乳腺癌的辅助内分泌治疗

内分泌治疗是激素受体阳性乳腺癌患者的重要治疗手段.他莫昔芬、阿那曲唑和卵巢功能抑制剂是乳腺癌内分泌治疗中的最常用药物,针对患者疾病分期和绝经状态的小同,内分泌治疗药物的选择不同.内分泌治疗被证实有很好的疗效的同时,也被证实会产生耐药,mTOR抑制剂、CDK4/6抑制剂和纤维母细胞生长因子受体抑制剂将为内分泌治疗耐药患者带来新的希望.     

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。     

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。      

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。     

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。     

CDK4/6抑制剂在激素受体阳性进展期乳腺癌治疗中的研究进展

内分泌治疗因其兼具良好的疗效及安全性,是激素受体阳性进展期乳腺癌患者的重要治疗手段。近年来内分泌领域进展迅速,很多新型药物相继出现,其中包括多种可以逆转或延迟内分泌耐药的周期蛋白依赖性激酶(cyclin-dependent kinase,CDK)4/6抑制剂。CDK4/6抑制剂联合内分泌治疗可为激素受体阳性进展期乳腺癌患者带来生存获益、延迟至化疗时间,正逐渐改变国内外激素受体阳性进展期乳腺癌的治疗模式。本文将就CDK4/6抑制剂在激素受体阳性进展期乳腺癌中的治疗进展进行综述。     

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。     

乳腺癌内分泌耐药机制及治疗对策的研究进展

内分泌治疗在激素受体阳性乳腺癌患者的治疗中占重要地位,但耐药的产生为内分泌治疗增加了难度。近年来,内分泌耐药发生的机制是研究的热点问题,已有研究证实内分泌耐药的发生与生长因子受体、磷脂酰肌醇3-激酶/蛋白激酶 B/哺乳动物雷帕霉素靶蛋白信号通路、细胞周期蛋白依赖性激酶及组蛋白去乙酰化酶有关。目前,针对耐药相关信号通路中的各个分子靶点已经研发了众多的靶向药物。本文将针对内分泌耐药的不同机制以及逆转耐药的治疗进行综述。     

激素受体阳性晚期乳腺癌的内分泌治疗进展

内分泌耐药是激素受体阳性晚期乳腺癌的治疗难题之一.根据耐药机制,内分泌治疗引入靶向药物有望逆转或延迟耐药,并已在临床研究中取得验证.寻找分子标志物,选择获益人群,是这个领域发展的重要方向.     

乳腺癌内分泌治疗药物药学服务指南(2023版)

内分泌治疗是激素受体阳性(HR+)乳腺癌患者的主要治疗方法之一。截至2023年6月1日, 国家药品监督管理局已批准56个用于HR+/人表皮生长因子受体2阴性(HER-2-)乳腺癌患者的内分泌治疗相关药物(含通过一致性评价的仿制药), 按照其作用机制可分为选择性雌激素受体调节剂、选择性雌激素受体下调剂、芳香化酶抑制剂、促黄体生成素释放激素类似物、孕激素类44个内分泌药物以及CDK4/6抑制剂、mTOR抑制剂、HDAC抑制剂12个内分泌治疗联合使用的靶向药物。内分泌药物不同的作用机制和药学特性以及长期用药等因素能直接影响患者的用药依从性和用药安全, 为规范乳腺癌内分泌治疗药物的药学服务, 促进临床合理用药, 中国药师协会肿瘤专科药师分会联合全国多学科专家, 基于临床循证证据、药事管理相关法规和药学服务实践, 采用推荐意见分级的评估、制定及评价证据分级法、德尔菲法和专家访谈, 制定了乳腺癌内分泌治疗药物药学服务指南(2023版)。指南主要聚焦于HR+/HER-2-乳腺癌患者的内分泌治疗, 由于篇幅所限指南中未纳入HER-2阳性靶向药物。指南涵盖内分泌治疗全程化药学服务的6个维度、22个关键问...     

