From cN2 to ypN0: Nodal Downstaging After Neoadjuvant Treatment in Breast Cancer—A Retrospective Cohort Study from a Tertiary Cancer Center

Background/Objectives: In patients with clinically node-positive breast cancer, axillary response to neoadjuvant systemic treatment is heterogeneous and might depend on tumor biology. In patients with cN2 disease, the identification of factors linked to nodal response could improve risk stratification and contribute to the development of individualized post-neoadjuvant axillary management strategies. Methods: This cohort study has a retrospective design and included 560 female patients with invasive breast cancer (proven via biopsy) and cN2 disease. All patients received neoadjuvant systemic treatment accompanied by breast and axillary surgery at the Institute of Oncology “Prof. Dr. Ion Chiricuță” Cluj-Napoca (IOCN), Romania, between 2017 and 2025. The primary endpoint was the rate of axillary pathological complete response (pCR) following neoadjuvant systemic therapy, defined as ypN0. Secondary endpoints included breast pCR (ypT0), overall pCR (ypT0N0), the association between breast and axillary pathological response and survival analysis, including overall survival (OS) and disease-free survival (DFS). Clinicopathological predictors were assessed using univariate and multivariate logistic regression, while survival outcomes were evaluated with time-to-event analyses. Results: Complete axillary pathological response occurred in 282/560 patients (50.4%), and it increased to 53.2% when ypN0, including ypN0(i+). Breast pathological complete response was achieved in 31.2%, while overall pCR was 27.0%. Axillary response was significantly different in terms of molecular subtype, as ypN0 rates were 26.6% in Luminal A-like, 32.5% in Luminal B-like, 78.9% in HER2-positive and 72.6% in TNBC (p < 0.001). Nottingham grade 3 and HER2-positive disease were independently related to increased odds of ypN0, while TILs <10% were associated with lower odds of complete axillary response when multivariate analysis was performed. Breast and axillary responses were significantly associated (but were not interchangeable), as ypT0 showed 53.5% sensitivity and 91.9% specificity for ypN0. Overall pCR was associated with improved DFS (p = 0.040), while ypN0 and ypT0 were not significantly associated with DFS. No significant OS differences were noticed regarding pathological response. Conclusions: Nearly half of patients with cN2 breast cancer presented a complete axillary response after the completion of neoadjuvant treatment. Molecular subtype, histological grade and TILs were strongly associated with axillary response. In our cohort, breast pathological response alone was insufficient in order to be regarded as a predictor of nodal clearance, further supporting independent assessments of breast and axillary response. Further prospective studies are needed to determine whether these findings can inform individualized axillary management after neoadjuvant treatment.