20th anniversary of adjuvant trastuzumab: reflections on a breakthrough moment.

Twenty years after its initial approval, trastuzumab remains a cornerstone in the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (eBC). Long-term follow-up from pivotal adjuvant trials has consistently demonstrated significant and durable improvements in survival outcomes across various risk groups and chemotherapy backbones. In parallel, trastuzumab-induced cardiotoxicity (TIC) remains overall infrequent, particularly in patients without prior exposure to anthracycline and appears comparable to the incidence observed in the general population after treatment completion. While real-world data further support the long-term efficacy and safety of trastuzumab, advancements such as more convenient subcutaneous formulations and the widespread availability of more accessible cost-effective biosimilars solidify its ongoing relevance in clinical practice. Conversely, despite two decades of clinical and translational research, no predictive biomarker beyond HER2 overexpression or amplification has yet been validated to guide trastuzumab use. Emerging candidates, including stromal tumor-infiltrating lymphocytes, circulating tumor DNA, and the HER2DX genomic assay, are not yet validated for use in clinical practice, although prospective studies are ongoing. Similarly, while clinical factors and imaging tools may help identify early on patients at higher risk of experiencing TIC, no cardioprotective strategy has yet demonstrated robust and conclusive benefit. Despite the emergence of newer anti-HER2 agents and evolving treatment paradigms, trastuzumab will probably continue to serve as a key therapeutic backbone, especially for patients with lower-risk HER2-positive eBC.