HR阳性转移性乳腺癌的精确治疗和新兴策略
Precision therapeutics and emerging strategies for HR-positive metastatic breast cancer
影响因子:82.20000
分区:医学1区 Top / 肿瘤学1区
发表日期:2024 Oct
作者:
Maxwell R Lloyd, Komal Jhaveri, Kevin Kalinsky, Aditya Bardia, Seth A Wander
摘要
基于抗雌激素的疗法通常与CDK4/6抑制剂结合使用，是当前的护理标准一线治疗，用于晚期激素受体阳性（HR+）乳腺癌患者。抗雌激素剂不可避免地会发生抗雌激素，这是由雌激素受体（ER）依赖性或与ER独立的机制介导的，这些机制驱动肿瘤进展。新兴的内分泌疗法包括但不限于靶向嵌合体的下一代口服ER降解器和蛋白水解，这对于ESR1突变乳腺癌患者可能特别有效。此外，在包括AKT和PI3K在内的致癌信号通路中具有驱动因素改变的癌症可能对涉及靶向抑制剂的新型组合策略敏感。下一代CDK2/4抑制剂是积极临床研究的领域，并且正在努力评估顺序CDK抑制的作用。被批准的和新兴的抗体 - 药物结合物利用新型靶抗原也表现出了有希望的临床活性。这些新颖的药物以及预测生物标志物的进一步鉴定和表征，希望能够继续改善临床结果，降低毒性的发生率，并限制该人群过度治疗的程度。在这篇综述中，我们描述了转移性HR+乳腺癌患者的不断发展的治疗范例，这些药物和生物标志物的不断增长将有助于塑造未来的治疗景观。这些策略有望涉及肿瘤分子分析以实现精确药物的递送。
Abstract
Anti-oestrogen-based therapies, often combined with a CDK4/6 inhibitor, are the current standard-of-care first-line therapy for patients with advanced-stage hormone receptor-positive (HR+) breast cancer. Resistance to anti-oestrogen agents inevitably occurs, mediated by oestrogen receptor (ER)-dependent or ER-independent mechanisms that drive tumour progression. Emerging endocrine therapies include, but are not limited to, next-generation oral ER degraders and proteolysis targeting chimeras, which might be particularly effective in patients with ESR1-mutant breast cancer. Furthermore, cancers harbouring driver alterations in oncogenic signalling pathways, including AKT and PI3K, might be susceptible to novel combination strategies involving targeted inhibitors. Next-generation CDK2/4 inhibitors are an area of active clinical investigation, and efforts are ongoing to evaluate the role of sequential CDK inhibition. Approved and emerging antibody-drug conjugates exploiting novel target antigens have also demonstrated promising clinical activity. These novel agents, as well as further identification and characterization of predictive biomarkers, will hopefully continue to improve clinical outcomes, reduce the incidence of toxicities, and limit the extent of overtreatment in this population. In this Review, we describe the evolving treatment paradigm for patients with metastatic HR+ breast cancer in light of the growing armamentarium of drugs and biomarkers that will help to shape the future therapeutic landscape. These strategies are expected to involve tumour molecular profiling to enable the delivery of precision medicine.