Secondary Analysis of the INSEMA Trial: Axillary Surgery in Breast Cancer Patients With 1 to 3 Sentinel Node Macrometastases Undergoing Breast-Conserving Therapy

Axillary nodal status remains a key prognostic factor in early breast cancer, influencing decisions regarding systemic treatment and postoperative radiotherapy. However, axillary surgery itself does not significantly impact breast cancer mortality and is primarily used as a staging procedure in patients with clinically node-negative (cN0) disease. The INSEMA trial was designed to evaluate the possibility of avoiding sentinel lymph node biopsy (SLNB) in patients with cN0 disease (randomization 1) or omitting completion axillary lymph node dissection (ALND) in pN1a(sn) patients. The first randomization demonstrated that omitting SLNB in cN0 patients undergoing breast-conserving surgery (BCS) was noninferior for invasive disease-free survival (IDFS). This article summarizes the results of the second randomization.

The INSEMA trial (NCT02466737), conducted between 2015 and 2019 in Germany and Austria, was a prospective, multicenter study. In the first randomization, patients with invasive early breast cancer (tumor size ≤5 cm, c/iN0) scheduled for BCS and postoperative whole-breast irradiation (WBI) were randomized 4:1 to SLNB versus no SLNB. In the second randomization, patients in the SLNB arm with 1 to 3 macrometastases were further randomized 1:1 to either SLNB alone or completion ALND. The primary objective was to compare IDFS after BCS between no axillary surgery and SLNB patients (first randomization). As a result of there being fewer than expected SLNB-positive patients, a protocol amendment downgraded IDFS analysis from a co-primary to a key secondary outcome. Noninferiority was defined as a 5-year IDFS >76.5% for SLNB alone (hazard ratio, <1.271), compared with an expected 5-year IDFS of 81% for completion ALND.

A total of 485 patients were included in the second randomization (intention-to-treat [ITT] set: SLNB alone, n=242; completion ALND, n=243). After excluding 99 patients, 386 patients (SLNB alone, n=217; completion ALND, n=169) were analyzed in the per-protocol (PP) set. After a median follow-up of 74.2 months, the completion ALND group had higher rates of postoperative chemotherapy (39.8% vs 33.6%; P=.239), conventionally fractionated WBI (87.0% vs 75.1%; P=.004), tumor bed boost (88.8% vs 80.6%; P=.035), and regional nodal irradiation (36.0% vs 20.6%; P=.019). Noninferiority for SLNB alone could not be demonstrated in the PP analysis (hazard ratio, 1.69; 95% CI, 0.98-2.94). Estimated 5-year IDFS rates were 86.6% (81.0%-90.7%) for SLNB alone versus 93.8% (88.7%-96.6%) for completion ALND (log-rank P=.058). Five-year overall survival (OS) rates were 94.9% (90.6%-97.2%) for SLNB alone and 96.2% (91.7%-98.3%) for completion ALND (log-rank P=.663). In the ITT analysis, no significant difference in IDFS was observed between arms (hazard ratio, 1.26; 95% CI, 0.80-1.99), with estimated 5-year IDFS rates of 86.0% (80.6%-90.0%) for SLNB alone and 89.3% (84.3%-92.8%) for completion ALND (log-rank P=.314). Locoregional recurrence rates were low, with 5-year cumulative incidences of 1.1% for SLNB alone and 0.0% for completion ALND (P=.405). Importantly, patients in the SLNB-alone group experienced lower rates of lymphedema, improved arm mobility, and reduced arm and shoulder pain.

After 6 years of follow-up, SLNB alone demonstrated no significant differences compared with completion ALND in terms of IDFS, OS, or locoregional recurrence in patients with clinically cN0 disease with positive SLNB undergoing BCS. Final 10-year follow-up data are anticipated in 2029.

Source: Reimer T, Stachs A, Veselinovic K, et al. Axillary surgery in breast cancer patients with one to three sentinel node macrometastases and breast-conserving therapy: secondary results of the INSEMA trial. Presented at: San Antonio Breast Cancer Symposium 2025. December 11, 2025; San Antonio, TX. Presentation GS2-02.