Axillary surgery in the cyclin-dependent kinase 4/6 inhibitors era: no time to move backward.

Abstract

Axillary lymph node involvement remains one of the strongest prognostic factors in early breast cancer and continues to guide both surgical and adjuvant treatment decisions. Historically, axillary lymph node dissection (ALND) represented the standard staging approach, but it is associated with substantial morbidity, including a significant risk of lymphedema. Over recent decades, robust evidence from multiple surgical de-escalation trials has demonstrated that less invasive approaches-most notably sentinel lymph node biopsy (SLNB) and omission of ALND in selected scenarios-have significantly reduced axillary morbidity without compromising oncologic outcomes. As a result, international guidelines support omission of ALND in clinically node-negative (cN0) tumors with limited nodal involvement. The monarchE trial introduced a new clinical dilemma. Abemaciclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, combined with endocrine therapy, showed a clinically meaningful improvement in invasive disease-free survival (IDFS) among patients with luminal human epidermal growth factor receptor 2 (HER2)-negative, high‑risk early breast cancer. Eligibility criteria required either ≥4 positive lymph nodes or 1-3 nodes with additional high-risk features. Consequently, some clinicians have questioned whether ALND should be reconsidered to ensure accurate identification of patients who may benefit from adjuvant CDK4/6 inhibition. However, accumulating evidence challenges this rationale. Randomized trials such as ACOSOG-Z0011, AMAROS and SENOMAC have shown no survival advantage from completion ALND in patients with 1-2 positive sentinel nodes, while analyses from large databases indicate that only a minority harbor ≥4 positive nodes. Moreover, recent post‑hoc analyses suggest that more than one hundred ALNDs would be required to prevent a single recurrence at five years, exposing many patients to unnecessary morbidity. Thus, the risk-benefit balance of performing ALND solely to expand eligibility for abemaciclib appears unfavorable. Emerging data from the NATALEE trial further broaden the therapeutic landscape by showing that ribociclib provides IDFS benefits not only in node-positive disease but also in high-risk node-negative patients. This expanded indication reduces the clinical relevance of extensive nodal staging for determining eligibility for CDK4/6 inhibition. Overall, current evidence does not support performing ALND solely to increase the number of patients eligible for abemaciclib, and nodal burden alone should not drive more aggressive axillary interventions in early breast cancer.