INSEMA Trial In Breast Cancer

The INSEMA trial:
- Citation:
  - Reimer T, et al. New England Journal of Medicine, 2024/2025 (INSEMA Investigators).
According to a study published in The New England Journal of Medicine:
- In this trial involving patients with clinically node-negative, T1 or T2 invasive breast cancer (90% with clinical T1 cancer and 79% with pathological T1 cancer):
  - Omission of surgical axillary staging was noninferior to sentinel-lymph-node biopsy:
    - After a median follow-up of 6 years
The trial also demonstrated that omission of SLNB resulted in:
- Lower rates of lymphedema
- Better arm mobility
- Less pain with arm or shoulder movement compared to SLNB:
  - As confirmed by both clinical and patient-reported outcomes
However, a slightly higher – but still low – rate of axillary recurrence was observed in the omission group:
- 1.0% vs. 0.3%:
  - With no impact on overall survival
These findings support the safety of omitting SLNB in carefully selected patients with early-stage, clinically node-negative breast cancer:
- Particularly those with favorable tumor biology:
  - When the absence of nodal status will not alter adjuvant therapy decisions
The INSEMA trial (Intergroup‑Sentinel‑Mamma, often abbreviated “INSEMA”):
- A large European randomized study (5,500+ patients):
  - Evaluating whether sentinel lymph node biopsy (SLNB) can be safely omitted in selected patients with early-stage breast cancer
Background and Design:
- Population:
  - Clinically node-negative invasive breast cancer (cT1 to cT2, ≤ 5 cm), mostly hormone receptor–positive, HER2-negative tumors
  - Patients candidates for breast‑conserving surgery and whole‑breast radiation
  - All had negative axilla by clinical exam:
    - Most centers used axillary ultrasound (AUS) as standard triage
- Trial Type:
  - Prospective, randomized non‑inferiority study:
    - Germany and Austria; 2015 to 2019
  - Randomized in a 4 : 1 ratio:
    - ~ 962 patients omitted SLNB versus ~ 3,896 who underwent standard SLNB
  - Primary Endpoint:
    - 5‑year invasive disease–free survival (iDFS):
      - With non‑inferiority margin HR ≤ 1.271 and lower bound ≥ 85% iDFS
Key Results (Median Follow‑up ≈ 73.6 months ≈ 6 years):
- Invasive Disease‑Free Survival (iDFS):
  - No‑SLNB group:
    - 5‑year iDFS ≈ 91.9% (95% CI: 89.9–93.5)
  - SLNB group:
    - 91.7% (95% CI: 90.8–92.6)
  - Hazard Ratio:
    - 0.91 (95% CI: 0.73–1.14), within non‑inferiority margin
- Overall Survival (OS):
  - No‑SLNB group:
    - 98.2% (95% CI: 97.1–98.9)
  - SLNB group:
    - 96.9% (95% CI: 96.3–97.5)
- Axillary Recurrence:
  - Slightly higher in no‑SLNB group:
    - ≈ 1.0% vs. ≈ 0.3%:
      - But still very low clinically
Secondary Outcomes:
- Quality of Life and Morbidity:
  - Lower rates of lymphedema, better arm mobility, and less pain with arm / shoulder movement in the no‑SLNB group
- Patient‑reported outcomes consistently favored omission:
  - Better arm symptom scores (BRAS) and overall quality of life scales (EORTC)
Clinical Implications:
- Omitting SLNB appears safe and non‑inferior for iDFS and OS:
  - In carefully selected cN0 patients undergoing breast‑conserving therapy
- Best suited for:
  - ≥ 50‑year‑old patients with low-risk tumors:
    - ≤ 2 cm, grade 1 to grade 2, HR-positive, HER2-negative
- Underrepresented groups (younger, grade 3, HER2‑positive or larger tumors):
  - Were under‑powered for definitive recommendations
Trial required whole‑breast radiation:
- No partial‑breast or omission of radiation was allowed, limiting generalizability
Although non‑SLNB led to slightly higher axillary recurrence (1% vs 0.3%):
- The absolute rates remained extremely low (< 1%), with meaningful improvements in arm morbidity and quality of life
Limitations and Cautions:
- Under‑powered subgroups:
  - T2 tumors, younger patients, grade 3, or HER2+ disease:
    - Had low representation and thus results may not apply
- No SLNB omission in the context of mastectomy, neoadjuvant therapy, or partial breast radiation:
  - These settings were excluded
- Patient selection remains critical:
  - Omitting nodal staging may impact systemic therapy decisions:
    - Chemotherapy, genomic testing
The INSEMA trial:
- Demonstrates that in clinically node-negative women with early-stage, low-risk invasive breast cancer:
  - Who are undergoing breast-conserving therapy with whole breast radiation:
    - Omitting sentinel lymph node biopsy is non‑inferior for disease‑free and overall survival:
      - While significantly reducing lymphedema risk and improving arm function and patient quality of life
- This de‑escalation strategy is particularly appropriate for:
  - Patients over age 50 with:
    - T1, grade 1 to grade 2, hormone receptor‑positive / HER2‑negative tumors
  - However, broader application to younger patients, higher‑risk tumors, or non‑lumpectomy contexts should be approached with caution and discussed in a multidisciplinary setting
References:
- Axillary Surgery in Breast Cancer — Primary Results of the INSEMA Trial. Reimer T, Stachs A, Veselinovic K, et al. The New England Journal of Medicine. 2025;392(11):1051-1064. doi:10.1056/NEJMoa2412063.
- Sentinel Lymph Node Biopsy Omission in Early-Stage Breast Cancer: Current Evidence and Clinical Practice. Huang T, Wang W, Sun X. Frontiers in Oncology. 2025;15:1598730. doi:10.3389/fonc.2025.1598730.
- Patient-Reported Outcomes for the Intergroup Sentinel Mamma Study (INSEMA): A Randomised Trial With Persistent Impact of Axillary Surgery on Arm and Breast Symptoms in Patients With Early Breast Cancer. Reimer T, Stachs A, Veselinovic K, et al. EClinicalMedicine. 2023;55:101756. doi:10.1016/j.eclinm.2022.101756.
- Axillary Surgery in Breast Cancer — Primary Results of the INSEMA Trial. Reimer T, Stachs A, Veselinovic K, et al. The New England Journal of Medicine. 2024;. doi:10.1056/NEJMoa2412063.