Reassessing the Role of Anthracyclines in Early HER2-Positive Breast Cancer in the Era of HER2-Targeted Therapy and Treatment De-Escalation: A Systematic Review and Narrative Synthesis.

Background: Anthracyclines have historically remained a cornerstone of treatment for early HER2-positive breast cancer. However, the emergence of dual HER2 blockade, antibody-drug conjugates, and response-adapted treatment strategies has changed the clinical context in which anthracycline use is considered. Whether anthracyclines continue to provide sufficient oncologic benefit to justify their additional cardiovascular toxicity remains uncertain. Objectives: This study aims to evaluate the contemporary role of anthracyclines in early HER2-positive breast cancer by synthesizing direct comparative evidence and contextual evidence from prospective de-escalation studies. Design: It involves a systematic review with narrative synthesis. Data Sources and Methods: PubMed, the Web of Science, and CENTRAL were searched for prospective studies published from January 2000 to 31 May 2026. A meta-analysis was initially planned, but only three clinically heterogeneous trials directly compared anthracycline-containing and anthracycline-free regimens. Direct comparative and contextual de-escalation evidence was therefore synthesized separately using a narrative approach. Results: Twelve studies were included. BCIRG-006, TRAIN-2, and TRYPHAENA provided direct comparative evidence; nine additional prospective trials provided contextual evidence on anthracycline-sparing or treatment de-escalation strategies. Direct comparisons generally indicated greater cardiac toxicity with anthracycline-containing regimens, although severe events were uncommon and cardiotoxicity definitions varied. Contextual studies supported the feasibility of contemporary anthracycline-sparing approaches in selected populations but did not provide direct estimates of the effect of anthracycline exposure. Conclusions: Anthracycline-containing regimens appear to confer greater cardiac risk than anthracycline-free regimens, but comparative evidence remains limited. The available evidence supports selective rather than routine anthracycline use, with treatment decisions guided by the anticipated oncologic benefit, cardiovascular risk, tumor characteristics, treatment setting, and patient preferences. Registration: PROSPERO CRD420261296599; registered on 29 January 2026.