HER2DX in early-stage HER2-positive breast cancer: a review of clinical utility.

Therapies targeting human epidermal growth factor receptor 2 (HER2)-positive breast cancer have substantially improved outcomes. Nevertheless, marked biological and clinical heterogeneity continue to drive variability in prognosis and treatment sensitivity in early-stage disease. While contemporary guidelines provide broad management frameworks, uncertainty remains when tailoring treatment intensity to individual patients. HER2DX is a genomic-clinical test developed to support individualized decision-making in stage I-III HER2-positive breast cancer by integrating tumor biology with key clinical variables, including tumor size and nodal status. The assay generates three clinically relevant outputs: a prognostic relapse risk score, a pathological complete response (pCR) score, and an ERBB2 messenger RNA expression score. Since its original development, a substantial body of new evidence has emerged. Large international individual-patient-level meta-analyses have demonstrated independent associations of the HER2DX risk score with survival outcomes and of the pCR score with pathologically documented response beyond standard clinicopathological factors. Translational studies further show that HER2DX captures complementary biological features, such as hormone receptor signaling, proliferation, HER2 pathway activation, and immune infiltration and organization, that are not fully reflected by conventional pathology. Prospective evaluations, including prespecified analyses from the ECOG-ACRIN EA1181 CompassHER2 pCR trial and a multicenter real-world decision-impact study in Spain, provide additional evidence regarding the potential clinical application of HER2DX in both neoadjuvant and adjuvant settings. This updated review synthesizes current evidence and discusses practical, scenario-based considerations for integrating HER2DX into routine clinical practice to help optimize treatment intensity in early-stage HER2-positive breast cancer.