Division of Medical Oncology and Hematology, University of Toronto and Princess Margaret Cancer Centre, Toronto, Canada, 700 University Ave, 7W 427, Toronto, ON, M5G 2M9, Canada.
Department of Medical Oncology, University of Medicine and Pharmacy "Grigore T. Popa" Iasi, Str. Universitatii nr 16, 700115, Iasi, Romania.
Breast. 2019 Feb;43:8-17. doi: 10.1016/j.breast.2018.10.001. Epub 2018 Oct 8.
Metastatic or advanced breast cancer (mBC/ABC) remains incurable despite many different systemic treatment options. Hormone receptor positive (HR+) disease represents the most common subtype in both early and advanced disease. A better understanding of the biology of this BC subtype, in particular regarding potential mechanisms of endocrine resistance, has led to the development of CDK4/6 inhibitors. All three selective CDK4/6 inhibitors, palbociclib, ribociclib and abemaciclib have shown to significantly improve progression-free survival (PFS) when combined to endocrine therapy as first-line treatment for patients with HR+/HER-2 negative ABC, who have progressed on or after adjuvant endocrine therapy. All three of them have also shown an improved PFS as 2nd line therapy for HR+/Her2 negative ABC. Their toxicity profile is favorable, with hematological toxicity (mainly neutropenia) being predominant, followed by diarrhea and fatigue. Quality of life has been maintained in the 1st line setting or improved in the 2nd line setting. Overall survival (OS) has been reported so far only in 2 out of 7 trials as first line therapy and the difference did not reach statistical significance. In this article we review the biology of CDK signaling pathway and its inhibitors, preclinical and clinical data of all three investigated selective CDK4/6 inhibitors and their toxicity. We also discuss how these agents are being included in current international guidelines and future directions for these agents in other subtypes of breast cancer, in both advanced disease and early-stage disease.
转移性或晚期乳腺癌（MBC/ABC）尽管有许多不同的系统治疗选择，但仍然无法治愈。激素受体阳性（HR+）疾病在早期和晚期疾病中都是最常见的亚型。对这种 BC 亚型生物学的更好理解，特别是关于内分泌抵抗的潜在机制，导致了 CDK4/6 抑制剂的发展。所有三种选择性 CDK4/6 抑制剂（帕博西尼、瑞博西林和阿贝西利）在与内分泌治疗联合作为 HR+/HER-2 阴性 ABC 的一线治疗时，当患者在辅助内分泌治疗后进展时，均显著改善了无进展生存期（PFS）。它们也都显示出作为 HR+/Her2 阴性 ABC 的二线治疗改善了 PFS。它们的毒性谱是有利的，主要是血液学毒性（主要是中性粒细胞减少症），其次是腹泻和疲劳。在一线治疗中保持了生活质量，或在二线治疗中提高了生活质量。迄今为止，只有 7 项临床试验中的 2 项报告了作为一线治疗的总生存期（OS），差异没有达到统计学意义。在本文中，我们回顾了 CDK 信号通路及其抑制剂的生物学、所有三种研究性选择性 CDK4/6 抑制剂的临床前和临床数据及其毒性。我们还讨论了这些药物如何被纳入当前的国际指南以及这些药物在其他类型的乳腺癌中的未来方向，包括晚期疾病和早期疾病。
