Toward Sustainable Care in HER2-Positive Metastatic Breast Cancer: Emerging Evidence for Treatment De-escalation

Major advances in the management of human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (MBC) have been achieved through treatment intensification with novel HER2-targeted agents and combination strategies, resulting in substantial survival gains. However, indefinite exposure to systemic therapy imposes cumulative toxicity, financial strain, and quality-of-life burdens. In contrast, the concept of treatment de-escalation, aimed at maintaining disease control with less intensive therapy, has only recently emerged as a complementary paradigm. This review highlights two evolving avenues of treatment de-escalation. First, in hormone receptor-positive/HER2+ disease, randomized trials have demonstrated that combining HER2 blockade with endocrine therapy and cyclin-dependent kinase 4 and 6 inhibitors can overcome endocrine resistance, offering a chemotherapy-sparing approach with outcomes comparable to chemotherapy or antibody-drug conjugates. Second, in long-term responders, retrospective analyses and ongoing prospective trials are evaluating whether discontinuation of prolonged maintenance HER2 therapy can safely reduce treatment burden while preserving disease control, with the added potential for effective rechallenge upon relapse. Together, these developments suggest that treatment de-escalation represents a rational and necessary treatment strategy. Future progress will depend on biomarker-driven patient selection and prospective validation. Redefining success in HER2+ MBC to include not only survival but also quality of life and sustainability represents an important step toward patient-centered cancer care.