Review

HR阳性转移性乳腺癌的精准治疗与新兴策略

Precision therapeutics and emerging strategies for HR-positive metastatic breast cancer

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Nature Reviews Clinical Oncology

影响因子:82.2

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

DOI: 10.1038/s41571-024-00935-6

keywords:

摘要

抗雌激素疗法，常与CDK4/6抑制剂联合使用，是目前晚期激素受体阳性（HR+）乳腺癌的标准一线治疗。抗雌激素药物的耐药性不可避免，主要由雌激素受体（ER）依赖或非依赖机制驱动肿瘤进展。新兴的内分泌治疗包括下一代口服ER降解剂和蛋白水解靶向嵌合体（PROTACs），这些药物在携带ER突变的乳腺癌患者中尤具潜力。此外，携带驱动性信号通路（如AKT和PI3K）突变的癌症，可能适合采用新型联合靶向策略。下一代CDK2/4抑制剂正处于临床研究的活跃阶段，相关研究也在评估序贯性CDK抑制的作用。已获批及新兴的抗体药物偶联物（ADC）也展现出良好的临床活性。这些新药物，以及对预后生物标志物的进一步识别和特征化，有望持续改善临床结局，减少毒性反应，并限制过度治疗。在本文中，我们将介绍随着药物和生物标志物不断丰富，未来转移性HR+乳腺癌的治疗范式演变。这些策略预计将涉及肿瘤分子谱分析，以实现精准医疗的目标。

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.