Bilgin Burak, Sendur Mehmet A N, Şener Dede Didem, Akıncı Muhammed Bülent, Yalçın Bülent
a Ankara Yıldırım Beyazıt University , Faculty of Medicine, Department of Medical Oncology , Ankara , Turkey.
Curr Med Res Opin. 2017 Sep;33(9):1559-1569. doi: 10.1080/03007995.2017.1348344. Epub 2017 Jul 25.
Resistance to endocrine treatment generally occurs over time, especially in the metastatic stage. In this paper, we aimed to review the mechanisms of cyclin-dependent kinase (CDK) 4/6 inhibition and clinical usage of new agents in the light of recent literature updates.
A literature search was carried out using PubMed, Medline and ASCO and ESMO annual-meeting abstracts by using the following search keywords; "palbociclib", "abemaciclib", "ribociclib", "cyclin-dependent kinase inhibitors" and "CDK 4/6" in metastatic breast cancer (MBC). The last search was on 10 June 2017.
CDKs and cyclins are two molecules that have a key role in cell cycle progression. Today, there are three highly selective CDK4/6 inhibitors in clinical development - palbociclib, ribociclib and abemaciclib. Palbociclib and ribociclib were recently approved by the US FDA in combination with letrozole for the treatment of MBC in a first-line setting, as well as palbociclib in combination with fulvestrant for hormone-receptor (HR)-positive MBC that had progressed while on previous endocrine therapy according to the PALOMA-1, MONALEESA-2 and PALOMA-3 trials, respectively. In the recently published randomized phase III MONARCH 2 trial, abemaciclib plus letrozole had longer progression-free survival and higher objective response rates with less serious adverse events in advanced HR-positive breast cancer previously treated with hormonal treatment.
CDK4/6 inhibition is a new and promising target for patients with hormone-receptor-positive MBC. Both palbociclib and ribociclib showed significant additive benefit for patients receiving first-line treatment for HR-positive, epidermal growth factor receptor-2-negative advanced breast cancer. Palbociclib and abemaciclib also had significant activity in combination with fulvestrant for patients with MBC that progressed on previous endocrine therapy.
对内分泌治疗的耐药通常会随着时间推移而出现，尤其是在转移阶段。在本文中，我们旨在根据近期文献更新情况，综述细胞周期蛋白依赖性激酶（CDK）4/6抑制的机制以及新药物的临床应用。
使用PubMed、Medline以及美国临床肿瘤学会（ASCO）和欧洲肿瘤内科学会（ESMO）年会摘要进行文献检索，检索关键词如下：转移性乳腺癌（MBC）中的“哌柏西利”“阿贝西利”“瑞博西利”“细胞周期蛋白依赖性激酶抑制剂”以及“CDK 4/6”。最后一次检索时间为2017年6月10日。
CDK和细胞周期蛋白是在细胞周期进程中起关键作用的两种分子。目前，有三种高选择性CDK4/6抑制剂正在进行临床开发——哌柏西利、瑞博西利和阿贝西利。根据PALOMA-1、MONALEESA-2和PALOMA-3试验，哌柏西利和瑞博西利最近分别被美国食品药品监督管理局（FDA）批准与来曲唑联合用于一线治疗MBC，以及哌柏西利与氟维司群联合用于既往内分泌治疗期间病情进展的激素受体（HR）阳性MBC。在最近发表的随机III期MONARCH 2试验中，阿贝西利加来曲唑在既往接受过激素治疗的晚期HR阳性乳腺癌中具有更长的无进展生存期和更高的客观缓解率，且严重不良事件较少。
CDK4/6抑制是激素受体阳性MBC患者的一个新的且有前景的治疗靶点。哌柏西利和瑞博西利对接受HR阳性、表皮生长因子受体-2阴性晚期乳腺癌一线治疗的患者均显示出显著的附加益处。哌柏西利和阿贝西利与氟维司群联合使用时，对既往内分泌治疗期间病情进展的MBC患者也具有显著活性。
