HER2/CEP17 ratio predicts residual cancer burden after neoadjuvant dual HER2 blockade: real-world data in patients with primary HER2-amplified breast cancer

Novel human epidermal growth factor receptor 2 (HER2)-directed therapies have significantly improved outcomes for patients with HER2-positive early-stage breast cancer. Our study assessed the impact of HER2/chromosome enumeration probe 17 (CEP17) ratio on residual cancer burden (RCB) and long-term prognosis following neoadjuvant chemotherapy with dual HER2-targeted therapy using trastuzumab and pertuzumab to identify candidates for chemotherapy de-escalation. Our study included 169 patients with primary invasive HER2-positive breast cancer who received neoadjuvant chemotherapy with trastuzumab and pertuzumab at the Medical University of Vienna from 2014 to 2020. HER2 (ERBB2) gene copy number and HER2/CEP17 ratio were assessed by in situ hybridization. RCB and pathologic complete remission (pCR) served as primary and secondary endpoints, respectively. Univariate and multivariate logistic regression models were applied to analyze associations between outcomes and predictor variables, focusing on the predictive role of HER2/CEP17 ratio, with cutoff values estimated. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. HER2/CEP17 ratio was significantly associated with response to dual-targeted neoadjuvant chemotherapy in primary HER2-positive breast cancer. Optimal HER2/CEP17 cutoff for predicting RCB 0/I was identified at 5.19. HER2/CEP17 ratio was also significantly associated with PFS as a continuous predictor. Multivariate analysis showed that hormone receptor status and the presence of an in situ tumor component significantly influenced therapy response. HER2/CEP17 ratio predicts therapy response and therefore might aid patient stratification for therapy de-escalation with respect to dual neoadjuvant HER2 blockade. Further investigations are warranted to confirm its relevance with other HER2-targeted agents.