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)

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-low_c) cases, when all cores were scored consistently as HER2-low (>0) and HER2-low discordant (HER2-low_d) cases, when at least one core was scored “0”. Results: First, HER2-low tumors were more likely to be HR + (p<0.001). 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-low_d and HER2-low_c irrespective of HR status (p<0.001). 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.