Low Rates of Discontinuation Unrelated to Disease Progression with Trastuzumab Deruxtecan in Metastatic Breast Cancer: A Real-World Study

Purpose: Trastuzumab deruxtecan (T-DXd) has significantly improved outcomes in patients with HER2-positive and HER2-low/ultralow metastatic breast cancer (MBC). However, most patients eventually discontinue treatment. In clinical trials, discontinuation without disease progression occurred in 30–60% of cases, but real-world data on the reasons for discontinuation and subsequent treatment strategies remain limited. This study aimed to describe T-DXd discontinuation patterns and post-discontinuation treatments in a real-world setting. Methods: We conducted a single-center retrospective observational study including consecutive patients with MBC treated with T-DXd between July 2018 and December 2025. Patients who discontinued T-DXd for any reason were included. Reasons for discontinuation, treatment duration, response outcomes, and subsequent systemic therapies were analyzed using descriptive statistics. Results: Overall, 93 patients were included: 71.0% had HER2-positive, 26.9% HER2-low, and 2.1% HER2 0 tumors. The primary reason for discontinuation was progressive disease (82.8%). Other reasons included adverse events (14.0%), non-treatment-related causes (2.2%) and patient decision (1.1%). Interstitial lung disease represented the most common toxicity leading to discontinuation (10.8%). The median treatment duration was 7.9 months overall and was longer in patients with HER2-positive than in thosewith HER2-low and HER2 0 disease. Among evaluable patients, overall response rate was 83.1% in HER2-positive tumors and 52% in HER2-low tumors. After discontinuation, 80.6% of patients received subsequent therapy. Patients discontinuing for reasons other than progression had longer treatment exposure. Conclusions: In this real-world cohort, most T-DXd discontinuations were due to disease progression, while adverse event-related discontinuations were less frequent than in clinical trials. Several factors may influence treatment persistence, including toxicity management. Further evaluation in larger, multicenter cohorts is warranted to better characterize their contribution.