Factors associated with neoadjuvant therapy insensitivity and its prognostic impact in HER2-positive breast cancer.

Objective: A subset of patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer shows insensitivity to neoadjuvant therapy (NAT), often evidenced by imaging results indicating stable disease (SD) or progressive disease (PD), which may reflect intrinsic resistance to treatment. We aimed to investigate the factors associated with NAT insensitivity and its prognostic value in HER2+ breast cancer. Methods: This study included consecutive patients with HER2+ breast cancer who received NAT consisting of chemotherapy combined with anti-HER2 monoclonal antibodies. NAT insensitivity was defined as SD or PD on the basis of treatment response evaluations. Statistical analyses were conducted on the collected clinical data, and HER2 heterogeneity was subsequently assessed. Results: A total of 541 patients were included in the study, among whom 63 (11.6%) were categorized as NAT-insensitive group and 478 (88.4%) as NAT-sensitive group. Hormone receptor (HR) status (P=0.033), HER2 status (P=0.036) and anti-HER2 therapy (P=0.007) were associated with NAT sensitivity. NAT-insensitive group had a significantly shorter event-free survival (EFS) (3-year: 69.4% vs. 94.3%; P<0.001) and remained an independent prognostic factor according to Cox models [hazard ratio (HR)=8.637; 95% confidence interval (95% CI), 3.091-24.136; P<0.001]. Exploratory analysis revealed a greater proportion of HER2 heterogeneity in the NAT-insensitive group (19.4% vs. 4.3%; P=0.035). Conclusions: HR positivity, HER2 2+/fluorescence in situ hybridization (FISH)+ status, and trastuzumab monotherapy are associated with NAT insensitivity, and NAT insensitivity independently indicates poor EFS. This study also highlights the need for prospective studies to clarify the role of HER2 heterogeneity and other mechanisms involved in predicting the response to NAT.