绝经后激素受体阳性晚期乳腺癌的内分泌治疗

随着内分泌新药的出现及对内分泌治疗耐药机制研究的不断发展,乳腺癌内分泌治疗近年取得显著进步。氟维司群、内分泌药物之间的联合治疗以及内分泌联合靶向治疗成为治疗绝经后激素受体阳性晚期乳腺癌的有效方案。     

晚期乳腺癌ESR1基因突变患者内分泌治疗相关研究进展

乳腺癌最常见的分子类型是管腔亚型，它表达雌激素受体(estrogen receptor, ER)和孕激素受体(progesterone receptor, PR),一般通过手术和辅助内分泌治疗(endocrine therapy, ET)进行治疗。乳腺癌的主要治疗包括剥夺雌激素和使用选择性雌激素调节剂或降解剂，这些方法在早期和晚期疾病的治疗中显示出功效。在雌激素受体阳性(ER⁺)晚期乳腺癌的芳香化酶抑制剂(aromatase inhibitor, AI)治疗期间获得不依赖配体的雌激素受体1(estrogen receptor 1,ESR1)基因突变是内分泌治疗耐药的常见机制。临床研究表明，ESR1基因突变可以发生在原发肿瘤中，并且在晚期乳腺癌转移过程中突变频率增加，大多数是通过芳香化酶抑制剂内分泌治疗后引起的。近年来已经有研究探索了ESR1突变作为乳腺癌潜在的预后和预测生物标志物的作用，并表明ESR1突变可能与乳腺癌的进一步侵袭性有关。针对ESR1基因突变的靶向治疗开发是对晚期乳腺癌的一个重要探索，本文主要阐明内分泌抵抗的适应机制，并重点讨论ESR1基因突变后如何...     

乳腺癌内分泌治疗耐药分子机制的研究进展

乳腺癌内分泌治疗针对激素受体阳性乳腺癌患者,但内分泌治疗的疗效却受到耐药的限制。随着高通量二代测序技术和基因组学研究的进展,乳腺癌内分泌治疗耐药的分子机制得到深入研究。ESR1基因、细胞生长旁路途径、细胞周期检查点等发生改变均可能导致乳腺癌的内分泌治疗耐药。目前,针对其中某些与肿瘤发生、发展和转移密切相关的分子靶点已研制出新型的靶向药物。利用靶向治疗联合内分泌治疗来克服特定人群的内分泌治疗耐药现象,可为激素受体阳性乳腺癌患者的精准治疗提供更多的选择。笔者就乳腺癌内分泌治疗耐药的分子机制及其可能克服耐药的靶向治疗进行综述。     

ESR1基因改变在乳腺癌内分泌治疗耐药中的研究进展

雌激素受体（ER）阳性乳腺癌内分泌治疗在一定程度上是有效的,但是内源性及获得性耐药现象一直是临床治疗的难题。ER是由ESR1基因编码的一种核蛋白,ESR1基因突变在ER阳性乳腺癌内分泌治疗耐药中具有重要作用,ESR1基因异常改变包括基因数量、基因重排以及错义点突变。ER配体结合域（LBD）突变的发现进一步加深了对内分泌耐药机制的理解。此外,研究表明,ER-LBD突变的激动构象和拮抗构象之间的动力学改变也可导致内分泌治疗耐药。目前,对内分泌治疗耐药的靶向治疗研究主要有提高氟维司群或他莫昔芬或其他选择性雌激素受体调节剂及选择性ER降解剂的剂量、靶向ER共激活因子（SRC-3抑制剂）或靶向ER信号通路下游的基因（CDK4／6抑制剂）,新型药物的研究有望解决内分泌治疗的耐药问题。     

