乳腺癌内分泌治疗耐药的研究进展

乳腺癌内分泌治疗作为乳腺癌综合治疗的方法之一,具有不可替代的重要性.然而,内分泌治疗的疗效因其耐药性受到限制.文章旨在对乳腺癌内分泌治疗耐药的机制及逆转耐药的治疗进展进行综述,为临床内分泌治疗提供新的方向.     

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。     

AIB1在乳腺癌中的研究进展

国外研究表明乳腺癌扩增性抗原1(amplified in breast cancer 1,AIB1)与乳腺癌的发生、发展、乳腺癌内分泌治疗耐药及不良预后关系密切,即过度表达的AIB1与表皮生长因子受体家族(HER2)共同降低内分泌治疗效果及无病生存期。AIB1在乳腺癌内分泌治疗耐药机制中的作用及临床上克服内分泌治疗耐药方法有待进一步研究。AIB1有可能是内分泌治疗耐药预测指标和乳腺癌抗肿瘤治疗靶点。     

HER2蛋白活化在HR阳性乳腺癌内分泌耐药中作用的研究进展

激素受体(hormone receptor,HR)阳性乳腺癌约占全部乳腺癌患者的70%,其重要治疗方式为抑制HR通路的内分泌治疗,此型乳腺癌预后虽然相对较好,但仍有30%~40%患者出现内分泌耐药,目前尚未解决。通路间的交联作用在内分泌耐药中发挥重要作用,受体磷酸化是各通路发挥作用的前提,越来越多研究表明人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)的活化与激素受体阳性乳腺癌内分泌耐药相关,故充分了解HER2蛋白活化与内分泌耐药间的关系,对延缓内分泌耐药具有重要意义。因此本文将顺序阐述HER2蛋白的表达、生物学特性、检测、活化以及HER2蛋白活化在乳腺癌内分泌耐药中的作用,为HR阳性乳腺癌的治疗提供思路。     

逆转乳腺癌内分泌治疗耐药研究进展北大核心CSCD

乳腺癌内分泌治疗耐药的管理在乳腺癌治疗中具有相当的挑战,内分泌耐药的逆转也是当今研究的热点。耐药发生的机制错综复杂,为逆转耐药、维持或增强内分泌治疗的疗效,研究者们在体内体外肿瘤生长抑制、信号转导、凋亡诱导、细胞周期阻滞等多个层面进行了大量尝试。目前内分泌联合分子靶向药物已然成为重点研究方向。本文就既往乳腺癌内分泌耐药逆转的研究作一概述,并探讨未来研究可能的发展方向。     

雄激素受体与乳腺癌内分泌耐药的研究进展

乳腺癌是女性最常见的恶性肿瘤。其中雌激素受体（ER）阳性乳腺癌对内分泌治疗敏感,通过规范的内分泌治疗,患者复发及死亡风险显著降低。但是,内分泌耐药的出现成为临床治疗中最大的障碍。雄激素受体（AR）在ER阳性乳腺癌中广泛表达,与ER之间存在串扰,影响乳腺癌发展、内分泌耐药及预后。本文就AR在ER阳性乳腺癌中的作用机制、预后及内分泌治疗影响,尤其是内分泌耐药的相关研究进展进行综述。     

ESR1基因突变与乳腺癌内分泌治疗耐药的相关性

乳腺癌是目前全世界最常见的女性恶性肿瘤。ER在乳腺癌的内分泌治疗占有中心地位,但内分泌治疗过程中获得性耐药逐渐成为突出的问题。近年来,研究者利用二代测序技术检测出了数量可观的ESR1基因突变,并对这些突变基因的功能进行了初步探索,提出ESR1基因突变对乳腺癌进展及内分泌治疗耐药的产生可能发挥重要作用;同时,新的基因突变检测平台也在不断开发。这些研究成果为解决乳腺癌内分泌治疗耐药问题提供了新的思路,并为构建耐药基因突变监测系统提供了可能。     

