Schmidt Marcus, Sebastian Martin
Department of Obstetrics and Gynecology, University Medical Center Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.
Department of Hematology/Oncology, Rheumatology, HIV, J.W. Goethe University, Frankfurt, Germany.
Recent Results Cancer Res. 2018;211:153-175. doi: 10.1007/978-3-319-91442-8_11.
During the last decades, much has been learned about with cyclin-dependent kinases (CDK) playing a pivotal role in the cell cycle regulation. CDK4/6 is the key regulator of the G1-S transition. Palbociclib (PD 0332991, Ibrance®) is the first oral CDK4/6 inhibitor showing a substantially improved median progression-free survival (PFS) in advanced estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) negative breast cancer. This PFS prolongation was seen both with letrozole as first-line therapy (24.8 vs. 14.5 months [PALOMA 2]) and with fulvestrant in endocrine pretreated patients (9.2 vs. 3.8 months [PALOMA-3]). The main toxicity is neutropenia due to cell cycle arrest which can be easily managed with dose interruption or dose reduction leading to a favorable safety profile with delayed deterioration of global quality of life (QoL). Palbociclib is approved by the Federal Drug Administration (FDA) and the European Medicines Agency (EMA) for ER-positive/HER2-negative advanced breast cancer. Despite the well-understood mode of action of palbociclib, predictive biomarkers are not yet defined. In conclusion, inhibition of CDK4/6 using palbociclib in combination with endocrine therapy is an efficient and well-tolerated treatment option in ER-positive/HER2-negative advanced breast cancer. Ongoing clinical trials are investigating the role of palbociclib in early breast cancer as well as in other types of cancer.
在过去几十年中，人们对细胞周期蛋白依赖性激酶（CDK）在细胞周期调控中发挥关键作用有了很多了解。CDK4/6是G1-S期转换的关键调节因子。哌柏西利（PD 0332991，爱博新®）是首个口服CDK4/6抑制剂，在晚期雌激素受体（ER）阳性和人表皮生长因子受体2（HER2）阴性乳腺癌中显示出显著改善的中位无进展生存期（PFS）。无论是来曲唑作为一线治疗（24.8个月对14.5个月[PALOMA-2]），还是氟维司群用于内分泌预处理患者（9.2个月对3.8个月[PALOMA-3]），均观察到PFS延长。主要毒性是由于细胞周期停滞导致的中性粒细胞减少，通过剂量中断或剂量减少很容易控制，从而产生良好的安全性，全球生活质量（QoL）延迟恶化。哌柏西利已获得美国食品药品监督管理局（FDA）和欧洲药品管理局（EMA）批准用于ER阳性/HER2阴性晚期乳腺癌。尽管哌柏西利的作用机制已为人熟知，但预测性生物标志物尚未明确界定。总之，在ER阳性/HER2阴性晚期乳腺癌中，使用哌柏西利联合内分泌治疗抑制CDK4/6是一种有效且耐受性良好的治疗选择。正在进行的临床试验正在研究哌柏西利在早期乳腺癌以及其他类型癌症中的作用。
