Abstract PS4-01-20: Clinico-pathological and genomic features of HER2-low early Breast Cancer (eBC). Results of retrospective analysis of seven adjuvant trials by the Hellenic Cooperative Oncology Group (HeCOG)

Abstract Background: HER2-low breast cancers are a mixture of luminal and triple negative tumors. Precise molecular characterization can help refine treatment strategies with novel antibody-drug conjugates and improve outcomes in this patient subgroup. Methods: We used central ER/PgR (HR) and HER2/ERBB2 IHC/FISH assessment to define HER2-low (IHC 1+ or 2+/FISH non-amplified), HER2-zero (IHC 0) and Luminal A/ Luminal B/ TNBC subtypes across 7 prospective adjuvant studies in which eBC patients were treated with dose dense sequential chemotherapy. Retrospective analysis of clinico-pathological data and IHC markers from tissue microarray cores was performed on N=2, 751 cases, whereas DNA next generation sequencing (NGS) data were available in a subset of N=1, 120 tumors. Heterogeneity was investigated by comparing HER2-low concordant (HER2-lowc) cases, when all cores were scored consistently as HER2-low (0) and HER2-low discordant (HER2-lowd) cases, when at least one core was scored “0”. Results: First, HER2-low tumors were more likely to be HR + (p0. 001). Second, within HR + disease only, the proportion of Luminal B was higher in HER2-low (51%) than HER2-zero (41. 6%), whereas Luminal A showed the opposite pattern (p 0. 001) ; PIK3CA mutations on the other hand were more common in HER2-zero (33. 6% vs. 24. 7%, p=0. 0036). Third, a statistically significant progressive increase in ERBB2 average copies was observed from HER2-zero to HER2-lowd and HER2-lowc irrespective of HR status (p0. 001). Finally, HER2 low was not associated with survival in either HR + or HR - disease. Conclusion: Our data suggests that HR + HER2-low and HER2-zero eBC differ with respect to the status of the estrogen receptor pathway. When accounting for inter-core variability, differences in HER2 IHC levels correlate with the underlying ERBB2 copy number; however, standard HER2 IHC scoring thresholds did not influence prognosis in this cohort. Citation Format: S. Lakis, E. Tsolaki, N. Korfiatis, A. Goussia, H. P. Kourea, A. Batistatou, M. Bobos, K. Papadopoulou, A. Charchanti, M. Bai, O. Tzaida, K. Petraki, P. Arapantoni, T. Koletsa, D. Pectasides, A. Koutras, D. Kalapanida, F. Dimitrakopoulos, E. Aravantinou-Fatorou, N. Spathas, A. Psyrri, H. Gogas, F. Zagouri, G. Fountzilas. Clinico-pathological and genomic features of HER2-low early Breast Cancer (eBC). Results of retrospective analysis of seven adjuvant trials by the Hellenic Cooperative Oncology Group (HeCOG) 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 PS4-01-20.