Abstract Background: The RxPONDER trial showed that in premenopausal breast cancer (BC) subjects who were hormone receptor positive (HR+), N1 lymph node status and had an OncotypeDx (RS) score ≤ 25, the use of adjuvant chemotherapy (AC) along with endocrine therapy (ET) had better disease free and distant relapse free survival than ET alone. Using a large national database, we wanted to see if adding AC improved overall survival in a similar cohort of node positive BC patients. Methods: The 2004-2018 National Cancer Database was used to include female BC patients aged 18-50 years. Inclusion criteria were N1-N3 lymph node status, M0 patients with any T stage, RS ≤ 25, HR+ and HER2-. Patients who received neoadjuvant chemotherapy were excluded. Logistic regression was used to evaluate AC utility trends. Kaplan-Meier (KM) and multivariate (MV) propensity score (PS) weighted Cox model were used to compare survival between patients with and without AC use. Results: 8628 women were included of which only 3519 (40.8%) received AC (AC+). 5109 (59.2%) did not receive AC (AC-). AC+ had the following age distribution: (18-40 years: 23.73%, 41-50 years: 76.27%), while AC- had the following: (18-40 years: 15.15%, 41-50 years: 84.85%). RS score distribution are as follows: AC+(0-11: 17.56%, 12-25: 82.44%), AC-(0-11: 35.49%, 12-25: 64.51%). Most of the cohort received ET (AC+: 94.74%, AC-: 93.25%) and majority were N1 (AC+: 92.61%, AC-: 98.9%). Factors associated with AC use includes caucasian race [african american vs caucasian: 0.777(0.647,0.934), p=0.0072], higher stage [II vs I: 1.825(1.598,2.084), p=< 0.0001, III vs I: 3.199(1.593,6.426), p=0.0011] and higher grade [G3 vs G1: 2.261(1.886,2.711), G2 vs G1: 1.467(1.301,1.655), p< 0.0001], radiation (RT) use [1.758(1.544,2.002), p< 0.0001], younger age [40-50 vs 18-40: 0.684(0.542,0.863), p=0.0013], higher RS [12-25 vs 0-11: 2.325(2.065,2.618), p< 0.0001], mastectomy [vs partial surgery: 1.668(1.469,1.894), p< 0.0001] and N2N3 nodal stage [N2N3 vs N1: 2.688(1.423,5.079), p=0.0023]. KM curves showed that AC+ had better survival at 10 years (93% vs 91%) (Table 1). Hazard Ratio (HR) comparison between the 2 groups favored AC+ [0.602(0.482,0.751), p< 0.0001] (Table). Subgroup analysis for overall mortality benefits from AC+, using MV adjusted HR showed favorable results in caucasian race [0.512(0.348,0.752)], both age groups of 18-40 years [0.429(0.217,0.847) and 40-50 years [0.585(0.394,0.869)], both poorly differentiated [0.404(0.186,0.874)] and well-differentiated [0.386(0.165, 0.903] grades and RS 12-25 [0.549(0.379,0.795)]. RS 0-11 did not reach significance [0.555(0.216,1.423]. Discussion: Based on our analysis, AC use was noted in 40.8% of young, lymph node and HR+ BC patients with an RS score of 0-25. This group of patients had an overall survival advantage of around 40% with AC use, further supporting the findings of the RxPONDER trial. This benefit is of particular significance in patients with a RS of 12-25. The survival advantage was present in all patients less than 50 years, regardless of the age subgroup used in our analysis. Possible mechanisms leading to these outcomes include direct cytotoxic effects and menopausal induction with AC use. Limitations of our study include the use of non-population-based data and the possibility of cofounding despite the use of PS matching. Moving forward, AC use along with hormone therapy may become standard practice in young HR + BC patients with lymph node involvement, regardless of the RS score. Table 1 Survival difference between AC+ and AC-. KM-Kaplan-Meier, AC-Adjuvant Chemotherapy, HR-Hazard Ratio, MV-Multivariate, PS-propensity score. Citation Format: Prashanth Ashok Kumar, Dongliang Wang, Danning Huang, Abirami Sivapiragasam. The impact of adjuvant chemotherapy on overall survival in hormone and node positive breast cancer patients with an Oncotype Dx score of 25 or less. A NCDB analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-01-02.