乳腺癌内分泌治疗加时代

激素受体（HR）阳性乳腺癌对内分泌治疗有效但也会产生耐药,以内分泌治疗为基础的联合治疗克服了耐药并提高了内分泌治疗的效果。乳腺癌的治疗已进入内分泌治疗加时代,这包括乳腺癌内分泌治疗联合分子靶向药物、血管生成抑制剂、磷脂酰肌醇-3激酶（PI3K）抑制剂、哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂、细胞周期素依赖激酶（CDK)4/6抑制剂、抗HER2剂和表观遗传调节剂。本文系统总结乳腺癌内分泌联合治疗的临床研究结果和潜在药物。     

BCAR1基因与乳腺癌抗雌激素药物耐药的相关研究

乳腺癌抗雌激素药物耐药是导致雌激素受体阳性患者内分泌治疗失败的重要原因之一。BCAR1/p130Cas蛋白能在活体外诱导雌激素依赖性乳腺癌细胞对抗雌激素药物产生耐药,是内分泌治疗的重要耐药因子,其诱导机制尚不能确定。但研究表明检测BCAR1/p130Cas蛋白表达水平可以提示乳腺癌临床内分泌治疗的效果。     

乳腺癌芳香化酶抑制剂耐药的研究进展

乳腺癌是女性常见的恶性肿瘤,约70%的患者为雌激素受体（estrogen receptor,ER）和（或）孕激素受体（progesterone receptor,PR）阳性,内分泌治疗是激素受体（hormone receptor,HR）阳性乳腺癌的主要治疗方式之一。近几十年来,内分泌治疗药物不断发展并应用于临床,乳腺癌患者的复发转移风险显著降低,预后得到长足改善。芳香化酶抑制剂（aromatase inhibitor,AI）在乳腺癌内分泌治疗中发挥重要作用,然而绝大部分患者会发生原发性或继发性耐药,因此克服内分泌治疗药物耐药对进一步提高临床疗效至关重要。从遗传学、表观遗传学及细胞内信号转导通路等方面对HR阳性乳腺癌患者AI治疗后耐药的机制及最新的研究进展进行综述,以期为临床诊疗及科研提供参考。     

Therapeutic implications of estrogen receptor signaling in HER2-positive breast cancers

There is considerable pre-clinical and clinical evidence demonstrating that HER2-positive breast cancers that express estrogen receptor (ER) exhibit intrinsic resistance to endocrine therapy. Therefore, in general, chemotherapy in combination with HER2-directed agents is recommended for all but the smallest HER2-positive early stage breast cancers regardless of ER status. This paradigm has recently come into question when responses to neo-adjuvant HER2-directed regimens were noted to vary based on ER expression, and pathologic complete response was noted not to be prognostic for ER-positive, HER2-positive breast cancers. These and other data suggest the possibility that a subset of HER2-positive, ER-positive breast cancers are driven primarily by ER, and biologically behave more like HER2-negative, ER-positive breast cancers. Identification of this subset of HER2-positive breast cancers is essential to avoid over-treatment of patients with small HER2-positive, ER-positive breast cancers, who may be optimally treated with endocrine therapy alone, or in combination with a HER2-directed agent, thereby avoiding the use of chemotherapy. Crosstalk between the ER and HER2 pathways has been established as playing a role in both intrinsic and acquired resistance to endocrine agents. Emerging data suggests that crosstalk between these pathways is also involved in resistance to HER2-directed agents. Unraveling the role of the ER pathway in resistance to HER2-directed agents could potentially result in therapeutic approaches that can improve outcome for patients with ER-positive, HER2-positive breast cancer.     