The next era of treatment for hormone receptor-positive,HER2-negative advanced breast cancer: Triplet combination-based endocrine therapies

Until recently, the standard of care for hormone receptor-positive (HR+) breast cancer was single-agent endocrine therapy, which aims to prevent estrogen receptor signaling. This therapeutic strategy has extended survival without the toxicity associated with chemotherapy, but primary endocrine therapy resistance is common, and secondary resistance develops over time. Adjunct downstream inhibition of the cyclin-dependent kinase (CDK)4/6 pathway, intended to delay and prevent endocrine therapy resistance, has further extended progression-free survival in patients receiving endocrine therapy; however, resistance still eventually develops in these patients. Addition of phosphatidylinositol-3 kinase (PI3K) or mammalian target of rapamycin (mTOR) inhibitors to combined CDK4/6 and endocrine inhibitor regimens may help prolong CDK4/6 inhibitor sensitivity. Early trials combining CDK4/6 inhibitors, PI3K or mTOR inhibitors, and endocrine therapy have shown encouraging signs of clinical activity. However, further research is needed to help understand the extent of treatment benefit from triplet therapy and where this strategy will fit in the treatment sequence for patients with HR+ breast cancer.     

CDK4/6抑制剂联合内分泌治疗晚期乳腺癌

内分泌治疗因疗效显著并具有安全性,是激素受体阳性(HR+)晚期乳腺癌患者的主要治疗方法。近年来内分泌领域发展迅速,如何延迟或逆转内分泌耐药及内分泌治疗新药物成为临床研究关注的焦点。研究发现,内分泌治疗耐药可能与CDK-RB-E2F通路有关,针对该通路的细胞周期蛋白依赖性激酶(CDK)4/6抑制剂可显著延缓HR+晚期乳腺癌患者内分泌耐药。CDK4/6抑制剂与内分泌药物联合使用,可提高HR+晚期乳腺癌患者的治疗客观缓解率,并可显著改善无进展生存期(PFS)。现就CDK4/6抑制剂的作用机制、药物有效性和安全性及相关临床试验做一综述。     

Therapy after cyclin-dependent kinase inhibition in metastatic hormone receptor-positive breast cancer: Resistance mechanisms and novel treatment strategies

Endocrine therapy has been the standard of care for patients with metastatic hormone receptor (HR)-positive, HER2-negative breast cancer since the 1970s, improving survival while avoiding the toxicities associated with cytotoxic chemotherapy. However, all HR-positive tumors ultimately develop resistance to endocrine therapy. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have more recently become an important component of the management of this breast cancer subtype, significantly delaying time to the disease progression and improving survival when combined with endocrine therapy. However, as with endocrine therapy alone, treatment resistance remains a universal phenomenon. As more women receive CDK4/6 inhibitors as part of their treatment, the management of de novo and acquired resistance to combined CDK4/CDK6 inhibitor plus endocrine therapy regimens has emerged as an important clinical challenge. Several resistance mechanisms have been described, including alterations in the CDK4/6/cyclin D complex or its major effector retinoblastoma protein (pRb), bypass signaling through other cyclin/CDK complexes and activation of upstream signaling pathways, in particular the PI3K/mTOR pathway, but robust biomarkers to predict resistance remain elusive, and the role for continuing CDK4/6 inhibitors after progression remains under investigation. Novel strategies being evaluated in clinical trials include the continuation of CDK4/6 inhibitors through progression, as well as triplet therapy combinations with PI3K inhibitors or immune checkpoint inhibitors.     

乳腺癌靶向治疗研究进展

乳腺癌靶向治疗是一种有效的治疗方案,其特异性强,毒副作用小,基本上不损伤正常组织。伴随药理学和分子生物学研究的深入,靶向药物的研究和应用取得了突破性进展,新治疗靶点药物的研发已成为人们关注的热点。本文主要对人类表皮生长因子受体2(HER-2)、哺乳动物雷帕霉素靶蛋白(mTOR)信号通路、血管内皮生长因子(VEGF)、上皮生长因子受体(EGFR)、聚腺苷二磷酸核糖聚合酶(PARP)、周期蛋白依赖性激酶4/6(CDK4/6)为靶点的乳腺癌靶向治疗药物研究进行综述。     

Comparative efficacy and safety of CDK4/6 and PI3K/AKT/mTOR inhibitors in women with hormone receptor-positive,HER2-negative metastatic breast cancer: a systematic review and network meta-analysis

