Abstract Introduction: The 21-gene Breast Recurrence Score® (RS) in the randomized NSABP B-20, SWOG S8814, and TAILORx studies predicted chemotherapy (CT) benefit for pts with N0 and N+ disease. Endocrine therapy was not inferior to chemoendocrine therapy in 6,711 randomized TAILORx pts with RS 11-25 and N0 disease. We characterized BCSM for the TAILORx-defined RS groups (0-10, 11-15, 16-20, 21-25, and 26-100) in the large population-based SEER study of pts treated based on RS results. Methods: RS results were provided electronically to SEER registries per their linkage methods (Petkov npj Breast Cancer 2016). Eligible pts were diagnosed Jan 2004 - Dec 2014 with N0 and N+(N1mic, 1-3 positive nodes[N1]), HR+, HER2-negative BC, and had no prior malignancy or multiple tumors, with follow-up information through Dec 2015. BCSM estimates by reported CT use yes vs. no/unknown were computed, and must be interpreted cautiously given lack of randomization. Results: There were 80,605 pts with RS results; 70,087 with N0 disease, 4,336 with N1mic, and 6,182 with N1. Median follow-up was 49 months, with 20,151 pts followed >76 months. 1,020 pts had experienced breast cancer death. There was a significant positive association between higher RS results and increased BCSM (p<0.001) without and with adjustment for nodal status, age, tumor size, and grade. Reported CT use increased with increasing RS result (Table). 9-y BCSM was <4% without CT for pts with RS 0-25 and N0 disease and for pts with RS 0-20 and N1 disease. For RS 26-100, 9-y BCSM was lower with CT use than without (Table). Similar results were seen in the 4,336 pts with N1mic disease. Pts treated with CT for every RS group, as expected, tended to have higher risk features (age, tumor size and grade), and multivariable models and adjustment by propensity scores will be presented to allow for more definitive conclusions. Table N0; CT Use No (N=55726)N0; CT Use Yes (N=14361)N1; CT Use No (N=3810)N1; CT Use Yes (N=2372)RS 0-10n139823891005283 9-y BCSM1.4% (1.0%, 2.1%)2.1% (0.7%, 5.9%)2.2% (1.0%, 4.8%)1.4% (0.4%, 4.6%)RS 11-15n1675810661193453 9-y BCSM2.0% (1.5%, 2.6%)2.7% (1.3%, 5.4%)1.5% (0.8%, 3.1%)4.4% (1.4%, 13.6%)RS 16-20n144842719992587 9-y BCSM2.2% (1.7%, 2.8%)1.9% (1.1%, 3.0%)3.8% (1.6%, 8.5%)4.2% (1.6%, 10.9%)RS 21-25n67043544397431 9-y BCSM3.9% (3.0%, 5.0%)3.4% (2.6%, 4.6%)7.1% (4.1%, 12.1%)5.7% (2.9%, 11.2%)RS 26-100n37986643223618 9-y BCSM8.8% (7.4%, 10.4%)7.0% (5.9%, 8.4%)15.2% (8.7%, 25.9%)10.8% (7.2%, 16.2%) Conclusion: In both N0 and N+ disease (up to 3 positive nodes), low RS results identify more than 70% of BC patients with excellent long-term outcomes and no apparent CT benefit, and high RS results (26-100) identifies an important minority of patients where CT reduces BCSM. Real-world evidence from SEER reconfirms that the 21-gene assay is prognostic and strongly suggests it is predictive of CT benefit, irrespective of nodal status. Citation Format: Hortobagyi GN, Shak S, Sledge, Jr. GW, Winer EP, Albain KS, Mamounas EP, Jakubowski DM, Petkov VI, Wolmark N. Breast cancer-specific mortality (BCSM) in patients (pts) with node-negative (N0) and node-positive (N+) breast cancer (BC) guided by the 21-gene assay: A SEER-genomic population-based study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-11-02.