乳腺癌内分泌耐药的临床研究进展

内分泌治疗是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的难题.雌激素受体通路与其他受体通路的交互效应是耐药机制之一.抑制磷脂酰肌醇3-激酶(PI3K)-蛋白激酶B(Akt)-哺乳动物雷帕霉素靶蛋白(mTOR)、表皮生长因子受体(EGFR)等分子通路逆转内分泌耐药的临床研究已取得一定的成果.     

Hormonal Resistance in Breast Cancer: Evolving Treatment Strategies

About 70% of breast cancers are hormone receptor (HR) positive, meaning an estrogen receptor (ER) and/or a progesterone receptor (PgR) are present in the tumor. Compounds that modulate ER or PgR signaling, by either competing for estrogen binding to estrogen receptors (synthetic estrogen receptor modulators [eg, tamoxifen]) or opposing the production of estrogen in the body (aromatase inhibitors in postmenopausal women), are dominant among those used to treat HR-positive breast cancer. Although HR-positive tumors are associated with a better prognosis, in the case of advanced disease, most will develop resistance to hormonal treatments over time. Multiple mechanisms of endocrine resistance have been proposed, including ER receptor loss and cross-talk between the ER and HER2/neu (human epidermal growth factor receptor 2; also known as ErbB-2) receptor signaling pathways. The phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homologue deleted on chromosome ten (PTEN)/Akt/mammalian target of rapamycin (mTOR) pathway is often implicated in sensitivity and resistance to therapy. Dysregulated signaling through the PI3K/PTEN/Akt/mTOR pathway may result from genetic alterations in critical components in this pathway. Therapeutic targeting of alternate pathways of growth signaling in ER-positive tumors has the potential to translate into practice-changing therapeutic strategies. This article discusses the concept of primary and secondary endocrine resistance, outlines the proposed mechanisms, and reviews the emerging evidence for interventions designed to overcome resistance and restore ER sensitivity. The recently reported result of the BOLERO-2 study using an mTOR inhibitor (everolimus or RAD001) in combination with an aromatase inhibitor (exemestane) is discussed in some detail.     

Inhibition of HER1 signaling pathway enhances antitumor effect of endocrine therapy in breast cancer

Epidermal growth factor receptor (EGFR)/HER1 is expressed at high levels in at least 20% of breast cancers. This high expression correlates with a poor prognosis in patients with breast cancer. Experimental and clinical findings suggest that aberrant activation of tyrosine receptor kinases, such as HER1 pathway, play a causal role in the development of antiestrogen resistance in breast cancer. Recent preclinical and clinical evidence shows that inhibition of growth factor signaling pathways suppresses the growth of malignant cells without serious toxicities. To test the hypothesis that inhibition of the HER1 signaling pathway enhances the antitumor effect of endocrine therapy, a promising signal transduction inhibitor (STI) of HER1 tyrosine kinase, gefitinib, and an estrogen receptor (ER) antagonist, fulvestrant, were administered to human breast cancer cells. Our experimental results have revealed that gefitinib additively enhances the antitumor effect of fulvestrant in estrogen receptor (ER)-positive breast cancer cells under estrogen-supplemented conditions. An additive increase in the protein expression level of a cyclin-dependent kinase inhibitor, p21 may play a key role of this additive cytostatic effect. The rationale and future perspectives of the combined use of STIs with endocrine therapy in breast cancer are discussed.     

Advanced concepts in estrogen receptor biology and breast cancer endocrine resistance: implicated role of growth factor signaling and estrogen receptor coregulators

Estrogen receptor (ER), mediating estrogen-signaling stimuli, is a dominant regulator and a key therapeutic target in breast cancer etiology and progression. Endocrine therapy, blocking the ER pathway, is one of the most important systemic therapies in breast cancer management, but de novo and acquired resistance is still a major clinical problem. New research highlights the role of both genomic and nongenomic ER activities and their intimate molecular crosstalk with growth factor receptor and other signaling kinase pathways in endocrine resistance. These signaling pathways, when overexpressed and/or hyperactivated, can modulate both activities of ER, resulting in endocrine resistance. Thus, these signal transduction receptors and signaling molecules may serve as both predictive markers and novel therapeutic targets to circumvent endocrine resistance. Compelling experimental and clinical evidence suggest that the epidermal growth factor/HER2/neu receptor (EGFR/HER2) pathway might play a distinct role in endocrine resistance, and especially in resistance to selective estrogen receptor modulators (SERMs) such as tamoxifen. Results from preclinical studies of treatment combinations with various endocrine therapy drugs together with several potent anti-EGFR/HER2 inhibitors are very promising, and clinical trials to see whether this new strategy is effective in patients are now ongoing.     

