Abstract PS3-09-16: Prognostic impact of human epidermal growth factor receptor 2 (HER2) expression level in hormone receptor-positive/HER2-negative, non-metastatic premenopausal breast cancer patients: A retrospective cohort study

Abstract Aims: With the advent of new antibody-drug conjugates, human epidermal growth factor receptor 2 (HER2) low expression is a new therapeutic category for breast cancer. However, the prognostic differences between categories corresponding to 1+ on immunohistochemistry (IHC) and 2+ on IHC with no amplification by ISH have not been sufficiently investigated. This study aimed to evaluate the prognostic impact of different HER2 expression levels in patients with hormone receptor-positive/HER2-negative, premenopausal breast cancer. Methods: Using data from our institutional database from 2008 to 2017, we enrolled hormone receptor-positive/HER2-negative, non-metastatic premenopausal breast cancer patients with pathological N0-1 disease treated with curative surgery. Hormone receptor-positive was defined as either estrogen receptor (ER)- or progesterone receptor (PR)-positive. ER and PR were considered positive if the IHC staining was positive in more than 1% of tumor cells. A HER2-negative result corresponded to a score of 0, 1+ on IHC, or 2+ on IHC with no amplification by ISH. We divided enrolled patients into three groups according to their HER2 expression levels: patients with HER2-zero (Group 1), HER2-1+ (Group 2), and HER2-2+ with no amplification by ISH (Group 3). Distant relapse-free survival (DRFS) among the 3 groups were estimated using the Kaplan-Meier method, and survival estimates were compared using the log-rank test. Cox proportional-hazards model with hazard ratio (HR) and 95% confidence interval (CI) was used to evaluate the independent prognostic effects of each variable on DRFS. Results: The median age was 45 years. Among 1011 patients enrolled, 269 patients (26.6%) had pN1 disease, 318 (31.5%) had pT2 disease, 193 (19.1%) had histological grade 3 disease. Group 1, 2, and 3 had 415 (41.1%), 465 (46.0%), and 129 (12.8%) patients, respectively. The median follow-up time after surgery was 8.2 years. During the follow-up period, 23 patients died from breast cancer, 7 patients died from causes other than breast cancer, and 58 patients had distant metastases. There were no differences in adjuvant treatment among the 3 groups, with mastectomy, chemotherapy, endocrine therapy (ET), and radiotherapy given to approximately 40%, 30%, 90%, and 60%, respectively. The duration of ET more than 5 years was given to approximately 50%. Patients in Group 3 had significantly worse DRFS than patients with Group 1 and 2 (8y-DRFS, 89.8% vs. 95.6%, P=0.0042, 89.8% vs. 94.9%, P=0.0048, respectively).Multivariable analysis revealed that the significant risk factors associated with worse DRFS were pT2 disease (HR 2.67; 95% CI 1.46-4.88; P=0.001), pN1 disease (HR 3.48; 95% CI 1.76-6.86; P<0.001), and HER2-2+ with no amplification by ISH (HR 3.26; 95% CI 1.61-6.61; P=0.001). HER2-1+ was not associated with worse DRFS (HR 1.18; 95% CI 0.64-2.16; P=0.587). The duration of ET more than 5 years was significantly associated with favorable DRFS (HR 0.11; 95% CI 0.06-0.23; P<0.001). Conclusions: The results from this single institutional database study suggested that HER2-2+ with no amplification by ISH may be one of the poor prognostic factors in hormone receptor-positive/HER2-negative, non-metastatic premenopausal breast cancer patients with pathological N0- 1 disease. Patients with HER2-2+ with no amplification by ISH may require a different treatment strategy than patients with HER2-zero and HER2-1+. Further evaluation in a larger cohort is needed. Citation Format: T. Murata, T. Shimoi, A. Saito, M. Onishi, M. Yoshida, N. Ogi, M. Chen, A. Ogawa, A. Nakashoji, H. Maeda, C. Watase, K. Sudo, K. Yonemori, S. Takayama. Prognostic impact of human epidermal growth factor receptor 2 (HER2) expression level in hormone receptor-positive/HER2-negative, non-metastatic premenopausal breast cancer patients: A retrospective cohort study [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 PS3-09-16.