BackgroundCDK4/6 inhibitors and PI3K/AKT/mTOR inhibitors are both emerging agents for hormonal receptor (HR) positive and human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer. Evidence for the comparisons from head-to-head comparative trials is currently insufficient. This meta-analysis assessed the comparative efficacy and safety of these two groups of agents for HR+/HER2- metastatic breast cancer.MethodsSystematic searches of PubMed, Embase, CENTRAL, SciSearch between January 2010 to December 2019 were conducted. Randomized controlled trials (RCTs) which evaluated clinical benefits and toxicities of CDK4/6 inhibitors or PI3K/AKT/mTOR inhibitors plus endocrine therapy were adopted. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoint was treatment-related adverse event (TRAE). Pooled hazard ratio (HR) and risk rate (RR) were used to assess the differences between CDK4/6 and PI3K/AKT/mTOR inhibitors.ResultsA total of twenty RCTs including 9771 participants were identified in this study. Pooled results showed that PFS was considerably prolonged by targeted therapy plus endocrine therapy. PFS was relatively better in CDK4/6 inhibitors than that of PI3K inhibitor group (HR, 1.43; 95%CrI, 1.12-1.61). Similar results were demonstrated in results after balancing lines of therapy or metastatic sites, both in viscera and bone-only. Coalesced outcomes revealed that CDK4/6 inhibitors plus endocrine therapy could significantly improve OS (HR, 0.78; 95%CrI, 0.65-0.94) than PI3K/mTOR inhibitors. Safety profiles of diarrhea and rash were consistent between CDK4/6 inhibitors and PI3K/AKT/mTOR inhibitors with no difference of estimated RR. Several TRAEs signified specificity, for instance, myelosuppression in CDK4/6 inhibitors or hyperglycemia in PI3K/mTOR inhibitors.ConclusionsClinical efficacy is in favor of CDK4/6 inhibitors, and safety profiles are comparable between CDK4/6 inhibitors or PI3K/AKT/mTOR inhibitors plus endocrine therapy.     

CDK4/6抑制剂的联合治疗模式

 细胞周期素依赖激酶（CDKs）抑制剂联合内分泌治疗已经用于晚期乳腺癌的治疗。除了内分泌治疗，CDK4/6抑制剂还可以联合表皮生长因子受体（EGFR）抑制剂、磷脂酰肌醇-3激酶（PI3K）/哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂、化学治疗、免疫治疗、分子靶向治疗和其他治疗。联合治疗模式克服了CDK4/6抑制剂的耐药并提高了临床疗效，开启了肿瘤精准治疗的一扇新窗口。     

Emerging data on improving response to hormone therapy: the role of novel targeted agents

Introduction: Hormone receptor positive (HR+) breast cancer represents the most common subtype of breast cancer. Metastatic HR+ breast cancer may develop resistance to standard hormone therapies, arising from genomic alterations in the estrogen receptor and/or upregulation of other signal transduction pathways.

Areas covered: In this review, we discuss hormone resistance and strategies to overcome it, from the pre-clinical and clinical perspectives. This review includes a discussion of inhibition of the PI3K/AKT/mTOR, CDK 4/6, histone deacetylation, fibroblast growth factor receptor, and immune pathways, based on review of relevant literature.

Expert commentary: Several emerging novel therapies to improve the response to hormone therapy are approved or are in development. The most promising agents at present are inhibitors of CDK 4/6 and mTOR, which have already been incorporated into treatment in the advanced stage setting and are under study for early stage disease.     

CDK4/6 inhibitor plus endocrine therapy for hormone receptor‐positive,HER2‐negative metastatic breast cancer: The new standard of care

Patients presenting with hormone receptor‐positive (HR⁺), human epidermal growth factor receptor 2‐negative (HER2^–) metastatic breast cancer (MBC) are usually treated with endocrine therapy (ET), except if there is a concern about endocrine resistance or a need to achieve rapid disease control due to visceral crisis. The combination of CDK4/6 inhibitor + ET has now replaced single‐agent ET as the standard first‐line treatment; and it can also be considered a standard option in the second‐line setting. This review briefly summarizes recently reported efficacy findings from the key phase III clinical trials of CDK4/6 inhibitor + ET in patients with HR⁺/HER2^– MBC, including evidence that adding a CDK4/6 inhibitor to ET improves overall survival and does so without reducing patients’ quality of life. There is still much to learn regarding the use of CDK4/6 inhibitors and how they may be optimally integrated into clinical practice. In particular, there is a need for specific biomarkers that help predict the likelihood of response or resistance to CDK4/6 inhibitor therapy; and for data to guide treatment decisions when a patient's disease progresses on a CDK4/6 inhibitor.