Edessa Dumessa, Sisay Mekonnen
Department of Pharmacy Practice.
Department of Pharmacology and Toxicology, School of Pharmacy, College of Health and Medical Sciences, Haramaya University, Oromia, Ethiopia.
Breast Cancer (Dove Med Press). 2017 Dec 6;9:567-579. doi: 10.2147/BCTT.S150540. eCollection 2017.
In normal cell cycle progression, transition of G0/G1 phase to synthesis (S) phase for breast and other cells is regulated by association of cyclin D and cyclin-dependent kinases 4 and 6 (CDK4/6) that leads to phosphorylation of retinoblastoma (Rb) protein. Imbalance of this cyclin D-CDK4/6-inhibitors of CDK4/6-Rb phosphorylation pathway is associated with tumorigenesis of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancers. Despite effective first-line endocrine therapy, HR+/HER2- metastatic breast cancers remain still incurable. Currently, advances in understanding of cell cycle checkpoints are evolving as promising strategy to target in treatment of various types of cancers including breast cancer. Therapies that target this cell cycle machinery in HR+/HER2- breast cancers are getting approval by the US Food and Drug administration (FDA) including ribociclib (LEE011). Ribociclib got the first FDA approval in March 13, 2017, as an initial therapy for HR+/HER2- advanced or metastatic breast cancer in combination with an aromatase inhibitor. This review, therefore, addresses the role of selective CDK4/6 inhibitors in advanced or metastatic breast cancer with a specific focus on ribociclib. Some findings of clinical trials involving ribociclib found pivotal benefits of ribociclib in HR+/HER2- metastatic breast cancer in terms of prolonging progression-free survival and objective response rates. Daily dosage range of the drug for such benefits is 50-900 mg with common daily doses of 400 or 600 mg and 600 mg in early and advanced breast cancer therapies, respectively. Along with its therapeutic benefits, however, more incident but manageable dose-limiting grade 3 or 4 toxicities, primarily hematologic adverse events, are common in patients treated with ribociclib. Generally, there are several active clinical trials undergoing to investigate the clinical efficacy and toxicity profile of the drug in various cancerous conditions other than breast cancer and will likely benefit patients with other cancer types.
在正常细胞周期进程中，乳腺细胞和其他细胞从G0/G1期过渡到合成（S）期是由细胞周期蛋白D与细胞周期蛋白依赖性激酶4和6（CDK4/6）结合来调控的，这会导致视网膜母细胞瘤（Rb）蛋白磷酸化。细胞周期蛋白D-CDK4/6-CDK4/6抑制剂-Rb磷酸化通路的失衡与激素受体阳性（HR+）、人表皮生长因子受体2阴性（HER2-）乳腺癌的肿瘤发生有关。尽管一线内分泌治疗有效，但HR+/HER2-转移性乳腺癌仍然无法治愈。目前，对细胞周期检查点的认识进展正在成为治疗包括乳腺癌在内的各种癌症的有前景的靶向策略。针对HR+/HER2-乳腺癌中这种细胞周期机制的疗法正在获得美国食品药品监督管理局（FDA）的批准，包括瑞博西尼（LEE011）。瑞博西尼于2017年3月13日首次获得FDA批准，作为HR+/HER2-晚期或转移性乳腺癌与芳香化酶抑制剂联合使用的初始治疗药物。因此，本综述探讨了选择性CDK4/6抑制剂在晚期或转移性乳腺癌中的作用，特别关注瑞博西尼。一些涉及瑞博西尼的临床试验结果发现，瑞博西尼在HR+/HER2-转移性乳腺癌中具有关键益处，可延长无进展生存期和提高客观缓解率。在早期和晚期乳腺癌治疗中，实现这些益处的该药物每日剂量范围为50-900毫克，常见每日剂量分别为400毫克或600毫克以及600毫克。然而，除了治疗益处外，但更常见且可控制的3级或4级剂量限制性毒性，主要是血液学不良事件，在接受瑞博西尼治疗的患者中很常见。一般来说，目前正在进行多项活跃的临床试验，以研究该药物在乳腺癌以外的各种癌症情况下的临床疗效和毒性特征，可能会使其他癌症类型的患者受益。
