PurposeNeoadjuvant systemic therapy with dual HER2-blockade, trastuzumab and pertuzumab, combined with chemotherapy has become a standard approach in patients with HER2-positive (HER2+) breast cancer (BC). However, the variability in treatment outcomes, such as pathological complete response (pCR) or relapse rates, underscores the need to identify predictive factors to optimize therapeutic strategies. This study aims to explore the relationship between clinicopathological factors and both pCR and disease-free survival (DFS) in an international cohort of patients with HER2+ BC, contributing to defining personalized treatment strategies.MethodsAn international, multicenter, retrospective cohort study was conducted, including 517 patients with HER2+ BC who received neoadjuvant therapy comprising trastuzumab, pertuzumab, and chemotherapy. Data were collected between January 2016 and December 2023. The relationship between clinicopathological factors and treatment outcomes was analyzed using univariate tests, logistic regression for pCR, and Cox proportional hazards regression for DFS. Kaplan-Meier survival curves with log-rank tests and hazard ratios were used to compare DFS across subgroups.ResultsMultivariable analysis revealed that hormonal receptor (HR) expression and nodal status significantly predicted the achievement of pCR in this cohort. Factors such as age, HR status, tumor grade, Ki-67 index, nodal status, and pathological response were associated with relapse risk.ConclusionOur real-world data demonstrates that a comprehensive approach considering pCR, age, HR status, and nodal involvement is essential for personalized treatment strategies. These factors should be taken into account when deciding whether to escalate or de-escalate treatment, contributing to improved HER2+ BC patient outcomes.