Advances in HER2-targeted therapies have improved the survival of patients with HER2-positive breast cancer. The standard-of-care treatment for localized disease has been chemotherapy and 1 year of adjuvant HER2-targeted therapy, typically with the anti-HER2 antibody trastuzumab. Despite the effectiveness of this treatment, disease relapse occurs in a subset of patients; thus, focus has been placed on escalating treatment by either combining different HER2-targeted agents or extending the duration of HER2-targeted therapy. Indeed, dual HER2-targeted therapies and extended-duration anti-HER2 therapy, as well as adjuvant therapy with the anti-HER2 antibody-drug conjugate T-DM1, have all been approved for clinical use. Emerging evidence suggests, however, that some patients do not derive sufficient benefit from these additional therapies to offset the associated toxicities and/or costs. Similarly, the universal use of chemotherapy might not benefit all patients, and treatment de-escalation through omission of chemotherapy has shown promise in clinical trials and is currently being explored further. The future of precision medicine should therefore involve tailoring of therapy based on the genetics and biology of each tumour and the clinical characteristics of each patient. Predictive biomarkers that enable the identification of patients who will benefit from either escalated or de-escalated treatment will be crucial to this approach. In this Review, we summarize the available HER2-targeted agents and associated mechanisms of resistance, and describe the current therapeutic landscape of early stage HER2-positive breast cancer, focusing on strategies for treatment escalation or de-escalation.

中文翻译：

---

针对早期 HER2 阳性乳腺癌的个性化治疗。

HER2 靶向治疗的进步提高了 HER2 阳性乳腺癌患者的生存率。局部疾病的标准护理治疗是化疗和 1 年的 HER2 靶向辅助治疗，通常使用抗 HER2 抗体曲妥珠单抗。尽管这种治疗有效，但仍有一部分患者出现疾病复发。因此，重点放在通过联合不同的 HER2 靶向药物或延长 HER2 靶向治疗的持续时间来升级治疗。事实上，双 HER2 靶向治疗和延长抗 HER2 治疗，以及抗 HER2 抗体药物偶联物 T-DM1 的辅助治疗，都已被批准用于临床。然而，新出现的证据表明，一些患者没有从这些额外疗法中获得足够的益处来抵消相关的毒性和/或成本。同样，普遍使用化疗可能不会使所有患者受益，通过省略化疗来降级治疗已在临床试验中显示出希望，目前正在进一步探索。因此，精准医学的未来应该包括根据每个肿瘤的遗传学和生物学以及每个患者的临床特征来定制治疗方案。能够识别将从升级或降级治疗中受益的患者的预测生物标志物对于这种方法至关重要。在这篇综述中，我们总结了可用的 HER2 靶向药物和相关耐药机制，并描述了早期 HER2 阳性乳腺癌的当前治疗前景，重点关注治疗升级或降级策略。