Real-World Outcomes of Neoadjuvant Dual Blockade in HER2-Positive Breast Cancer: The Role of Tumor Biology and pCR

<b>Background/Objectives</b>: Neoadjuvant dual HER2 blockade is standard for HER2-positive breast cancer, yet response rates vary based on tumor biology. This multicenter study aimed to identify clinicopathological predictors of pathological complete response (pCR), focusing on quantitative hormone receptor (HR) expression and HER2 staining intensity, and to evaluate their impact on survival. <b>Methods</b>: This multicenter retrospective study included 290 female patients diagnosed with HER2-positive early or locally advanced breast cancer treated with neoadjuvant trastuzumab and pertuzumab-based regimens (anthracycline-based [AC-THP] or non-anthracycline [TCHP]) across six centers. HR expression was stratified into low (<50%) and high (≥50%) categories. Multivariable regression analyses identified predictors of pCR, Disease-Free Survival (DFS), and Overall Survival (OS). <b>Results</b>: The pCR rate was 51.4%. Multivariate analysis identified HR negativity (OR = 2.80; <i>p</i> < 0.001) and strong HER2 overexpression (IHC Score 3) (OR = 2.20; <i>p</i> = 0.037) as primary predictors. Uniquely, patients with low HR expression (<50%) achieved significantly higher pCR rates (65.9%) than strongly positive cases (36.6%; <i>p</i> = 0.001), biologically mimicking hormone-negative disease. The non-anthracycline TCHP regimen showed a strong trend toward superior efficacy (OR = 2.22; <i>p</i> = 0.054). pCR was the sole independent predictor of OS (HR = 0.134; <i>p</i> = 0.009). Crucially, adjusting for pCR unmasked hormone-negative status as a significant risk factor for recurrence (HR = 2.49; <i>p</i> = 0.028), highlighting its dual nature: high chemosensitivity but inherent biological aggression. <b>Conclusions</b>: "Strong" HER2 positivity and "weak" HR expression (<50%) are the primary determinants of pCR. pCR remains the strongest surrogate for survival, neutralizing initial risk factors. These findings support using quantitative biomarker thresholds for personalization and reinforce the efficacy of non-anthracycline regimens.