激素受体阳性乳腺癌靶向治疗进展

内分泌治疗是激素受体阳性乳腺癌的主要治疗手段。内分泌耐药是这部分患者肿瘤复发或进展的主要原因。近期研究发现一系列导致激素受体阳性乳腺癌不依赖雌激素的抵抗机制,开发出相应的靶向治疗药物,其中包括细胞周期蛋白依赖性激酶4/6抑制剂、mTOR抑制剂、表皮生长因子受体抑制剂、抗血管生成药物、组蛋白去乙酰化酶抑制剂、成纤维细胞生长因子受体抑制剂、胰岛素样生长因子受体抑制剂,以及免疫检查点抑制剂等。这些药物被用于阻断耐药通路并提高内分泌治疗疗效,其中已经被批准上市的靶向药物有依维莫司和palbociclib。本文将对内分泌联合靶向治疗的药物研究进展进行综述。      

乳腺癌内分泌治疗耐药相关信号通路的研究进展

内分泌治疗在乳腺癌综合治疗中占有重要的地位,但原发性与继发性耐药是当前内分泌治疗面临的难题.研究证明,雌激素受体通路与各种因子信号通路的交叉效应是导致乳腺癌内分泌耐药的主要机制之一,针对各种通路的靶向治疗药物也成为了热点.许多临床试验结果表明靶向阻断这些信号通路的药物联合内分泌治疗药物可显著提高患者的生存率.本文根据PubMed检索获取相关资料,就近年来与乳腺癌内分泌耐药相关的信号通路及治疗策略研究进展进行综述.     

克服乳腺癌内分泌耐药的靶向治疗新进展

内分泌治疗是激素受体阳性乳腺癌最有效的治疗方式,然而其有效性通常受到耐药的制约,这在进展期乳腺癌患者中几乎是不可避免的。最近,有许多研究对这些耐药模式的分子机制进行了探索,但仍未阐明其确切的机制,不过许多研究都将雌激素受体和生长因子受体信号通路之间的相互作用视为雌激素依赖性乳腺癌内分泌耐药的关键点。一些研究还探讨了介导内分泌耐药的不同分子途径,并对一些治疗靶点进行了评估。尽管大多数信号通路靶向制剂都还处于Ⅰ期或小范围Ⅱ期临床试验阶段,但一些研究已取得令人鼓舞的结果。本文旨在对乳腺癌内分泌治疗耐药的新进展进行综述。     

MicroRNA在乳腺癌内分泌耐药中的研究新进展

内分泌治疗可显著改善雌激素受体阳性的乳腺癌患者的无病生存期和总生存期,但内分泌耐药是导致治疗失败的重要原因。微小RNA（microRNA,miRNA）是肿瘤研究领域中的热点,新近研究证实miRNA的表达变化是乳腺癌耐药机制之一。miRNA通过上调药物外排转运、抗凋亡蛋白、调节多药耐药信号传导网络等方式促成上皮 间质转化并形成肿瘤干细胞。miRNA亦可能通过调节雌激素受体α表达、受体酪氨酸激酶信号传导、细胞生存信号及细胞凋亡等途径引发耐药。miRNA可能成为激素受体阳性乳腺癌的预后因子、内分泌治疗疗效评估的预测因子以及新的靶点。     

乳腺癌内分泌治疗耐药机制的研究进展

内分泌治疗是雌激素受体阳性乳腺癌的重要系统治疗手段,但原发性与继发性耐药是当前内分泌治疗面临的难题。耐药机制主要包括:ER表达缺失或表观遗传修饰;共调因子表达失衡;雌激素受体通路与生长因子受体（growth factor receptor,GFR）通路的交叉效应;特异性miRNA表达改变;乳腺癌上皮间质转化（EMT）等。根据PubMed检索获取相关资料,就近年来雌激素受体阳性乳腺癌内分泌耐药机制及治疗策略研究进展进行综述。     

三阳性乳腺癌内分泌治疗联合靶向治疗的研究进展

三阳性乳腺癌(triple-positive breast cancer,TPBC)是指雌激素受体、孕激素受体和人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)表达均为阳性的乳腺癌,占所有乳腺癌病理学类型的5%～10%。TPBC是Luminal B型乳腺癌亚型的一种特殊类型,既可以接受内分泌治疗,又可以接受靶向治疗。目前国内外指南推荐TPBC的治疗首选抗HER2靶向治疗联合化疗,但TPBC新辅助治疗的病理学完全缓解率却低于激素受体阴性/HER2阳性乳腺癌,且雌激素受体表达>30%的患者从抗HER2靶向治疗联合化疗中获益较小。目前随着多种抗HER2靶向药物不断问世,以及细胞周期蛋白依赖性激酶4和6抑制剂的临床应用,使得临床上对于高选择的患者首选靶向治疗联合内分泌治疗成为可能。本文就TPBC内分泌治疗联合靶向治疗的最新研究进展进行综述。     

The sequential use of endocrine treatment for advanced breast cancer: where are we?