Endocrine-resistant breast cancer: Underlying mechanisms and strategies for overcoming resistance

Estrogen plays important roles in the development and progression of breast cancer. However, one-third of breast cancers fail to respond to endocrine therapy and most endocrine-responsive breast cancers subsequently become resistant to endocrine therapy. A tremendous effort has been made to elucidate the mechanisms responsible for the development of endocrine-resistance in breast cancer. Since the main target molecule of estrogen in breast cancer is estrogen receptor (ER)-alpha, most studies have focused on investigating quantitative and qualitative changes in ER-alpha in endocrine-resistant breast cancer. Breast cancers expressing no ER-alpha fail to respond to endocrine therapy. Some breast cancers expressing ER-alpha also fail to respond to endocrine therapy and most breast cancers with acquired endocrine resistance retain ER-alpha expression, which suggests that the disappearance of ER-alpha in breast cancer cells is not a common cause of resistance to endocrine therapy. Recent molecular biological studies have shown evidence that qualitative and functional changes, such as gene mutations and phosphorylation of ER-alpha, cause endocrine resistance in breast cancer. In addition, it has been suggested that endocrine resistance could be induced by epigenetic changes, such as hypoxia, in breast cancer tissues. Understanding the precise mechanisms that underlie endocrine resistance may enable clinicians to develop new strategies for retarding or overcoming endocrine resistance in 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.     

Detection of estrogen receptor in bone marrow from patients with metastatic breast cancer

We devised a method of detecting estrogen receptors (ER) in bone marrow metastases from patients with breast cancer. The method involves a sequential double-staining immunocytochemical technique, with a monoclonal antibody to ER and a polyclonal antibody recognizing epithelial membrane antigen to confirm the epithelial nature of suspected tumor cells. Twenty-seven patients were assessed: ten were found to have ER-positive tumor cells in the bone marrow; ten had ER-negative cells; and the remaining seven patients had no tumor cells in the bone marrow smears. Of the ten patients with ER-positive cells, eight (80%) either had a response to endocrine therapy, implying that they possess ER-positive breast cancers, or had ER-positive primary tumors as determined by the dextran-coated charcoal biochemical assay (DCC). Of the ten patients with ER-negative cells in the bone marrow, eight failed to respond to endocrine therapy. This technique therefore provides a means of predicting which patients will respond to endocrine therapy, and is particularly important in those patients whose ER status is unknown.     

Prognostic implications of estrogen receptor pattern of both tumors in contralateral breast cancer

Estrogen receptor (ER) status is important for breast cancer survival, it is however unclear how prognosis of contralateral breast cancer (CBC) is affected by ER-status of the two tumors. We conducted a large, population-based study of ER-status of both tumors in CBC patients and its influence on prognosis. The cohort consisted of all women diagnosed with CBC in Stockholm, Sweden during 1976-2005, with information on ER-status from medical records (N = 933). Prognosis was modeled as incidence rates of distant metastasis via Poisson regression. The proportion of CBCs with both cancers of the same ER-status was significantly larger than expected by chance. For synchronous (simultaneous) cancers the prognosis was significantly affected by the combined ER-status of both tumors (p = 0.01). Compared to unilateral breast cancer patients the incidence rate ratio (IRR) for patients with double ER-positive tumors was 1.25 (95 % CI: 0.88-1.76), for ER-discordant tumors 2.19 (95 % CI: 1.18-4.08) and for double ER-negative tumors 3.95 (95 % CI: 1.77-8.81). For metachronous (non-simultaneous) cancers, women with double ER-positive tumors had similarly bad prognosis (IRR = 2.95; 95 % CI: 2.39-3.64) as women with double ER-negative tumors (IRR = 2.88; 95 % CI: 1.83-4.52). Both shorter time span between first and second cancer and endocrine therapy for the first cancer further worsened prognosis of women with double ER-positive metachronous CBC. For synchronous CBC patients, ER-pattern of both tumors is an important prognosticator, while among metachronous CBC patients, double ER-positive tumors confer equally bad prognosis as double ER-negative cancers. Our results indicate that this might be due to endocrine therapy resistance.     

Biology of progesterone receptor loss in breast cancer and its implications for endocrine therapy.

