Abstract Background: Oral contraceptives (OC) and hormone replacement therapy (HRT) are well-established risk factors for ER positive breast cancer. Infertility is associated with an increased breast cancer risk and there is conflicting data on the influence of fertility treatments on breast cancer risk. The impact of exogenous estrogen exposure on breast cancer characteristics is not well described. Methods: A single center retrospective cohort study comprising all women with ER positive, human epidermal growth factor receptor 2 (HER2) negative, EBC whose tumors were sent to OncotypeDX analysis and were treated in our institute between 2005 and 2012. Data on exogenous estrogen exposure were collected including: OC and HRT use and prior fertility treatments. The impact of these exposures was assessed on pre-specified histopathological features including: tumor size, nodal status, ER and progesterone receptor (PR) staining, grade, Oncotype recurrence score (RS), ki67, lymphovascular and perineural invasion. Results: A total of 620 women were included, 79% (Num) were postmenopausal. Prior exposure to OC, HRT and fertility treatments was documented in 19% (103), 30% (136) and 11% (62), respectively. OC use was associated with smaller (≤1cm) tumors (30% vs. 20%, p=0.023) and were less likely to have grade 3 disease (10% vs. 19%, p=0.049). No other associations were found between exogenous estrogen exposures and tumor characteristics (Table). Conclusions: Use of OC may be associated with breast cancer with a distinct features compared to women with luminal breast cancer without history of OC use. Large scale studies are needed to better characterize these findings. Fertility treatmentHRT ≥ 2 yearsHRTOCPNo (%)Yes(%)PNo(%)Yes (%)PNo (%)Yes (%)PNo(%)Yes(%)0.1722254252165150.7002355222057240.7002255232456200.023205723304426T≤1 cm 1<T≤2 T>2 cm0.85917180.09815200.09815210.6671815Node positive0.06479138891100.29982126761590.29982135771590.207791488795IDC ILC Other0.1671864181473130.5001667181664190.5001667171762210.049186319187310Grade 1 230.18922078329680.70811781122770.70811781221780.7392227732275ER intensity≤1 1<ER⇐2 ER>20.1121470.67116150.67116140.103148PR Negative1.000530.455520.455530.28252PNI present0.772670.351780.351570.056105LVI present0.18620290.36222190.36223180.5282218Ki67 >20%0.85917180.78718160.78717180.5701816Oncotype RS>25 Citation Format: Orly Yariv, Rinat Yerushalmi, Assaf Moore, Tzippy Shohat, Ofer Rotem, Yasmin Korzets Ceder, Hadar Goldvaser. The impact of exogenous estrogen exposure on the characteristics of estrogen receptor (ER) positive, early-stage breast cancer (EBC) [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 PS8-21.