Abstract 2524: Molecular and clinicopathologic landscape of HER2 positive breast cancer: A single institution study

Abstract Background: Human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase that is encoded by the ERBB2 gene, located on chromosome 17. Expression levels of HER2 are a key pathogenic and treatment-associated factor in breast carcinomas, with HER2 expression reported as per the ASCO/CAP scoring guidelines. Outside the intense focus on the HER2 overexpression few studies currently exist that look at the comprehensive molecular profile of these aggressive tumors. Design: Our institutional pathology database was searched for patients with breast carcinoma diagnosed between 2009 and 2013 and with HER2 scored as 3+ based on immunohistochemistry, or HER2 2+ with confirmatory positive FISH results. Comprehensive next-generation sequencing (NGS) was performed using the Illumina TruSight Oncology 523 gene panel, and clinicopathologic data were gathered from the institutional electronic health record system. A CoMutation plot was made using the CoMut python library. Results: The mean age of the patients at time of diagnosis was 56. 1±12. 7 years. The tumors were overwhelmingly high-grade, with 26/30 being grade 3 and the remaining 4/30 being grade 2 and a mean size of 2. 6 cm. All were histologically invasive ductal carcinoma, and 26/30 were scored as HER2 3+ on IHC while 4/30 were HER2 2+ with positive FISH. ER was positive in 30% of cases (9/30), PR was positive in 23. 3% (7/30), p53 was positive by IHC in 53. 3% (16/30), and the mean Ki-67 proliferative index was 47. 1%. 20 of the 30 (66%) cases meeting the inclusion criteria had pathogenic mutations detected by NGS testing. Several distinct molecular subgroups were seen on the CoMutation plot (figure 1). The mean tumor mutational burden (TMB) was 14. 1 mutations per megabase. A significant subset of the tumors 70% (14/20) showed TP53 mutations, and 30% (6/20) show PIK3CA mutations. Of interest, only 1/14 tumors showed a co-occurring homologous recombination repair gene mutation and one tumor (1/20) showed mutations in 2 homologous recombination pathway genes (FANCA and BRCA1) as well as numerous additional mutations (tumor mutational burden of 65. 3 mutations per megabase). Conclusion: Overall the mean TMB was 14. 1 mutations/megabase in this HER2-positive breast cancer study set. Over 2/3 of our HER2-positive breast cancer cases also had TP53 mutations. In addition, 1/3 had PIK3CA mutations, suggesting that a subset of HER2-positive carcinomas also harbor other potentially actionable mutations which may increase the effectiveness of our existing interventions. Additional studies are needed to further subclassify genetically distinct subsets of HER2-positive breast cancers and to further understand clinical, pathologic and treatment-related differences in this aggressive breast cancer subset. Citation Format: Gokce Deniz Ardor, Zachary M. Coty-Fattal, Luis Z. Blanco, Kalliopi Siziopikou. Molecular and clinicopathologic landscape of HER2 positive breast cancer: A single institution study abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2524.