ASO Visual Abstract: Do HER2-Low Tumors Have a Distinct Clinicopathologic Phenotype?

Background Breast cancer subtypes, distinguished by hormone receptor (HR) and HER2 status, have different clinicopathologic features. With recognition of the clinical relevance of HER2-low, there is debate as to whether this is a distinct subtype. Our study aimed to determine whether HER2-low breast cancers have specific clinicopathologic features that differ from those of HER2-negative and HER2-positive cancers. Patients and Methods A total of 11,072 patients undergoing upfront surgery from 1998 to 2010 were identified from a single-institution prospectively maintained database. HER2 status was classified by immunohistochemistry (IHC)/fluorescence in situ hybridization (FISH) as HER2 negative (41.2%), HER2 low (45%; IHC 1+ or 2+ with negative FISH), and HER2 positive (13.7%), and stratified by HR status. Univariate (UVA) and multivariable multinomial logistic regression analysis (MVA) were performed to determine associations among variables and subtypes. Results Compared with HER2-negative tumors, HER2 low was associated with lymphovascular invasion [odds ratio (OR) 1.2, 95% confidence interval (CI) 1.06–1.36; p = 0.003], multifocality (OR 1.26, 95% CI 1.12–1.42; p < 0.001), nodal micrometastasis (OR 1.15, 95% CI 1.02–1.31; p = 0.024), and lower rates of ≥ 3 positive nodes (OR 0.77, 95% CI 0.66–0.90, p = 0.001). When stratified by HR expression, in both HR-positive and HR-negative tumors, age and multifocality were associated with HER2 low on UVA. On MVA, no variables were independently associated with both HR-negative and HR-positive/HER2-low tumors compared with HER2-negative tumors. In contrast, HER2-positive tumors, regardless of HR status, were associated with multifocality and an extensive intraductal component. Conclusion Clinicopathologic features of HER2-low tumors appear to be primarily related to HR status. Our findings do not support the characterization of HER2 low as a separate subtype.