This clinical scenario is associated with an unfavorable prognosis and elevated risk of metastasis. The study, coordinated in Spain by the academic group SOLTI, has counted on the participation of the Clínic Barcelona Comprehensive Cancer Centre (4CB)—center driven by Clínic, IDIBAPS, and UB—with representation on the study's Steering Committee as the sole Spanish representative, in addition to contributing to patient inclusion and results interpretation.
"The question was whether trastuzumab deruxtecan could improve the results obtained so far with T-DM1", explains Dr. Aleix Prat, director of the Clínic Barcelona Comprehensive Cancer Center, head of the Translational Genomics and Targeted Therapies in Solid Tumours group at IDIBAPS and national coordinator of the study on behalf of SOLTI.
"The data show yes, and very markedly: the risk of invasive recurrence is reduced by approximately half in a group with historically elevated risk", he adds.
A Cohort Representing the Highest Risk Cases
DESTINY-Breast05 included 1,635 patients with early HER2-positive breast cancer who had received standard neoadjuvant treatment—taxane-based chemotherapy and anti-HER2 targeted therapy—and who presented invasive residual disease after surgery. Most also showed lymph node involvement or had been initially diagnosed with locally advanced disease, configuring a high clinical risk population. In Spain the study was carried out in 50 hospitals and in Portugal in 10 centers.
After surgery, participants were randomized to receive for approximately one year one of the two compared treatments: trastuzumab deruxtecan or T-DM1. The median follow-up was about 30 months in both groups.
Results: A Consistent and Clinically Relevant Benefit
The analysis performed showed a clear benefit of T-DXd versus T-DM1. At three years of follow-up, 92.4% of patients treated with T-DXd remained free of invasive recurrence, versus 83.7% of the T-DM1 group.
This difference translates into a 53% relative risk reduction, meaning that patients treated with T-DXd have half the probability of recurring than those treated with the currently standard treatment. "This is a magnitude of benefit uncommon in early disease", notes Dr. Prat. "Achieving that more than 90% of these patients remain without invasive recurrence at three years represents a notable clinical advance and changes prognosis expectations in this subgroup".
A New Standard in Post-Neoadjuvant Treatment
The DESTINY-Breast05 results support the incorporation of trastuzumab deruxtecan as the new reference treatment in the post-surgery period for patients with residual HER2-positive early disease. This represents a significant change in clinical practice and anticipates a direct impact on long-term recurrence reduction.
"Spain has highly specialized breast units and extensive experience in targeted therapies", concludes Dr. Prat. "This will allow incorporating these results quickly, ensuring that patients benefit from a treatment that substantially improves their cure expectations".
Safety: A Known Profile with Specific Monitoring Needs
The safety profile observed for T-DXd in DESTINY-Breast05 matches that described in previous studies of the drug. Among the most frequent adverse effects are gastrointestinal symptoms (such as nausea and vomiting) and hematological alterations. In the case of T-DM1, hepatic alterations and platelet decrease predominate.
The most relevant toxicity identified with T-DXd is interstitial lung disease (ILD). Although most cases were low or moderate severity, the study reinforces the importance of protocolized monitoring, especially in a curative intent treatment scenario. "The benefit-risk balance is clearly favorable, but requires structured surveillance", emphasizes Dr. Prat. "ILD is infrequent, but clinically relevant. Its early detection and management are fundamental to ensure treatment safety". The implementation of this new standard will require clinical teams to strengthen pulmonary monitoring protocols, optimize care pathways, and review therapeutic sequencing strategies in case of subsequent recurrence.
DESTINY-Breast05 opens new relevant lines of research: evaluating the definitive impact on overall survival, identifying which patients could benefit from escalation or de-escalation strategies, developing biomarkers to guide therapeutic selection, and deepening prevention and management of pulmonary toxicity.
The DESTINY-Breast05 study is a collaborative trial designed and executed between SOLTI, the National Surgical Adjuvant Breast and Bowel Project (NSABP), the AGO-B Breast Study Group, the German Breast Group (GBG), and supported by the Daiichi-Sankyo-AstraZeneca Alliance.
Study reference:
Loibl S, Park YH, Shao Z, Huang CS, Barrios C, Abraham J, Prat A, Niikura N, Im SA, Li W, Li H, Wang Y, Yao H, Kim SB, Geng CZ, Rodriguez Pantigoso W, Ramírez Godinez FJ, Song C, Ching Chang Y, Antoniazzi A, Chen SC, Li Z, Nowecki Z, Lim J, Mathias E, Sato Y, Lu W, Abdel-Monem H, Untch M, Geyer CE Jr; DESTINY-Breast05 Trial Investigators. Trastuzumab Deruxtecan in Residual HER2-Positive Early Breast Cancer. N Engl J Med. 2025 Dec 10. doi: 10.1056/NEJMoa2514661.
