A Randomized Trial of Sentinel Node Biopsy Omission After Neoadjuvant Systemic Therapy in Clinically Node-Negative or Selected Node-Positive Breast Cancer

Abstract

Purpose: Axillary surgery is increasingly omitted in patients with early-stage breast cancer undergoing upfront surgery, as supported by trials such as SOUND and INSEMA. However, in the neoadjuvant setting, the omission of axillary surgery has only been explored in small single-arm studies involving highly selected patients with confirmed breast pathologic complete response (pCR). The NeoNAUTILUS trial aimed to evaluate the oncologic safety of omitting sentinel lymph node biopsy (SLNB) in patients with a high probability of achieving an axillary pCR (ypN0) following neoadjuvant systemic therapy (NST), regardless of breast pCR status.

Methods: NeoNAUTILUS is a prospective, multicenter, randomized, controlled, non-inferiority trial conducted at 12 tertiary centers in Korea. Eligible participants were women with clinical T1-T3, N0, or selected N1 invasive breast cancer, who completed NST and were candidates for breast-conserving surgery (BCS). Prior to enrollment, all patients underwent axillary ultrasound after NST completion to exclude suspicious lymph nodes. Patients with clinical N0 disease of any subtype were eligible for inclusion. Patients with clinical N1 disease with human epidermal growth factor receptor 2-positive or triple-negative tumors may be included if their primary tumor demonstrates a > 30% reduction on magnetic resonance imaging after NST. Participants were randomized 1:1 to undergo BCS with or without SLNB, stratified by clinical nodal status and tumor subtype. Patients were randomized and remained blinded until surgery. The primary endpoint is the 5-year invasive disease-free survival. A total of 464 patients are expected to be enrolled over 3 years, with a 5-year follow-up period.

Discussion: NeoNAUTILUS is the first randomized trial to assess the omission of axillary surgery after NST based on the predicted nodal response, independent of breast pCR. This study may redefine axillary management in the neoadjuvant setting by identifying patients who can safely avoid SLNB, thereby reducing surgical morbidity without compromising oncologic outcomes.

Trial registration: ClinicalTrials.gov Identifier: NCT06704945. Registered on November 26, 2024.

Keywords: Breast Neoplasms; Clinical Trial; Multicenter Study; Neoadjuvant Therapy; Sentinel Lymph Node Biopsy.

Figure 1. Study design.

Proposed randomized trial evaluating the of omission axillary surgery after NST based on axillary response rather than breast pCR. Eligible patients included those with cT1-T3 and cN0 breast cancer of any subtype and selected cN1 patients with a favorable axillary response. Patients were randomized to undergo BCS with or without SLNB, with 5-year invasive disease-free survival as the primary endpoint. NST = neoadjuvant systemic therapy; pCR = pathologic complete response; BCS = breast-conserving surgery; SLNB = sentinel lymph node biopsy; US = ultrasound; cT = clinical tumor stage; cN = clinical node stage; HER2+ = human epidermal growth factor receptor 2-positive; TNBC = triple-negative breast cancer; MRI = magnetic resonance imaging; QoL = quality of life; EORTC QLQ = European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire; ITT = intention-to-treat; PP = per-protocol.

Figure 2. Timeline for enrollment, interventions, and assessments.

X: mandatory, △: not mandatory. SLNB = sentinel lymph node biopsy; BCS = breast-conserving surgery; MRI = magnetic resonance imaging; EORTC QLQ = European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire.