Clinical characteristics and drug–drug interactions in human epidermal growth factor receptor 2-positive breast cancer treated with trastuzumab deruxtecan: real-world data from the DE-REAL study

Background Trastuzumab deruxtecan (T-DXd) reshaped clinical practice in human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC). The impact of clinical characteristics and drug–drug interactions (DDIs) on outcomes in patients receiving T-DXd is still under investigation. Methods We retrospectively analyzed data of patients from the Italian DE-REAL study. Clinical features including age, body mass index (BMI), toxicity and DDIs were assessed and correlated with clinical outcomes. The Drug-PIN software was used to evaluate DDIs. Results Among 143 patients, age did not significantly affect progression-free survival (PFS) but influenced overall survival (OS), with younger patients (<65 years) showing better outcomes (median overall survival [mOS]: 12 vs. 10 months, P=0.02). Patients with BMI >25 demonstrated significantly longer PFS (11 vs. 9 months, P=0.04), which was confirmed as independent predictor of better PFS at multivariate analysis (P≤0.05), but experienced higher toxicity rates, particularly nausea (P=0.019). Drug-PIN classification showed no impact on survival outcomes, although patients with high-risk DDIs experienced more nausea and asthenia compared to those with low-risk interactions (P=0.0018 and P=0.003, respectively). Conclusion T-DXd efficacy appears consistent across different age groups, although elderly patients showed reduced OS. Higher BMI was associated with improved PFS but increased toxicity. While DDIs did not affect survival outcomes, they influenced specific adverse events. Our results reinforce the efficacy and favorable safety profile of T-DXd in a broad real-world population, including patients with polypharmacy or comorbidities, while highlighting that personalized monitoring and supportive care strategies may be particularly beneficial for elderly patients and those with higher BMI.