Heterogeneity of survival outcomes in ypN1 breast cancer after neoadjuvant therapy: The role of residual nodal burden in axillary de-escalation

Abstract Background: The management of residual axillary disease after neoadjuvant therapy (NAT) remains controversial, as current recommendations often treat ypN1 breast cancer as a homogeneous entity despite potential prognostic heterogeneity. Evidence supporting uniform axillary surgical strategies across different levels of residual nodal burden is limited. We investigated whether survival associations related to axillary surgical evaluation differ according to residual nodal burden in ypN1 disease, using an adjuvant cohort to validate a SEER-based proxy for surgical extent. Methods: Patients with 1–3 positive lymph nodes were identified in the SEER database (2000–2022) and stratified into neoadjuvant (NAT; n=30,560) and adjuvant (AT; n=197,586) cohorts. Axillary surgical evaluation was categorized as limited (2–3 examined nodes) or extensive (≥10 examined nodes). Survival was analyzed using Kaplan–Meier methods and log-logistic accelerated failure-time models, adjusted with inverse probability of treatment weighting. Results: In the ypN1 cohort, limited axillary evaluation was not associated with inferior overall survival among patients with a single residual positive node (IPTW-adjusted HR: 1.15, p=0.134; time ratio [TR]: 0.86, p=0.184). In contrast, limited evaluation was associated with worse survival in patients with two positive nodes (HR: 1.70, 95%CI 1.54–1.87; TR: 0.58, 95%CI 0.53–0.64). The findings were similar when using breast cancer-specific survival as the endpoint. Conclusions: Survival associations related to axillary surgical evaluation after NAT vary according to residual nodal burden. Axillary de-escalation appears feasible in patients with a single residual positive node but cannot be extrapolated to those with multiple residual nodes, underscoring heterogeneity within ypN1 disease.