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研究进展

内分泌治疗(ednocrine therapy,ET)是乳腺癌综合治疗中的重要措施之一,选择性雌激素受体调节剂(selectiveestrogen receptor modulators,SERMs)、第三代芳香化酶抑制剂(aromatase inhibi-tors,AIs)和氟维司群是重要的内分泌治疗药物。但目前内分泌疗法面临的最大难题是原、继发耐药,其确切机制尚不清楚,近年来的研究发现,多种因素与耐药相关,如ER信号传导途径中的共激活与共抑制因子的比例,HER-2生长因子受体的高表达,各生长因子和激酶的串话调节,雌激素受体基因关键氨基酸位点的突变和多态、芳香化酶基因的突变与多态以及他莫昔芬(tamoxifen,TAM)代谢异常等。     

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.     

Biologic basis of sequential and combination therapies for hormone-responsive breast cancer

Although pharmacologic therapies that reduce or block estrogen signaling are effective treatments of estrogen receptor (ER)-positive breast cancer, acquired resistance to individual drugs can develop. Furthermore, this approach is ineffective as initial therapy for a subgroup of receptor-positive patients. The mechanisms of drug resistance are not completely understood, but the presence of alternative signaling pathways for activating ER response appears to play a significant role. Cross-talk between signaling pathways can activate ERs when conventional ER pathways are blocked or inactivated. For example, signaling via epidermal growth factor or HER-2 receptors, mitogen-activated protein kinases, phosphatidylinositol 3' kinase/protein kinase B, and vascular endothelial growth factor receptor can lead to estrogen-independent stimulation of ERs and tumor growth. The discovery that alternative pathways are involved in estrogen signaling has prompted development of newer endocrine therapies, such as aromatase inhibitors and pure estrogen antagonists, with distinct mechanisms for interrupting signal transduction. The existence of multiple pathways may explain the effectiveness of follow-up therapy with a different class of endocrine agents after failure of prior endocrine treatment. Because they do not have the partial agonist activity of tamoxifen that is enhanced by the adaptive hypersensitivity process, these alternative endocrine agents may play an increasingly important role in the treatment of ER-positive breast cancer. Although optimal sequencing of these agents has not been determined and is continuing to evolve, current evidence allows rational recommendations to be made. The multiple pathways involved in activating ERs also provide a rationale for combining endocrine and non-endocrine therapies that block different signaling pathways, which may have synergistic and overlapping interactions.     

Overcoming acquired resistance to letrozole by targeting the PI3K/AKT/mTOR pathway in breast cancer cell clones

Development of resistance to endocrine therapy is a clinical issue in estrogen receptor (ER)-positive breast cancer. Here we show that persistent activation of AKT/mTOR signaling is crucial to the acquisition of letrozole resistance in cell clones generated from MCF-7/AROM-1 aromatase-expressing breast cancer cells after prolonged letrozole exposure. ERα plays a marginal role in this context. As a proof of concept, the association between PI3K/AKT/mTOR signaling and insensitivity to endocrine therapies was confirmed in breast cancer patients who developed early letrozole resistance in neoadjuvant setting. In addition our results suggest that, regardless of the mechanism mediating the activation of AKT/mTOR pathway, either RAD001 or NVP-BEZ235 treatment may represent a promising strategy to overcome acquired resistance to letrozole in breast cancers dependent on AKT/mTOR signaling.     

mTOR抑制剂在激素受体阳性乳腺癌治疗中的研究进展

靶向激素受体（hormone receptor,HR）和人类表皮生长因子（human epidermal growth factor receptor 2,HER-2）对激素受体阳性乳腺癌的治疗至关重要,然而原发或继发内分泌治疗耐药及后续的疾病进展仍不可避免。人哺乳动物雷帕霉素位点（mammalian target of rapamycin,mTOR）是细胞生长和分化的关键调节因子,参与细胞不可控性生长。目前许多研究表明mTOR通路的激活可能与乳腺癌内分泌治疗耐药相关,阻断此通路有助于消除耐药,维持药物的敏感性。许多靶向mTOR通路的药物均表现出强大的抗肿瘤效应,在乳腺癌治疗中具有良好前景,且已有许多临床试验结果表明mTOR抑制剂联合内分泌治疗可显著提高患者的生存率。本文对mTOR信号通路及其抑制剂在内分泌治疗耐药的乳腺癌中的新进展进行综述。      

Unraveling the mechanisms of endocrine resistance in breast cancer: new therapeutic opportunities.

