Davis Andrew A, Hesse Jennifer, Pereira Patrícia M R, Ma Cynthia X
Division of Oncology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
NPJ Breast Cancer. 2025 May 13;11(1):42. doi: 10.1038/s41523-025-00743-w.
Antibody-drug conjugates (ADCs) are rapidly changing the way we treat patients with breast cancer. Despite this progress, many unanswered questions remain regarding the sequencing of different ADCs with similar payloads, optimal combinations, drug design strategies to limit off-target toxicities, biomarkers to define antigen positivity, and the use of ADCs in the neoadjuvant and adjuvant settings. In this review, we summarize novel ADC approaches in breast cancer treatment, including potential improvements in ADC payloads, linkers, targets, and drug delivery. We also evaluate novel strategies to combine ADCs with other agents, such as targeted drugs and immune checkpoint inhibitors. To improve patient selection, the development of quantitative biomarkers is reviewed, including HER2 mRNA, immunofluorescence-based assays, mass spectrometry, liquid biopsies, digital pathology, and molecular imaging-based approaches. Lastly, we evaluate the potential to incorporate ADCs into the early-stage setting, including evaluating currently published and ongoing clinical trials. This review highlights the potential for ADCs to shift the treatment paradigm in both the advanced and early-stage settings. We further demonstrate the complexity and challenges of improving ADCs to enhance targeting of tumor vulnerabilities while limiting toxicity through rationale drug development strategies to enhance the therapeutic window, linker technology, and payload variability to continue to improve outcomes for patients with breast cancer.
抗体药物偶联物（ADCs）正在迅速改变我们治疗乳腺癌患者的方式。尽管取得了这一进展，但关于具有相似有效载荷的不同ADC的序贯使用、最佳组合、限制脱靶毒性的药物设计策略、定义抗原阳性的生物标志物以及ADC在新辅助和辅助治疗中的应用等问题，仍有许多未解之谜。在本综述中，我们总结了乳腺癌治疗中的新型ADC方法，包括ADC有效载荷、连接子、靶点和药物递送方面的潜在改进。我们还评估了将ADC与其他药物（如靶向药物和免疫检查点抑制剂）联合使用的新策略。为了改善患者选择，我们回顾了定量生物标志物的发展，包括HER2 mRNA、基于免疫荧光的检测、质谱分析、液体活检、数字病理学和基于分子成像的方法。最后，我们评估了将ADC纳入早期治疗的潜力，包括评估目前已发表的和正在进行的临床试验。本综述强调了ADC在晚期和早期治疗中改变治疗模式的潜力。我们进一步展示了通过合理的药物开发策略来改善ADC以增强对肿瘤脆弱性的靶向作用，同时通过限制毒性来扩大治疗窗口、改进连接子技术和增加有效载荷的多样性，从而继续改善乳腺癌患者治疗效果的复杂性和挑战。
