Abstract PS3-04-03: Inter-chromosomal focal amplifications frequently co-carry multiple oncogenes in aggressive breast cancer, accumulating oncogenic elements during breast cancer progression

Abstract BACKGROUND: Focal copy number amplification is known to play a crucial role in oncogenesis of breast cancer (BC). Especially, the amplification of interchromosomal oncogenic translocation such as t(8;11), t(8,17) and t(11;17) is known to be the main feature of BCs. However, there is a lack of clinical evidence that such interchromosomal focal amplifications promotes tumor progression. Here, we investigated the prevalence of interchromosomal focal amplifications in primary and metastatic BCs collected at a single hospital. METHODS: 65 primary tumors were collected from BC surgical specimens obtained after curative surgery following NAC (neoadjuvant chemotherapy), and 10 metastatic BC tumors from post-adjuvant biopsies. Whole genome sequencing (mean coverage 62X, range 51∼74X for tumors; mean coverage 33X, range 30∼40X for patient-matching normal bloods) was generated and analyzed to profile focal amplifications and genomic characteristics. BCs were categorized into three prognostic groups: primary with dismal prognosis (TP-D; total N = 34; HER2+ N = 12), primary with good prognosis (TP-ND, total N = 31; HER2+ N = 6), and metastatic (TM; total N = 10; HER2+ N = 6). Genomic characteristics including focal amplifications were compared between these three prognostic groups. Results: Interchromosomal focal amplifications co-carrying ERBB2/CDK12/C17orf37 were highly prevalent in HER2+ TM (5/6: 83.3%) and TP-D (10/12: 83.3%) patients compared to HER2+ TP-ND (1/6: 16.7%) (P = 0.040 in TM vs TP-ND; P = 0.013 in TP-D vs TP-ND; one-sided Fisher’s exact tests), indicating that those amplifications may be early events during aggressive tumor progression in HER2+ BCs. Interestingly, we also found that interchromosomal oncogenic focal amplifications cargo more oncogenes as the patients carrying those amplifications have worse prognosis (TP-ND: mean 6.5 oncogenes; TP-D: mean 15.3 oncogenes; TM: mean 21.4 oncogenes present in interchromosomal oncogenic focal amplification), which was statistically significant (P = 0.0043 in TM vs. TP-ND; P = 0.034 in TP-D vs TP-ND; wilcox ranksum test). CONCLUSION: The high prevalence of ERBB2/CDK12/C17orf37 co-amplified interchromosomal focal amplifications in HER2+ poor prognosis groups (TM and TP-D) indicate a role for these amplicons in tumor progression. Additionally, the correlation between an increasing number of oncogenes in interchromosomal focal amplifications and poor prognosis suggests that these amplifications may evolve by accumulating oncogenic elements during tumor progression, thereby promoting tumor aggressiveness. Citation Format: J. Kim1, C. HyeongJin2, H. Lee3, E. Cho3, J. Lee4, S. Kim4, Y. Park1, H. Kim2. Inter-chromosomal focal amplifications frequently co-carry multiple oncogenes in aggressive breast cancer, accumulating oncogenic elements during breast cancer progression [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-04-03.