Adjuvant Trastuzumab Deruxtecan Versus Trastuzumab Emtansine by Residual Cancer Burden in HER2-Positive Early Breast Cancer: A Decision Analysis

Background: For patients with HER2-positive early breast cancer and residual disease after neoadjuvant therapy, escalating adjuvant treatment improves outcomes. In high-risk patients, DESTINY-Breast05 found that trastuzumab deruxtecan (T-DXd) reduced the 3-year risk of recurrence compared with trastuzumab emtansine (T-DM1). T-DXd also carries a risk of fatal interstitial lung disease (ILD). The US FDA approval for adjuvant T-DXd includes all patients with residual disease, including lower-risk patients not represented in the trial. We used decision modeling to project 10-year survival across recurrence-risk groups to aid in clinical decision-making. Methods: We modeled outcomes for 50-year-old patients receiving T-DXd or T-DM1 using DESTINY-Breast05 data and published literature. The primary outcome was projected 10-year overall survival (OS); secondary outcomes were breast cancer and ILD deaths per 1,000 patients. Results were stratified by residual cancer burden (RCB) class and estrogen receptor (ER) status. Results: Across 1,000 simulations, mean projected OS differences favored T-DXd in every subgroup, with 10-year gains ranging from 0.3 (95% uncertainty interval [UI], -2.1 to 1.6; RCB-I ER-positive) to 9.7 percentage points (95% UI, 5.7 to 14.1; RCB-III ER-positive). T-DXd yielded higher OS in 71% of RCB-I ER-positive simulations and 94% of RCB-I ER-negative simulations. Per 1,000 patients, T-DXd averted 16 to 113 breast cancer deaths and caused 13 ILD deaths compared with T-DM1, assuming a conservative fatal ILD risk. Conclusion: These findings favor T-DXd for patients with RCB-II or RCB-III disease. For RCB-I patients, particularly those with ER-positive tumors, the projected survival gain is smaller and sensitive to fatal ILD assumptions.