BackgroundHormone receptor-positive advanced breast cancer is an increasing health burden. Although endocrine therapies are recognised as the most beneficial treatments for patients with hormone receptor-positive advanced breast cancer, the optimal sequence of these agents is currently undetermined.MethodsWe reviewed the available data on randomised controlled trials (RCTs) of endocrine therapies in this treatment setting with particular focus on RCTs reported over the last 15 years that were designed based on power calculations on primary end points.ResultsIn this paper, data are reviewed in postmenopausal patients for the use of tamoxifen, aromatase inhibitors and fulvestrant. We also consider the available data on endocrine crossover studies and endocrine therapy in combination with chemotherapy or growth factor therapies. Treatment options for premenopausal patients and those with estrogen receptor-/human epidermal growth factor receptor 2-positive tumours are also evaluated.ConclusionWe present the level of evidence available for each endocrine agent based on its efficacy in advanced breast cancer and a diagram of possible treatment pathways.     

乳腺癌新辅助内分泌治疗与靶向治疗联合应用研究进展北大核心

新辅助内分泌治疗是雌激素受体(estrogen receptor,ER)阳性乳腺癌患者的一种潜在的治疗选择,但由于缺乏与新辅助化疗疗效的对比和治疗持续时间的可靠数据,且病理完全缓解率(pathological complete response,pCR)低,目前仅在年老体弱的患者中使用。然而,靶向药物如细胞周期蛋白依赖激酶(Cyclin-dependent kinase,CDK)4/6抑制剂、哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)抑制剂等结合内分泌治疗,已经在晚期乳腺癌的治疗中取得了成功,为患者带来了显著的获益。在早期乳腺癌的新辅助治疗中,内分泌治疗联合靶向治疗仍处于研究阶段,最近的数据展现出了有希望的应用前景。本文旨在评估新辅助内分泌治疗联合靶向治疗在ER阳性乳腺癌治疗中的现状,希望为后续的临床研究及应用提供参考。     

激素受体阳性晚期乳腺癌内分泌治疗选择

激素受体阳性乳腺癌占所有乳腺癌的70%。内分泌治疗是这个亚型乳腺癌的主要治疗手段,最常见药物有他莫昔芬和芳香酶抑制剂如阿拉曲唑、来曲唑和依西美坦。全文重点总结新型内分泌治疗药物,如雌激素受体降解剂(Fulvestrant),以及新的靶向药物如mTOR抑制剂(Everolimus)、CDK4/6抑制剂(Palbociclib、Ribociclib和Abemaciclib)和PI3K抑制剂(Alpelisib、Buparlisib和Pictilisib)等。新的靶向药物联合内分泌治疗已经改变了临床实践,延长激素受体阳性晚期乳腺癌患者的生存期。     

Optimizing Endocrine Therapy for Metastatic Breast Cancer

New therapies and advances in molecular biology provide opportunities for progress in the management of patients with advanced estrogen receptor-positive breast cancer. The near universal exposure of patients with early stage disease to endocrine therapy poses challenges of resistance when disease recurs. Analysis of tumor tissue at the time of recurrence, and after subsequent endocrine therapy where possible, is critical to understanding the most productive strategies for development and ultimately for individual patients.     

