Evolving First-Line Treatment Strategies in ERBB2 -Positive Metastatic Breast Cancer

Importance: The treatment landscape of ERBB2 (formerly HER2)-positive metastatic breast cancer has evolved substantially during the past decade, with emerging therapies challenging the long-standing induction-maintenance paradigm established by the CLEOPATRA trial (NCT00567190). However, optimal treatment selection, sequencing, and duration remain uncertain, particularly in the context of increasing therapeutic complexity and biologic heterogeneity. Observations: Taxane-based chemotherapy combined with trastuzumab and pertuzumab has long been the standard first-line induction regimen, followed by maintenance anti-ERBB2 therapy with or without endocrine therapy based on hormone receptor status. Recent data from the DESTINY-Breast09 trial (DB09; NCT04784715) demonstrate superior progression-free survival with trastuzumab deruxtecan plus pertuzumab, supporting its recent US Food and Drug Administration approval and prompting questions regarding the necessity of chemotherapy, optimal duration of antibody-drug conjugate therapy, and the role of a dual ERBB2 blockade. Maintenance strategies have also expanded, particularly in hormone receptor-positive disease, with incorporation of endocrine therapy and CDK4/6 inhibitors, as demonstrated in the PATINA trial (NCT02947685). The HER2CLIMB-05 trial (NCT05132582) provided an additional maintenance approach using a triplet anti-ERBB2 strategy. These nonchemotherapy maintenance options are designed to have fewer toxic effects and better quality of life than chemotherapy-based strategies. These developments raise questions regarding the necessity of chemotherapy, optimal duration of antibody-drug conjugate therapy, and the role of dual ERBB2 blockade. Emerging biomarker-driven approaches, including the HER2DX assay and circulating tumor DNA, remain investigational and are not yet part of routine clinical practice but aim to optimize treatment selection. Novel strategies, such as chemotherapy-free regimens and sequential multiagent approaches, as in the SAPPHO study (NCT06439693), are challenging traditional paradigms. Conclusions and Relevance: The management of ERBB2-positive metastatic breast cancer is transitioning toward a more individualized approach that balances efficacy, toxic effects, and patient preferences. Integrating biomarker-driven strategies will be essential to optimize treatment selection, duration, and sequencing, with the goal of improving long-term outcomes while preserving quality of life.