Mattia Rediti, MD, Institut Jules Bordet, Anderlecht, Belgium, discusses the identification of biologically-driven HER2-positive breast cancer subgroups associated with prognosis after adjuvant trastuzumab in the Phase III ALTTO (NCT00490139) trial. A supervised top-down approach identified 4 biologically-driven clusters in HER2-positive breast cancer which can be integrated with PAM50. Overall, these findings support the evaluation of de-escalation approaches in luminal and immune-enriched subgroups. This interview took place at the European Society for Medical Oncology (ESMO) 2022 Congress in Paris, France.