Novel Strategies in Hormone Receptor-Positive Advanced Breast Cancer: Overcoming Endocrine Resistance

Resistance to standard endocrine therapies in hormone receptor-positive advanced breast cancer represents a significant clinical challenge. Different intracellular signaling pathways mediate independent activation of the estrogen receptor (ER), promoting tumor cell proliferation despite anti-hormonal treatment. Recently, the inhibition of cell cycle regulators, CDK4 and CDK6, has demonstrated to significantly enhance the effectiveness of endocrine therapy by overcoming or delaying resistance to estrogen blockade. Strategies such as inhibition of the PI3K/mTOR pathway or epigenetic modulation of ER-related gene expression are closely following the trail of CDK inhibitors. Here, we seek to review the most recent efforts to improve outcomes in these patients, in an attempt to extend endocrine treatment and defer the need for cytotoxic regimens. We also discuss future directions to be considered in the treatment of ER-positive disease, as mechanisms of resistance to these new agents arise.     

Fulvestrant and the sequential endocrine cascade for advanced breast cancer

Following relapse on endocrine therapy for advanced, hormone receptor-positive breast cancer, it is common for patients to experience responses to alternative endocrine agents. Fulvestrant ('Faslodex') is a new type of endocrine treatment--an oestrogen receptor (ER) antagonist with no agonist effects. Fulvestrant downregulates cellular levels of the ER resulting in decreased expression of the progesterone receptor. This unique mode of action means that it is important that fulvestrant is placed optimally within the sequence of endocrine therapies to ensure that patients gain maximum benefit. Fulvestrant has shown efficacy when used after progression on tamoxifen or anastrozole in postmenopausal women with advanced breast cancer. After progression on fulvestrant, subsequent endocrine treatments can produce responses in many patients, demonstrating that fulvestrant does not lead to crossresistance with other endocrine therapies. Responses to fulvestrant have also been observed in patients heavily pretreated with prior endocrine therapy. Fulvestrant is a versatile endocrine agent that may be integrated into the therapeutic sequence prior to, or subsequent to, other hormonal therapies, and represents a valuable additional antioestrogen for the treatment of postmenopausal women with advanced breast cancer.     

Estrogen receptor degradation: a CUE for endocrine resistance?

Despite the undoubted success of adjuvant endocrine therapies that target the estrogen receptor pathway, not all women with estrogen receptor-positive breast cancer respond to these therapies, and many who initially respond will subsequently relapse. Deregulation of various aspects of estrogen receptor signaling has been highlighted as a mechanism of resistance and as a basis for alternative therapeutic approaches. However, a recent publication refocuses attention on the estrogen receptor itself by showing that the ubiquitin-binding CUE domain-containing protein 2 is a regulator of estrogen receptor protein degradation and a marker of endocrine resistance in breast cancer.     

Overcoming endocrine resistance in breast cancer: importance of mTOR inhibition

Approaches to treatment for many patients with advanced breast cancer are based on the expression of specific receptors. Treatments targeting the hormone receptor (typically the estrogen receptor) are used to reduce signaling through these receptors and thereby inhibit proliferation of breast cancer cells expressing these receptors. Although these treatments are effective for many patients, resistance to treatment is common. Recent clinical trials suggest that using multiple agents targeting the same pathway is not sufficient to overcome resistance. New treatment approaches are needed for these patients. Inhibition of the mTOR signaling pathway, a key point of confluence for multiple signaling cascades, offers a promising approach to restoring sensitivity to endocrine therapy in breast cancer. This article reviews the current data from studies of mTOR inhibitors everolimus and temsirolimus in combination with endocrine therapies to overcome treatment resistance in patients with advanced breast cancer.     

Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer

Approximately 70−75% of breast cancers express the estrogen receptor (ER), indicating a level of dependence on estrogen for growth. Endocrine therapy is an important class of target-directed therapy that blocks the growth-promoting effects of estrogen via ER. Although endocrine therapy continues to be the cornerstone of effective treatment of ER-positive (ER+) breast cancer, many patients with advanced ER+ breast cancer encounter de novo or acquired resistance and require more aggressive treatment such as chemotherapy. Novel approaches are needed to augment the benefit of existing endocrine therapies by prolonging time to disease progression, preventing or overcoming resistance, and delaying the use of chemotherapy.