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In advanced HER2-positive breast cancer, the standard taxane-trastuzumab-pertuzumab (THP) regimen faces competition from new therapies, emphasizing the need for biomarkers to guide treatment. This study evaluates the HER2DX ERBB2 mRNA score as a prognostic predictor, aiming to tailor treatment strategies. We retrospectively analyzed 94 patients treated with the THP regimen between 2010 and 2024. The HER2DX ERBB2 mRNA score was categorized as low ( n  = 14), medium ( n  = 20), or high ( n  = 60), and its correlation with progression-free survival (PFS) and overall survival (OS) was assessed using Cox regression models. The median follow-up was 31.5 months. Patients with ERBB2 -high scores had significantly better median PFS (33.9 vs. 10.6 months, hazard ratio [HR] = 0.40, 95% CI: 0.24–0.69, p  < 0.001) and OS (not reached vs. 30.8 months, HR = 0.26, 95% CI: 0.13–0.49, p  < 0.001) compared to ERBB2 -low patients. Based on these findings, further validation of this biomarker in tumor samples from the CLEOPATRA phase III trial is ongoing, which could help optimize treatment strategies in this population.