The response to endocrine therapy in breast cancer correlates with estrogen receptor (ER) and progesterone receptor (PR) status. ER-positive/PR-negative breast cancers respond less well to selective ER modulator (SERM) therapy than ER-positive/PR-positive tumors. The predictive value of PR has long been attributed to the dependence of PR expression on ER activity, with the absence of PR reflecting a nonfunctional ER and resistance to hormonal therapy. However, recent clinical and laboratory evidence suggests that ER-positive/PR-negative breast cancers may be specifically resistant to SERMs, whereas they may be less resistant to estrogen withdrawal therapy with aromatase inhibitors, which is a result inconsistent with the nonfunctional ER theory. Novel alternative molecular mechanisms potentially explaining SERM resistance in ER-positive/PR-negative tumors have been suggested by recent experimental indications that growth factors may downregulate PR levels. Thus, the absence of PR may not simply indicate a lack of ER activity, but rather may reflect hyperactive cross talk between ER and growth factor signaling pathways that downregulate PR even as they activate other ER functions. Therefore, ER-positive/PR-negative breast tumors might best be treated by completely blocking ER action via estrogen withdrawal with aromatase inhibitors, by targeted ER degradation, or by combined therapy targeting both ER and growth factor signaling pathways. In this review, we will discuss the biology and etiology of ER-positive/PR-negative breast cancer, highlighting recent data on molecular cross talk between ER and growth factor signaling pathways and demonstrating how PR might be a useful marker of these activities. Finally, we will consider the clinical implications of these observations.     

Overexpression of c-erbB2 is an independent marker of resistance to endocrine therapy in advanced breast cancer

The present study investigated the interaction between c-erbB2 overexpression and the response to first-line endocrine therapy in patients with advanced breast cancer. The primary tumours of 241 patients who were treated at first relapse with endocrine therapy were assessed for overexpression of c-erbB2 by immunohistochemistry. c-erbB2 was overexpressed in 76 (32%) of primary breast cancers and did not correlate with any other prognostic factor. The overall response to treatment and time to progression were significantly lower in patients with c-erbB2-positive tumours compared to those that were c-erbB2-negative (38% vs 56%, P = 0.02; and 4.1 months vs 8.7 months, P < 0.001, respectively). In multivariate analysis, c-erbB2 status was the most significant predictive factor for a short time to progression (P = 0.0009). In patients with ER-positive primary tumours treated at relapse with tamoxifen (n = 170), overexpression of c-erbB2 was associated with a significantly shorter time to progression (5.5 months vs 11.2 months, P < 0.001). In conclusion, overexpression of c-erbB2 in the primary tumour is an independent marker of relative resistance to first-line endocrine therapy in patients with advanced breast cancer. In patients with ER-positive primary tumours, the overexpression of c-erbB2 defines a subgroup less likely to respond to endocrine therapy.     

Advances in estrogen receptor biology: prospects for improvements in targeted breast cancer therapy

Estrogen receptor (ER) has a crucial role in normal breast development and is expressed in the most common breast cancer subtypes. Importantly, its expression is very highly predictive for response to endocrine therapy. Current endocrine therapies for ER-positive breast cancers target ER function at multiple levels. These include targeting the level of estrogen, blocking estrogen action at the ER, and decreasing ER levels. However, the ultimate effectiveness of therapy is limited by either intrinsic or acquired resistance. Identifying the factors and pathways responsible for sensitivity and resistance remains a challenge in improving the treatment of breast cancer. With a better understanding of coordinated action of ER, its coregulatory factors, and the influence of other intracellular signaling cascades, improvements in breast cancer therapy are emerging.     

Advances in estrogen receptor biology: prospects for improvements in targeted breast cancer therapy

Estrogen receptor (ER) has a crucial role in normal breast development and is expressed in the most common breast cancer subtypes. Importantly, its expression is very highly predictive for response to endocrine therapy. Current endocrine therapies for ER-positive breast cancers target ER function at multiple levels. These include targeting the level of estrogen, blocking estrogen action at the ER, and decreasing ER levels. However, the ultimate effectiveness of therapy is limited by either intrinsic or acquired resistance. Identifying the factors and pathways responsible for sensitivity and resistance remains a challenge in improving the treatment of breast cancer. With a better understanding of coordinated action of ER, its coregulatory factors, and the influence of other intracellular signaling cascades, improvements in breast cancer therapy are emerging.