Trastuzumab deruxtecan (T-DXd) offers substantial benefits for individuals with HER2-positive or HER2-low advanced breast cancer (ABC), though it carries a distinctive adverse event profile, notably interstitial lung disease (ILD). A retrospective observational cohort analysis was performed to assess the safety and effectiveness of T-DXd in patients with HER2-positive/low ABC managed at the European Institute of Oncology between December 2019 and April 2025. Key outcomes encompassed the cumulative ILD incidence, rates of grade ≥3 neutropenia across the cohort, and real-world progression-free survival (rwPFS) stratified by breast cancer subtype. ILD risks were evaluated in relation to factors such as age, smoking history, presence of lung metastases, subtype, previous immunotherapy exposure, and number of prior chemotherapy regimens. Grade ≥3 neutropenia was examined against age and neutrophil-to-lymphocyte ratio (NLR) measured on day 1 of cycle 3 (C3D1).
The study enrolled 112 patients, of whom 43% (n=48) had HER2-positive and 57% (n=64) had HER2-low ABC. Patients had received a median of 3.0 prior treatment lines for ABC [interquartile range (IQR) 2.0-5.0]. Previous antibody-drug conjugate therapy was noted in 58% (n=28) of HER2-positive cases and 17% (n=11) of HER2-low cases. De novo metastatic disease was present in 23% (n=26). With a median follow-up of 9 months (IQR 5.1-21.7 months), the 12-month cumulative ILD incidence reached 13 percent [95 percent confidence interval (CI) 7.2%-20.6%], including two fatal (grade 5) events (2%). Multivariable analysis indicated trends toward elevated ILD risk with prior immunotherapy (hazard ratio 3.22, 95 percent CI 1.06-9.72, P=0.052) and smoking history (hazard ratio 2.71, 95 percent CI 1.00-7.34, P=0.062). Grade ≥3 neutropenia affected 10 patients (9%) and was linked to lower NLR at C3D1 (hazard ratio 0.10, 95 percent CI 0.02-0.53, P<0.001). Real-world PFS was 21.82 months (95 percent CI 17.98-not reached) in HER2-positive ABC and 6.90 months (95 percent CI 4.93-10.19) in HER2-low ABC. This real-world evaluation supports the established safety and efficacy of T-DXd in advanced breast cancer. Potential ILD risk factors including prior immunotherapy and smoking, along with low NLR as a predictor of severe neutropenia, warrant additional research.
