Project Summary/Abstract Sentinel lymph node biopsy (SLNB), which involves removal of the first few draining lymph nodes, is the standard method for staging the axilla in patients with clinically node-negative (cN0) breast cancer undergoing neoadjuvant chemotherapy (NAC) and is widely accepted, with minimal morbidity. In patients with clinically positive nodes, axillary lymph node dissection (ALND), or removal of the majority of axillary lymph nodes, was once the standard of care; however, NAC can eradicate disease in the axillary nodes, with nodal pathologic complete response (pCR) rates of 40%, thus reducing the need for ALND and consequently minimizing the risk of lymphedema. Initial small retrospective studies showed that SLNB was inaccurate in this population, with false-negative rates (FNRs) of 21%-33%. More recently, 4 prospective multi-institutional trials showed that patients presenting with limited axillary nodal metastases (cN1) can be reliably staged with SLNB after NAC, with FNRs of <10% with the use of dual-tracer mapping and retrieval of ≥3 sentinel lymph nodes. Patients presenting with locally advanced breast cancer (LABC)—defined as disease in the breast with skin or chest wall involvement (cT4) and/or extensive disease in the nodes (cN2/N3)—have not been considered candidates for SLNB, owing to their heavy disease burden at presentation and the limited evidence that SLNB is accurate after NAC in this patient population. Furthermore, it was presumed that the substantial tumor burden in patients with LABC would result in low rates of pCR to NAC, precluding surgical downstaging. However, a recent retrospective study of 321 patients with LABC treated at Memorial Sloan Kettering Cancer Center demonstrated high nodal pCR rates (38%), with similar rates between patients with cN1 (43%), cN2 (36%), and cN3 (32%) disease (p=0.23). The magnitude of reduction in tumor burden with modern NAC in patients presenting with LABC suggests that a substantial number of women may not benefit from ALND and may be subjected to unnecessary morbidity. These patients may be candidates for SLNB after NAC, provided that the procedure accurately predicts axillary nodal status in this population. We hypothesize that a heavy disease burden in the breast or the regional nodes at presentation is not a contraindication to SLNB in patients whose disease is downstaged with NAC. We propose a multi-institutional, prospective, single-arm trial to evaluate the feasibility and FNR of SLNB after NAC in patients presenting with LABC. Eligible patients whose disease is reduced to cN0 after NAC will undergo SLNB with dual-tracer mapping followed by ALND to assess the FNR of SLNB. Study findings could lead to significant advances in the surgical management of the axilla after NAC in patients with LABC, reducing the need for ALND and improving quality of life of survivors.