Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato - Oncology (DIPO), University of Milan, Milan, Italy.
Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy; Laster and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
Cancer Treat Rev. 2023 Jun;117:102569. doi: 10.1016/j.ctrv.2023.102569. Epub 2023 Apr 28.
Endocrine therapy (ET) is the cornerstone of management in hormone receptor (HR)+ breast cancer (BC). Indeed, targeting the estrogen receptor (ER) signaling at different levels is a successful strategy, since BC largely relies on the ER signaling as a driver of tumorigenesis and progression. In metastatic BC, progression of disease typically occurs due to either ligand-independent ER signaling, which favors tumor proliferation and survival in the absence of hormonal stimuli, or an ER-independent signaling, which exploits alternative transcription pathways. For instance, estrogen receptor 1 (ESR1) mutations induce constitutive ER activity, in turn upregulating ER-dependent gene transcription and causing resistance to estrogen depleting therapies. The largest unmet need lies after progression on ET + cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, where fulvestrant alone provides an average 2-3-month PFS. In this context, novel oral selective estrogen receptor degraders (SERDs) and other next-generation ETs are being investigated, both as single agents and in combination with targeted therapies. Elacestrant, the next generation ET in most advanced clinical development and the first to be FDA approved, demonstrated improved outcomes compared to standard ETs in ET pre-treated HR+/HER2- metastatic BC in the phase 3 EMERALD clinical trial. Additionally, other agents are showing promising results in both preclinical and early phase clinical settings. In this review, emerging data related to oral SERDs and other novel ETs in managing HR+/HER2- BC are presented. Major challenges and future perspectives related to the optimal sequence of therapeutic options and the molecular landscape of endocrine resistance are also provided.
内分泌治疗 (endocrine therapy, ET) 是激素受体 (hormone receptor, HR)+ 乳腺癌 (breast cancer, BC) 管理的基石。事实上，靶向雌激素受体 (estrogen receptor, ER) 信号转导的不同水平是一种成功的策略，因为 BC 在很大程度上依赖 ER 信号作为肿瘤发生和进展的驱动因素。在转移性 BC 中，疾病的进展通常是由于配体非依赖性 ER 信号，其有利于在没有激素刺激的情况下肿瘤增殖和存活，或者 ER 非依赖性信号，其利用替代转录途径。例如，雌激素受体 1 (estrogen receptor 1, ESR1) 突变诱导组成性 ER 活性，进而上调 ER 依赖性基因转录，并导致对雌激素耗竭治疗的耐药性。最大的未满足需求在于 ET+细胞周期蛋白依赖性激酶 4 和 6 (cyclin-dependent kinases 4 and 6, CDK4/6) 抑制剂进展后，单独使用氟维司群平均提供 2-3 个月的无进展生存期 (progression-free survival, PFS)。在这种情况下，正在研究新型口服选择性雌激素受体降解剂 (selective estrogen receptor degraders, SERDs) 和其他下一代 ET，包括作为单一药物和与靶向治疗联合使用。在 3 期 EMERALD 临床试验中，在接受 ET 预处理的 HR+/HER2-转移性 BC 中，与标准 ET 相比，处于最先进临床开发阶段的下一代 ET 依维莫司 (elacestrant) 显示出改善的结局。此外，其他药物在临床前和早期临床环境中也显示出有希望的结果。在这篇综述中，介绍了管理 HR+/HER2- BC 中口服 SERDs 和其他新型 ET 的最新数据。还提供了与治疗选择的最佳顺序和内分泌抵抗的分子图谱相关的主要挑战和未来展望。
