Breast cancers with HER2/CEP17 ratio ≥ 2.0 and an average HER2 copy number <4.0 per cell: frequency, Immunohistochemical correlation, and Clinicopathologic features.

The 2013 American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP) guidelines classified breast cancers with a florescence in situ hybridization (FISH) dual probe HER2/CEP17 ratio ≥ 2 as "amplified", inclusive of cases with a HER2 copy number< 4. The 2018 ASCO/CAP update assigns HER2/neu status for the latter group in a fashion that is highly dependent on the associated immunohistochemical findings. Herein, the authors define the frequency, immunohistochemical correlates, and other clinicopathologic features of breast cancers with HER2/CEP17 ratio ≥ 2 and HER2/neu copy number< 4 (group-A), based on an analysis of an institutional cohort assessed for HER2/neu status by both FISH and immunohistochemistry and scored using 2013 ASCO/CAP criteria. Group-A cases were compared to a group-B of HER2/neu-amplified breast cancers with a HER2/neu copy number ≥ 4 regarding a variety of clinicopathologic features. 169 (14%) of 1201 cases were HER2/neu-amplified, 18 (10.7%) in group-A and 151 (89.3%) in group-B. By immunohistochemistry, 61.1% of group-A cases were HER2/neu-negative, 7 (38.9%) were equivocal and none were positive. In contrast, 66.9% of group-B cases were HER2-positive (3+). We could not demonstrate statistically significant differences between the 2 groups regarding standard clinicopathologic variables. In summary, our group-A cases account for 1.5% of breast cancers, and 10.7% of all HER2/neu-amplified cancers classified as such based on 2013 ASCO/CAP criteria. They are predominantly HER2/neu-negative by immunohistochemistry, which suggests that they are biologically different from classically HER2/neu-amplified cases, and which validates the 2018 ASCO/CAP guideline against automatically classifying such cases as HER2/neu-amplified.