BackgroundIn clinically node-negative (cN0) early stage breast cancer (EBC) undergoing primary systemic treatment (PST), post-treatment positive sentinel lymph node (SLN+) directs axillary lymph node dissection (ALND), with uncertain impacts on outcomes and increased morbidities.Patients and MethodsWe conducted an observational study on imaging-confirmed cN0 EBC, who underwent PST and breast surgery that resulted in SLN+ and underwent ALND. The association among baseline/postsurgical clinic–pathological factors and positive nonsentinel additional axillary lymph nodes (non-SLN+) was analyzed with logistic regression. LASSO regression (LR) identified variables to include in a predictive score of non-SLN+ (ALND-predict). The accuracy and calibration were assessed, an optimal cut-point was then identified, and in silico validation with bootstrap was undertaken.ResultsNon-SLN+ were detected in 22.2% cases after ALND. Only progesterone receptor (PR) levels and macrometastatic SLN+ were independently associated to non-SLN+. LR identified PR, Ki67, and type and number of SLN+ as the most efficient covariates. The ALND-predict score was built based on their LR coefficients, showing an area under the curve (AUC) of 0.83 and an optimal cut-off of 63, with a negative predictive value (NPV) of 0.925. Continuous and dichotomic scores had a good fit (p= 0.876 andp= 1.00, respectively) and were independently associated to non-SLN+ [adjusted odds ratio (aOR): 1.06,p= 0.002 and aOR: 23.77,p< 0.001, respectively]. After 5000 bootstrap-adjusted retesting, the estimated bias-corrected and accelerated 95%CI included the aOR.ConclusionsIn cN0 EBC with post-PST SLN+, non-SLN+ at ALND are infrequent (~22%) and independently associated to PR levels and macrometastatic SLN. ALND-predict multiparametric score accurately predicted absence of non-SLN involvement, identifying most patients who could be safely spared unnecessary ALND. Prospective validation is required.Supplementary InformationThe online version contains supplementary material available at 10.1245/s10434-023-13231-x.