Background: As tumor biology has taken precedence over anatomic staging, NCCN guidelines now allow for genomic profiling to make adjuvant treatment recommendations for Nmi-N1 breast cancer (BC). This makes nodal status, determined by sentinel lymph node biopsy (SLNB), less influential. Although generally safe, SLNB adds an incision, operative time, monetary costs, and carries risks of chronic paresthesia (9%) or lymphedema (2-6%). We hypothesized that, if ultrasound (US) excludes occult nodal metastasis and genomic profiling is used in making chemotherapy recommendations for N0-N1 disease, SLNB will be the sole indicator of a need for chemotherapy in Methods: This was a retrospective data and tissue analysis of patients treated at our breast center (11/2011 – 12/2015). Postmenopausal women with ER positive, HER2 negative, pT1-2 BC with non-suspicious axillary US who underwent SLNB without preoperative chemotherapy were included. For each patient, we compared recommended adjuvant therapy (per NCCN guidelines) based on SLNB results, versus the recommendation had SLNB been negative. For N0-N1 cases, we used Oncotype DX Breast Recurrence Score® test to determine chemotherapy. For Nmi-N1 cases, chemotherapy was considered for Recurrence Score® (RS) 18-25 and recommended for RS > 25. When not in the electronic medical record (EMR), RS result was obtained from stored specimens, with patient consent. Patients without a RS result were excluded from the chemotherapy outcomes analysis. Results: Of 217 included patients, nodal status was as follows: N0, n=184 (85%); Nmi-N1, n=29 (13%); N2-3, n=4 (2%). Therefore, in 85% of patients SLNB did not influence any adjuvant treatment recommendation. In 4.1% of patients, SLNB resulted in a recommendation for axillary lymph node dissection (Table). In 15.2% of patients (n=33), SLNB resulted in a consideration (13.4%) or recommendation for (1.8%) nodal irradiation. RS result was available in 147 patients (68% of cohort). However, only 8 of those with unknown RS result (4% of cohort) were node-positive; for node-negative patients, RS would not affect any study outcome (change in treatment based on SLNB). Among patients with RS result, based on actual SLNB result, chemotherapy was recommended or considered in 30 patients. In 23 of these, chemotherapy would have been recommended regardless of SLNB result based on RS > 25. Therefore, SLNB made a difference in whether to recommend or consider chemotherapy in 4.7% of patients (7/147). Conclusions: SLNB changed the recommendation whether to receive chemotherapy (no to yes, or no to consider) in only 4.7% of patients. More often, SLNB influenced the chemotherapy regimen recommended (2nd vs. 3rd generation), or local therapy recommendations. With increasing role for genomic profiling, the role of SLNB in determining adjuvant therapy is diminishing. When chemotherapy would not be considered, omission of SLNB may be considered in postmenopausal patients with ER positive, T1-2 BC and negative axillary US. If genomic profiling were performed prior to surgery, the results could change surgical management. In women with RS 0-11, SLNB is highly unlikely to alter the recommendation against chemotherapy. In women with RS > 25, chemotherapy is recommended regardless of SLN status, but a positive SLN would affect the regimen recommended. SLNB is most influential in patients with RS 18-25. Use of genomic profiling preoperatively to tailor whether SLNB is performed should be prospectively validated. Table. Comparison of adjuvant treatment recommendations based on SLNB result vs. presumed negative SLNBBased on presumed negative SLNBBased on actual SLNB result% for whom SLNB would change treatment recommendation8Axillary lymph node dissection recommended1094.1% (9/217)Nodal irradiation recommended2041.8% (4/217)Nodal irradiation considered302913.4% (29/217)Chemotherapy recommended423240.6% (1/147)Chemotherapy considered5064.1% (6/147)Third-generation chemotherapy recommended6064.1% (6/147)Third-generation chemotherapy considered7064.1% (6/147)1)For >2 positive SLN, or gross extranodal extension (ENE). Since surgeon determination of gross ENE was not consistently available, > 2 mm of ENE on pathology was used to defined “gross” extension. 2)For N2-3 disease 3)For Nmi-N1 disease 4)For RS > 25, or N2-3 5)For Nmi-N1 disease, with RS 18-25 6)For Nmi-N1 disease with RS > 25; or N2-3; this group is a subset of those for whom chemotherapy would be recommended 7)For Nmi-N1 disease with RS 18-25; this group is a subset of those for whom chemotherapy would be recommended 8)Patients without Recurrence Score result were excluded from analysis of chemotherapy outcomes; fractions are included to show the denominator used for each calculation. Citation Format: Rubie Sue Jackson, Elaine Lee, Carol Tweed, Charles Mylander, Laura Martino, Martin Rosman, Kip Waite, Nicholas Huerta, Lorraine Tafra. Can genomic profiling eliminate the need for SLNB in ER positive, T1-2 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 PD4-03.