TNBC cases were not significantly differentiable compared to TNBC.Conclusions: The study indicates that EGFR and FolR1 could serve as useful biomarkers to determine TNBC prognosis. Further studies will be needed to evaluate EGFR and Folate pathways in order to screen out the molecular targets which may be meaningfully used for clinical stratification, intervention, and treatment.     

Triple‐negative breast cancer: Present challenges and new perspectives

Triple‐negative breast cancers (TNBC), characterized by absence of estrogen receptor (ER), progesterone receptor (PR) and lack of overexpression of human epidermal growth factor receptor 2 (HER2), are typically associated with poor prognosis, due to aggressive tumor phenotype(s), only partial response to chemotherapy and present lack of clinically established targeted therapies. Advances in the design of individualized strategies for treatment of TNBC patients require further elucidation, by combined ‘omics’ approaches, of the molecular mechanisms underlying TNBC phenotypic heterogeneity, and the still poorly understood association of TNBC with BRCA1 mutations. An overview is here presented on TNBC profiling in terms of expression signatures, within the functional genomic breast tumor classification, and ongoing efforts toward identification of new therapy targets and bioimaging markers. Due to the complexity of aberrant molecular patterns involved in expression, pathological progression and biological/clinical heterogeneity, the search for novel TNBC biomarkers and therapy targets requires collection of multi‐dimensional data sets, use of robust multivariate data analysis techniques and development of innovative systems biology approaches.     

三阴性乳腺癌靶向治疗最新进展

三阴性乳腺癌(triple-negative breast cancer,TNBC)是一种特殊类型的乳腺癌,占乳腺癌总确诊的15%~20%。其雌激素受体(estrogen receptor,ER)、孕激素受体(progesterone receptor,PR)和人表皮生长因子受体(human epidermal growth factor receptor-2,HER-2)表达均阴性,具有独特的生物学特性和临床病理特征,肿瘤异质性很高,临床上具有复发高、转移早和预后差等特点。目前,临床上缺少有效的治疗手段。该综述介绍了TNBC的临床病理特征、分子亚型、几条重要的通路和靶点,以及目前各靶向药物临床试验研究进度,希望为今后TNBC的治疗提供新的临床思路。     

肿瘤干细胞在三阴性乳腺癌治疗耐药中的作用及机制研究进展

三阴性乳腺癌（TNBC）是雌激素受体（ER）、孕激素受体（PR）、人类表皮生长因子受体2（HER-2）蛋白均呈阴性的临床亚型,占所有乳腺癌病例的15%~20%。与其他亚型相比,TNBC更具侵袭性,其预后差、复发转移率和病死率高。一直以来,TNBC的治疗面临着巨大的挑战,由于治疗靶点的缺乏,细胞毒性化疗是唯一被批准用于TNBC的全身治疗方案。为了改善TNBC患者的疗效,研究者们开展了大量的临床试验来探索更多有效的治疗手段。乳腺癌干细胞（BCSC）的自我更新分化是乳腺癌发生发展的重要机制,能够调控乳腺癌的侵袭转移和治疗抵抗,TNBC中肿瘤干细胞（CSC）比例的升高与化疗耐药和不良预后相关。本综述阐述了TNBC的治疗现状以及CSC在TNBC的发生发展、治疗耐药中的作用机制,探讨了CSC及相关信号因子作为TNBC治疗靶点的潜在价值。     

Identification of new candidate therapeutic target genes in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a subgroup of breast cancer that is negative for estrogen and progesterone receptor and ERBB2 protein expression. It is characterized by its aggressive behavior and by the lack of targeted therapies. To identify new therapeutic targets in TNBC, we used real-time quantitative RT-PCR to analyze 63 TNBC samples in terms of their mRNA expression of 26 genes coding for the major proteins currently targeted by drugs used to treat other cancers or undergoing clinical trials in breast cancer. Six of the 26 genes tested (VEGFA, SRC, PARP1, PTK2, RAF1, and FGFR3) were significantly upregulated in 13% to 46% of the TNBCs. None of the 6 genes was specifically upregulated in the TNBCs compared with 3 other classical breast tumor subtypes. No association was observed between overexpression of these 6 genes (except for FGFR3) and PIK3CA mutation status. These results confirm the interest of targeting VEGFA and PARP1 in ongoing clinical trials in TNBC patients and also identify new target genes (SRC, PTK2, RAF1, and FGFR3). Clinical trials could be initiated easily with existing drugs. Our results also suggest that these target genes might serve as predictive biomarkers of the TNBC treatment response.