Abstract Background: The optimal systemic therapy strategy, neoadjuvant vs adjuvant therapy, for patients with small clinically node negative HER2+ breast cancers is uncertain. The goal of this study was to evaluate the incidence of pathologic nodal disease in cT1-2 N0 HER2+ patients, treated with upfront surgery or neoadjuvant chemotherapy (NAC), to better define selection criteria for initial treatment approach. Methods: Our prospectively maintained database was queried for cT1-2 N0 HER2+ breast cancer patients diagnosed 2/12/2015 - 10/13/2020 (after publication of the Adjuvant Paclitaxel and Trastuzumab trial). Patients without axillary surgery were excluded (n =23). HER2 positivity was defined per ASCO/CAP guidelines. Pre-NAC and/or pre-operative axillary ultrasound was not routinely performed. Patient characteristics and rates of pN+ disease were compared by treatment strategy using Chi square and Wilcoxon rank-sum tests. Nodes with isolated tumor cells were considered negative (pN0) in the upfront surgery setting but positive (pN+) after NAC. Logistic regression determined factors associated with pN+ disease. Results: A total of 579 eligible patients were identified; 368 (63.6%) were treated with upfront surgery and 211 (36.4%) with NAC. Upfront surgery patients were older (median 55 years [range 23-88] vs 49 [24-79], p<0.001); less frequently had grade 3 disease (58.4% vs 67.3%, p=0.008); less frequently had T2 tumors (14.4% vs 82.5%, p<0.001); and less frequently underwent axillary ultrasound (21.2% vs 62.6%, p<0.001). NAC included multi-chemotherapy regimens in 46 (21.8%) and more than one HER2-targeted regimens in 165 (78.2%). The incidence of pN+ disease was 73/368 (19.8%) among upfront surgery patients and 26/211 (12.3%) among NAC patients (p=0.021). Among upfront surgery patients, there was a significant difference in the distribution of pN+ across T categories (p<0.001) with an increased rate in patients with cT1c and cT2 tumors (Table 1). There was no difference in use of ALND between upfront surgery (22/368 [6.0%]) and NAC patients (18/211 [8.5%], p=0.173). Hormone-receptor status did not impact rate of pN+ disease (OR 1.024, 95% CI: 0.601-1.747, p=0.929). Among upfront surgery patients, adjuvant systemic therapy (excluding endocrine therapy) was given in 269 (73.1%) including paclitaxel/trastuzumab in 158 (42.9%) and other regimens to include multi-chemotherapy regimens in 111 (30.2%). Conclusions: In this large cohort of cT1-2 N0 HER2+ breast cancer patients, treatment with NAC was associated with lower rates of pN+ compared to those undergoing upfront surgery. Despite these differences, ALND rates were similar. In upfront surgery patients, the higher rate of pN+ disease in patients with cT1c-T2 tumors suggests an opportunity for more comprehensive radiographic examination of the axilla in this subgroup. Further investigation could also focus on tailoring NAC regimens for HER2+ cN0 patients who are presently undergoing upfront surgery. Table 1.Pathologic nodal stage among upfront surgery and NAC patientsUpfront Surgery (N=368)pN+pN0P valuecT category< 0.001T1mi (N=48)6 (10.4%)42 (89.6%)T1a (N=26)3 (11.5%)23 (88.5%)T1b (N=87)7 (8.0%)80 (92.0%)T1c (N=154)38 (24.7%)116 (75.3%)T2 (N=53)19 (35.8%)34 (64.2%)NAC (N=211)ypN+ypN0P valuecT category0.719T1b (N=7)1 (14.3%)6 (85.7%)T1c (N=30)5 (16.7%)25 (83.3%)T2 (N=174)20 (11.5%)154 (88.5%) Citation Format: Anna Weiss, Adrienne G. Waks, Alison Laws, Sara M. Tolaney, Eric P. Winer, Elizabeth A. Mittendorf, Ann H. Partridge, Tari A. King. Pathologic nodal staging and systemic therapy among patients with cT1-2N0 HER2+ breast cancer: A prospective single institution cohort analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-02.