Trastuzumab deruxtecan in breast cancer: Current status and future directions

• Author Details:   
• Praloy Basu ^*

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Breast cancer is the most prevalent malignancy in women globally, with HER2-positive disease constituting approximately 15–20% of cases. The advent of HER2-targeted therapies has significantly improved outcomes; however, therapeutic resistance in metastatic settings remains a challenge. Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody–drug conjugate (ADC) made up of a humanized anti-HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload through a cleavable linker. A high drug-to-antibody ratio and a bystander effect has resulted in a significant efficacy in HER2-positive metastatic breast cancer (mBC), particularly those who have received multiple lines of therapy, as shown in DESTINY-Breast01 and DESTINY-Breast03 trials. Furthermore, the DESTINY-Breast04 study established T-DXd as the first effective therapy for HER2-low mBC. This led to a redefinition of the categories of HER2 expression. T-DXd is also under investigation in early-stage disease, with encouraging results in neoadjuvant and adjuvant settings. While generally well tolerated, interstitial lung disease (ILD) remains a notable risk, necessitating vigilant monitoring. Patient-reported outcomes indicate maintained or improved quality of life with T-DXd. Ongoing research is focused on expanding its role through combination strategies, exploring its use in HER2-ultralow tumors, and identifying predictive biomarkers such as HER2 mRNA levels and topoisomerase I expression. Additionally, T-DXd is being evaluated in other HER2-expressing malignancies including lung, gastric, and colorectal cancers. Overall, T-DXd represents a paradigm shift in HER2-targeted therapy, offering clinical benefit across a broader spectrum of breast cancer subtypes and treatment settings.