13P HER2DX ERBB2 mRNA score in first-line metastatic HER2-positive (HER2+) breast cancer (BC): Implications for treatment stratification

In first-line metastatic HER2+ BC, the standard regimen of taxane-trastuzumab-pertuzumab (THP) is increasingly challenged by new therapies like antibody-drug conjugates. This shift accentuates the necessity for precise biomarkers to guide treatment decisions. Our study focuses on using HER2DX ERBB2 mRNA score to predict treatment responses and long-term prognosis, aiming to identify patients who would benefit more from escalation or de-escalation therapies. We evaluated 85 patients with advanced HER2+ BC from Hospital Clinic of Barcelona, IOB-QuironSalud and Hospital Universitario 12 de Octubre, treated with the standard THP regimen between 2010 and 2024. HER2DX analysis was performed on formalin-fixed paraffin-embedded tumor samples. We correlated HER2DX ERBB2 mRNA score as a continuous variable and as pre-defined categories (low, medium, high) with progression-free survival (PFS) and overall survival (OS) using Cox regression models. The distribution of low, medium, and high HER2DX ERBB2 scores in our cohort was 16.5%, 23.5%, and 60.0%, respectively. With a median follow-up of 44.2 months (0.72-162.5), our cohort consisted of hormone receptor-positive cases (64.7%), patients with visceral disease (70.6%), brain metastasis (14.1%), and de novo metastatic disease (50.6%). Median PFS and OS to THP regimen were 27.1 and 62.7 months, respectively. HER2DX ERBB2 score was significantly associated with both PFS and OS, particularly in the ERRB2-high group, which showed significantly better PFS (28.6 vs. 12.5 months; hazard ratio=0.45, 0.26-0.78, p=0.005) and OS (not reached vs. 29.8 months; hazard ratio=0.23, 0.12-0.44, p<0.001). All patients without progression over 5 years and no death over 8 years (n=4) had ERBB2-high disease. These associations persisted in multivariable analyses. The HER2DX ERBB2 mRNA score shows a significant association with improved survival in metastatic HER2+ BC patients treated initially with THP. Additional validation of the HER2DX ERBB2 score and integration of prognostic clinical factors might refine and optimize treatment strategies in this clinical setting.