Clinicopathologic Characteristics and Follow-Up Outcomes of Invasive Breast Carcinoma With Different Positive HER2 Fluorescence In Situ Hybridization Patterns: Experience From a Single Academic Institution

Abstract

Human epidermal growth factor receptor 2 (HER2)-positive breast carcinoma (BC) encompasses a spectrum of molecular subtypes, characterized by varying HER2/CEP17 ratios and HER2 copy numbers, influencing responses to anti-HER2 therapy. This study stratified HER2 fluorescence in situ hybridization (FISH)-positive patients into 3 distinct groups—group 1 with high copy number (G1-HC: ratio ≥2, copy number ≥6), group 1 with low copy number (G1-LC: ratio ≥2, copy number ≥4 and <6), and group 3 (G3: ratio <2.0, copy number ≥6.0)—and evaluated their clinicopathologic features, response to anti-HER2 therapy, and outcomes. In a cohort of 2702 continuous primary BCs, G1-HC BCs accounted for 304 cases (11.3%), G1-LC for 37 cases (1.4%), and G3 for 75 cases (2.8%). G1-HC BCs were associated with younger age, higher tumor grade, and estrogen receptor negativity compared with G1-LC BCs. Furthermore, G1-HC BCs exhibited increased progesterone receptor negativity and HER2 immunohistochemistry 3+ compared with G1-LC and G3 BCs. Analysis of the subgroup of HER2 immunohistochemistry 2+-only cases (n = 166) showed similar results. Notably, G1-HC patients exhibited significantly enhanced responses to anti-HER2 neoadjuvant chemotherapy compared with G1-LC and G3 patients. Conversely, G1-LC patients displayed a lower likelihood of disease-free status compared with G1-HC and G3 patients, albeit with no significant differences in overall survival, distant metastasis, or local recurrence among the groups. These findings offer valuable clinicopathologic insights into different HER2 FISH positive subgroups, potentially informing future criteria for interpreting HER2 FISH results.