What are the recommendations for an adult female with breast cancer considering the Insema (Investigational New Drug) trial?

INSEMA Trial in Breast Cancer: Sentinel Lymph Node Biopsy Omission

The INSEMA trial demonstrated that omitting sentinel lymph node biopsy (SLNB) in clinically node-negative early breast cancer patients results in significantly better arm and breast symptoms without compromising oncologic outcomes, supporting the option to forgo SLNB in appropriately selected patients. 1

Key INSEMA Trial Design and Population

The INSEMA trial (NCT02466737) enrolled 5,502 patients between 2015-2019 with clinically node-negative breast cancer, randomizing them to either SLNB (4,124 patients) versus no SLNB (1,030 patients). 2 The trial specifically required whole-breast irradiation (WBI) for all patients, which is critical because WBI incidentally treats a portion of the level I axilla—upon central review, 50% of patients received at least 80% of the prescribed breast radiation dose to the level I axilla, potentially providing therapeutic benefit for low-volume nodal disease. 1

Patient-Reported Outcomes: The Strongest Evidence

Patients who avoided SLNB experienced clinically meaningful and statistically significant reductions in arm symptoms at all postoperative time points, with differences in mean arm symptom scores ≥5.0 points (the threshold for clinical relevance). 2 Specifically:

• Arm symptoms (pain, swelling, impaired mobility) were significantly worse in the SLNB group at 1,3,6,12, and 18 months post-surgery, with the highest difference at one month 2
• Breast symptoms also favored the no-SLNB group at all post-baseline assessments 2
• Global quality of life (QLQ-C30 scores) showed no relevant differences between groups, indicating that avoiding SLNB improves arm function without compromising overall well-being 2
• Questionnaire completion remained high (>70%) throughout follow-up, ensuring robust data quality 2

Clinical Application: Who Should Avoid SLNB

Based on the 2025 ASCO guideline incorporating INSEMA results, SLNB may be omitted in patients age ≥65 years with T1, ER-positive, HER2-negative tumors who will receive whole-breast irradiation and endocrine therapy. 1 The rationale is straightforward:

• 85% of appropriately selected patients do not have pathologically involved nodes warranting treatment 1
• The low likelihood of nodal involvement combined with incidental axillary irradiation from WBI provides adequate regional control 1
• These same patients are also candidates for partial breast irradiation per ASTRO guidelines, though WBI was required in INSEMA 1

Critical Radiation Therapy Requirements

The INSEMA protocol mandated specific radiation approaches that evolved during the trial 1:

• Initial protocol: 50-50.4 Gy in 25-28 fractions to the whole breast, plus 10-16 Gy boost in 5-8 fractions to the lumpectomy cavity 1
• Amended protocol: Permitted moderate hypofractionation (40 Gy in 15 fractions), simultaneous integrated boost (only with conventional fractionation), and boost omission in patients >60 years with small, favorable tumors at low recurrence risk 1
• Key distinction from SOUND trial: INSEMA required WBI for all patients, whereas SOUND allowed 10% to receive intraoperative radiotherapy (ELIOT) alone, which does not provide incidental axillary coverage 1

Important Caveats and Contraindications

Do not omit SLNB in patients who will not receive whole-breast irradiation, as the incidental axillary treatment from tangential fields is assumed to be curative for low-volume nodal disease. 1 Additionally:

• Patients with clinically suspicious axillary nodes should undergo standard axillary staging 1
• The decision to omit radiotherapy should not be altered by SLNB omission in women ≥70 years with cT1N0M0, ER-positive disease on endocrine therapy 1
• For patients meeting monarchE criteria (≥4 positive nodes or 1-3 positive nodes with high-risk features), SLNB remains necessary to identify candidates for adjuvant abemaciclib plus endocrine therapy 1

Comparison with Other De-escalation Strategies

The INSEMA findings align with broader trends toward axillary surgery de-escalation 1:

• Patients appropriately selected for SLNB omission based on INSEMA criteria are also candidates for partial breast irradiation, which has shown equivalent local control and survival to WBI in multiple randomized trials 1
• In women ≥70 years with T1, ER-positive, HER2-negative tumors, omission of both SLNB and radiotherapy may be considered when patients are committed to endocrine therapy, given the low locoregional recurrence risk 1

Practical Implementation Algorithm

1. Confirm eligibility: Age ≥65 years, T1 tumor, ER-positive, HER2-negative, clinically node-negative 1
2. Ensure commitment to adjuvant therapy: Patient must receive whole-breast irradiation and endocrine therapy 1
3. Exclude high-risk features: No clinical suspicion of nodal involvement, no need for staging to determine systemic therapy eligibility (e.g., monarchE criteria) 1
4. Counsel on arm symptom benefits: Emphasize the clinically meaningful reduction in arm pain, swelling, and mobility impairment without compromising oncologic outcomes 2
5. Plan radiation appropriately: Ensure tangential fields will provide incidental level I axillary coverage 1