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。     

CDK4/6抑制剂联合内分泌治疗晚期乳腺癌研究进展

摘 要：近年来,多项研究显示细胞周期蛋白依赖性激酶4和6( CDK4/6) 抑制剂对于激素受体阳性晚期乳腺癌患者具有较好的疗效,甚至可改善内分泌耐药问题。相关研究表明CDK4/6抑制剂联合内分泌治疗在临床应用中极具前景。     

CDK4/6抑制剂治疗激素受体阳性人表皮生长因子受体2阴性乳腺癌的研究进展

细胞周期蛋白依赖性激酶(CDK)4/6抑制剂联合传统内分泌治疗能显著改善激素受体阳性人表皮生长因子受体2阴性乳腺癌患者的无进展生存和总生存, 但不同的药物、给药剂量、用药周期会给患者带来不同的疗效和安全事件。确认CDK4 /6抑制剂对我国乳腺癌患者是否同样适用, 既是国内临床医生关注的热点, 也是实际诊疗工作中的需要。文章介绍了不同药物的经典临床试验及最新研究进展。     

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.     

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抑制剂在乳腺癌治疗中的研究进展

CDK4/6抑制剂与内分泌治疗的组合策略被越来越多地应用于晚期乳腺癌患者的治疗中.然而,CDK4/6抑制剂不仅仅用于ER阳性、HER2阴性晚期乳腺癌患者的治疗中,其研究应用也扩展到了其他的乳腺癌类型中.本文旨在阐述CDK4/6抑制剂的耐药机制和进展后的后续治疗,以及其在三阴性乳腺癌、HER2阳性乳腺癌、肿瘤免疫和生活质...     

CDK4/6抑制剂联合mTOR抑制剂在乳腺癌中的作用机制

CDK-RB-E2F通路和PI3K-AKT-mTOR通路对乳腺癌耐药机制起到了关键作用。通过对两个通路的研究发现,在治疗激素受体阳性的乳腺癌时,CDK4/6抑制剂与内分泌药物联合使用可以提高患者的生存率,mTOR抑制剂也显示出抗肿瘤的实力。最近的研究表明,mTOR抑制剂和CDK4/6抑制剂联合使用可以进一步抑制CDK-RB-E2F通路激活,协同控制肿瘤细胞增殖。同时发现CDK4/6抑制剂耐药患者的CDK-RB-E2F通路重新激活,仍对mTOR抑制剂敏感。还有研究表明CDK4/6抑制剂和mTOR抑制剂可以通过自噬作用协同控制肿瘤的发生。本文针对两药联合在乳腺癌中的作用机制进行综述。     

CDK4/6抑制剂耐药机制的研究进展

细胞周期依赖性激酶4/6（cyclin-dependent kinase 4/6,CDK4/6)抑制剂能作用于过度活化的CDK4/6,恢复正常细胞周期,并通过触发免疫,改变肿瘤微环境等发挥抗肿瘤作用。目前,CDK4/6抑制剂的问世极大地改善了激素受体阳性（hormone receptor-positive,HR+）、人表皮生长因子受体2阴性（human epidermal growth factor receptor 2-negative,HER2-)晚期乳腺癌患者的预后,使无进展生存期(progression-free-survival,PFS)增加近一倍,且不良反应可控。尽管如此,这类患者最终仍会因CDK4/6抑制剂耐药而出现疾病进展。CDK4/6抑制剂的耐药机制十分复杂,尚未完全明确。预测其早期耐药或治疗敏感的生物标记物也有待确定。本文对CDK4/6抑制剂治疗的作用机制及耐药机制进行梳理和总结,并对疾病进展后的治疗策略作简要讨论。     

CDK4/6抑制剂在乳腺癌中的研究进展

摘 要：细胞周期的失调是肿瘤生长和转移的典型标志之一,通过CDK抑制剂重新建立细胞周期的调控在肿瘤靶向治疗的发展中已经成为有吸引力的方向。三种选择性靶向CDK4/6的口服药物已经被研发：palbociclib、abemaciclib和LEE011。当前的研究表明CDK4/6抑制剂与内分泌药物联合治疗激素受体阳性乳腺癌是一个新的标准。全文就细胞周期调控、乳腺癌中cyclinD-CDK4/6-Rb途径及相关蛋白p16和survivin的异常表现、CDK4/6抑制剂的相关临床试验及其结果进行总结。     

细胞周期蛋白依赖激酶4和6抑制剂研究进展

多项临床研究证实细胞周期蛋白依赖激酶4和6(CDK4/6)抑制剂联合芳香化酶抑制剂(AI)治疗绝经后激素受体阳性、HER-2阴性晚期乳腺癌患者,可以显著改善患者的无进展生存期。笔者通过回顾临床研究数据,探讨CDK4/6抑制剂联合AI的安全性和有效性、治疗期间不良事件的评估和管理、潜在获益人群的筛选,及治疗敏感预测分子研究的最新进展,旨在为临床医师治疗决策提供更多参考。     

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.     

