a Cell Biology and Biotherapy Unit , Istituto Nazionale Tumori-IRCCS-"Fondazione G. Pascale" , Naples , Italy.
Expert Opin Drug Metab Toxicol. 2018 Sep;14(9):891-900. doi: 10.1080/17425255.2018.1514720. Epub 2018 Sep 3.
Cyclin-dependent kinases (CDKs) 4 and 6 regulate the transition from G0/G1-phase to S-phase of the cell cycle and have been identified as key drivers of proliferation in hormone receptor (HR)-positive breast cancer. The CDK4/6 inhibitor palbociclib in combination with endocrine therapy has been approved for treatment of HR-positive/HER2-negative breast cancer patients. Areas covered: In this article, we provide an update of the data on pharmacodynamics, pharmacokinetics, preclinical, and clinical studies of palbociclib in breast cancer. We performed a search of data on palbociclib in the PubMed and the clinicaltrials.gov databases, in the FDA website and in the ASCO and AACR proceedings. Expert opinion: In order to optimize the clinical outcome of HR-positive breast cancer patients treated with palbociclib, predictive biomarkers allowing patient selection are urgently needed. A recent study suggested that early dynamics of PIK3CA mutations in circulating tumor DNA might be a potential predictive biomarker for CDK4/6 inhibitors. Several clinical trials are ongoing with the aim to explore the activity of combinations of palbociclib with targeted agents and/or immunotherapy in the different subtypes of breast cancer in both metastatic and early phases of the disease. These combinations might allow improving the sensitivity and overcoming mechanisms of resistance.
细胞周期蛋白依赖性激酶（CDKs）4 和 6 调节细胞周期从 G0/G1 期到 S 期的转变，并且已被确定为激素受体（HR）阳性乳腺癌增殖的关键驱动因素。CDK4/6 抑制剂帕博西利与内分泌治疗联合已被批准用于治疗 HR 阳性/HER2 阴性乳腺癌患者。
本文提供了 CDK4/6 抑制剂帕博西利在乳腺癌中的药效学、药代动力学、临床前和临床研究数据的最新更新。我们在 PubMed 和 clinicaltrials.gov 数据库、FDA 网站以及 ASCO 和 AACR 会议录中搜索了有关帕博西利的数据。
为了优化接受帕博西利治疗的 HR 阳性乳腺癌患者的临床结局，迫切需要预测性生物标志物来进行患者选择。最近的一项研究表明，循环肿瘤 DNA 中 PIK3CA 突变的早期动力学可能是 CDK4/6 抑制剂的潜在预测性生物标志物。目前正在进行几项临床试验，旨在探索帕博西利与靶向药物和/或免疫疗法联合用于转移性和疾病早期不同亚型乳腺癌的活性。这些组合可能会提高敏感性并克服耐药机制。
