Right-sizing treatment for HER2-positive breast cancer: evolving algorithms across the disease continuum.

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer has undergone one of the most profound therapeutic transformations in oncology. Once associated with poor outcomes, it is now a highly curable disease in the early-stage setting, and a substantial proportion of patients with metastatic disease survive beyond 5 years. This progress reflects the development of multiple HER2-targeted therapies, including monoclonal antibodies, antibody-drug conjugates and tyrosine-kinase inhibitors. Most notably, the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan has rapidly been moved into earlier lines of therapy, with emerging roles in the first-line metastatic setting, adjuvant treatment of high-risk residual disease and neoadjuvant therapy. This expansion creates new opportunities, but also crucial evidence gaps regarding optimal sequencing, retreatment and selection of patients for treatment intensification. As treatment options expand, the central challenge is to right-size therapy across the disease continuum, which is the focus of this Review. In patients with early-stage disease, this right-sizing involves carefully de-intensifying treatment for those with low-risk tumours, optimizing neoadjuvant chemotherapy backbones and escalating therapy for those with residual disease; in patients with advanced-stage disease, it requires optimizing maintenance treatment strategies (for example, using palbociclib or tucatinib) after induction therapy, while integrating these maintenance regimens with the novel option of first-line trastuzumab deruxtecan plus pertuzumab, for which the optimal treatment duration and subsequent sequencing remain uncertain. Tissue, plasma and dynamic imaging-based biomarkers are beginning to inform this process, with several showing promising potential for clinical implementation.