An Evaluation of Clinicopathological Correlation and Outcome of Human Epidermal Growth Factor Receptor 2 Subgroups Reclassified According to the Latest ASCO/CAP Guideline

The latest American Society of Clinical Oncology/College of American Pathologists update re-categorized the diagnosis of uncommon HER2 in situ hybridization categories. Despite that, there is no robust clinical evidence to support this categorization. In this study, we sought to compare the clinicopathological characteristics and outcomes of these groups with typical amplified and non-amplified cases to gain further insights into their biology and the relevance of this revised classification. Background: The latest American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline has updated the interpretation of uncommon human epidermal growth factor receptor 2 (HER2) in situ hybridization (ISH) patterns (groups 2-4) with concomitant HER2 immunohistochemistry, leading to changes in the diagnosis of these subgroups. We sought to assess the clinicopathological features and outcomes in these subgroups in detail with our local cohort. Patients and Methods: Clinicopathologic features of groups 2 to 4 were compared to the typical amplified group (group 1: HER2/CEP17 >= 2, HER2 >= 4) and non-amplified group (group 5: HER2/CEP17 >= 2, HER2 < 4). Results: Group 2 (HER2/CEP17 >= 2, HER2 < 4) cases showed lower Ki67 expression and grade (P <=.002) than group 1 but no differences compared with group 5. Group 4 (HER2/CEP17 < 2, HER2 = 4-6) cases were associated with less necrosis, more estrogen receptor positivity, lower grade, more nodal metastases, and more special histotypes (P <=.037) than group 1, but higher grade and more nodal metastases (P <=.021) than group 5. Except for presenting as a larger tumor and of special histotypes, group 3 (HER2/CEP17 < 2, HER2 >= 6) cases showed no other significant differences from group 1, but were of higher grade and Ki67 level than groups 2, 4, and 5. Group 4, similar to group 5, showed worse survival than group 1 (disease-free survival: log-rank = 5.547, P = .019; overall survival: log-rank = 4.678, P =.031). The rate of relapse was similar in group 4 with and without anti-HER2 therapy, albeit with limited cases. Conclusion: Our findings indicate more similarities among groups 2, 4, and 5 than between groups 1 and 3, supporting the HER2 categorization in the latest guideline. Additional studies may be warranted to assess the outcomes of these patients with different management approaches. (C) 2021 Elsevier Inc. All rights reserved.