"Neoadjuvant trastuzumab deruxtecan for high-risk HER2-positive early breast cancer: Does the evidence support its use as a new standard-of-care?".

The therapeutic landscape for HER2-positive breast cancer (BC) is evolving rapidly with the advent of antibody-drug conjugates such as trastuzumab deruxtecan (T-DXd). Recently, positive results from the Destiny Breast 011 (DB11) randomized clinical trial were reported, seemingly supporting T-DXd followed by paclitaxel, trastuzumab, and pertuzumab as a potential new neoadjuvant treatment option for high-risk, HER2-positive early breast cancer (eBC). However, in our view, several elements of the trial's design and conduct may have affected the results both qualitatively and quantitatively. These concerns include the selection of the primary endpoint, the sample-size calculation, potential source of bias and the suboptimal post-recurrence therapies administered to patients enrolled. Taken together, these limitations substantially constrain the interpretability of the trial's findings. In this commentary, we discuss why, although the DB11 results are encouraging and justify continued exploration of this innovative therapeutic strategy, the current evidence remains insufficient to support upfront neoadjuvant T-DXd as a standard-of-care option for patients with high-risk, HER2-positive eBC.