Two thirds of breast cancers express the estrogen receptor (ER), which contributes to tumor development and progression. ER-targeted therapy is therefore widely used in breast cancer to inhibit signaling through ER and disrupt breast cancer growth. This therapeutic strategy, particularly using the antiestrogen tamoxifen, is proven to increase the cure rates in early breast cancer, improve patient outcomes in advanced disease, and reduce breast cancer incidence in the prevention setting. Despite the recent integration of more powerful endocrine agents into breast cancer care, resistance to all forms of endocrine therapy remains a major problem. New insight into ER biology and progress in understanding resistance mechanisms, mediated by molecular crosstalk between ER and various growth factor signaling pathways, are generating tremendous promise for new therapeutic opportunities to target resistance and improve breast cancer disease outcomes.     

Overcoming endocrine resistance in breast cancer—are signal transduction inhibitors the answer?

Endocrine therapy is probably the most important systemic therapy for hormone receptor positive breast cancer. Hormonal manipulation was the first targeted treatment employed in breast cancer therapy even before the role of the estrogen (ER) and progesterone receptors (PR) had been elucidated. Unfortunately, a substantial proportion of patients, despite being ER and/or PR positive, are either primarily resistant to hormone therapies or will develop hormone resistance during the course of their disease. Signaling through complex growth factor receptor pathways, which activate the ER are emerging as important causes of endocrine resistance. Targeted therapies, such as signal transduction inhibitors (STIs), are being explored as agents to be able to potentially overcome this crosstalk and thus, resistance to hormone treatment. This article reviews the biology of the ER, the proposed mechanisms of endocrine resistance, and ongoing clinical trials with STIs in combination with hormonal manipulation as a means to overcome endocrine resistance.     

Endocrine Therapy in the Preoperative Setting and Strategies to Overcome Resistance

Endocrine therapy remains the mainstay for treatment of hormone receptor-positive breast cancer in both adjuvant and metastatic settings. Due to the cytostatic property of endocrine therapy, cytotoxic chemotherapy is more commonly used for cytoreduction in preoperative setting to promote breast-conserving surgery. Nevertheless, recent clinical trials demonstrated that preoperative endocrine therapy can also be used to facilitate breast conservation in patients with locally advanced breast cancer, particularly in postmenopausal women with low proliferative tumors. Multiple markers have been shown to be predictive of endocrine responsiveness, including estrogen and progesterone receptor expression as well as other molecular profiles such as the 21-gene recurrence score assay and PAM-50 assay. The preoperative setting offers a unique situation to rapidly prioritize novel treatment combination and to identify the mechanisms of resistance. Several strategies to overcome resistance, including co-targeting other signaling pathways, particularly human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor (VEGF), and PI3K/Akt/mTOR, are discussed in this review article.     

Endocrinology and hormone therapy in breast cancer: New insight into estrogen receptor-α function and its implication for endocrine therapy resistance in breast cancer

Estrogen and its receptor (ER) are critical for development and progression of breast cancer. This pathway is targeted by endocrine therapies that either block ER functions or deplete ER's estrogen ligand. While endocrine therapies are very effective, de novo and acquired resistance are still common. Laboratory and clinical data now indicate that bidirectional molecular crosstalk between nuclear or membrane ER and growth factor receptor pathways such as HER2/neu is involved in endocrine resistance. Preclinical data suggest that blockade of selected growth factor receptor signaling can overcome this type of resistance, and this strategy is already being tested in clinical trials     

Life following aromatase inhibitors--where now for endocrine sequencing?

The third-generation non-steroidal aromatase inhibitors (AIs) are challenging tamoxifen as treatments of choice for early and advanced breast cancer in postmenopausal women with estrogen receptor (ER)-positive disease. However, patients who initially respond to AIs eventually develop resistance to treatment and experience disease progression. To establish the optimal endocrine therapy following AI resistance, it is essential to understand the mechanisms that contribute to the loss of response. Data from in vitro models have suggested that acquired AI resistance is due to enhanced sensitization to low estrogen levels during long-term estrogen deprivation (LTED). Cross-talk between the ER and various growth-factor-receptor signaling pathways, including human epidermal growth factor receptor 2, and the insulin-like growth factor pathway, may also be implicated. Therefore, endocrine therapies that abolish estrogen signaling via removal of the ER could be effective in patients with AI-resistant disease. Fulvestrant ('Faslodex') is a new ER antagonist with no agonist effects that binds, blocks and degrades the ER. Due to its unique mode of action and lack of cross-resistance with existing treatments, fulvestrant is an effective therapeutic agent for use in sequential endocrine regimens. Fulvestrant has established efficacy in tamoxifen-resistant disease and there is a growing body of evidence demonstrating its efficacy in patients with AI-resistant disease. In preclinical models, MCF-7 cells undergoing LTED are refractory to tamoxifen but sensitive to fulvestrant, suggesting fulvestrant is a more appropriate choice following AI resistance. The steroidal AI, exemestane is also an option in non-steroidal AI-resistant disease. Clinical trials are underway to compare fulvestrant with exemestane as an appropriate therapy following the onset of AI resistance.