Abstract Background: Indications for post-mastectomy radiotherapy (PMRT) in T1-T2, node negative (N0) breast cancer patients with “high-risk” features are controversial based on lack of consensus as to what constitutes “high-risk”, and variable results of small retrospective studies. The EORTC 22922 and MA20 trials reporting improved 10-year disease-free survival with nodal irradiation included high-risk N0 patients but these patients were not analyzed separately and did not receive modern systemic therapy. We sought to evaluate long-term locoregional control in T1-T2N0 patients with high-risk features undergoing mastectomy in the contemporary era. Methods: We retrospectively identified patients with T1-T2N0 breast cancer with ≥1 high-risk feature treated with mastectomy from 1/2006-12/2011. High-risk features were defined as age <40 years, multifocal/multicentric disease, lymphovascular invasion (LVI), medial or central tumor location, and high nuclear grade. The primary outcome of interest was rate of LRR. Results: Among 672 patients meeting inclusion criteria, 187 (28%) had 1 risk factor: 21 (3%) were age <40 years, 132 (20%) were multifocal/multicentric, and 34 (5%) had LVI; 449 (67%) patients had ≥2 high-risk features, and 36 patients with unknown grade were excluded from risk analysis. PMRT was received by only 15 (2%) patients. Clinicopathologic characteristics of the 657 patients treated without PMRT are shown in Table 1. Table 1: Clinicopathologic characteristics, n = 657 Median (Range)Age, years49 (24-89)Tumor size, cm1.4 (<0.1-5.0) n (%)Ductal histology566 (86%)High nuclear grade*266 (40%)LVI232 (35%)Multifocal/multicentric447 (68%)Medial/central tumor226 (34%)Receptor status** ER+/HER2-438 (67%)HER2+123 (19%)ER-/HER2-70 (11%) n (%)Rate of LRR# of risk factors* 1183 (28%)3.8%2265 (40%)5.3%3143 (22%)4.9%4 or 532 (5%)9.4%*Unknown grade in 34 cases, excluded from risk analysis **Unknown receptor status in 26 cases Sentinel node biopsy alone was performed in 98% of these patients. A median of 4 lymph nodes were retrieved (range 1-15). Adjuvant systemic therapy was received by 86% of patients. At median 5.6 years of follow-up, overall LRR rate was 4.7% (n = 31), with the majority (55%) of events involving the chest wall. Increasing tumor size was associated with LRR (HR 1.70, 95% CI 1.26–2.29, p = 0.006), while age, histology, grade, subtype, LVI, multifocality/multicentricity, and tumor location were not (all p > 0.05). Although rate of LRR increased from 3.8% to 9.4% with 1 vs. ≥4 high-risk features, a comparison of 1 vs. 2 vs. 3 vs. ≥4 risk factors was not significant by Kaplan-Meier estimation (p = 0.54). Conclusions: A low LRR rate of 4.7% was seen in this large unselected cohort of T1-T2N0 cancers with "high-risk" features treated by mastectomy and systemic therapy without PMRT. While increasing tumor size was predictive, other features did not confer a higher risk of LRR either independently or together, and do not by themselves mandate the use of PMRT in this population. Citation Format: Mamtani A, Patil S, Stempel M, Morrow M. Are there patients with T1-T2, node-negative breast cancer who are high-risk for locoregional recurrence? [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-13-07.