Introduction: 20-25% of breast cancers overexpress the human epidermal growth factor receptor-2 (HER2) and have an aggressive clinical behavior; 50-70% of them also express both estrogen (ER) and progesterone (PR) receptors. Multiple regulatory and signaling pathways regulate and affect breast cancer response to various therapies. Breast cancer that overexpress HER2 and both ER and PR receptors, which represents nearly 10-15% of all breast cancers, are recently recognized as a subtype (triple-positive: TPBC) with distinctive behavior and response to treatment. However, the idea of separating this type of breast cancer according to the level of ER and PR expression is still debated. In this study, we retrospectively investigate the clinical features and treatment outcomes of early-stage TPBC patients treated at a tertiary care center, and how survival patterns are affected by levels of HR expression. Methods: Adult patients with pathologically confirmed diagnosis of early-stage (stage I-III) TPBC were included. ER or PR were considered positive if staining of tumor cell nuclei was ≥ 1%. Due to drug approval and availability, 50 (16.0%) patients (Cohort A) had not received trastuzumab throughout their treatment and were treated with chemotherapy alone (anthracycline and taxane-based regimens). The rest of the patients received standard adjuvant chemotherapy and trastuzumab and were divided based on level of HR expression into two cohorts; patients whose immunohistochemical staining displayed ≥ 50% in both ER and PR scores were classified as Cohort B and constituted 41.7% of the study population (n=130) while patients who displayed < 50% ER and/or PR staining scores were designated to Cohort C and comprised 42.3% of the population (n=132).The primary endpoint was DFS, defined as the time from the date of diagnosis to the date of the first occurrence of local recurrence in the breast or axilla, the development of ipsilateral or contralateral breast cancer, distant metastasis, or death by any cause without evidence of disease. Moreover, overall survival (OS) of all the patients was defined as the time from the date of diagnosis until the death from any cause. Results: Between 2006 and 2016, a total of 312 patients were included. Median age (range) was 47 (20-83) years and majority were premenopausal (n=190, 61.3%). Moreover, 170 (54.7%) patients had grade-III tumors at diagnosis while 223 (71.5%) presented with positive axillary lymph nodes; significantly higher in Cohort C (79.5%) compared to 66.9% in Cohort B and 62.0% in Cohort A, p=0.02. The median follow-up time was 47 months. Among the whole group, distant metastasis, with or without local recurrence, was documented in 47 patients (15.1%) while 12 (3.8%) others had local recurrence only and 5 (1.6%) died while disease-free. The 5-year OS and DFS of the population was estimated to be 86.3%, and 75.4%, respectively. Patients in Cohort A had the highest percentage of events (28.0%, n=14), followed by Cohorts B (23.1%, n=30) then C (15.2%, n=20). The estimated 5-year DFS rate of all the patients was also calculated to be worst (56.2%) for patients of Cohort A, who did not receive anti-HER2 therapy. On the other hand, 5-year DFS for the two cohorts who received trastuzumab were 75.4% and 80.8% for cohort B and cohort C, respectively. The DFS curves continued to separate after 5-years with an estimated DFS rate at 7-years of 67.1% for patients in Cohort B, who had higher ER and PR scores, and 78.0% for patients in cohort C with lower ER/PR scores. The log-rank test showed a significant difference in the DFS rates between the three cohorts (p < 0.001). Conclusions: HER2+ tumors are not homogeneous; stronger ER/PR co-expression may weaken the beneficial effect of anti-HER2 therapy. Such findings may have potential implication on modifying anti-HER2 treatment based on strength of HR expression. Citation Format: Hikmat Abdel-Razeq, Sarah Edaily, Sereen Iweir, Mourad Salam, Yacob Saleh, Maher Sughayer, Osama Salama, Rawan Mustafa, Yosra Almasri, Rayan Bater, Ayat Taqash. Effect of level of hormone-receptor expression on treatment outcomes of “triple-positive” early-stage breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-30.