Tracy Philip D, Bopp Emily, Milner Emily, Garrido-Castro Ana C, Giordano Antonio, Mayer Erica L, Tolaney Sara M, Tarantino Paolo, Schlam Ilana
Department of Hematology/Oncology, Tufts Medical Center, Boston, MA, 02111, USA.
Tufts University School of Medicine, Boston, MA, 02111, USA.
Curr Oncol Rep. 2025 May 28. doi: 10.1007/s11912-025-01689-9.
Since the introduction of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) as the first-line treatment for metastatic hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative (HR+/HER2-) breast cancer, there has been a significant expansion in the number of therapeutic options for subsequent lines of therapy. Many new agents are being studied, with potential for future regulatory approval. The increased number of therapeutic options raises questions about the optimal selection and sequencing of therapies for individual patients. These advances represent an important clinical challenge in this rapidly evolving field, given the introduction of new therapies targeting various pathways (alone or in combination) and new therapeutic classes being studied.
Recently approved targeted therapies have demonstrated improvements in progression free survival (PFS) for patients whose cancer harbors mutations in the PI3K/AKT pathway, ESR1, BRCA1/2, and/or PALB2. Data to support continuation of CDK4/6 inhibition after progression on a prior CDK4/6i remains mixed, though some studies suggest a subset of patients may benefit from this approach. Several agents with unique mechanisms of action have shown promise in data from early phase trials, and have the potential to enter the treatment lexicon in the coming years. Examples include CDK2- and CDK4-selective inhibitors, complete estrogen receptor antagonists (CERANs), proteolysis targeting chimeras (PROTACs), and next-generation PI3K pathway inhibitors. In this narrative review, we summarize the current and upcoming treatments for metastatic HR+/HER2- breast cancer after progression on a CDK4/6i plus ET, with a focus on the following: an overview of first-line regimens of CDK4/6i plus ET and observed mechanisms of resistance; currently approved second-line therapy options; and upcoming options currently under exploration in clinical trials. We focus primarily on new therapy classes that may offer therapeutic options beyond currently available treatments.
自细胞周期蛋白依赖性激酶4和6抑制剂（CDK4/6i）联合内分泌治疗（ET）被引入作为转移性激素受体（HR）阳性、人表皮生长因子受体2（HER2）阴性（HR+/HER2-）乳腺癌的一线治疗方案以来，后续治疗线的治疗选择数量显著增加。许多新型药物正在研究中，有望获得未来的监管批准。治疗选择数量的增加引发了关于个体患者治疗的最佳选择和排序的问题。鉴于针对各种途径（单独或联合）的新疗法以及正在研究的新治疗类别不断推出，这些进展在这个快速发展的领域中代表了一项重要的临床挑战。
最近获批的靶向治疗已证明，对于癌症在PI3K/AKT途径、ESR1、BRCA1/2和/或PALB2中存在突变的患者，无进展生存期（PFS）有所改善。关于在先前使用CDK4/6i治疗进展后继续抑制CDK4/6的数据仍存在分歧，不过一些研究表明部分患者可能从这种方法中获益。几种具有独特作用机制的药物在早期试验数据中显示出前景，并且有可能在未来几年进入治疗方案。例子包括CDK2和CDK4选择性抑制剂、完全雌激素受体拮抗剂（CERANs）、靶向蛋白水解嵌合体（PROTACs）以及下一代PI3K途径抑制剂。在这篇叙述性综述中，我们总结了在CDK4/6i加ET治疗进展后转移性HR+/HER2-乳腺癌的当前和即将出现的治疗方法，重点关注以下方面：CDK4/6i加ET一线治疗方案概述及观察到的耐药机制；目前获批的二线治疗选择；以及目前正在临床试验中探索的即将出现的选择。我们主要关注可能提供现有治疗之外治疗选择的新治疗类别。
