Background: Prosigna is a standardized test based on the PAM50 gene signature which provides information on intrinsic subtype and risk of recurrence (ROR) score predicting 10y recurrence probability (NanoString Technologies, Inc., Seattle, WA). We evaluated Prosigna’s impact on adjuvant treatment decision beyond immunohistochemistry (IHC) testing. Methods: 125 pre- and postmenopausal EBC patients with ER+, HER2-, pT1-T2 pN0/pN1mi were enrolled (12 centers; 8/2015-11/2016). FFPE specimens were centrally analyzed using Prosigna to classify patients according to the intrinsic tumor subtype and ROR score. The primary endpoint was the impact of the Prosigna test on adjuvant treatment decision. Results: 64% of tumors were classified by PAM50 as Lum A, 35% as Lum B, 0% Basal, 1% HER2-E. The intrinsic subtype concordance between immunohistochemistry (IHC) and Prosigna (n = 119) was 61.3%. In Lum B tumors by IHC the discordance rate was the highest (48% were reclassified as Lum A by Prosigna) as shown in the Table. ROR risk groups were as follows: ROR low (54; 43%), ROR interm. (38; 30%), and ROR high (33; 27%). Prosigna results led to a treatment recommendation change in 49 (39%) patients. In the 76 (61%) cases with the initial recommendation of Hormonal Therapy (HT) alone the final decision changed to chemotherapy (CT)+HT (CHT) in 24 (32%) patients. In the 49 (39%) cases in which the initial recommendation was CHT the final decision changed to HT in 25 (51%) patients. Among the 38 patients with Prosigna intermediate risk, 21 (55%) were allocated to HT. Conclusions: In this prospective decision impact study, Prosigna results led to a 39% change in adjuvant therapy indication. Patients with initial indication of CHT were changed to HT alone in > 50% of cases. Thus, Prosigna results influenced the treatment decisions and reinforced its clinical utility in real-world settings. The intrinsic subtype classification based on IHC didn’t show to be an adequate surrogate for the genomic subtypes as determined by Prosigna.