CDK4/6抑制剂治疗乳腺癌的研究进展

对于HR+/HER-2-乳腺癌患者来说,内分泌治疗扮演着非常重要的角色。长久以来,医学工作者对于此类患者的内分泌耐药机制以及相关治疗方法的讨论也层出不穷。近年来,CDK4/6抑制剂为HR+患者的带来了福音,CDK4/6抑制剂单药治疗与联合内分泌治疗已经用于晚期乳腺癌的治疗。除了内分泌治疗之外,CDK4/6抑制剂还可以与抗HER-2药物、PD-L1、PD-L1抑制剂或其他靶向药物联合,联合治疗在一定程度上克服了CDK4/6抑制剂的耐药情况,并提高了治疗疗效,为乳腺癌患者的精准治疗带来了福音。     

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。      

Mechanisms of therapeutic CDK4/6 inhibition in breast cancer

Cyclin dependent kinase (CDK) 4/6 inhibitors have advanced the treatment of metastatic breast cancer by targeting the cell cycle machinery, interrupting intracellular and mitogenic hormone signals that stimulate proliferation of malignant cells. Preclinical evidence demonstrated that derangements of cyclin D1, CDK4/6, and retinoblastoma expression are common in breast cancer, and suggested a therapeutic benefit from interrupting this axis required for cell cycle progression. Studies of cell lines and animal models of breast cancer have demonstrated the complex interplay between the cell cycle and estrogen receptor and human epidermal growth receptor 2 signaling, which informs our understanding of synergistic use of CDK4/6 inhibitors with endocrine therapy, as well as mechanisms of resistance to endocrine therapy. Interestingly, estrogen receptor activity leads to upregulation of cyclin D1 expression, but the estrogen receptor is also in turn activated by cyclin D1, independent of estrogen binding. Early CDK inhibitors were nonspecific and limited by systemic toxicities, while the current generation of CDK4/6 inhibitors have shown promise in the treatment of hormone receptor-positive breast cancer. Preclinical investigations of the three CDK4/6 inhibitors approved by the US Food and Drug Administration (palbociclib, ribociclib, and abemaciclib) lend further insight into their mechanism of action, which will hopefully inform the future use and refinement of these therapies. Finally, we summarize evidence for additional novel CDK4/6 inhibitors currently in development.     

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.     

Drug-drug interactions in breast cancer patients treated with CDK4/6 inhibitors

CDK4/6 inhibitors are a new class of anticancer drugs used for the treatment of women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. Polypharmacy is a well-known problem in advanced cancer causing potential drug-drug interactions (DDIs), which, in turn, may limit the therapeutic value of CDK4/6 inhibitors. Therefore, understanding the mechanisms underlying potential DDIs in patients taking CDK4/6 inhibitors may be useful in decision-making processes and represent an important step towards treatment personalization. The present review is aimed at describing the potential DDIs that might occur in breast cancer patients receiving CDK4/6 inhibitors based on direct evidence from the literature and mechanistic considerations tailored on specific class of drugs used in combination.     

HMGB1 is a key factor for tamoxifen resistance and has the potential to predict the efficacy of CDK4/6 inhibitors in breast cancer

Breast cancer is the leading cause of cancer death in women. Hormone-receptor-positive breast cancer (HR + BC) is the most common pathological type of breast cancer, of which the main treatment method is endocrine therapy. Unfortunately, primary or acquired drug resistance greatly limits its efficacy. In recent years, the newly launched CDK4/6 inhibitors could effectively reverse endocrine resistance in breast cancer. However, considering their expensive price and side effects, it is particularly important to find out effective biomarkers and screen sensitive patients. Here, we found through bioinformatics analysis that high mobility group box 1 (HMGB1) expression increased in endocrine-resistant HR + BC. In clinical specimens, the higher expression of HMGB1 was associated with shorter progression-free survival (PFS) for HR + BC patients with endocrine therapy after surgery. For endocrine-resistant breast cancer, compared with HMGB1-negative patients, HMGB1-positive patients who received CDK4/6 inhibitors treatment benefited more in PFS. Moreover, we demonstrated that HMGB1 promoted tamoxifen resistance by combining with the Toll-like receptor 4 (TLR4) and activating nuclear factor kappa B (NF-κB) pathway. CDK4/6 inhibitors could downregulate the expression of HMGB1 and suppress the TLR4-NF-κB pathway, and in turn reverse tamoxifen resistance. These results illuminated the critical role of HMGB1 in the process of tamoxifen resistance, explained the mechanism of CDK4/6 inhibitors reversing tamoxifen resistance, and suggested the feasibility of HMGB1 as a potential biomarker for screening sensitive patients receiving CDK4/6 inhibitors.     

Ribociclib for the treatment of hormone receptor-positive,human epidermal growth factor receptor 2-negative advanced breast cancer

Introduction: The emergence of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors marked a significant advancement in the treatment of advanced breast cancer. Ribociclib is an orally bioavailable, highly selective inhibitor of CDK4/6. In combination with various endocrine therapies, ribociclib has demonstrated clinical activity as a first-line therapy for patients with HR+, HER2? advanced breast cancer, without compromising the favorable toxicity profile associated with endocrine therapy. Thus, ribociclib is now considered a new standard of care for HR+, HER2? advanced breast cancer.

Areas covered: This review provides a concise overview of the preclinical and clinical development of ribociclib, including evidence of its clinical activity and safety profile when combined with endocrine therapy in HR+, HER2? advanced breast cancer.

Expert commentary: CDK4/6 inhibition represents a promising treatment option for patients with HR+ metastatic breast cancer. Ribociclib significantly improved progression-free survival in patients receiving first-line endocrine therapy for HR+, HER2? advanced breast cancer. Planned and ongoing trials investigating ribociclib in combination with other endocrine therapies and in various clinical settings will help to determine the optimal treatment sequence for different patient populations.