Axillary De-Escalation After Neoadjuvant Therapy in cN2/N3 HER2-Positive and Triple-Negative Breast Cancer: Navigating Biological Promise and Clinical Uncertainty

Axillary de-escalation after neoadjuvant systemic therapy (NST) is established in cN1 breast cancer, but the trials validating sentinel lymph node biopsy (SLNB), targeted axillary dissection (TAD) and omission of regional nodal irradiation (RNI) largely excluded cN2/N3 disease. In HER2-positive and triple-negative disease, NST achieves axillary pathological complete response (pCR) in about one-third of cN2/N3 patients and 70–80% of those achieving breast pCR—establishing biological plausibility, not technical or trial-validated eligibility. The prospective evidence base comprises 87 patients evaluated against completion axillary lymph node dissection (cALND), only 41 informative for false-negative rate. Much of this evidence is defined by node count rather than by matting or fixation, so it applies directly to patients with more than three suspicious but mobile nodes—AJCC cN1 by fixation criteria, but sharing the same multi-node technical problem—while being correspondingly less confined to AJCC-defined cN2/N3 than the label implies. Across non-randomised cohorts, no oncological penalty has emerged after de-escalation in selected responders, though only three supply an axillary-recurrence numerator confined to advanced nodal disease. Within these limits, omission of cALND may reasonably be offered to selected excellent responders with cN2a or level I/II-predominant disease and TAD-confirmed nodal pCR, provided RNI is retained, and the decision is multidisciplinary-team supported and documented. Omitting RNI as well rests on extrapolation from NSABP B-51/RTOG 1304, which excluded this population, and should remain within prospective evaluation, as should cALND omission for residual disease. Level I/II TAD/SLNB does not sample the compartments defining cN2b, cN3a, or cN3c disease and samples only the axillary component of cN3b disease, which cALND does not sample either; comprehensive RNI remains indicated in these subgroups. In cN2b, the axilla is clinically uninvolved, so cALND is not required, and axillary staging by SLNB alone is appropriate. cN2/N3-specific validation of false-negative rate and outcomes remains the priority.