What are the implications of the INSEMA (Investigational New Drug or Device) trial for patient treatment?

INSEMA Trial: Implications for Early-Stage Breast Cancer Treatment

Direct Answer

Sentinel lymph node biopsy (SLNB) can be safely omitted in patients with clinically node-negative (cN0), T1-T2 invasive breast cancer undergoing breast-conserving surgery, as the INSEMA trial demonstrated non-inferiority for invasive disease-free survival while significantly reducing arm and breast symptoms. 1

Key Trial Results

The INSEMA trial randomized 5,542 patients with early-stage breast cancer (90% clinical T1, 79% pathological T1) to either SLNB (n=3,896) or omission of axillary surgery (n=962). 1 After median follow-up of 73.6 months:

• 5-year invasive disease-free survival (IDFS) was equivalent: 91.9% in the no-axillary-surgery group versus 91.7% in the SLNB group (HR 0.91,95% CI 0.73-1.14), confirming non-inferiority. 1

• Significantly fewer long-term complications occurred without SLNB: 1

  • Arm/shoulder mobility restriction: 2.0% vs 3.5%
  • Lymphedema: 1.8% vs 5.7%
  • Pain with arm/shoulder movement: 2.0% vs 4.2%

Patient Selection Criteria for SLNB Omission

Based on the well-represented INSEMA population, SLNB can be omitted in patients meeting ALL of the following criteria: 1

• Clinical T1-T2 tumors (≤5 cm)
• Clinically node-negative by physical exam and ultrasound
• Planned breast-conserving surgery
• Predominantly postmenopausal status
• Hormone receptor-positive, HER2-negative disease
• Invasive ductal carcinoma histology
• Median tumor size approximately 1.1 cm

Populations Requiring Caution

Exercise caution or avoid SLNB omission in underrepresented groups: 1

• Age <50 years (only 10.8% in INSEMA)
• Grade 3 tumors (only 3.6% in INSEMA)
• Ki-67 >20% (only 12.9% in INSEMA)
• HER2-positive disease (only 3.6% in INSEMA)
• Triple-negative breast cancer (only 1.2% in INSEMA)
• Invasive lobular or mixed lobular carcinoma (12.7% in INSEMA)

Critical Radiation Therapy Considerations

Whole breast irradiation (WBI) was used in >80% of INSEMA patients, and this is a crucial caveat for implementing SLNB omission. 1

WBI Provides Incidental Axillary Coverage

• WBI delivers full therapeutic dose (>95% of prescribed dose) to 65% of sentinel lymph nodes incidentally. 2
• At least 50% of patients receive ≥85% of prescribed dose to axillary level I with WBI. 3
• This incidental coverage likely contributed to the excellent outcomes in INSEMA. 1

Partial Breast Irradiation (PBI) Is NOT Equivalent

Combining SLNB omission with PBI should NOT be considered standard practice and requires further investigation. 2 The dosimetric data show:

• PBI provides full therapeutic dose to only 10% (3D-CRT) or 3% (VMAT) of sentinel lymph nodes, compared to 65% with WBI. 2
• Since INSEMA patients predominantly received WBI, extrapolating results to PBI is not evidence-based. 1, 2

Quality of Life Impact

Patient-reported outcomes strongly favor SLNB omission: 4

• Breast symptoms (BRBS) and arm symptoms (BRAS) scores were significantly better in the no-SLNB group at all post-baseline assessments. 4
• Arm symptom differences were clinically relevant (≥5.0 points) at all time points, with highest difference at one month post-surgery. 4
• No relevant differences in overall quality of life (QLQ-C30) were observed between groups. 4
• Questionnaire completion remained >70% throughout follow-up, indicating robust data quality. 4

Clinical Decision-Making Without Nodal Staging

When SLNB is omitted, treatment decisions must rely on tumor biological parameters rather than nodal status: 5

• In INSEMA, only 13.1% of patients with negative axillary ultrasound had 1-3 positive nodes on surgery, and 0.6% had ≥4 positive nodes. 1
• For luminal-like tumors, chemotherapy decisions should be guided by tumor grade, Ki-67, genomic assays, and tumor size. 5
• Regional nodal irradiation decisions (excluding axilla) must be based on primary tumor characteristics. 5

Common Pitfalls to Avoid

1. Do not combine SLNB omission with PBI outside of clinical trials - the evidence base is for WBI only. 1, 2

2. Do not extrapolate to mastectomy patients - INSEMA only included breast-conserving surgery. 1, 5

3. Do not apply to high-risk histologies or biology - stick to the well-represented population (hormone receptor-positive, HER2-negative, low-grade). 1

4. Ensure negative axillary ultrasound - clinical node-negativity must include imaging confirmation. 1

5. Do not use in younger patients (<50 years) without careful consideration - this group was underrepresented. 1

Implementation Algorithm

For patients with early-stage breast cancer being considered for SLNB omission: 1

1. Confirm clinical T1-T2, cN0 by exam AND negative axillary ultrasound
2. Verify hormone receptor-positive, HER2-negative, invasive ductal carcinoma
3. Confirm breast-conserving surgery is planned
4. Ensure WBI (not PBI) will be delivered
5. If patient is age ≥50, postmenopausal, with grade 1-2 tumor and Ki-67 ≤20% → SLNB can be safely omitted
6. If any high-risk features present (age <50, grade 3, Ki-67 >20%, triple-negative, HER2-positive, lobular histology) → proceed with SLNB