What are the eligibility criteria for adjuvant trastuzumab deruxtecan (Enhertu) in patients with HER2‑positive breast cancer?

Adjuvant Enhertu Eligibility Criteria

Adjuvant trastuzumab deruxtecan (Enhertu) is indicated for patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant chemotherapy and anti-HER2 therapy, particularly those with node-positive disease at surgery or inoperable disease at diagnosis.

Primary Indication Based on DESTINY-Breast05

The FDA-approved adjuvant use of Enhertu is specifically for the post-neoadjuvant setting in high-risk patients 1, 2. This represents a paradigm shift from the previous standard of T-DM1 in this population.

Specific Eligibility Criteria:

Required Disease Characteristics:

• HER2-positive breast cancer (confirmed by validated testing)
• Residual invasive disease present at surgery after completing neoadjuvant therapy
• AND one of the following high-risk features:
  • Node-positive disease at final surgical pathology (any N+)
  • Inoperable disease at initial diagnosis

Prior Treatment Requirements:

• Must have received neoadjuvant chemotherapy combined with anti-HER2 therapy
• Must have completed definitive surgery
• Residual invasive cancer must be documented pathologically (non-pCR)

Dosing and Duration:

• 5.4 mg/kg intravenously every 3 weeks
• Continue for up to 14 cycles (approximately 10 months) 2

Clinical Context and Decision-Making

The DESTINY-Breast05 trial demonstrated superior invasive disease-free survival with T-DXd compared to T-DM1 in this population (92.4% vs 83.7% at 3 years; HR 0.47, P<0.001) 2. This represents a 53% reduction in recurrence risk, making T-DXd the new standard for post-neoadjuvant therapy in patients with residual disease.

Key Exclusion Considerations:

Patients NOT eligible for adjuvant Enhertu:

• Those who achieved pathological complete response (pCR: ypT0/is, ypN0) after neoadjuvant therapy—these patients should complete 1 year of pertuzumab-trastuzumab instead 3, 4
• Patients who went directly to surgery without neoadjuvant therapy
• LVEF <50% or history of clinically significant cardiac disease 1
• Active or history of interstitial lung disease requiring treatment

Important Safety Monitoring Requirements:

• Baseline LVEF assessment required; monitor regularly during treatment 1
• Complete blood counts before each dose (neutropenia risk) 1
• Vigilant monitoring for interstitial lung disease (ILD)—occurs in 9.6% of patients, with 2 fatal cases reported in DESTINY-Breast05 2
• Pregnancy testing required before initiation; effective contraception mandatory during treatment and for 7 months after last dose 1

Critical Safety Caveat

The most important risk with adjuvant Enhertu is interstitial lung disease, which occurred at significantly higher rates than with T-DM1 (9.6% vs 1.6%) 2. Patients must be counseled about symptoms (cough, dyspnea, fever) and monitored closely. Any new or worsening respiratory symptoms require immediate evaluation, and symptomatic ILD (Grade ≥2) mandates permanent discontinuation 1.

Practical Algorithm:

1. Confirm HER2-positive status by validated assay
2. Verify residual invasive disease at surgery after neoadjuvant therapy
3. Check nodal status at surgery—if node-positive, patient qualifies
4. Assess cardiac function—LVEF must be ≥50%
5. Screen for lung disease—baseline imaging and pulmonary assessment
6. Verify adequate blood counts—particularly neutrophils
7. Confirm pregnancy status if applicable
8. Initiate T-DXd 5.4 mg/kg IV q3weeks for 14 cycles

This represents a major advance over T-DM1, but requires heightened vigilance for ILD and appropriate patient selection based on cardiac and pulmonary fitness 2.